Genetic Disorders Among Arab Populations

Genetic Disorders Among Arab Populations . Ahmad S. Teebi Editor Genetic Disorders Among Arab Populations Second E...

Author: Ahmad S. Teebi

1843 downloads 9231 Views 8MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

Genetic Disorders Among Arab Populations

.

Ahmad S. Teebi Editor

Genetic Disorders Among Arab Populations Second Edition

Editor Ahmad S. Teebi Weill Cornell Medical College in Qatar Qatar Foundation Doha Education City Qatar [email protected]

First edition published by Oxford University Press, 1997. ISBN 978-3-642-05079-4 e-ISBN 978-3-642-05080-0 DOI 10.1007/978-3-642-05080-0 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2010932676 # Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To my parents, brothers and sisters, and my children Saeed, Basel, Asil and Asma and the whole Arab Family.

.

Acknowledgements

The editor is grateful to the authors of the individual chapters who welcomed the initiative and were keen to provide their contributions on time. Special thanks to Professor Charles R. Scriver, who made the effort to write the foreword to this book. I am thankful to my wife Mrs. Amal Teebi for her encouragement and support and to Saeed Teebi for his assistance in some parts of the manuscript. The assistance of Mrs. Mariette D’ Souza, Gemma Fabricante and Martin Marion from Weill Cornell Medical College in Qatar, in preparation of some chapters and maps, is greatly appreciated. I express my gratitude also to Springer press and in particular to Andrea Pillman and Ursula Gramm for their help in the publication of this book.

vii

.

Foreword

Genetic Disorders among Arab Populations by Ahmad S. Teebi and co-authors appears here in its second edition. The first edition (in 1997) shows how one could tap into a rich load of information on human and medical genetics, a source probably too little mined until now. One can be pleased that the first edition was warmly welcomed by Prof. Victor McKusick, the author of the Foreword to that edition. The authors of this edition have taken pains to remind us again that persons and patients, and the corresponding families and communities, represent a stream of human history and a region of the world that embraces ethnic, cultural and religious attributes more diverse than we might have imagined, yet with a commonality that gives “coherence to an account of it and a usefulness [when it is considered] as a unit” (VA McKusick, Foreword to first edition). Arab populations have their repertoire of genetic disorders, both universal and particular. Genetic diversity within these source populations, along with the fact that rates of inbreeding are often high and family sizes are often large, constitutes conditions that facilitate the emergence and detection of phenotypes explained notably by autosomal recessive inheritance, in which case, the use of homozygosity gene mapping will facilitate discovery of the corresponding genes. Meanwhile, the interval between the publication of the first and second editions of genetic disorders has witnessed emergence of the Middle East Genetic Association of America and the creation of ethnic (Arabic)-related, locus-specific mutation databases to serve as nodes in the network of related interests. Driven by relevant research interests, initiatives are emerging in the Arabic world to address issues such as taxonomy and fine-grained descriptions of variant disease phenotypes, their origins, distributions and frequencies in populations, their molecular infrastructure, and with a better knowledge of their pathogenetic processes, better opportunities to address counseling, prevention and treatment. The authors of the second edition have again chosen not to provide an exhaustive list of relevant genetic disorders; that can be done eventually when there is a curated online database. Rather, the authors again highlight various issues and perspectives that can be seen through the windows offered by a number of prevalent genetic disorders in the Arabic world. Accordingly, the attitudes and responses generated ix

x

Foreword

by these problems, as they are influenced by Islamic perspectives, wisely constitute the recurrent underlying theme in the book, because the cultures and faith of the Arabic communities yield quite different responses and perspectives from the corresponding encounters in the non-Islamic world. It is a particular form of a larger issue attracting notice (viz. Suther and Kiros, Genet Med 11:655–662, 2009; Krotoski et al. Genet Med 11:663–668, 2009). The authors use prevalent, pan-Arabic disorders (Table 1.1), along with a selection of rarer “founder” disorders (Table 1.2), to delve into the biological explanations for their occurrence and impact. These disorders set the scene to explain important demographic issues, the related population dynamics, indicators of individual collective health, and the impacts of endogamy and consanguinity on the frequencies and distribution of the disorders. Familial Mediterranean Fever, for example, illustrates these perspectives well and is highlighted accordingly. The authors examine 15 different countries and regions harbouring Arabic populations, to discern issues with more specific aspects. One might say that in this diversity, there is a unity and vice versa. Consolidations of the expanding information on genetic disorders in Arabic populations improves our knowledge of them. Whether that leads to better wisdom, in how we help the individuals, families and communities harboring them, is, I am convinced, a sincere motivation to pursue the course undertaken by Professor Teebi and his co-authors. It has indeed yielded this enhanced second edition of Genetic Disorders among Arab Populations. Charles R. Scriver MDCM FRS Alva Professor Emeritus of Human Genetics Professor of Pediatrics and Biology McGill University Montreal, Canada

Contents

Part I 1

Introduction

Introduction: Genetic Diversity Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Ahmad S. Teebi

Part II

Demography, Economy, and Genetic Services in Arab Countries

2

Arab Demography and Health Provision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Sulayman S. Al-Qudsi

3

Influences of Systems’ Resources and Health Risk Factors on Genetic Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Amal A. Saadallah and Ahmad S. Teebi

4

Endogamy and Consanguineous Marriage in Arab Populations . . . . . . 85 Alan H. Bittles and Hanan A. Hamamy

Part III

Selected Disease Entities Prevalent Among the Arabs

5

Familial Mediterranean Fever and Other Autoinflammatory Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Hatem El-Shanti and Hasan Abdel Majeed

6

Muscular Dystrophies and Myopathies in Arab Populations . . . . . . . . . 145 Mustafa A.M. Salih

7

New Syndromes First Reported Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . 181 Ahmad S. Teebi

xi

xii

Contents

Part IV

Genetic disorders in Arab Countries Geographic Regions

8

Genetic Disorders in Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Samia A. Temtamy, Mona S. Aglan, and Nagwa A. Meguid

9

Genetic Disorders in Ancient Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Chahira Kozma

10

Genetic Diseases in Iraq . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Hanan Ali Hamamy

11

Genetic Disorders in Jordan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Majed Dasouki and Hatem El-Shanti

12

Genetic Disorders in Kuwait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 Nawal Makhseed

13

Genetic Disorders in Lebanon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Vazken M. Der Kaloustian

14

Genetic Disorders in Libya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Tawfeg Ben-Omran

15

Genetic Disorders in Morocco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Abdelaziz Sefiani

16

Genetic Disorders in Oman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Anna Rajab

17

Genetic Disorders Among the Palestinians . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Bassam Abu-Libdeh and Ahmad Said Teebi

18

Genetic Disorders in Qatar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Ahmad S. Teebi and Tawfeg Ben-Omran

19

Genetic Disorders in Saudi Arabia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Zuhair N. Al-Hassnan and Nadia Sakati

20

Genetic Disorders in Sudan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Mustafa A.M. Salih

21

Genetic Disorders in Tunisia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Elham Hassen and Lotfi Chouchane

Contents

xiii

22

Genetic Disorders in the United Arab Emirates . . . . . . . . . . . . . . . . . . . . . 639 Lihadh Al-Gazali and Bassam R. Ali

23

Genetic Disorders Among Jews from Arab Countries . . . . . . . . . . . . . . . 677 Efrat Dagan and Ruth Gershoni-Baruch

Part V

Cultural and Religious Attitudes Towards Genetic Issues

24

Prevention and Care of Genetic Disorders: An Islamic Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705 Aida I. Al Aqeel

25

Genetic Counseling in the Middle East . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 Shelley J. Kennedy and Muna Al-Saffar

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

.

Contributors

Hasan Abdel Majeed Professor Emeritus of Pediatrics, University of Jordan, Amman, Jordan Bassam Abu-Libdeh Makassed Hospital & Al-Quds University, Jerusalem, [email protected] Mona S. Aglan Professor of Clinical Genetics, Clinical Genetics Department, Human Genetics and Genome research division, National Research Centre, Cairo, Egypt, [email protected] Aida I. Al Aqeel Pediatrics, Medical Genetics and Endocrinology, Department of Pediatrics, Riyadh Military Hospital, P. O. Box 7897, Riyadh 11159, Kingdom of Saudi Arabia, [email protected], [email protected] Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia Lihadh Al-Gazali Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates, [email protected] Zuhair N. Al-Hassnan Associate Prof. of Genetics, College of Medicine, Alfaisal University Consultant, Department of Medical Genetics, MBC-75, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia, [email protected] Bassam R. Ali Faculty of Medicine and Health Sciences, Department of Pathology, UAE University, Al-Ain, United Arab Emirates Sulayman S. Al-Qudsi Chief Economist and Head of Research Department-Arab Bank, PLC. Amman-Jordan.Shaker bin Zeid Street, Shmeisani Area, 950545, Amman, Jordan, [email protected]; [email protected] Muna Al-Saffar Certified Genetic Counsellor, Children’s Hospital Boston, MA, USA

xv

xvi

Contributors

Project Manager, Dubai Harvard Foundation for Medical Research (DHFMR), Dubai Health Care City, Dubai, United Arab Emirates Tawfeg Ben-Omran Section of Clinical and Metabolic Genetics, Qatar Medical Genetics Center, Hamad Medical Corporation, Doha, Qatar, [email protected] Alan H. Bittles Centre for Comparative Genomics, Murdoch University, South Street, Perth, WA 6150, Australia, [email protected] Lotfi Chouchane Professor of Genetic Medicine and Immunology, Genetic Medicine Department, Weill Cornell Medical College, Qatar, loc2008@qatar-med. cornell.edu Efrat Dagan Institute of Human Genetics, RAMBAM Health Care Campus and Department of Nursing, University of Haifa, Haifa, Israel Majed Dasouki Professor of Pediatrics & Internal Medicine University of Kansas, Kansas City, Kanasa, USA Vazken M. Der Kaloustian Emeritus Professor of Pediatrics and Human Genetics, Mchill University, Montreal, Quebec, Canada, [email protected] Hatem El-Shanti Director, Shafallah Medical Genetics Center, Doha, Qatar; Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA, [email protected] Ruth Gershoni-Baruch Institute of Human Genetics, RAMBAM Health Care Campus and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Institute of Technology, Haifa, Israel, [email protected] Hanan A. Hamamy Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland (formely Al-Mustansiriyah Medical College, Baghdad, Iraq), [email protected] Elham Hassen Molecular Immuno-Oncology Laboratory, Faculty of Medicine, Monastir, Tunisia, [email protected] Shelley J. Kennedy Certified Genetic Counsellor, Ontario Newborn Screening Program & Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, [email protected] Chahira Kozma Department of Pediatrics, Georgetown University Hospital, 3800 Reservoir Rd N.W., Washington DC, USA, [email protected]; cck2@ gunet.georgetown.edu Nawal Makhseed Department of Pediatrics, Jahra Hospital, Ministry of Health, Kuwait, [email protected] Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department, Human Genetics and Genome, research division, National Research Centre, Cairo, Egypt, [email protected]

Contributors

xvii

Anna Rajab Consultant Clinical Geneticist, Genetic Unit, Ministry of Health, Sultanate of Oman, [email protected] Amal A. Saadallah Medical College, Ain Shams University, Cairo, Egypt, [email protected] Nadia Sakati Consultant, Department of Pediatrics, MBC-58, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia Mustafa A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia, mustafa_salih05 @yahoo.com; [email protected] Abdelaziz Sefiani Department of Medical Genetics, National Institute of Heath/ University Mohammed V Souissi, Rabat 27, Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco, [email protected] Ahmad S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar, [email protected] Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department, Human Genetics and Genome research division, National Research Centre, Cairo, Egypt, [email protected] Nagwa A. Meguid Profssor of Human Genetics, National Research Centre, Tahrir street Dokki, Giza, Egypt, [email protected]

.

Part I Introduction

Chapter 1

Introduction: Genetic Diversity Among Arabs Ahmad S. Teebi

There is perhaps no region with a richer history or a more diverse ethnic, cultural and religious makeup than the Arab world. It is the cradle of civilization and birthplace of the world’s three major monotheistic religions. Despite their heterogeneity, the Arab countries are united by their common language and location in the largest arid zone of the world: the Sahara and African deserts and their contiguous semi-arid lands. The geographical area of the Arab world covers about 14 million km2 and spans two continents, covering a distance of 6,375 km from Rabat on the Atlantic to Muscat on the Arabian (Persian) Gulf (Bolbol and Fatheldin 2005) (Fig. 1.1). Consequently, the Arab populations, currently exceeding 300 million, representing 5% of the world populations, are mainly concentrated in the relatively fertile regions, particularly along the Nile River, in the valleys of the Euphrates and the Tigris, and along the coastal area of North Africa, Syria, Lebanon and Palestine/ Israel. These four regions account for 84% of the Arab populations and only 54% of their income. The GCC countries (Gulf Co-operation Council), comprising Saudi Arabia, Kuwait, United Arab Emirates, Qatar, Bahrain and Oman, have about 45% of the income but only 10% of the Arab populations (Grissa 1994). With two thirds of the Arab countries producing oil, there is little doubt that it is the single most important factor in the region’s economic development (Raffer 2007).

Past and Present The history of the Arabs extends back more than 5,000 years. Around 3500 BC, Semitic-speaking people of Arabian origin migrated into the valley of the Tigris and Euphrates rivers in Mesopotamia, eventually becoming the Assyro-Babylonians.

A.S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_1, # Springer-Verlag Berlin Heidelberg 2010

3

4

A.S. Teebi

Fig. 1.1 Map of the Arab world

Another group of Semites left the Arabian Peninsula about 2500 BC and settled along the eastern shore of the Mediterranean; some of these migrants became the Amorites and Canaanites of later times (Bram and Dickey 1993). Beginning from the seventh century, Arabs, proclaiming the new religion of Islam, ventured from the Arabian Peninsula and conquered the wide area from the Arabian/Persian Gulf to the Atlantic ocean. The Arab civilization soon became the world’s most prominent, and Arab and Islamic science and medicine flourished. Islamic medicine was based on Greek medicine and also on Quranic teachings and the model set by the prophet Mohammad in the Hadith. Islamic medical scholars and centers flourished and several authors, including Al-Ruhawi and Al-Tabari, wrote on Islamic medicine and medical ethics (Rispler-Chaim 1993). During the past few decades, good but inconsistent economic progress has been made by the Arab countries of the Middle East and North Africa. In the same period, most Arab countries have maintained high total fertility rates. Only recently have these rates declined, and only in a few Arab countries, notably Bahrain, Egypt, Tunisia and Lebanon (Faour 1989). Infant mortality has fallen by more than half and life expectancy has increased from 48 to 67 years. High inbreeding continues to prevail in most Arab countries. Education levels have improved: primary school enrollment is nearly 100%, secondary school enrollment has tripled and female enrolment has increased fivefold (World Bank 1994). Language is what unites the Arabs. Formal Arabic is the official language in all the 22 countries of the Arab League. The overwhelming majority of Arabs (over 90%) are Muslim, and predominantly Sunni. In some countries such as Iraq,

1 Introduction: Genetic Diversity Among Arabs

5

Lebanon and Bahrain, Shi’ite Muslims exist in proportions similar to or slightly higher than Sunnis. A number of Arab countries contain sizeable Christian communities; in Lebanon, for example, 43% of the population is Christian (Husseini 1994). On the health front, the region, while undergoing tremendous transformations (reduced mortality rates, the eradication of several epidemics and the improved overall health conditions) still suffers from an increased incidence of nutritional problems, malaria and tuberculosis, in addition to the rise in importance of health problems that are related to modern lifestyles – smoking, stress, heart disease, diabetes mellitus and genetic disorders. Furthermore, the interplay of culture, economics, natural endowments and man-made pollution activities results in health problems, some of which are genetically related.

Ethnic Diversity Despite its linguistic, religious and cultural cohesion, the Arab world is also rich in diversity. In addition to Muslim and Christian Arabs, the area is home to Kurds, Druze, Berber, Armenians, Circassians, Jews and other minorities. The Arabs themselves, in most parts of the Arab world, are the result of admixture with other populations in the area, through migration to or from other parts of the world, or across the borders (such as Persians, Turks, South-East Asians, Europeans and Africans). Wars throughout history, particularly the Crusades, have contributed to this unique mosaicism. Other than this mosaic of genetically heterogeneous populations, relatively homogeneous populations or isolates exist. These include some Bedouin tribes, Nubians and Druze among others.

The Arab/Muslim Family Among Arabs, descent is reckoned through males rather than females. Married men and their wives live with their father in one large household (or at least very close to him) whenever possible, and marriages with relatives are favored. Although polygamy is allowed in Islam, it is practiced only on a narrow scale and mainly with the aim of producing more children. In some societies, such as in Tunisia, polygamy is strictly controlled. Broadly speaking, the Arab man or woman values being related to a large tribe or extended kindred. He or she can often trace back his or her origin through several generations. Many tribes, in GCC countries for instance, keep family trees that contain information going back ten or more generations. The number of children per family is large, averaging more than four. The average family size that includes the parents (from 1987 to 1993) varied between five in Egypt and eight in Kuwait.

6

A.S. Teebi

Religion, Culture and Genetic Issues The Arab family, Muslim or Christian, typically has strong faith in God. Muslims believe the occurrence of disease to be God’s will, as explained in the Quran (Surah 57, pp. 22–23), “No misfortune can happen on earth or in your souls but it is recorded in a decree before We bring it into existence” (Ali 1991). Such belief helps parents to alleviate feelings of guilt by relating the reason for the child’s problem to God’s purposeful, non-questionable action, rather than to a “blind probabilistic event” (Panter-Brick 1992). In Arab countries, prenatal diagnosis is acceptable for purposes of reassurance or therapy. Termination of pregnancy, however, at any stage is absolutely forbidden (Haram), unless the mother’s life is endangered (Hathout 1972). Under Islamic law, according to some interpretations, termination of pregnancy is considered a crime (Shaltout 1959). However, couples may avoid pregnancy if they are at an unacceptably high risk of having a child with a certain genetic defect. On the other hand, while artificial insemination using the husband’s sperm (AIH) and in vitro fertilization using the husband’s sperm are acceptable (Mubah), using donor sperm is absolutely forbidden. In general, assisted reproduction using the husband’s and wife’s gametes is acceptable. Adoption has been practised since the early ages of Islam. However, “legal adoption” is not permitted (For details see Al-Aqeel 2007).

Consanguineous Marriage and Endogamy Consanguineous marriage is common in most Arab populations and is not necessarily limited to geographic or religious isolates or ethnic minorities. Unlike its largely taboo status in Western countries, the practice is deeply rooted in the Arab culture and has been over many generations. The rates are generally high. They range between 25% in Beirut (Khlat and Khudr 1984) up to 60% in Saudi Arabia and 90% in some Bedouin communities in Kuwait and Saudi Arabia (Al-Roshoud and Farid 1991; Panter-Brick 1992). An average figure of about 40% appears to be true in most Arab countries. The most common form of intermarriage is between first cousins, particularly paternal first cousins and includes double first-cousin marriage. Uncle/niece, aunt/nephew marriages are forbidden by Quran and are in fact non-existent (Teebi and Marafie 1988). Consanguineous marriage is more common among Muslims than among Christians, though it is strictly a cultural feature and not a religious prescription. In fact, and according to some religious scholars, Islam discourages consanguineous marriages, though it does not forbid it. Inbreeding is more common in rural areas than in urban regions, although it does not seem to correlate with the economic status. However, in some rich families and tribes, consanguineous marriages prevail because of the attachment of people to their families or villages and to keep the property within the family or tribe. One of the reasons favoring cousin marriage can be extrapolated from the common Arabic saying “a spouse that you know is better

1 Introduction: Genetic Diversity Among Arabs

7

than the one you don’t know, and a cousin takes better care of you” (Panter-Brick 1992). Another contributing factor is the popular belief that consanguineous marriage offers a major advantage in terms of compatibility of the bride and her husband’s family, particularly her mother-in-law (Jaber et al. 1994). Some studies have reported a secular decline in consanguineous marriage, for example, in Kuwait (Radovanovic et al. 1999), Saudi Arabia (Al-Abdulkareem and Ballal 1998), Jordan (Hamamy et al. 2005), and Israeli Arab and Palestinians (Jaber et al. 2000; Zlotogora et al. 2002; Sharkia et al. 2008; Assaf and Khawaja 2009). By comparison, in the UAE (Al-Gazali et al. 1997), Yemen (Jurdi and Saxena 2003) and Qatar (Bener and Alali 2006), the overall levels of consanguineous marriage, including first-cousin unions, have actually increased. This suggests that future trends may depend on the local political, economic and social factors. Similar to most Arab populations, the consanguinity rate among the semi-isolated Druze community in Israel is 49% (Freundlich and Hino 1984). On the other hand, as an exception, marriages within the clan are forbidden among the Nubian people (Bayoumi and Saha 1987), and consanguinity studies among four tribes living in western Sudan found no incidence of consanguineous marriages among the indigenous people living within the Nuba mountains. However, this may not be exactly the case of the Egyptian Nubian people of Kom Ombo.

Autosomal Recessive Disorders When a rare autosomal recessive mutation is present in a family, the chance that a disease will manifest in this family increases if a consanguineous marriage occurs and when the number of children is large. Such conditions are optimal in the Arab world, where previous observations demonstrated an increase in the frequencies of autosomal recessive conditions (Teebi 1994; Hamamy and Alwan 1994; Teebi and Teebi 2005; Al-Gazali et al. 2006). Autosomal recessive disorders among Arabs have a characteristic pattern that will be subsequently discussed according to their conspicuous features.

Hemoglobinopathies Hemoglobinopathies constitute a major health problem in Arab countries. The genes for sickle cell hemoglobin (HbS) and a and b thalassemias are found in all Arab countries with different frequencies in different Arab countries and even within different regions within the same country, as is the case in Saudi Arabia. The sickle cell trait frequency ranges from less than 1% along the Nile in Egypt to 20% or more in Siwa oasis in Egypt, Bahrain and some parts of Saudi Arabia. Generally, HbC is very rare except in Morocco, where it is twice as common as HbS. A number of new Hb variants have been reported also, including HbO-Arab,

8

A.S. Teebi

HbJ-Cairo, Hb-Riyadh and Hb-Khartoum among others. Hb S/O-Arab is a severe sickling hemoglobinopathy similar to homozygous sickle cell anemia; however, it is rarely found (Zimmerman et al. 1999). Molecular studies of HbS indicate that an independent mutation (Arab-Indian or Saudi-Indian haplotype) occurred in eastern Saudi Arabia and the Indian subcontinent region and spread from there to other parts of the Arab world, while in the western region of Saudi Arabia and North African countries, the gene may have been transported from Benin and Senegal in Africa (Benin and Senegal haplotypes). No specific ß thalassemia mutations are confined to Arabs and the Mediterranean and Asian mutations are encountered at variable frequencies. a thalassemias, however, generally result from a gene deletions.

FMF and Other Auto-inflammatory Disorders Familial Mediterranean fever (FMF), also known as paroxysmal polyserositis, is an important clinical and public health problem in a number of Arab countries. It is very common in Lebanon, Jordan and among Palestinians. The frequency among Palestinians and Jordanians was estimated to be at least 1 in 2,000, a figure similar to that of Armenians and Sephardic Jews (Barakat et al. 1986; Majeed and Barakat 1989). FMF is present also in Iraq, Syria, Kuwait, Egypt and Saudi Arabia. In a number of situations, the diagnosis is missed and the chronic nature of the problem taxes the medical care facilities. Patients with amyloidosis as a complication of FMF form a large proportion of the load of dialysis and kidney transplantation in a number of Arab countries. FMF is caused by mutations in MEFV gene on chromosome 16 (Pras et al. 1992). The most frequent MEFV mutations found among the Arabs from Jordan, Palestine, Syria, Iraq, and Egypt, according to their magnitude of frequency, are M694V, V726A, 694I, and M680I (Majeed et al. 2005; El-Shanti et al. 2006). The most common mutations among patients from the Maghreb are M694V and M694I (Belmahi et al. 2006). A744S mutation seems specific to Arab pouulations and R761H is frequently found in the Lebanese (Medlej-Hashem et al. 2004). There seems to be distinctive clinical picture in Arab patients with FMF (El-Shanti et al. 2006). Other auto-inflammatory disorders including Majeed syndrome are discussed elsewhere in the book.

Muscular Dystrophies and Myopathies The magnitude of disease entity is apparently large, mostly due to autosomal recessive conditions. In two surveys, one in the eastern part of Saudi Arabia (Al-Rajeh et al. 1993) and the other in Kelbia in Tunisia (Romdhane et al. 1993), the prevalence rate of anterior horn cell diseases, including Werdnig-Hoffmann

1 Introduction: Genetic Diversity Among Arabs

9

disease, was 133 and 177 per million respectively compared to 12 per million from the World Survey (Emery 1991). Similar high incidence was observed in the Egyptian Karaite community in Israel (Fried and Mundel 1977). In a Libyan study, the estimated overall frequency of muscular dystrophies was 132 per million (Radhakrishnan et al. 1987). On the other hand, in the Saudi study, the frequency of Duchenne muscular dystrophy and myotonic dystrophy was 44 and 88 per million compared to the same World Survey of 32 and 50 per million respectively. The figures do not appear to be remarkably different in the two surveys. A severe childhood autosomal recessive muscular dystrophy (SCARMD) resembling Duchenne muscular dystrophy was first noted in several families from Sudan and Tunisia. Subsequently, the disease was found to be prevalent in other Maghreb countries and in the Arabian Peninsula. Recent data comparing Tunisian and Algerian patients with patients from Morocco indicate genetic homogeneity of disease in the Maghreb countries (El-Kerch et al. 1994) In a study from Tunisia, the frequency of this form of muscular dystrophy was found to be equivalent to that of Duchenne muscular dystrophy (Ben Hamida and Marrakchi (1980). Meanwhile, in Kuwait the proportion of families with this autosomal recessive disease was found to constitute at least 36.3% of all ascertained Duchenne or Duchenne-like muscular dystrophies (Farag and Teebi 1990) compared to 5% in North America and United Kingdom (Emery 1987). Because this disease is characteristically highly prevalent among Arabs, it is considered, however, an example of Arab diseases (Table 1.1). Details of molecular bases of SCARMD are found elsewhere in this book. Other relatively common disorders include SCARMD-like disorders, Duchenne and Becker muscular dystrophy, congenital muscular dystrophy, congenital myopathies, mitochondrial myopathies and Schwartz-Jampel syndrome. The latter seems to be more common in the United Arab Emirates.

New Genetic Syndromes First Reported Among Arabs In the last three decades, the area of new genetic syndromes among Arabs became a hot point of research and publications. Reports describing new syndromes and variants came from countries with established genetic services such as in Israel, Lebanon, Kuwait, UAE, Oman, Egypt, Qatar and Saudi Arabia. In this book, an exhaustive list of all such syndromes has been compiled. However, it remains inclusive of very early reports, reports that do not mention the origin of the patient (s) or reports published in unindexed periodicals. The list contains 160 syndromes, compared to 113 syndromes in the first edition of this book, published in 1997. Of these, 133 syndromes are autosomal recessive, 27 are autosomal dominant and five are possible X-linked, autosomal recessive or mitochondrial disorders. Many other “newly” characterized disorders were not included in the recent review, either because they are awaiting further characterization or because of some overlap with previously known disorders requiring molecular etiologic characterization. Despite the fact that most Arab populations are still poorly studied genetically, the

10

A.S. Teebi

Table 1.1 Arab genetic diseases: autosomal recessive disorders that are characteristically highly prevalent among Arabs Disease MIM # Estimated frequency/ References livebirths Bardet-Biedl syndrome 209900 1–2/13,000 Farag and Teebi (1988a, Farag and Teebi 1989a) Congenital chloride 214700 1/5,500–13,000 Kagalwalla (1994), diarrhea (Arabian Badawi et al. (1998) Peninsula) Congenital 241410 Unknown; most Sanjad et al. (1991), hypoparathyroidism, reported patients Marsden et al. (1994), seizure, growth are from Arabian Naguib et al. (2009) failure, dysmorphic Peninsula features Meckel syndrome 249000 1/3,500 Teebi et al. (1992), Familial Mediterranean 249100 1-1500-2000 Majeed and Barakat (1989), fever Palestinians and El-Shanti et al. (2006) Jordanians Werdnig-Hoffmann 253300 1/1,000–1,500 Al-Rajeh et al. (1993), Romdhane disease et al. (1993) Severe childhood 253700 1/3,500 (approximate) Ben Hamida and Marrakchi autosomal recessive (1980), Farag and Teebi muscular (1990) dystrophy (SCARMD) Nesidioblastosis of 256450 1/2,675 (Saudi Arabia) Mathew et al. (1988), pancreas Cherian and Abduljabbar (2005), Karawagh et al. 2008) Osteopetrosis with renal 259730 Unknown; 70% of all Ohlsson et al. (1986), Fathallah tubular acidosis reported patients et al. (1994) are Arabs

number of autosomal recessive syndromes characterized so far appears relatively large for a group constituting no more than 5% of the world populations. More than half of the new autosomal recessive disorders were described among people from Jordan, Palestine and Lebanon, who collectively constitute less than 5% of the Arab populations. This may reflect the genetic diversity of the Palestinians or Jordanians and Lebanese as a result of their admixture over time with many populations, including Arabs, Turks, Kurds, Europeans and Jews, among others. The apparent clustering of new syndromes and other rare genetic disorders among the Palestinians and Lebanese may also be an indication that they have access to genetic services that are not yet available in many other parts of the Arab world. Seven major groups of syndromes are noted among the newly described syndromes among Arabs. They include Neurological/neuromuscular/muscular, Dysmorphic syndromes, Ophthalmological and Hearing disorders, Bone dysplasia and Skeletal disorders, Dermatological and Fertility syndromes and Inborn Errors of Metabolism. Many of the newly described syndromes were thought to be “private”, or limited to single families. Subsequent reports negated the concept of privacy in syndromes. One of those syndromes was the Nablus mask-like facial syndrome. An autosomal

1 Introduction: Genetic Diversity Among Arabs

11

Table 1.2 Examples of genetic disorders reported to have definite tribal occurrence or limited to extended kindreds or isolates Disorder MIM # Community References Arthrogryposis multiplex 208100 Palestinian Jaber et al. (1995) congenita, neurogenic type Bardet-Biedl syndrome 209900 Bedouin in Israel Kwitek-Black et al. (1993) Cerebrotendinous 213700 Druze in Israel Leitersdorf et al. (1994) xanthomatosis Cystic fibrosis 219600 Bedouin tribe in Qatar Abdul Wahab et al. (2001), Deafness, Autosomal recessive 220290 Northern Tunisia Ben Arab et al. (2004) Homocystinuria 236200 Bedouin tribe in Qatar El-Said et al. (2006) Hypophosphatemic rickets and 241530 Bedouin tribe in Israel Tieder et al. (1987) hypercalcuiria Metachromatic leucodystrophy 250100 Palestinian Zlotogora et al. (1994a), Heinisch et al. (1995) Krabbe disease 255200 Palestinian; Druze in Zlotogora et al. (1991), Israel Oehlman et al. (1993) Pseudohermaphroditism 264300 Palestinian in Rosler (2006) (male)-17-b-Ketosteroid Gaza strip dehydrogenase def. Ozand et al. (1990a, 1992) GM2 gangliosidosis, Sandhoff 268800 Bedouin in variant Saudi Arabia Glanzmann thromboasthenia 273800 Palestinian Rosenberg et al. (2005) Usher syndrome type I 276900 Samaritans in Nablus Bonne´-Tamir et al. (1994)

recessive example is the Limb/pelvis-hypoplasia/aplasia syndrome described first in a Palestinian from Kuwait (Al-Awadi et al. 1985). Subsequently, reports also came from Brazil, Saudi Arabia, Egypt, Israel, Italy and again from Kuwait in a Bedouin family. Recently the causative gene was elucidated (Woods et al. 2006). The other example was a new hypogonadism syndrome reported in a Jordanian family from Kuwait, later seen in a Lebanese family, and recently reported in two sisters of consanguineous parents from Turkey (Tatar et al. 2009). One of the newly described syndromes was initially described in five siblings of a Bedouin family in Kuwait (Teebi et al. 1988). The same syndrome was found in several sibships of the same tribe, an example of the founder effect (Teebi and Al-Awadi 1991). Several examples of autosomal recessive disorders relatively common in Qatar, but rare elsewhere, were recently documented (See Qatar Chapter in this book). They represent classical examples of founder effect. Table 1.2 provides examples of disorders with definite tribal occurrence or restricted to large kindred or isolates.

Inborn Errors of Metabolism Data on metabolic diseases among Arabs are becoming available due to the introduction of diagnostic facilities and nationwide neonatal screening in several

12

A.S. Teebi

Arab countries (Saadallah and Rashed 2007). However, such data are almost nonexistent from several other countries in the Arab world.

Classic Phenylketonuria and Other Hyperphenylalaninemia In Egypt, Phenylketonuria (PKU) patients constituted 2.3% of the mentally retarded (Temtamy et al. 1991). In Kuwait, PKU was found to have a frequency between 1.6% and 1.86% among institutionalized mentally retarded patients. Six inmates with PKU belonged to three sibships in a large Kuwaiti kindred originating in Iran. At least 20 other patients were ascertained at the genetic clinics or elsewhere (Teebi 1994). A Bedouin family was reported recently (Usha et al. 1992). The incidence of classic PKU in Kuwait was found to be 1:6,479 livebirths as estimated in the course of a neonatal screening project, versus the North American incidence of 1:11,000. The incidence of classic PKU in the United Arab Emirates was found to be 1: 20,050 (Al-Hosani et al. 2003). On the other hand, no case of PKU was detected among 70,000 newborns screened by Aramco in the eastern province in Saudi Arabia, a nearby area (Abu-Osba et al. 1992). However, at a referral center in Saudi Arabia, patients with Hyperphenylalaninemia (HPA) secondary to 6-pyruvoyltetrahydropterin synthase deficiency were frequently seen and appeared to be more common than classic PKU patients (Al-Aqeel et al. 1991; Ozand et al. 1992). Mutations and polymorphisms at the phenylalanine hydroxylase (PAH) gene were studied in 36 Palestinian families in Israel (Kleiman et al. 1994). Four mutations previously identified in Europe were found among the Palestinians, indicating that gene flow from Europe into the Palestinian gene pool could have occurred at previous periods in history. In addition, three PAH mutations unique to Palestinian Arabs (IVSnt 2, ED(197-205) and R2705) were identified, indicating high genetic diversity of this population. A study of patients from Kuwait and Egypt showed the presence of four common European haplotypes, in addition to four rare haplotypes and three unclassified ones (Bender et al. 1994). In addition, a new MspI-polymorphism was found in one Egyptian family and one individual control from Kuwait. The same polymorphism has been described in American blacks (Hoffmann et al. 1991). This may indicate that the associated mutation probably originated from Africa and spread within Africa to Arabia as well as to America. Another study on Egyptian patients showed a high degree of molecular heterogeneity at the PAH locus (Effat et al. 1999). From Paris, 26 families with at least one child affected with HPA were studied together with 100 unrelated families from North Europe and the Mediterranean region (Berthelon et al. 1991). An exclusive or preferential linkage disequilibrium between a particular haplotype and PAH mutation with clear geographic partitioning of the mutations was observed. The spectrum of mutations commonly observed in North European populations differed from that observed among patients from the Mediterranean with specificity within this group; interestingly, the majority of North African patients were homozygous cases rather than compound heterozygote states. A novel specific mutation, Glu!lys at codon 280, was identified in endogamous North African families, and it was later

1 Introduction: Genetic Diversity Among Arabs

13

demonstrated to be the most frequent in the whole Maghreb (Lyonnet et al. 1989). This mutation was also identified in a French family, thus raising the question of a relation with the Arab invasion of France during the seventh century AD (Lyonnet et al. 1989). In another study (Be´nit et al. 1994), novel frame shift deletions were found in two Arab patients from north Africa. One of these patients had a 22 bp deletion previously described in an Arab patient from Israel (Kleiman et al. 1994).

Other Inborn Errors of Metabolism Homocystinuria is among the common aminoacidopathies observed in Saudi Arabia and Kuwait (Ozand et al. 1992; Teebi 1994; Al-Essa et al. 1998). Recently, the incidence homocystinuria in Qatar was found to be greater than 1 in 3,000, representing the highest incidence in the world (El-Said et al. 2006). Based on figures from the national neonatal screening program, the incidence of homocystinuria among the National Qatari newborns was 1 in 1,400. Other frequently diagnosed disorders include branched-chain aminoaciduria (MSUD) in classic and intermediate forms (Ozand et al. 1992), non-ketotic hyperglycinemia, cystinuria, tyrosinemia type I and tyrosinemia type II (Hashem 1982; Yadav and Reavey 1988; Teebi 1994; Charfeddine et al. 2006). Urea cycle defects, in particular the autosomal recessive types, are also common. Among these are Citrullinemia, Argininosuccinic aciduria and Carbamoyl phosphate synthase deficiency (Yadav and Reavey 1988; Issa et al. 1988b). Organic acidemias, namely Methylmalonic acidemia, 3-Hydroxyl-3-methylglutaryl coenzyme A lyase deficiency and Propionic acidemia are common (Ozand et al. 1992; Teebi 1994; Rashed et al. 1994). Methylmalonic acidemia and other organic acidopathies were found to have characteristic tribal occurrence in Saudi Arabia (Ozand et al. 1992) and other Gulf countries. Also, they were found to have high frequency among the Palestinians (Zlotogora 1996, personal communication). Lysosomal storage disorders (LSD) constitute a large sector of the diagnosable neurometabolic disorders among the Arabs in Kuwait, Saudi Arabia, Egypt and Israel. Among the commonly diagnosed conditions are the Hurler and Hurler– Scheie syndromes, Morquio syndrome, Maroteaux-Lamy syndrome, Sanfilippo syndrome – type B, GM1 gangliosidosis, GM2 gangliosidosis – Sandhoff variant, multiple sulfatase deficiency, ceroid lipofuscinosis, Niemann Pick – types A, B, and C, Canavan disease, Metachromatic leucodystrophy, Krabbe disease, Gaucher disease – neuropathic type and Neuroaminidase deficiency (Hashem 1982; Ozand et al. 1990a, b, 1992; Teebi 1994). A new variant of multiple sulfatase deficiency, which differs clinically from the classic neonatal, childhood and juvenile-onset multiple sulfatase deficiency, was described in eight Saudi patients. (Al-Aqeel et al. 1992). Some of these disorders have shown definite tribal occurrence and might even be restricted to certain Bedouin tribes or large kindred. They include GM2 gangliosidosis – Sandhoff’s variant, mucolipidosis Sanfilippo’s syndrome – type B, Canavan disease, neuroaminidase deficiency and Niemann-Pick – type C.

14

A.S. Teebi

Metachromatic leucodystrophy was found to be more frequent among Arabs living in two restricted areas in Israel (Heinisch et al. 1995). While multiple mutations are responsible for this high frequency, a single origin for the most frequent mutation was found (Zlotogora et al. 1994a). It is suggested that this mutation may have been introduced into Jerusalem at the time of the Crusades. Among the Arab Druze community in Israel, Hurler syndrome and mucolipidosis – type III are highly prevalent (Zlotogora, personal communication). Tay-Sachs disease is a common disorder among the Jews, particularly Ashkenazis and Moroccan Jews, but rarely described among Arabs (Jacoub 1938; Navon et al. 1981). In Kuwait, at least three families were found to have one or more affected members (Farag et al. 1993a; Teebi 1994; Shaabani et al. 2010), and in Egypt, six families were ascertained in one center in Cairo (Hashem 1982). Recently, an Israeli Arab with Tay-Sachs disease was found to have G786A transition in the HEX A gene (Drucker and Navon 1993). This specific mutation was originally described in a British infantile patient (Triggs-Raine et al. 1991), which raises the question of whether this mutation was introduced into Palestine during the Crusades or is a recurrent mutation. Molecular studies on Arab patients with LSD have shown wide ranges of causative mutations (Bargal et al. 2006; Brautbar et al. 2008; Kaya et al. 2008a, b) Dyggve–Melchior–Clausen disease, a condition resembling Morquio syndrome in some aspects, was suggested to have a high gene frequency in the Lebanese (Naffah 1976; Bonafede and Beighton 1978) and Lebanese from Montreal. It was also described in Moroccan Jews and Palestinians from Gaza (Schorr et al. 1977. Glycogen storage disorders, notably types I & III, are commonly diagnosed in several parts of the Arab world. Other relatively common disorders are fatty acid oxidation defects, in particular VLCAD in Saudi Arabia. MCAD incidence was found to be close to that of the Caucasians, with one mutation identified in 72% of cases (Al-Hassnan, personal communication 2009). Primary hyperoxaluria type 1 is particularly frequent in Tunisia, where it was described in 23 cases (Ben Moussa et al. 1993). On the other hand, classic congenital adrenal hyperplasia due to 21 hydroxylase defiency was found to be more frequent in Kuwait than in Europe and Canada (Lubani et al. 1990). Vitamin D-dependent rickets type I and Wilson disease are also apparently common in Kuwait (Teebi 1994).

Cystic Fibrosis and Congenital Chloride Diarrhea Although rare in blacks and Asians, Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian populations. In this sense, the old belief that CF is rare or non-existent in Arabs, who are Caucasian by descent, is surprising. The first report on CF in Arabs came from Lebanon (Salem and Idrees 1962). This was followed by reports from other Arab countries (Al-Hassani 1977; Aluwihare et al. 1981; Kamal and Nazer 1984; Kolberg 1986; Nazer et al. 1989; Farag and

1 Introduction: Genetic Diversity Among Arabs

15

Teebi, 1989b; Dawson and Frossard 1994). The diagnosis was often missed because of mild manifestations or atypical presentation with metabolic alkalosis in the Arabian Peninsula’s hot and humid weather (Issa et al. 1988a; Mathew et al. 1991), or because many deceased infants were labeled as having succumbed to gastrointestinal and/or respiratory infections, the two leading causes of infant deaths in Arab children. Recent data concerning CF have shown that the estimated incidence among Arab populations ranges from 1/2,188 to 1/4,243 livebirths; these are similar to figures from Europe and North America. A study of 70 patients from 46 families from Saudi Arabia has identified eight novel mutations, with1548delG being the most prevalent (Banjar et al. 1999; Kambouris et al. 2000). In a Bedouin tribe from Qatar with approximately 40,000–50,000 people, at least 70 children were documented to have CF, accounting for an incidence higher than 1 in 1,000 Qatari-livebirths. All patients belonging to this tribe have homozygous I1234V mutation in exon 9 of CFTR gene (Abdul Wahab et al. 2001). This extremely high incidence of CF with a single mutation provides a classical example of genetic drift due to a Founder effect. Data from Israel have shown that the DF508 mutation, which accounts for approximately 70% of all CF chromosomes in a worldwide survey, was found to account for 22–25% of CF chromosomes in Palestinians and Israeli Arabs (Lerer et al. 1990; Shoshani et al. 1992). Four mutations (DF508, G542X, W1282X and N1303K) accounted for 55% of the CF alleles in Arab patients (Abeliovich et al. 1992). In a study of 38 Tunisian families, the common allele was DF508, accounting for 18.4% of CF chromosomes. In addition, several other mutations were found at lower frequencies, including a few new mutations and a strikingly high number of true homozygotes of rare alleles. In the UAE, eight unrelated patients were all observed to have the same S549R mutation (Frossard et al. 1994), a rare mutation previously observed in a Jewish family from Israel (Kerem et al. 1990). In Kuwait, a Bedouin family of three affected individuals was studied for six CF mutations (DF508, D1007, G542X, S549N, G551D and R553X). Of these mutations, none was detected in this family (Farag et al. 1994b). Wei et al. (2006) performed carrier screening on 805 Arab-Americans, testing for at least the original 25 mutations recommended by the American College of Medical College. The observed carrier frequency was 1 in 115; this could be an underestimate due to the expected rare and novel mutations, specific to the population, that were not in the panel of testing. Congenital Chloride Diarrhea (CLD) is a rare and treatable autosomal recessive disorder of chloride transport that was diagnosed in 16 Kuwaiti patients, mostly Bedouins. The incidence was estimated to be 7.6/100,000 livebirths, which is similar to that in Finland (Lubani et al. 1989; Badawi et al. 1998). In a study from Saudi Arabia (Kagalwalla 1994), a remarkably high incidence of 1/5,500 livebirths was observed. Thus far, all reports of Arab patients with CCD came from the Arabian Peninsula, suggesting that this condition is especially common there (Kagalwalla 1994). Allelic diversity of CLD was studied in high incidence populations of Poland, Finland, Saudi Arabia and Kuwait. A major founder effect was found in Arab patients (Hoglund et al. 1998).

16

A.S. Teebi

Osteopetrosis Syndromes Data from Saudi Arabia indicate that the severe autosomal recessive form of osteopetrosis is common in the Arabian Peninsula (Mahdi 1988; Abdel-Al et al. 1994). The estimated minimum prevalence appears to be higher than in other countries (Abdel-Al et al. 1994). Osteopetrosis with renal tubular acidosis and cerebral calcification due to carbonic anhydrase II deficiency has been reported frequently in the Arabian Peninsula and the Maghreb countries (Ohlsson et al. 1986; Bejaoui et al. 1991; Al-Rasheed et al. 1998), and in fact 72% of the cases reported were Arabs (Fathallah et al. 1994). Among the four mutations described, a splice junction mutation at the 50 end of intron 2 in the CA II gene was reported to underlie the molecular defects of this syndrome in six Arab kindred from various countries (Hu et al. 1992). A recent study of ten Tunisian patients revealed that they were homozygous to the same unique mutation (Fathallah et al. 1994); this mutation appears to be confined to Arabs.

Persistent Hyperinsulinemic Hypoglycemia Also called Nesidioblastosis of Pancreas (NP), it is an autosomal recessive disorder, frequently diagnosed among Bedouin and nationals of Saudi Arabia and Kuwait. Glaser et al. (1990) described seven pedigrees from Israel, including a large Bedouin family and an Arab family. In a Saudi population with high consanguinity rate, Mathew et al. (1988) established the incidence as 1/2,675 livebirths, compared to 1/50,000 in a randomly mating population (Bruining 1990). A large number of families were also reported in Saudi Arabia (Cherian et al. 1994; Bin-Abbas et al. 2003; Cherian and Abduljabbar 2005; Karawagh et al. 2008). Also, it was reported in Bedouin children from Kuwait (Ramadan et al. 1999). Thomas et al. (1995) used the homozygosity mapping strategy to localize the mutation for this disorder on 11p in five consanguineous Saudi Arabian families.

Sanjad-Sakati Syndrome The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD) or Sanjad-Sakati syndrome is a relatively common autosomal recessive disorder reported almost exclusively among the Arabs mainly from Saudi Arabia, Kuwait, Israel and Palestinian territories (Sanjad et al. 1991; Marsden et al. 1994; Parvari et al. 2002; Hershkovitz et al. 2004; Naguib et al. 2009). Data suggest that a common founder mutation of TBCE gene accounts for Arab patients (Hershkovitz et al. 2004; Naguib et al. 2009). Preimplantation diagnosis was possible as a tool for the prevention of the disease in Saudi Arabia (Hellani et al. 2004).

1 Introduction: Genetic Diversity Among Arabs

17

Malformation Syndromes When considered collectively, malformation syndromes are common; individually, however, they are extremely rare. Nonetheless, a few autosomal recessive malformations appear to be common in Arab countries. Bardet-Biedl syndrome (BBS), for example, is common in Kuwait, particularly among the Bedouin, Kuwaiti, Syrian and Palestinian populations (Farag and Teebi, 1988a). The estimated prevalence among the whole Bedouin community is 1/13,500, about 15 times higher than that of Switzerland. The incidence of BBS among Bedouins in a small geographic area was 1/6,900 livebirths (Farag and Teebi, 1989a). Similar findings were noted in Bedouin tribes and Palestinian Arabs (Leitersdorf et al. 1994; Zlotogora 1997). BBS also appears to be common in Egypt, Lebanon and Israel. Another very common disorder is Meckel syndrome, which has an incidence of at least 1/3,530 livebirths in Kuwait (Teebi et al. 1992). High frequencies of Meckel syndrome were reported also among Tatars (Lurie et al. 1984) and in Gujarati Indians (Young et al. 1985). Multiple pterygium syndrome is a frequently diagnosed disorder in Kuwait, Saudi Arabia, and Qatar. An estimated prevalence of 1/31,000 was found in the general population in Kuwait (Teebi and Daoud 1990). Autosomal recessive hydrocephalus of prenatal onset was found to be common among Palestinian Arabs in Kuwait and Israel (Teebi and Naguib 1988; Zlotogora et al. 1994b; Zlotogora 1997). On the other hand, autosomal recessive microcephaly with normal intelligence or associated with mental retardation and severe neurologic defects appears to be common among various Arab communities in Kuwait, Saudi Arabia and Qatar. Familial intestinal atresias, particularly the apple-peel variant, and the autosomal recessive congenital diaphragmatic hernia are not uncommon based on reports from Lebanon and Kuwait (Mishalany and Najjar 1968; Mishalany and Der Kaloustian 1971; Farag et al. 1993b, 1994a).

Xeroderma Pigmentosum Xeroderma Pigmentosum (XP) appears to be common in several Arab countries, including Kuwait, Lebanon, Syria, Iraq, Jordan, the Palestinian territories Egypt, UAE and the Maghreb countries (German et al. 1984; El-Hayek et al. 2004; Zghal et al. 2005). Molecular studies are available from some countries, some of which have confirmed potential founder effect by haplotype analysis in Tunisian patients (Matsumura et al. 1995; Falik-Zaccai et al. 2006; Ben Rekaya et al. 2009). The prevalence is unknown but the disease accounts for 9–14% of childhood malignancies in Tunisia (Miller 1977; Maalej et al. 2007). This is partly due to an environmental effect owing to the sunny climate in that region.

18

A.S. Teebi

Non-Syndromic Deafness Non-syndromic deafness is very common among Arabs. It is not unexpected that the majority of the cases belong to the autosomal recessive inheritance, a remarkably heterogeneous group. In a large Palestinian kindred originating from the West Bank, 13 cases in several sibships were reported to have uncomplicated profound deafness from early infancy (Kabarity et al. 1981). High incidence of profound deafness reaching 2% of the inhabitants of a Palestinian/Israeli village was documented (Zlotogora and Barges 2003). Most cases were due to mutations in Connexin-26 gene. A large Israeli–Arab pedigree with sensorineural deafness was determined simultaneously by two loci-one mitochondrial and one autosomal recessive (Jaber et al. 1992; Bu et al. 1993). Further studies in the same family and three unrelated families with aminoglycoside-induced deafness showed an A-to-G transition at nucleotide 1,555 in the 12 S r-RNA gene (Prezant et al. 1993). This mutation is responsible for antibiotic-induced ototoxity as well as non-syndromic deafness. Other studies among the Palestinians and Bedouin in Israel have shown high incidence of prelingual deafness with remarkable genetic heterogeneity (Fischel-Ghodsian et al. 1995; Scott et al. 1996; Shahin et al. 2002; Walsh et al. 2006). In Tunisia, sensorineural deafness became an active area of research in the last few years. Several autosomal recessive genes and many mutations have been identified. Data from Northern Tunisia have shown that the prevalence of nonsyndromic deafness ranges between 2% and 8% in the isolates there (Ben Arab et al. 2004). Evidence for genetic heterogeneity was provided, even within isolates. However, the most frequent was the 35delG mutation of GJB2 gene (Ben Arab et al. 2000, 2004). Somewhat similar circumstances related to high frequencies of nonsyndromic deafness in relation to consanguinity and isolation are also found in other Arab countries (Al-Gazali 1998; Tabchi et al. 2000; Al-Khabori and Khandekar 2004).

Osteochondrodysplasias Skeletal dysplasia are frequently diagnosed in the Arab world, though the delineation needs an expert opinion in many instances. A study from UAE has shown that 36 out of 38,046 births had some type of skeletal dysplasia (almost 1:1,000) (Al-Gazali et al. 2003). Half of them (18) were attributed to autosomal recessive genes. The most common recessive type was fibrochondrogenesis followed by chondrodysplaia punctata. An unpublished study from Qatar showed an incidence of 5:1,000 births, which is half of the UAE figure. Lethal chondrodystrophies were frequently diagnosed as well. Other relatively common skeletal/connective tissue disorders include the spondyloepiphyseal dysplasia tarda with progressive arthropathy (Teebi and Al-Awadi 1985;

1 Introduction: Genetic Diversity Among Arabs

19

Hurvitz et al. 1999) in Jordan and Lebanon, Stueve_Wiedemann syndrome (Langer et al. 2007) in the UAE and an arterial tortuosity syndrome with skeletal manifestations in Qatar and Saudi Arabia (Al Fadley et al. 2000; Faiyaz-UlHaque et al. 2008, 2009)

Genetic Predisposition to Non-disjunction A study from Kuwait (Alfi et al. 1980) showed that Down syndrome (DS) was four times more frequent among the children of closely related parents (p > 0.005). Another study from Kuwait (Naguib et al. 1989) suggests an association between consanguinity and occurrence of non-disjunction, though a single gene effect was not observed. The other study from Kuwait showed a DS incidence of 4.5/1,000 livebirths in an area inhabited mainly by Bedouins, whereas in an area with a mixed Arab population, the incidence was 1.7/1,000 livebirths (Farag and Teebi 1988b). A remarkably higher incidence of DS was noted in the higher inbreeding coefficient group with nearly similar maternal ages, suggesting the existence of some recessive elements predisposing to non-disjunction. Comparable high frequencies of DS were also reported from West Jerusalem and among the Negev Bedouins in Israel (Harlap 1974; Abeliovich et al. 1986). It is not uncommon to find examples of recurrent aneuploidies in the same family among the Bedouins in Kuwait or other locations (Farag and Teebi 1988b; Krishna Murthy and Farag 1995). This may provide support to the hypothesis of existence of a recessive gene or genes controlling non-disjunction. Recently, based on a case report of a child with DS and neural tube defect, it was suggested that the altered folate status plus homozygous mutation of the MYHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21 (Al-Gazali et al. 2001).

Male Pseudohermaphroditism Familial male pseudohermaphroditism (MPH) due to defects in steroid metabolism or due to persistent mullerian duct syndrome are common among the Arabs (Rosler et al. 1992; Farag 1993; Al-Attia 1997; El-Gohary 2003). MPH due to 17-bhydroxysteroid dehydrogenase 3 deficiency is particularly common in Palestinian territories and the Gaza Strip. Eighty-five males with this disorder were identified among Palestinians and 57 studied over 25 years. The founders of this defect originated in the mountainous regions of Lebanon and Syria, but most of the families live in Jerusalem, Hebron, the Tel-Aviv area, and Gaza, where the frequency of affected males is estimated at 1 in 100 to 150 (Rosler 2006).

20

A.S. Teebi

Other Disorders Frequently Diagnosed Among Arabs Autosomal recessive epidermolysis bullosa, Cutis laxa, Wrinkly skin syndrome, Gerodermia osteodyslastica, autosomal recessive icthyosis and mal de meleda are among the relatively common genodermatosis syndromes. Clinical anophthalmia or nonsyndromic microphthalmia with CHX10 mutations is prevalent in Gaza and Qatar with clear founder effect in one Qatari tribe (Kohn et al. 1988; Bar-Yosef et al. 2004; Faiyaz-Ul-Haque et al. 2007). Cytochrome b5-reductase deficiency was found to be prevalent in Algeria, mostly in the south, with a heterozygous frequency of 3% (Reghis et al. 1981). Homozygous cases are associated with cyanotic methemoglobinemia with or without mental retardation and neurologic impairment (Vieira et al. 1995). Glanzmann thromboasthenia was described in 12 Jordanian patients in 9 families (Awidi 1983). A founder mutation was found to predominate in Palestinian patients (Rosenberg et al. 2005). It was found to be frequent among the Iraqi Jews and Arabs in Israel (Coller et al. 1987; Kannan and Saxena 2009). Brain or CNS malformations are frequently diagnosed; they have received some attention in the past few years. Several new forms have been delineated so far. Several examples of study cohorts are available. Homozygosity for the two autosomal recessive traits in the same sibship is not rare. Numerous examples were observed in the highly inbred population of Kuwait, particularly among the Bedouins. Some of these examples were recorded (Teebi 1994).

Autosomal Dominant and X-Linked Disorders Apart from the apparent rarity of Huntington disease and the increased frequencies of homozygotes for familial hypercholesterolemia, the pattern and apparent frequencies of autosomal dominant disorders in Arab countries are not remarkably different from those in Western countries. On the basis of studies in Lebanon, Khachadurian (1964) first established the existence of homozygous familial hypercholestrolemia (FHC). In Lebanon the frequency of FHC homozygotes due to low-density lipoprotein receptor gene defect is more than ten times higher than in other parts of the world (Lehrman et al. 1987). Presumably, this is the result of an increased rate of consanguinity as well as a high frequency of the trait. The allele was named the Lebanese allele and was also found in patients from Syria, as well as in five Christian Arab kindred from Israel (Oppenheim et al. 1991). Several other mutations were found among Arabs and named according to the country of origin or community from which the patients came from; they include FH Bahrain, FH Syria, FH Algeria, FH Kuwait, FH Druze, etc. (McKusick 1994). In Kuwait the frequency of homozygotes of FHC was found to be 1/23,000 in a mostly Bedouin population (Palkovic et al. 1994). Of the 502

1 Introduction: Genetic Diversity Among Arabs

21

screened card samples from the same population, ten neonates were detected with total cholesterol over the 98th percentile (unpublished data). An autosomal dominant example of a new syndrome originally described is the hypertelorism syndrome resembling craniofontonasal dysplasia, found in an Iraqi kindred with 16 affected individuals living in Kuwait (Teebi 1987). The same diagnosis was subsequently reported in Caucasian and black families from the USA (Stratton 1991; Toriello and Delp 1994; Tsai et al. 2002; Han et al. 2006), Japan (Tsukahara et al. 1995), Germany (Koenig 2003) and South America (Machado-Paula and Guion-Ameida 2003). Glucose-6-phosphate dehydrogenase deficiency (G6PD) is an example of an X-linked disorder that has a special importance in the Arab world. The trait has polymorphic frequencies throughout the region with wide variations ranging from 0.02 and 0.03 in Jordan, parts of Saudi Arabia and Lebanon to 0.58 among the Kurdish Jews and 0.65 in the Qatif oasis in Saudi Arabia (Kurdi-Heidar et al. 1990). The latest figures are the highest in the world (Sheba et al. 1961; El-Hazmi et al. 1986). G6PD-Mediterranean, a common variant in the Middle East, is characterized by severe enzyme deficiency underlying not only acute hemolytic crisis following the ingestion of fava beans (a popular meal in the Middle East), but also neonatal jaundice and acute hemolytic anemia triggered by drugs or infection. Studies from Oman, a country with frequency of G6PD deficiency of 0.25–0.27 in males and 0.10–0.11 in females (White et al. 1993; Daar et al. 1996; Al-Riyami and Ebrahim 2003), showed that despite such high frequencies, the oxidative hemolytic syndromes are very uncommon, supporting earlier findings reviewed and stressed by Beutler (1991). Kurdi-Heidar et al. (1990) concluded that the large majority of Middle Eastern subjects with G6PD-Mediterranean may have the same mutation found in Italy and that the mutation probably arose on a chromosome that already carried the silent mutation, an independent polymorphism in the Middle East.

Interest in the Genetic Disease Among Arabs It had been my hope that the first edition of this book would stimulate interest and research in the Arab world on this important set of diseases prevalent among the Arabs, with a view to potential preventability. Soon after its publication, interest began to foment with the formation of Middle East Genetic Association of America, which held its first scientific meetings in Tunisia in December 1997 (Fathallah et al. 1998) and in Egypt in 1999 (Teebi and Shawky 2000). This was followed by the establishment of the first curated Arab Genetic Disease Database based at the Hospital for Sick Children in Toronto. This was in response to Human Genome Organisation Initiative to establish ethnic genetic databases (Teebi et al. 2002) (This database was later discontinued due to lack of funding). In 2005, a different database was formed in Dubai (Tadmouri et al. 2006). The interest in genetic disease among the Arabs is continuing and receiving wide attention

22

A.S. Teebi

internationally, and has given rise to a better understanding of the prevalent disorders, the establishment of collaborations with many first class world-centers and an improvment in quality and quantity of publications. I hope that we are able to continue stimulating active research in the many aspects of Arab genetic disorders, including their characterization, frequencies and distribution, molecular bases, pathogenesis and origins. Genetic services and research in the field of medical genetics are still far from being adequate in many parts of the Arab world (Teebi and Teebi 2005; Al-Gazali et al. 2006). Genetic diversity among Arabs, high rates of inbreeding and large family size are optimal for the manifestation of many autosomal recessive disorders (Teebi and El-Shanti 2006). There is little doubt that genetic disease from this part of the world has the potential of becoming a major area of research, one that has the potential to benefit mankind at large.

This Edition This is the second edition of the book “Genetic Disorders Among Arab Populations”, first published by Oxford University Press in 1997. Rather than provide the reader with an exhaustive list of genetic disorders among the Arabs, our intention in this book is to highlight the prevalent conditions, genes and mutations involved, the frequencies of diseases and mutations when available, their characteristics and the global pattern of genetic disorders at large and the contributing factors. In addition, we discuss the attitudes of people toward both genetic counseling and the available options on the ground, options that are influenced by the Islamic perspective. Indeed, the attitudes are largely affected by the culture and faith of the Arabs and are remarkably different in many aspects from those of the Western world. To achieve these goals, I have designed this book with four major sections. After the introductory chapter, an overview of the monograph, the first section contains three chapters dealing with the unique demographic and economic characteristics in the Arab world. In addition to population dynamics and health indicators, endogamy and consanguinity are also discussed as prominent demographic features of great importance among Arabs. The second section contains three chapters discussing in some detail selected common entities: autoinflammatory disorders including FMF, muscular dystrophies and myopathies, and new syndromes first reported among Arabs. Fourteen Arab countries or geographic regions are represented in the 15 chapters of the third section, with the aim of discussing aspects of genetic disease in each. These entities include the Jews from Arab countries, in addition to a chapter discussing genetic disorders in ancient Egypt. For the purpose of avoiding redundancy, a separate chapter on Bedouins has been omitted from this edition, as much of the data are provided in the chapters on Saudi Arabia, Kuwait, Qatar, Oman, UAE and Palestine. Although some aspects of genetic disease in other countries such as Syria, Yemen, Mauritania and Somalia can be found in other chapters,

1 Introduction: Genetic Diversity Among Arabs

23

they are not included in this section owing to the extreme scarcity of genetic information from them. The fourth section includes two chapters examining issues related to the prevention and care of genetic disorders from an Islamic perspective, as well as the related issue of genetic counseling in the Middle East, including its medical, genetic and psychological implications and real, everyday practice. Genetic information generated so far from some Arab countries provides a valuable indicator of the prevailing disorders in the Arab world at large. However, such information is quite fragmentary in several other parts of the Arab world. It is often largely based on case reports and case series studies, rather than prospective epidemiological and molecular studies. Nonetheless, it is felt that such information is useful, as it well emphasizes the points of weakness and strength in the available knowledge, as well as what could be done to improve it. In comparison with the first edition, data in this book show that the research has certainly taken a remarkable step forward. The book has been mostly re-written and in some chapters, the information has been extensively revised and updated. A large part of the book was written by a new generation of experts in the field. The reader will recognize the genetic diversity among the Arabs from the varied clinical phenotypes and genotypes within the same region or country and or between individual Arab Countries. The information provided here will prove beneficial to those planning to implement health services in the Arab world, as well as to national and international bodies that provide advice to these. It will also helpf physicians and medical students in the Arab world who are confronted with the varied aspects of genetic disease. Physicians in the West who encounter Arab patients as immigrants or seeking help in specialized centers will also find this book useful.

References Abdel-Al YK, Shabani IS, Lubani MM, Al-Ghanem MA, Ibrahim MD, Al-Mohtaseb S, Duodin K (1994) Autosomal recessive osteopetrosis in Arab children. Ann Trop Paediatr 14:59–64 Abdul Wahab A, Al-Thani G, Dawod ST, Kambouris M, Al-Hamed M (2001) Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). J Trop Pediatr 47:110–112 Abeliovich D, Atia Y, Sarov B (1986) Down syndome in Negev region. Am J Med Genet 25:183 Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cuttnig GR (1992) Screening for five mutations detects 97% of Cystic Fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in The Jewish Ashkenazi population. Am J Hum Genet 51:951–956 Abu-Osba YK, Mallouh A, Salaman M, Hann R, Thalji A, Hamdan J, Sa’di AR (1992) Comprehensive newborn screening program: Aramco experience, the national need and recommendations. Ann Saudi Med 132:235–240 Al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse side effects on the offspring. J Commuinty Health 23:75–83 Al-Aqeel AI (2007) Islamic ethical framework for research into and prevention of genetic disease. Nat Genet 39:1293–1298

24

A.S. Teebi

Al-Aqeel A, Ozand PT, Brismar J, Gascan GG, Nester M, Sakati N (1992) Saudi variant of multiple Sulfutase deficiency. J Child Neurol 7(12(Suppl)):20 Al-Aqeel A, Ozand PT, Gascon G, Nester M, Al-Nasser M, Brismar J, Blau N, Hughes H, Subramanyan SB, Reynolds CT (1991) Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruoyl tetrahydropterin synthase. Neurology 41:730–737 Al-Attia HM (1997) Male pseudohermaphroditism due to 5 alpha reductase-2 deficiency in an Arab kindred. Postgrad Med J 73:802–807 Al-Awadi SA, Teebi AS, Farag TI, Naguib KM, El-Khalifa MY (1985) Profound limb deficiency, thoracic dystrophy, unusual faces and normal intelligence: a new syndrome. J Med Genet 22:36–38 Al-Essa M, Rashed M, Ozand PT (1998) Saudi experience with classic homocystinuria. Ann Saudi Med 18:230–233 Al Fadley F, Al Manea W, Nykanen DG, Al Fadley A, Al Haless Z (2000) Severe tortuosity and stenosis of the systemic, pulmonary and coronary vessels in 12 patients with similar phenotypic features: a new syndrome? Cardiol Young 10:582–589 Alfi OS, Chang R, Azen S (1980) Evidence for genetic nondisjunction in man. Am J Hum Genet 32:477–483 Al-Khabori M, Khandekar R (2004) The prevalence and causes of hearing impairment in Oman: a community-based cross-sectional study. Int J Audiol 43:486–492 Al-Gazali LI (1998) A genetic survey of severe childhood deafness in the United Arab Emirates. J Trop Pediatr 44:156–160 Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghes M, Haas D, Bener A, Padmanabhan R, Abdulrrazzaq YM, Dawadu A (2003) Birth prevalence and pattern pf osteochondrodysplasias in an inbred high risk population. Birth Defects Res A Clin Mol Teratol 67:125–132 Al-Gazali LI, Bener A, Abdulrazzaq YM, Al-Khayat MR, AI GT (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. BMJ 333:831–834 Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, Pogribna M, Bakir M, Hamid ZA, Abdulrazzaq Y, Dawodu A, James SJ (2001) Abnormal folate metabolism and genetic polymorphism of the folate pathway in a child with Down syndrome and neural tube effect. Am J Med Genet 103:128–132 Al-Hassani M (1977) Cystic fibrosis in Iraqi children. J Trop Med Hyg 23:136–137 Al-Hosani H, Salah M, Saade D, Osman H, Al-Zahid J (2003) United Arab Emirates national newborn screening programme: an evaluation 1998–2000. East Mediterr Health J 9:324–332 Ali AY (1991) English translation of the meanings of the Holy Qur’an. Amana Corporation, Brentwood, MD, p 1227 Al-Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, Al-Freihi H, Assuhaime S, Borollosi M, Al-Shammasi S (1993) A community survey of neurological disorders in Saudi Arabia. The Thugbah Study. Neuroepidemiology 12:164–178 Al-Rasheed SA, Al-Mohrij O, Al-Jurayyan N, Al-Herbish A, Al-Mugeiren M, Al-Salloum A, Al-Hussain M, El-Desouki M (1998) Osteopetrosis in children. Int J Clin Pract 52:15–18 Al-Riyami A, Ebrahim GJ (2003) Genetic blood disorders survey in the Sultanate of Oman. J Trop Pediatr 49(1(Suppl)):11–20 Al-Roshoud R, Farid S (1991) Kuwait child health survey. Ministry of Health Publications, Kuwait Aluwihare APR, Ali SM, Ahmad MS, Mirghani GA, Mohacsy J (1981) Cystic fibrosis in Kuwait. Lancet ii:1056 Assaf S, Khawaja M (2009) Consanguinity trends and correlates in the Palestinian territories 41:107–124 Awidi AS (1983) Increased incidence of Glanzmanns thromboasthenia in Jordan compared with Scandanavia. Scand J Haematol 30:218–222

1 Introduction: Genetic Diversity Among Arabs

25

Badawi MH, Zaki M, Ismail EA, Majid Molla A (1998) Congenial chloride diarrhoea in Kuwait: a clinical reappraisal. J Trop Pediatr 44:296–299 Banjar H, Kambouris M, Meyer BF, Al-Mehaidib A, Mogarri I (1999) Geographic distribution of cystic fibrosistransmembrane regulator gene mutations in Saudi Arabia. Ann Trop Paediatr 19:69–73 Barakat MH, Karnik AM, Majeed HWA, El-Sobki NI, Fenech FF (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs – a study of 175 patients and review of literature. Q J Med 60:837–847 Bar-Yosef U, Abuelaish I, Harel T, Hendler N, Ofir R, Birk OS (2004) CHX10 mutations cause non-syndromic microphthalmia/anophthalmia in Arab and Jewish kindreds. Hum Genet 115:302–309 Bargal R, Zeigler M, Abu-Libdeh B, Zuri V, Mandel H, Ben Neriah Z, Stewart F, Elcioglu N, Hindi T, Le Merrer M, Bach G, Raas-Rotchschild A (2006) When Mucolipidosis III meets Mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab 88:359–363 Bayoumi RA, Saha N (1987) Some blood genetic markers of the Nuba and Hawazma tribes of Western Sudan. Am J Phys Anthropol 43:103–112 Bejaoui M, Kamoun A, Barraket M, Bourguiba H, Lakhoua R (1991) Le syndrome associant: osteopetrose, acidose tubulaire, retard mental et calcification intracraniennes par de´ficit en anhydrase carbonique II. Arch Fr Pediatr 48:711–714 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode C (2006) Prevalence and distrtibution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329(2):71–74 Ben Arab S, Hmani M, Denovelle F, Boulila-Elgaied A, Chardenoux S, Hachicha S, Petit C, Ayadi H (2000) Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates. Clin Genet 57:439–443 Ben Arab S, Masmoudi S, Beltaief N, Hachicha S, Avadi H (2004) Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic deafness. Genet Epidemiol 27:74–79 Ben Hamida M, Marrakchi D (1980) Dystrophie musculaire progressive de type Duchenne et Tunisie: a propos de 13 familles et 31 cas d’une forme en apparence recessive autosomique. J Genet Hum 28:1–9 Ben Moussa F, Kamoun A, El-Younsi F, Lakhoua H, Ben Maiz H (1993) Primary hyperoxaluria type I – study of 23 cases. Saudi Kidney Dis Transplant Bull 4(suppl):CN 23 Ben Rekaya M, Messaoud O, Talmoudi F, Nouira S, Ouragini H, Amouri A, Boussen H, Boubaker S, Mokni M, Mokthar I, Abdelhak S, Zghal M (2009) High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54:426–429 Bender C, B€uchler A, Schmidt-Mader B, Schlotter M, Teebi AS, Konecki DS, Trefz FK (1994) Haplotype analysis and a new MspI-polymorphism at the phenylalanine hydroxylase gene in the Arab population. Eur J Pediatr 153:392 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatar poulation. J Biosoc Sci 38:239–246 Be´nit P, Rey F, Melle D, Munnich A, Rey J (1994) Novel frame shift deletions of the phenylalanine hydroxylase gene in phenylketonuria. Hum Mol Genet 3:675–676 Berthelon M, Cailland C, Rey F, Labrune P, Melle D, Feingold J, Frezal J, Briard ML, Farriaux JP, Guibaud P, Journel H, Maurin N, Le Marrec B, Nivelon JL, Planchu H, Saudubray JM, Tron P, Rey J, Munnich A, Lyonnet S (1991) Spectrum of phenylketonuria mutations in western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus. Hum Genet 86:355–358 Beutler E (1991) Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 324:169–174 Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA (2003) Persistent hyperinsulinemic hypoglycemia of infancy in 38 children. Saudi Med J 24:890–894 Bolbol A, Fatheldin A (2005) Intra-Arab exports and direct investment: an empirical analysis. AMF, Abu Dhabi

26

A.S. Teebi

Bonafede RP, Beighton P (1978) The Dyggve–Melchior–Clausen syndrome in adult siblings. Clin Genet 14:24–30 Bonne´-Tamir B, Korostishevsky M, Kalinsky H, Seroussi E, Becker R, Weiss S, Godel V (1994) Genetic mapping of the gene for Usher syndrome: linkage analysis in a large Samaritan kindred. Genomics 20:36–42 Bram L, Dickey NH (eds) (1993) Funk and Wagnalls new encyclopedia. Funk and Wagnalls Corporation, New York Brautbar A, Abrahamouv A, Hadas-Halpern I, Elstein D, Zimran A (2008) Gaucher disease in Arab patients at an Israel referral clinic. Isr Med Assoc J 10:600–602 Bruining GC (1990) Recent advances in hyperinsulinism and the pathogenesis of diabetes mellitus. Curr Opin Pediatr 2:758–765 Bu X, Shohat M, Jaber L, Rotter JI (1993) A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: evidence from pedigree segregation analysis. Genet Epidemiol 10:3–15 Charfeddine C, Monastiri K, Mokni M, Laadimi A, Kaabachi N, Perin O, Nilges M, Kassar S, Keirallah M, Guediche MN, Kamoun MR, Tebib N, Ben Dridi MF, Boubaker S, Ben Osman A, Abdelhak S (2006) Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: identification and structural characterization of two novel TAT mutations. Mol Genet Metab 88:184–191 Cherian MP, Abduljabbar MA (2005) Persistent hyperrinsulinemic hypoglycemia of infancy (PHHI): long-term outcome following 95% pacreatectomy. J Pediatr Endocrinol Metab 18:1441–1448 Cherian MP, Haddad MJ, Sa´adi AR, Mathew PM (1994) Familial nesidioblastosis: more evidence for autosomal recessive inheritance (review). Ann Trop Pediatr 14:287–291 Coller BS, Seligsohn U, Little PA (1987) Type 1 Glanzmann thromboasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis. Blood 69:1696–1703 Daar S, Vulliamy TJ, Kaeda J, Mason PJ, Luzzatto L (1996) Molecular characterization of G6PD deficiency in Oman. Hum Hered 46:172–176 Dawson K, Frossard P (1994) Cystic fibrosis in the UAE: I. Clinical presentation. Emerg Med J 12:245–247 Drucker L, Navon R (1993) Tay-Sachs disease in an Israeli Arab family: Try26 6stop in the a subunit of hexosaminidase A. Hum Mut 2:415–417 El-Hayek M, Lestringant GG, Frossard PM (2004) Xeroderma pigmentosum in four siblings with three different types of malignancies simultaneously in one. J Pediatr Hematol Oncol 26:473–475 El-Hazmi MAF, Swailen AR, Faleh FZ, Warsy AS (1986) The frequency of glucose-6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population. Hum Hered 36:45–49 Effat L, Kuzmin A, Kasem N, Meguid NA, Kotb S, Eisensmith RC, Temtamy SA, Rushdi S, Woo S, El-Awady M (1999) Haplotypes and mtations of the PAH ocus in Egyptian families with PKU. Eur J Hum Genet 7:259–262 El-Gohary MA (2003) Laproscopic management of persistent mullerian duct syndrome. Pediatr Surg Int 19:533–536 El-Kerch F, Sefiani A, Azibi K, Boutaleb N, Yahyaoui M, Bentahila A, Vinet M-C, Leturcq F, Bachner L, Beckmann J, Campbell KP, Tome´ FMS, Fardeau M, Kaplan J-C (1994) Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in North Africa. J Med Genet 31:342–343 El-Said MF, BadiiR BMS, Shahbek N, El-Ali MG, El-Marikhie M, El-Zyoid M, Salem MS, Bener A, Hoffmann GF, Zschocke J (2006) A common mutation in the CBS gene explains a high incidenceof homocystinuria in the Qatari population. Hum Mutat 27:719–724 El-Shanti H, Majeed HA, El-Khateeb M (2006) Familial Mediterranean fever in Arabs. Lancet 367 (9515):1016–1024

1 Introduction: Genetic Diversity Among Arabs

27

Emery AEH (1987) Duchenne muscular dystrophy. Oxford University Press, New York Emery AEH (1991) Population frequencies of inherited neuromuscular diseases – a world survey. Neuromuscul Disord 1:19–29 Faiyaz-Ul-Haque M, Zaidi SH, Al-Mureikhi MS, Peltekova I, Tsui LC, Teebi AS (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72:164–166 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009) A novel missence and recurrent mutation in SLC2A10 gene of patients affected with arterial tortousity syndrome. Atherosclerosis 203:466–471 Faiyz-Ul-Haque M, Zaidi SHE, Wahab AA, Altohami A, Al-Mureikhi MS, Al-Thani G, Peltekova VD, Tsui L-C, Teebi AS (2008) Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome from 10 Qatari patients. Clin Genet 74:189–193 Falik-Zaccai T, Kfir N, Laskar M, Segel R, Khyat M, Slor H (2006) Clinical biochemical and molecular characterization of rare genetic disorders, related to nucleotide excision repair (NER) system. Harefuah 145(889–894):942 Faor M (1989) Fertility policy and family planning in the Arab countries. Stud Fam Plann 20(4): 254–263 Farag TI, Al-Awadi SA, El-Badramany MH, Aref MA, Kasrawi B, Krishna-Murthy DS, El-Khalifa MLY, Yadav G, Marafie MJ, Bastaki L, Wahba RA, Mohammed FM, Abul Hassan S, Redha AA, Redha MA, Al-Aboud H, Al-Hijjis S, Al-Dighashem D, Al-Hasash N, Al-Jeryan L, Al-Khorafi H, Qurban EA, Al-Sulaiman I (1993a) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44:329–334 Farag TI, Al-Awadi SA, El-Badramany MH, Usha R, El-Ghanem M (1993b) Second family with “apple peel” syndrome affecting four siblings. Autosomal recessive inheritance confirmed. Am J Med Genet 47:119–121 Farag TI, Bastaki L, Marafie M, Al-Awadi SA, Krsz J (1994a) Autosomal recessive congenital diaphragmatic defects in the Arabs. Am J Genet 50:300–301 Farag TI, Samilchuk E, AbulHasan S, Al-Awadi SA, Kandil H, Mady SA, El-Ghanem M (1994b) Cystic fibrosis in Kuwait and neighbouring populations. J Kuwait Med Assoc 26: 176–179 Farag TI, Teebi AS (1988a) Bardet-Biedl and Laurence-Moon syndromes in a mixed Arab population. Clin Genet 33:78–82 Farag TI, Teebi AS (1988b) Possible evidence for genetic predisposition to nondisjunction in man. J Med Genet 25:136–137 Farag TI, Teebi AS (1989a) High incidence of Bardet-Biedl syndrome among the Bedouin. Clin Genet 36:463–465 Farag TI, Teebi AS (1989b) Observations on cystic fibrosis (CF) in Kuwait. Am J Hum Genet 45(4(Suppl)):A238 Farag TI, Teebi AS (1990) Duchenne-like muscular dystrophy in the Arabs. Am J Med Genet 37:290 Farag TI (1993) Familial persistant M€ ullerian duct syndrome in Kuwait and neighbouring populations. Am J Med Genet 47:432–434 Fathallah DM, Bejaoui M, Sly WS, Lakhoua R, Dellagi K (1994) A unique mutation underlying carbonic anhydrase II deficiency syndrome in patients of Arab descent. Hum Genet 94:581–582 Fathallah DM, Dellagi K, Qumsiyeh MB, Teebi AS (1998) Recent advances in molecular genetics of the Maghreb and the Middle East populations: the first Middle East Association of America (MEGA) conference. Am J Med Genet 78:90–91 Fischel-Ghodsian N, Prezant TR, Fournier P, Stewart IA, Maw M (1995) Mitochondrial mutation associated with nonsyndromic deafness. Am J Otolaryngol 16:403–408 Freundlich F, Hino N (1984) Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci 20:1035–1038

28

A.S. Teebi

Fried K, Mundel G (1977) High incidence of spinal muscular atrophy type I (Werdnig-Hoffmann disease) in the Karaite community in Israel. Clin Genet 12:250–251 Frossard P, John A, Dawson K (1994) Custic fibrosis in the UAE: II. Molecular genetic analysis. Em Med J 12:249–254 German J, Hashem N, El-Hefnawi M, Cleaver JE (1984) Xeroderma pigmentosum in Egypt. III. ABO blood grouping in 22 affected families. Ann Hum Genet 48(Pt1):61–64 Glaser B, Philip M, Carmi R, Lieberman E, Landau H (1990) Persistant hyperinsulinemic hypoglycemia of infancy (“nesidioblastosis”): autosomal recessive inheritance in 7 pedigrees. Am J Med Genet 37:511–515 Grissa A (1994) Arab economic integration: current reality and future prospects. Economic Research Forum. Working paper 9405 Hamamy H, Alwan A (1994) Hereditary disorders in the eastern Mediterranean region. Bull WHO 72:145–154 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Han XD, Cox V, Slavotinek A (2006) Atrioventricular block and wiry hair in Teebi hypertelorism syndrome. Am J Med Genet A 140:1960–1964 Harlap S (1974) Down’s syndrome in west Jerusalem. Am J Epidemiol 97:225–232 Hashem N (1982) Preventable aspects of genetic morbidity. Proceedings of the first international conference, Ain Shams University, Cairo, Egypt Hathout H (1972) Abortion and Islam. Leb Med J 25:237–239 Heinisch U, Zlotogora J, Kafert S, Gieselmann V (1995) Multiple mutations are responsible for the high frequency of metachromatic leucodystrophy in a small geographic area. Am J Hum Genet 65:51–57 Hellani A, Aqueel A, Jaroudi K, Ozand P, Coskun S (2004) Pregnancy after preimplantation genetic diagnosis for Sanjad-Sakati syndrome. Prenat Diagn 24(4):302–306 Hershkovitz E, Parvari R, Diaz GA, Gorodischer R (2004) Hypoparathyroidism–retardation–Dysmorphism (HRD) syndrome – a review. J Pediatr Endocrinol Metab 17:1583–1590 Hoglund P, Auraren M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J (1998) Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 63:760–768 Hoffmann KJ, Steel G, Kazazian HH, Valle D (1991) Phenylketonuria in US blacks; molecular analysis of the phenylalanine hydroxylase gene. Am J Hum Genet 48:791–798 Hu PY, Roth DE, Skaggs LA, Venta PJ, Tashian RE, Guibaud P, Sly WS (1992) A splice junction mutation in intron 2 of carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. Hum Mut 1:288–292 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Fuga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Ezai-Delui H, Leguis E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98 Husseini S (1994) La redistribution territoriale des Chre´tiens au Liban. Cah Orient 32–33:145–174 Issa ARA, Teebi AS, Issa MA, Shaabani IS, Ramadan D (1988a) Metabolic alkalosis in cystic fibrosis: atypical presentation in Kuwait. Ann Trop Pediatr 8:271–272 Issa ARA, Yadav G, Teebi AS (1988b) Intra-familial variability in citrullinemia. J Inherit Metab Dis 11:306–307 Jaber L, Bailey-Wilson JE, Haj-Yehia M, Hernandez J, Shohat M (1994) Consanguineous matings in an Israeli-Arab community. Arch Pediatr Adolesc Med 148:412–415 Jaber L, Halpern GJ, Shohat T (2000) Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin Genet 58:106–110 Jaber L, Shohat M, Bu X, Fischel-Ghodsian N, Yang H-Y, Wang S-J, Rotter J (1992) Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J Med Genet 29:36–39

1 Introduction: Genetic Diversity Among Arabs

29

Jaber L, Weitz R, Bu X, Fischel-Ghodsian N, Rotter JI, Shohat M (1995) Arthrogryposis multiplex congenita in an Arab kindred: update. Am J Med Genet 55:331–334 Jacoub B (1938) Tay-Sachs disease in Egypt. J Egypt Med Assoc 21:377 Jurdi R, Saxena PC (2003) The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries. J Biosoc Sci 35:1–13 Kabarity A, Al-Awadi SA, Farag TI, Mallalah G (1981) Autosomal recessive “uncomplicated” profound childhood deafness in an Arabic family with high consanguinity. Hum Genet 57:444–446 Kagalwalla AF (1994) Congenital chloride diarrhea: a study in Arab children. J Clin Gastrol 19:36–40 Kamal MF, Nazer H (1984) Cystic fibrosis in Jordan: a pilot study. Ann Trop Paediatr 4:243–246 Kambouris M, Banjar H, Mogarri I, Nazer H, Al-Hamed M, Meyer BF (2000) Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations. Eur J Pediatr 159:303–309 Kannan M, Saxena R (2009) Glanzmann’s thrombasthenia: an overview. Clin Appl Thromb Hemost 15:152–165 Karawagh AM, Abdullah LS, Gasim AM, Abdelaziz MM (2008) Noninsulinoma pancreatogenous hypoglycemia syndrome in Saudi male. Saudi Med J 29:1654–1657 Kaya N, Al-Zahrani F, Al-Odaib A, Rahbeeni Z, Al-Hassnan Z, Al-Sharif F, Ozand P, Al-Sayed M (2008a) Identification of Gaucher disease mutations found in Saudi Arabia. Blood Cells Mol Dis 41:200–201 Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF (2008b) Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med 10:675–684 Kerem B, Zielewski J, Markiewicz D, Bozon D, Gazit E, Yahaf J, Kennedy D, Riordan JR, Collins FS, Rommens JR, Tsui L-C (1990) Identification of mutations in regions corresponding to 2 putative nucleotide (ATP) binding folds of the cystic fibrosis gene. Proc Natl Acad Sci USA 87:8447–8451 Khachadurian AK (1964) The inheritance of essential familial hypercholesterolemia. Am J Med 37:402–407 Khlat M, Khudr A (1984) Cousin marriages in Beirut, Lebanon: is the pattern changing? J Biosoc Sci 16:369–373 Kleiman S, Avigad S, Vanagaite L, Shamuelevitz A, David M, Eisensmith RC, Brand N, Schwartz G, Rey F, Munnich A, Woo SLC, Shiloh Y (1994) Origins of hyperphenylalaninemia in Israel. Eur J Hum Genet 2:24–34 Koenig R (2003) Teebi hypertelorism syndrome. Clin Dysmorphol 12:187–189 Kohn G, el Shawwa R, el Rayyes E (1988) Isolated “clinical anophthalmia” in an extensively affected Arab kindred. Clin Genet 33:321–324 Kolberg H (1986) Cystic fibrosis in Kuwait. J Trop Paediatr 32:293–294 Langer R, Al-Gazali L, Raupp P, Varady E (2007) Radiological manifestations of the skeleton, lungs and brain in Stueve-Wiedemann syndrome. Australas Radiol 51:203–210 Krishna Murthy DS, Farag TI (1995) Recurrent regular trisomy 21 in two Bedouin families. Parental mosaicism versus genetic predisposition. Ann Genet 38:1–8 Kurdi-Heidar B, Mason PJ, Berrebi A, Ankra-Badu G, Al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47:1013–1019 Kwitek-Black AE, Carmi R, Duyk GM, Buetow KH, Elbedour K, Parvari R, Naidu Yandava C, Stone EM, Sheffield VC (1993) Linkage of Bardett-Biedl syndrome to chromosome 16q and evidence for genetic heterogeneity. Nat Genet 5:135–139 Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, Russell DW, Goldstein JL (1987) The Lebanese allele at the low density lipoprotein receptor locus: nonsense mutation

30

A.S. Teebi

produces truncated receptor that is retained in the endoplasmic retuculum. J Biol Chem 262:401–410 Leitersdorf E, Safadi R, Meiner V, Reshef A, Bjorkhem I, Friedlander Y, Morkos S, Berginer VM (1994) Cerebroteninous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Am J Hum Genet 55:907–915 Lerer I, Cohen S, Chemke M, Sanilevish A, Rivlin J, Golan A, Yahav J, Friedman A, Abeliovich D (1990) The frequency of the DF508 mutation on cystic fibrosis chromosomes in Israeli families: correlation to CF haplotypes in Jewish communities and Arabs. Hum Genet 85:416–417 Lubani MM, Doudin KI, Sharda DC, Shaltout AA, Al-Shab TS, Abdul-Al YK, Said MA, Salhi MM, Ahmed SA (1989) Congenital chloride diarrhoea in Kuwaiti children. Eur J Pediatr 148:333–336 Lubani MM, Issa ARA, Bushnaq R, Al-Saleh QA, Dudin KI, Reavy PC, El-Khalifa MY, Manadhar DS, Abdul-Al YK, Ismail EA, Teebi AS (1990) Prevalence of congenital adrenal hyperplasia in Kuwait. Eur J Pediatr 149:391–392 Lurie IW, Prytkov AN, Meldere LY (1984) Meckel syndrome in different populations. Am J Med Genet 18:661–669 Lyonnet S, Cailland C, Rey F, Betthelon M, Frazal J, Rey J, Munnich A (1989) Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am J Hum Genet 44:511–517 Maalej M, Hentati D, Slimene M, Kenon S, Hechiche M, Ben Romdhane K, Ben Abdallah M (2007) Skin cancer in Tunisia: a retrospective study: 1379 cases and risk factors. Tunis Med 85:728–733 Machado-Paula L, Guion-Ameida ML (2003) Teebi hypertelorism syndrome: additional cases. Am J Med Genet A 117A:181–183 Mahdi AH (1988) Osteopetrosis in Saudi children: a report of 10 cases. Ann Trop Paediatr 8:112–115 Majeed HA, Barakat M (1989) Familial mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 148:636–641 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34:813–818 Marsden D, Nyhan WL, Sakati NO (1994) Syndrome of hypoparathyroidism, growth hormone deficiency and multiple minor anomalies. Am J Med Genet 52:334–338 Matsumura Y, Sato M, Nishigori C, Zghal M, Yagi T, Imamra S, Takebe H (1995) High prevalence of mutations in the p53 gene in poorly differentiated squamous cell carcinomas in xeroderma pigmentosum patients. J Invest Dermatol 105:399–401 McKusick VA (1994) Mendelian inheritance in man. A catalog of human genes and genetic disorders, 11th edn. Johns Hopkins University Press, Baltimore Mathew PM, Hamdan JA, Nazer H (1991) Cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis. Eur J Pediatr 150:264–266 Mathew PM, Young JM, Abu-Osba YK, Mulhem BD, Hammoudi S, Hamdan JA, Saadi AR (1988) Persistent neonatal hyperinsulinism. Clin Pediatr 27:148–151 Medlej-Hashem M, Loiselet J, Lefranc G, Megarbane A (2004) Familial mediterranean fever (FMF): from diagnosis to treatment, Sante 14:261–266 Miller RW (1977) Ethnic differences in cancer occurrence: genetic and environmental influences with particular references to neuroblastoma. In: Mulvihill JJ, Miller RW, Fraumeni JF Jr (eds) Genetics of human cancer. Raven Press, New York, pp 1–14 Mishalany HG, Der Kaloustian VM (1971) Familial multiple level intestinal atresia: report of two siblings. J Pediatr 79:124 Mishalany HG, Najjar FB (1968) Familial jejunal atresia: three cases in one family. J Pediatr 73:753–755 Naffah J (1976) The Dyggve-Melchior-Clausen syndrome. Am J Hum Genet 28:607–614

1 Introduction: Genetic Diversity Among Arabs

31

Naguib KK, Al-Awadi SA, Moussa MAA, Farag TI, Teebi AS (1989) Effect of paternal age, birth order and consanguinity on nondisjunction in the population of Kuwait. J Kuwait Med Assoc 23:37–43 Naguib KK, Gouda SA, Elshafey A, Mohammed F, Bastaki L, Azab AS, Al-Awadi SA (2009) Sanjad-Sakati syndrome/Kenny-Caffey syndrome type 1: a study of 21 cases in Kuwait. East Mediterr Health J 15:345–352 Navon R, Nutman J, Kopel R, Gaber L, Gadoth N, Goldman B, Nitzan M (1981) Hereditary heat labile hexosaminidase B: its complications for recognizing Tay-Sachs genotypes. Am J Hum Genet 33:907–915 Nazer H, Riff E, Harfi H, Sakati N, Mathew R, Majeed-Saidan MA (1989) Cystic fibrosis in Saudi Arabia. Eur J Pediatr 148:330–332 Oehlman R, Zlotogora J, Wenger DA, Knowlton RG (1993) Localization of the Krabbe disease gene (GALC) on chromosome 14 by multipoint analysis. Am J Hum Genet 53:1250–1255 Ohlsson A, Cumming WA, Paul A, Sly WS (1986) Carbonic anhydrase deficiency II syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 77:371–381 Oppenheim A, Friedlander Y, Dann EJ, Berkman N, Schwartz SP, Leitersdorf E (1991) Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at low density lipoprotein receptor gene locus and by an additional independent major factor. Hum Genet 88:75–84 Ozand PT, Devol EB, Gascon GG (1992) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Center. J Child Neurol 7(Suppl):4–11 Ozand PT, Gascon GG, Al-Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990a) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inter Metab Dis 13:849–861 Ozand PT, Gascon GG, Dhalla M (1990b) Aspartocylase deficiency and Canavan disease in Saudi Arabia. Am J Med Genet 35:266–268 Palkovic M, Rajaram LU, Al-Ghanim MM, Khawam EM, Kandil HH, Al-Awadi SA, Farag TI (1994) Hyperlipoproteinemia among Bedouins: cord blood study. Ann J Hum Genet 55 (Suppl): A1662 Panter-Brick C (1992) Coping with an affected birth: genetic counseling in Saudi Arabia. J Child Neurol 7:569–575 Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loevs B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD, HRD/ Autosomal Recessive Kenny-Caffey Syndrome Consortume (2002) Mutation of TBCE causes hypoparathyroidism-retardation-dysmorphism and autosomal recessive Kenny-Caffey syndrome. Nat Genet 32(3):448–452 Pras E, Aksentijevich I, Gruber L, Balow JE, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509–1513 Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qui W-Q, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Fischel-Ghodsian N (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and nonsyndromic deafness. Nat Genet 4:289–294 Radhakrishnan K, El-Mangoush MA, Gerryo SE (1987) Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 75:95–100 Radovanovic Z, Shah N, Behbehani J (1999) Prevalence and correlates to consanguinity in Kuwait. Ann Saudi Med 19:206–210 Raffer K (2007) Macro-economic evaluations of Arab economies: a foundation for structural reforms. OFID Pamphlet series 36, OPEC Vienna Ramadan DG, Badawi MH, Zaki M, El Mazidi Z, Ismail EA, El Anzi H (1999) Persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis): a report from Kuwait. Ann Trop Paediatr 19(1):55–59

32

A.S. Teebi

Rashed M, Ozand PT, Al-Aqeel A, Gascon GG (1994) Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev 16 (Suppl):1–6 Reghis A, Benabadji M, Tchen P, Kaplan JC (1981) Quantitative variations of red cell cytochrome b5 reductase (NADH-methemoglobin reductase) in Algerian populations. Hum Genet 59:148–153 Rispler-Chaim V (1993) Islamic medical ethics in the twentieth century. Leiden, New York Romdhane NA, Ben Hamida M, Mrabet A, Larnaout A, Samoud S, Ben Hamda A, Ben Hamda M, Oueslati S (1993) Prevalence study of neurologic disorders in Keliba (Tunisia). Neuroepidemiology 12:285–299 Rosenberg N, Hauschner H, Peretz H, Mor-Cohen R, Landau M, Shenkman B, Kenet G, Coller BS, Awidi AA, Seligsohn U (2005) A 13-bp deltion in alpha(llb) gene is a founder mutation that predominates in Paletentian-Arab patients with Glanzmann thrombasthenia. J Thromb Haemost 3:2764–2772 Rosler A (2006) 17-beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev 3(3(Suppl)):455–461 Rosler A, Belanger A, Labrie F (1992) Mechanisms of androgen production in male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 75:773–778 Saadallah AA, Rashed MS (2007) Newborn screening: experiences in the Middle East and North Africa. J Inherit Metab Dis 30:482–489 Salem M, Idrees H (1962) Cystic fibrosis in the Middle East. J Med Liban 15:61–74 Sanjad SA, Sakati NA, Abu Osba YK, Kaddora R, Milner RDG (1991) A new syndrome of congenital hypoparathyroidism, seizure, growth failure and dysmorphic features. Arch Dis Child 66:193–196 Schorr S, Legum C, Ochshorn M, Hirsch M, Moses S, Lasch EE, El-Masri M (1977) The DyggveMelchior-Clausen syndrome. Am J Toentgen 128:107–113 Scott DA, Carmi R, Elbedour K, Yosefsberg S, Stone EM, Sheffield VC (1996) An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA p[ooling using two inbred Bedouin kindreds. Am J Hum Genet 59:385–391 Shaabani I, Ben-Omran T, Teebi AS (2010) Tay-Sachs disease among the Arabs. Qatar Medical Journal (In press) Shahin H, Walsh T, Sobe T, Lynch E, King MC, Avraham KB, Kanaan M (2002) Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet 100:284–289 Shaltout M (1959) Al-Fatwa, General culture administration at Al-Azhar, Cairo, Egypt Sharkia ZM, Athmna A, Cohen D, Azem A, Zalan A (2008) The changing pattern of consanguinity in a selected region of the Israeli Arab community. Am J Hum Biol 20:72–77 Sheba C, Szeinberg A, Adam A, Ramot B. 1961. Distribution of glucose-6-phosphate dehydrogenase deficiency (G6PD) among various communities in Israel. International Congress, Ser 32 Excerpta Medica, Amsterdam, pp 633–634 Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, Seret H, Yaar L, Kerem E, Kerem B (1992) Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet 50:222–228 Stratton RF (1991) Teebi hypertelorism syndrome (Brachycephalofrontonasal dysplasia) in a U.S. family. Am J Med Genet 39:78–80 Tabchi B, Rassi B, Akl E, Fares G (2000) Epidemiology of profound neurosensory deafness in Lebanese children. J Med Liban 48:294–297 Tadmouri GO, Al Ali MT, Al-Haj Ali S, Khaja N (2006) CTGA: the database for genetic disorders in Arab populations. Nucleic Acids Res 34:D602–D606 Tatar A, Ocak Z, Tatar A, Yesilyurt A, Borekci B, Oztas S (2009) Primary hypogonadism, partial alopecia, and Mullerian hypoplasia: report of third and review. Am J Med Genet A 149A: 501–504

1 Introduction: Genetic Diversity Among Arabs

33

Teebi AS (1987) New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28:581–591 Teebi AS (1994) Autosomal recessive disorders among Arabs. An overview from Kuwait. J Med Genet 31:224–233 Teebi AS, Al-Awadi SA (1985) Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J Med Genet 23:189–191 Teebi AS, Al-Awadi SA (1991) Kuwait type faciodigito-genital syndome. J Med Genet 28:805–808 Teebi AS, Al-Saleh QA, Odeh H (1992) Meckel syndrome and neural tube defects in Kuwait. J Med Genet 29:140–144 Teebi AS, Daoud AS (1990) Multiple pterygium syndrome: a relatively common disorder among Arabs. J Med Genet 27:791–792 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research, and policy. Lancet 367(9515):970–971 Teebi AS, Marafie MJ (1988) Uncle-Niece/Aunt-Nephew marriages are not existing in Muslim Arabs. Am J Med Genet 30:981 Teebi AS, Naguib KK, Al-Awadi SA, Al-Saleh QA (1988) New autosomal recessive faciodigitogenital syndrome. J Med Genet 25:400–406 Teebi AS, Naguib KK (1988) Autosomal recessive nonsyndromal hydrocephalus. Am J Med Genet 31:467–470 Teebi AS, Shawky RM (2000) Population and molecular genetic update: the second Middle East Genetic Association of America (MEGA) conference. Am J Med Genet 92:293–294 Teebi AS, Teebi SA (2005) Genetic diversity among the Arabs. Community Genet 8:21–26 Teebi AS, Teebi SA, Porter CJ, Cuticchia AJ (2002) Arab genetic disease database (AGDDB): a population specific clinical and mutation database. Hum Mutat 19:615–621 Temtamy SA, Adbel-Salam M, Hussein FA, Meguid NA, El-Gindy E (1991) Clinical biochemical and cytogenetic studies of mental retardation in Egyptian children. J Egypt Public Health Assoc 65(Suppl):189–199 Thomas PM, Cote GJ, Hallman DM, Mathew PM (1995) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 56:416–421 Tieder M, Modai D, Shaked U, Samuel R, Arie R, Halabe A, Maor J, Weissgarten J, Abverbakh Z, Cohen N, Edelstein S, Liberman UA (1987) Idiopathic hypercalciuria and hereditary hyophosphatemic rickets: two phenotypical expressions of a common genetic defect. N Engl J Med 316:125–129 Toriello HV, Delp K (1994) Teebi hypertelorism syndrome: report of a third family. Clin Dysmorphol 3:335–339 Triggs-Raine BL, Akerman BR, Clarke JTR, Gravel RA (1991) Sequence of DNA flanking the exons of the Hex A gene and identification of mutations in Tay-Sachs disease. Am J Hum Genet 49:1041–1045 Tsai AC, Robertson JR, Teebi AS (2002) Teebi hypertelorism syndrome: report of a family with previously unrecognized findings. Am J Med Genet 113:302–306 Tsukahara LM, Uchida M, Shinohara T (1995) Teebi hypertelorism syndrome: further observations. Am J Med Genet 59:59–61 Usha R, Uma R, Farag TI (1992) Late diagnosis of phenylketonuria in a Bedouin mother. Am J Med Genet 44:713–715 Vieira LM, Kaplan JC, Kahn A, Leroux A (1995) Four new mutations in the NADH-Cytochrome b5 reductase gene in patients with recessive congenital methemoglobinemia type II. Blood 85:2254–2262 Walsh T, Abu Rayan A, Abu Sa’ed K, Shahin H, Shepshelovich J, Lee MK, Hirschberg K, Tekin M, Salhab W, Avraham KB, King MC, Kanaan M (2006) Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population. Hum Genomics 2:203–211

34

A.S. Teebi

Wei S, Feldman GL, Monaghan K (2006) Cystic fibrosis testing among Arab-Americans. Genet Med 8:255–258 White JM, Christie BS, Nam D, Daar S, Higgs DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 World Bank (1994) Forgoing a partnership for environmental action: An environment strategy toward sustainable development in the Middle East and North Africa. World Bank Yadav GC, Reavey PC (1988) Aminoacidopathies: a review of 3 years experience of investigation in a Kuwait hospital. J Inherit Metab Dis 11:277–284 Young ID, Rickett AB, Clarke M (1985) High incidence of Meckel syndrome in Gujarati Indians. J Med Genet 22:301–304 Woods CG, Stricker S, Seemann P, Stern R, Cox J, Sherridan E, Roberts E, Springell K, Scott S, Karbani G, Sharif SM, Toomes C, Bond J, Kumar D, Al-Gazali L, Mundlos S (2006) Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am J Hum Genet 79:402–408 Zimmerman SA, O’Branski EE, Rosse WF, Ware RE (1999) Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol 60:279–284 Zghal M, El-Fekih N, Fazaa B, Fredj M, Zhioua R, Mokhtar I, Mrabet A, Ferjani M, Gaigi S, Kamoun MR (2005) Xeroderma pigmentosum. Cutaneous, oscular, and neurologic abnormalities in 49 Tunisian cases. Tunis Med 83:760–763 Zlotogora J (1997) Autosomal recessive diseases among Palestinian Arabs. J Med Genet 34: 765–766 Zlotogora J, Barges S (2003) High incidence of profound deafness in an isolated community. Genet Test 7(2):143–145 Zlotogora J, Furman-Shaharabani Y, Harris A, Barth ML, Von Figura K, Gieselmann V (1994a) A single origin for the most frequent mutation causing late infantile metachromatic leucodystrophy. J Med Genet 31:672–674 Zlotogora J, Habiballa H, Odatalla BS (2002) Changing family structure in a modernizing society: a study of marriage patterns in a single Muslim village in Israel. Am J Hum Biol 14:680–682 Zlotogora J, Levy-Lahad E, Legum C, Iancu TC, Zeigler M, Bach G (1991) Krabbe disease in Israel. Isr J Med Sci 31:196–198 Zlotogora J, Sagi M, Cohen T (1994b) Familial hydrocephalus of prenatal onset. Am J Med Genet 49:202–204

Part II Demography, Economy, and Genetic Services in Arab Countries

Chapter 2

Arab Demography and Health Provision Under Stressed Economics Sulayman S. Al-Qudsi

Introduction The chapter is concerned with the dynamics of health profile of Arab economies in the changing context of demographic transitions and volatile economic growth, both globally and regionally, and in the midst of rapid technological change that transforms the health sector and changes the relative importance of health priorities, in terms of investment spending and importance at the family and public policy agenda. The dynamic transformation of the health sector is closely intertwined with socio-economic and technological developments. To illustrate, the current global economic downturn of 2008 and 2009 has adversely impacted on the region and beyond economics, specifically, the global economic downturn threatens the very sustainability of health and education progress – by reducing the ability of both households and governments to invest in education and health sectors. The crisis could lead to spending cuts if governments cannot find additional financing in the event that private capital inflows and domestic fiscal revenues drop sharply. For instance, it is estimated that a 50 percent drop from the 2007 net assistance level from advanced to developing countries would reduce health support for developingcountry health programs by more than US$ 2.5 billion (USAID, 2009). Children and young people may be pressed to drop out of school to work more hours at home or take on outside jobs. In addition, the newly emerging diseases such as Swine flu coupled with pandemics of chronic diseases are likely to challenge both

Disclaimer: All the analysis and views presented here are strictly those of the author and do not in any way represent the views or judgments of the Arab Bank or its affiliates where Sulayman Al-Qudsi works as the Chief Economist. Arab Bank is not liable in any way for the accuracy, completeness, representation, or implications of the information and opinions reported or expressed here. S.S. Al-Qudsi Chief Economist and Head of Research Department-Arab Bank, PLC. Amman-Jordan.Shaker bin Zeid Street, Shmeisani Area, 950545, Amman, Jordan e-mail: [email protected]; [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_2, # Springer-Verlag Berlin Heidelberg 2010

37

38

S.S. Al-qudsi

the global and regional health systems. Economic volatility and stressed financial and economic conditions with fluctuations in oil prices are likely to affect the growth of the pharmaceutical industry adversely. The economic downturns may also worsen the already high out-migration of the Arab health workforce, especially doctors, nurses, and paramedical staff. While the broad objective here is to provide a basic assessment of the Arab health profile with the overall context of Arab economic transformations both overall and among constituent economies, the chapter assesses such issues as overall health sector provision, accessibility and inequities, size of employment in the health activities, mortality and morbidity issues, and the “brain drain” of health sector workers. The chapter highlights some of the policy challenges and imperatives that the dynamic interactions between volatile economic times and demography induce for the health services provision. These imperatives require immediate policy focus to safeguard the future for successive Arab generations.

Geography, History, and Ethnicity Geographically, the Arab world straddles two continents, covering a distance of 6,370 km from Rabat on the Atlantic to Muscat on the Gulf (Bolbol and Fatheldin 2005). Representing nearly 10% of the world’s geography and with a share of 3% of the world’s GDP, the Arab World has nearly 300 million inhabitants or about 5% of the world’s population. The region gained increasing importance during the period 2002–2007, which witnessed massive increases in the prices of commodities such as oil and natural gas. Being resource-rich, the region was sizzling with economic growth and trade and investment in-and-out-flows. Many oil-exporting countries of the region experienced unprecedented growth and realized huge foreign reserves accumulations. These petro-surpluses led to enhancements of sovereign wealth funds (SWFs) that were largely invested in the international financial centers of the world, notably in the USA and the EU. Despite its linguistic, religious, and cultural cohesion, the Arab region is also rich in diversity. In territorial size, some countries (Sudan and Saudi Arabia) comprise vast areas that approach one million square miles, while others (Bahrain) are small enough to fit into a major Western city. It is the home of diverse ethnic and religious groups including Muslim and Christian Arabs, Kurds, Druze, Berbers, and Armenians. It is also a fountain of political and ideological ferment and a locus of some of the most persistently explosive conflicts in the world. No country on earth can be unconcerned with the course of major developments in the region (Held 1993). The history of Arabs goes back a few 1,000 years before Christ. The origin of the word “Arab” remains obscure, although philologists have offered various explanations. One such explanation associates the term with nomads; the root “Ahbar” means to move or pass. Arabs themselves seem to have used the word at an early date to distinguish the Bedouin from the Arabic speaking town and village dwellers;

2 Arab Demography and Health Provision

39

and indeed, this use persists to some extent (Lewis 1993). The earliest known events in Arabian history are migrations from the Arabian Peninsula into neighboring areas. About 3,500 BC, Semitic-speaking peoples of Arabian origin migrated into the valley of the Tigris and Euphrates rivers in Mesopotamia, supplanted the Sumerians, and became the Assyro–Babylonians. Another group of Semites left Arabia about 2,500 BC and settled along the eastern shore of the Mediterranean Sea; some of these migrants became the Amorites and Canaanites of later times (Bram and Dickey 1992). Beginning in the seventh century (AD), Arabs, proclaiming the new religion of Islam, ventured out from the Arabian Peninsula to conquer wide regions extending from the Arabian/Persian Gulf to the Atlantic Ocean. Arabic became the language of all the peoples who lived between Baghdad and Cordoba – a significant aspect of Islamic civilization. It became both the language of daily life and the language of science and literature, completely replacing Coptic, Aramaic, Greek, and Latin. The strategic geographical position of Islamic countries enabled them to dominate international trade in the middle Ages and to attract and nurture intellectuals from all over the world (Hassan and Hill 1986). Islamic science and medicine thrived; scholars such as Abu Bakr al-Razi and Jabir B. Hayyan were world renowned; scientific institutions flourished – for example, Bayt al-Hikma (House of Wisdom). The common denominator among residents of the Arab world is their language. Formal Arabic is the official language in all countries of the Arab League. In addition to their common language, most Arabs follow the same religion. The overwhelming majorities (over 90%) are Muslims, predominantly of the Sunni persuasion, and Islam is a vital force in everyday life. However, being the home of the three revealed religions, the Arab world is home for prominent Christian minorities especially in Palestine, Egypt, Lebanon, Iraq, and Syria. In addition, Jewish Arab enclaves live in such countries as Iraq, Morocco, and Yemen. Geopolitically, the region has been the center of intellectual debates and controversy that culminated in September 11, 2001 in the aftermath of the terrorist attack on the twin towers, which brought to the center stage the issue of the clash of civilizations. The ensuing adversarial political and military standing of the G.W. Bush administration subjected the region to wars, conflict, and mass killings and deteriorated regional integrity and cohesion. Not surprisingly, the policies were vehemently opposed by some of the region’s best think tanks. Realizing apparent deficiencies in the whole concept, they posed the counterarguement that the world is interdependent and that globalization leads to a common global destiny irrespective of the diversity of cultural and ethnic backdrop. That is to say, diversity is a common feature on earth and in fact in the whole universe and does not, per se, imply or lead to conflict. For instance, the Arab scholar, Edward Said (2001) mocked the whole thesis of clash of civilization dubbing it “the clash of ignorance” and concluded that “The real question is whether in the end we want to work for civilizations that are separate, or whether we should be taking the more integrative, but perhaps more difficult path, which is to see them as making one vast whole, whose exact contours are impossible for any person to grasp, but whose certain existence we can intuit and feel and study”.

40

S.S. Al-qudsi

Perhaps it is not difficult to understand the economic and resource underpinnings of the conflict theories. The region contains more than 60% of the world’s proven oil reserves and more than 25% of the world’s natural gas reserves. With two thirds of Arab countries producing oil, crude is undoubtedly the most important factor in the region’s economic development (Raffer 2007). The economies of the Arab world exhibit great diversity in income and structure. The variety is highlighted by the fact that GDP per capita of the wealthiest country, Qatar, is 73 times higher than that of the poorest country, Mauritania. In addition, the economies are characterized by a multiplicity of structures. Some countries have accumulated significant wealth through the extraction of natural resources, while others follow more traditional trajectories of development, starting with lower-end manufacturing and slowly moving up the value chain. These differences affect the competitive performance in many ways, the most important being the availability of resources for public investment. The organization of this chapter is as follows. Section “Stylized Economic and Financial Facts” provides an overall summary of Arab volatile economic development and economic stylized facts. The re-assessment of these stylized facts and global regional and economic turmoil is taken up in Section “Reevaluation of Stylized Facts” followed in section 3 by a review of Arab population dynamics including demographic transition and rural–urban migration. Section “Health Systems and Health Expenditures” presents the health system and the Arab health expenditures including the pharmaceuticals markets and trade. The section deals also with health inequality indicators within and across Arab countries. The final section summarizes salient issues and policy implications.

Stylized Economic and Financial Facts The conventional wisdom about Arab economies is that the region’s natural resource endowments provide ample financial capital and foreign exchange for economic diversification and for the transformation of oil wealth into versatile portfolio of human capital that could ultimately generate high value-added growth path for the Arab economies. On the downside however, Arab mineral resource endowments pose challenges associated with the so-called “resources curse” and Dutch disease syndromes which affect the exchange rates and in the process, could cause de-industrialization. Perhaps more seriously, they introduce frequent and sharp economic and financial volatilities which could set limits on the growth potential of a region that already has high population momentum and rapidly rising labor supply and high unemployment and inactivity rates. Figure 2.1A–F displays growth volatility in several Arab economies that are resource-based. The figures demonstrate how economic volatility derives in part from resource price volatility; that is how oil and natural gas prices affect the trends and cyclical patterns of economic growth of these economies. Moreover, and despite impressive transformations, the region is still considered lagging in requisite quality human capital stock which adversely affects international

2 Arab Demography and Health Provision

41

competitiveness. In addition, compared with international levels, the annual infusions of physical capital and R&D investment rates are insufficient and the region is virtually in the early stages of fostering its organizational capabilities and corporate governance. These forces tend to drag the overall productivity to levels below the region’s long-term potential. This is corroborated by recent work that indicated that the role of total factor productivity (TFP) in determining economic growth in Arab countries is insignificant and often detrimental. Most of the growth is due to the accumulation of physical capital and improvements in the quality of labor (Al-Qudsi, 2006; Al-Qudsi and Abu-Dahesh, 2004). Last but not least, Arab economic performance has been adversely influenced by protracted conflict conditions and by geopolitical and global competition to secure reliable supply of hydrocarbon energy sources. (1980–2007) 10

300000

8

250000

6

GDP (%)

8

10

6

Natural Gas US Henry Hub ‡

GDP (LCU m) 350000

8

4

6

2 4

200000

4 0

2

2 –2

150000 1990

1980

2010

2000

Real GDP(m LCU) (LHS) Natural Gas US Henry Hub

1990

2000

2010

GDP Growth Rate% Natural Gas US Henry Hub

(1980–2007)

GDP( LCU m)

GDP(%)

120000

10

25

10

100000

8

20

8

80000

6

15

6

4

10

4

2

5

60000 40000 1990

2000

2

2010

1980

Real GDP(LCU m )(LHS) Natural Gas US Henry Hub

(1980–2007)

800000

80

700000

60

600000

40 20

500000

0

400000 1990

2000

Real GDP(LCU m)(LHS) WTI( $/bbl ‡)

Fig. 2.1 Continued

2000

2010

GDP Growth Rate Natural Gas US Henry Hub

GDP(LCUm)

1980

1990

2010

GDP(%)

10

80 60

5

40 0

20 0

–5 1980

1990

2000 GDP Growth Rate WTI( $/bbl ‡)

2010

WTI($/bbl ‡)

1980

Natural Gas US Henry Hub ‡

1980

42

S.S. Al-qudsi

(1980–2007) GDP (%)

20000

80

150

80

15000

60

100

60

10000

40

50

40

5000

20

0

20

0

0 1980

1990

2000

–50

0 1980

2010

WTI($/bbl ‡)

GDP(LCUm)

2000

1990

Real GDP(LCU m)(LHS)

2010

GDP Growth Rate WTI( $/bbl ‡)

WTI( $/bbl ‡)

(1980–2007)

GDP(LCUm)

80

400000

GDP (%)

30

80

60 10

40

40 0

200000

20

WTI($/bbl ‡)

20 60 300000

20 –10

0

100000 1980

1990

2000

0

–20

2010

1980

Real GDP(LCUm)(LHS) WTI( $/bbl ‡)

1990

2000

2010

GDP Growth Rate WTI( $/bbl ‡)

(1980–2007) GDP(LCU m)

GDP (%) 80

18000

60

16000

40

10

80

60 5 40 0

20

14000

0

12000 1980

1990

2000

2010

WTI($/bbl ‡)

20000

20

0

–5 1980

1990

2000

Real GDP(LCU m)(LHS)

GDP Growth Rate

WTI( $/bbl ‡)

WTI( $/bbl ‡)

2010

Fig. 2.1 (a) Algeria’s GDP versus natural gas price. (b) Qatar’s GDP versus natural gas price. (c) KSA’s GDP versus WTI. (d) Kuwait’s GDP versus WTI. (e) UAE’s GDP versus WTI. (f) Libya’s GDP versus WTI Source: IMF and EIU

2 Arab Demography and Health Provision

43

Reevaluation of Stylized Facts However, these stylized facts have recently become subject to reevaluation and reassessment because of several emerging trends. First, most Arab countries have recently initiated and are implementing structural reforms that enabled them to enhance their economic growth which proceeded at an estimated average rate of 5.4% over 2000–2007, Table 2.1. While individual country growth rates varied in the latest available year, 2006, the regional average economic growth reached an all time high rate of 6.6% in 2006. Due to an amalgam of forces including the rapid population and labor growth rates and the mismatch between the education system and labor markets requirements, the region suffers from high unemployment which hovers around 15% on average. Also, while inflation used to be mild, it has recently picked up momentum, Fig. 2.2. Even in the traditionally low inflation economies of the GCC, inflation is becoming an increasingly painful issue. To combat high unemployment rates as well as the region’s rising cost of living, recent reform policies have focused on sustaining Table 2.1 Real GDP growth (Annual change, in percent) Avg. 2002 2003 1998–2001 Middle East & Central Asia 3.8 4.3 6.3 Oil Exporters 3.6 4.8 7.5 Algeria 3.6 4.7 6.9 Bahrain 4.8 5.2 7.2 Iraq 8.2 7.8 41.4 Kuwait 2.5 5.1 13.4 Libya 1.7 3.3 9.1 Oman 3.6 2.6 2 Qatar 7.4 7.3 5.9 Saudi Arabia 1.5 0.1 7.7 Syria 2.4 3.7 1 UAE 4 2.6 11.9 Low-income countries 4.9 5.4 5.9 Mauritania 3.1 1.1 5.6 Sudan 5.7 6.4 4.9 Yemen 4.3 3.9 3.1 Emerging Markets 4 3.1 4.4 Egypt 5.1 3.2 3.1 Jordan 4.3 5.8 4.2 Lebanon 1.9 2.9 5 Morocco 3.6 3.2 5.5 Tunisia 4.4 1.7 5.6 CIS 6 7.8 8.7 MENA 3.7 4.1 6.3 Of which GCC 2.5 1.6 8.5 Maghreb 3.5 3.6 6.6 Source: IMF 2008

2004

2005

2006

2007

6 6.1 5.2 5.4 46.5 6.2 4.6 5.6 11.2 5.3 3.1 9.7 6.2 5.2 5.2 2.6 5.8 4.1 8.4 6 4.2 6 9 5.4

6.3 6.6 5.3 6.9 3.7 8.5 3.5 6.7 6.5 6.6 2.9 8.5 7.2 5.4 7.9 3.8 5.7 4.9 7.2 1 1.7 4.2 10.9 5.5

6.6 6.6 4.9 7.1 4 6.2 5 7.1 6.7 5.8 3.2 11.5 9.2 14.1 12.1 3.9 5.9 5.6 6 -3.2 7.3 5.8 10.8 6.1

6.2 6.2 5 6.3 14.4 4.7 4.6 5.7 4.7 6.5 3.7 5.8 8.4 10.6 11.3 2.5 5.9 5.6 5 5 3.3 6 11 5.5

6.6 5

7.1 4

7.2 5.8

6.1 4.8

44

S.S. Al-qudsi

Jordan

Kuwait

Sep08: 18.5%

20 15 10 5 0

Apr09: –1.6%

Aug08: 11.6%

12 11 10 9 8 7

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

Jan09: 6.8%

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

KSA

Oman

Jul&Oct08: 11%

12 10 8 6 4

Apr09: 5.2%

Jun08: 14%

14 12 10 8 6

Mar09: 6.9% 2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

2008m1 2008m4 2008m7 2008m10 2009m1 2009m4

Morocco 6 5 4 3 2

Tunisia Apr08: 6%

May08: 5.4%

6 5

Feb&Mar09: 3.1%

4 3

Jan08: 1.8% 2008m1

2008m4

2008m7 2008m10 2009m1

2009m4

2008m1

2008m4

2008m7 2008m10 2009m1

2009m4

Fig. 2.2 Consumer price index, selected countries Source: Economic Intelligence Unit, EIU

economic growth, and curbing inflation and joblessness, the three main challenges faced by Arab economies in general. Second, the utilization of “petro-dollar” surpluses in the oil-producing Arab countries appears more prudently managed, which induced favorable internal and external balances relative to historical records. For instance, Saudi public debt has declined from 93% of GDP to the current 28%. In the non-oil-exporting countries of the Mashreq region, growth accelerated in 2006 in the context of an upturn in foreign direct investment and an overall favorable external environment. Third and equally important, however, is the fact that, in the course of time, Arab countries have gradually nurtured their nascent and banking. Infrastructures and applied policies that incrementally benefitted from the oil-induced financial surpluses on one hand and also embodied invaluable lessons gained from stressful financial episodes that occurred in other regional settings in Asia, North and Latin Americas, and Europe. The sustained growth of the region during 2002–2008 came to a halt when the global economy was hit by the financial crisis which initially started with the subprime crisis in the USA in August 2007 but was rapidly transmitted into Europe and the emerging economies including that of the MENA region. These profound developments were transmitted to the region and by now, there is little doubt that

2 Arab Demography and Health Provision

45

Arab economies in the Middle East and North African region, MENA, have been adversely affected by the global economic downturns. The main drivers of the contraction were lower and more volatile oil prices, reduced trade and contracted investment flows, and reduced trade and investment flows and lower investor and consumer confidence in key sectors such as construction and real estate. To exacerbate the downward trend, many government and private investors and SWFs in our region have endured major investment losses. According to one estimate by a senior GCC minister and Kuwaiti Harvard graduate, Dr. Mohammed Al-Sabah, “the financial crisis has cost the Arab world US$2.5 trillion in the past 4 months alone”. He estimates that “Up to 60% of the region’s development projects had been canceled or postponed”. The crash in oil prices has hit the region just as hard.

Arab Population Dynamics According to the revised population estimates of the United Nations, the population of Arab countries rose from 171.6 million in 1980 to 300.2 million in 2002. Table 2.2 summarizes population estimates in selected Arab countries. In terms of medium variant projections, the population of the 22 countries of the Arab region is expected to reach 385.2 million in 2015 and 631.2 million in 2050. The average, Table 2.2 Population in Arab countries, figures in thousands (2001–2007) Country Populations 2001 2002 2003 2004 2005 2006

Gr. rate 4,940 5,070 5,200 5,350 5,470 5,595 5,724 2.3 3,488 3,754 4,041 4,368 4,105 4,175 5,215 1.72 654.62 672.123 689.418 707.16 724.695 742.561 760.168 1.68 9,650.6 9,748.9 9,839.8 9,932.4 10,031.1 10,130 10,238 1.08 3,083 31,281 31,738 3,236 32,786 33,278 33,810 1.6 545 557 570 583 600 616.8 618.9 3 20,957.6 21,486.72 22,022.11 22,563.89 23,118.99 23,678.8 24,242.6 2.4

Jordan UAE Bahrain Tunisia Algeria Djibouti Saudi Arabia Sudan 31,913 32,769 33,648 Syria 16,720 17,171 17,635 Somalia 9,691 9,787 9,885 Iraq 24,813 25,565 26,340 Oman 2,478 2,538 2,341 Palestine 3,381.75 3,562.001 3,844.044 Qatar 648.744 682.434 717.766 Kuwait 2,182.61 2,262.959 2,325.44 Lebanon 3,636 3,675 3,714 Libya 5,300 5,581 5,669 Egypt 65,298 66,628 67,976 Morocco 29,170 29,631 30,088 Mauritania 2,568 2,669 2,913 Yemen 18,948 19,631 20,357 Total 287,814 294,722.1 301,553.6 Source: WHO, Statistical database, 2009

34,512 17,793 9,983 27,139 2,416 3,922.06 744.029 2,390.591 3,754 5,880 69,330 30,590 2,983 21,104 279,281.1

35,397 18,138 10,082 27,954 2,452 4,106.455 789.392 2,457.257 3,794 6,097 69,997 31,101 3,054 21,868 314,122.9

35,470 18,581 10,083 28,793 2,489 4,297.07 885.359 2,525 3,835 6,263 70,473 31,620 3,186 22,649 319,366

2007

36,400 19,175 10.184 29,656 2,526 4,491.72 918.16 2,666.4 3,876 6,431 71,844 32,150 3,262 23,464 317,479

2.63 2.45 1 3 1.5 3.4 1.5 5.6 1.07 2.7 1.9 1.5 2.4 3.5 2.4

46

S.S. Al-qudsi

exponential growth rate of 2.6% per annum during the period 1980–2002 could drop to 1.9% per annum during 2002–2015, and is likely to fall after 2025 to approximately 1.3% per annum during the period 2025–2050. High population growth rates reflect high fertility. In fact the single most remarkable demographic aspect of the Arab region is the nearly universal high level of fertility – the average level of childbearing is six children per woman. While fertility levels are high in general, disparities exist within and across countries. In Algeria in 1988, for instance, women still gave birth to more than six children in the southern part of the country but less than four in the north. Lebanon, despite its small size, harbors strong regional contrasts: Beirut (2.3 children/woman) versus the north (4.3 children/woman), for instance. In Egypt, the average family numbers only 3.6 children in Port Said but 8.2 in Fayoum (Fargues 1994). Similar to other developing regions, fertility did drop markedly, however, when considered over longer time horizons. For instance, it dropped from 5.7 births per woman in Egypt during the 1970–1975 to 3.3 births per woman during 2000–2005. Similar downward trend is discerned in other countries: in Iraq the corresponding drop was from 7.2 to 4.8 live births per woman during 1975–2005. Jordan’s total fertility dropped from 7.8 to 3.5 and in Lebanon, the drop was from 4.8 to 2.3 live births per woman. In Saudi Arabia, the drop was from 7.4 to 4.1 and in Syria total fertility declined from 7.5 to 3.5 live births per woman (Sanchez-Barricarte and Veira-Ramos 2008). The region’s rapid population growth was the result of a substantial decline in mortality triggered by the increasing use of antibiotics, by vaccinations, and by the spread of disease control and sanitation programs. Most countries of the region have made considerable progress in improving health conditions for their citizens, and these conditions still fall short of aspirations. “Good health” is obviously a multidimensional, complex phenomenon; measuring it is correspondingly difficult. Life expectancy at birth and infant mortality rates are two indicators of health conditions that are widely used. Life expectancy at birth has improved substantially throughout the Arab world. In most countries, a newly born child can expect to live 20 years longer than his or her parents. While mortality in the MENA declined over time, the decline in the number of “births per woman” did not occur until the mid-1970s and beyond as discussed earlier. As a result, the second half of the twentieth century witnessed explosive population growth throughout the region as births far outnumbered deaths. The region’s growth rate reached a peak of 3% a year around 1980. Currently, the population of MENA is growing at about 2% a year, still higher than the world average. The world as a whole reached its peak of population growth of 2% a year in the mid-1960s and is currently growing at 1.2% a year. The aforementioned demographic pattern produced youthful population structure and invariably reduced the median age of the Arab countries as shown in Table 2.3. One of the results of the youthful population structure is the rapid increase in labor force and in the face of sluggish economic growth and inability to create productive jobs; unemployment rates remain high, greater than 25% for the young age cohorts.

2 Arab Demography and Health Provision Table 2.3 Demographic and socioeconomic statistics Median Under Over Annual growth rate age 15(%) 60(%) (%|) 2007 2007 2007 1987–1997 1997–2007 Egypt 23 33 7 2 1.8 Jordan 22 36 5 4.5 2.7 Kuwait 30 23 3 0.5 4.4 Lebanon 28 28 10 2.3 1.2 Libya 25 30 6 2.1 2 Morocco 25 29 8 1.7 1.2 Oman 23 32 4 3.2 1.3 Qatar 31 21 3 3 4.2 Saudi Arabia 24 34 4 2.9 2.5 (KSA) Sudan 20 40 6 2.5 2.2 Syria 21 36 5 2.8 2.6 Tunisia 28 25 9 1.8 1.1 UAE 30 20 2 5.5 4.7 Yemen 17 45 4 4.2 3 Source: WHO Statistics, 2009

47

Living in urban areas (%) 1990 2000 2007 43 42 43 72 80 78 98 98 98 83 86 87 79 83 77 48 55 56 65 72 72 92 95 96 77 80 81 27 49 60 79 21

36 50 63 77 25

43 54 66 78 30

The high population growth rates make the population histograms of many Arab countries flat-based, reduce the doubling time (the time during which the population will become double its current size if population growth rate remain at current levels), enhance the population momentum, increase the dependency ratio, and temporally put tremendous pressure on the labor markets. Such transition crops the question about the demographic consequences for longrun per capita GDP growth. Recent research has highlighted the importance of demographic transitions in explaining cross-country differences in per capita GDP growth. In short, what matters for economic growth is not the rate of population growth per se, but rather the changing age distribution of populations as countries move from conditions of high fertility and mortality to low levels in both. Thus, when a large share of the population is dependent, nonworking, and under the age of 14 or over 65, an economy carries a demographic burden that lowers labor input per capita, depresses the savings rate, and reduces the rate of GDP per capita growth. This was the case in Asia and Latin America in the 1950s and 1960s. Conversely, countries are endowed with a demographic gift when a larger share of the population is economically active (between the ages of 15 and 64), raising the labor force per capita, capital accumulation, and GDP per capita growth as was the case in Asia during the miracle years of the 1970s and 1980s, East Asia in particular. From this perspective, one is able to understand the role of demography in MENA in the past and its potential contribution in the future (Yousef 2005). Because of the dynamics of international migration that the region witnessed during the past decades, many countries of the region have a high male-to-female sex ratio. In the oil-producing countries, for instance, the selectivity of the immigration process and policies render the sex ratio predominantly male. In fact, seven Arab countries top the list of the world’s most-male countries. In the United Arab

48

S.S. Al-qudsi

Emirates, there are 206 men for every 100 women; Qatar, 168; Bahrain, 145; Kuwait, 133; Saudi Arabia, 119; Oman, 110; and Libya, 110 (The Economist 1991). Dynamic population mobility is yet another notable characteristic of the Arab Middle East, both by choice and necessity. For example, the Bedouins of the Arabian Peninsula migrate from one geographic location to another in search of hunting and grazing land. Other movements are mandated by political reasons, such as the displacement of Palestinians in 1948 following the establishment of the state of Israel. Similarly, Syrians, Egyptians, and Lebanese have all been subjected to displacement due to the Arab-Israeli wars; the Lebanese conflict has led to massive population dislocation; the Iraq–Iran war has led to a large influx of Kurds into Turkey; and the conflict between the North and the South in Sudan has led to movement of refugees to the capital and other cities, creating large squatter settlements. Other forces causing population displacement include man-induced engineering developments. For instance, the construction of the Aswan Dam in 1964 submerged agricultural land in Aswan and Merowe in Egypt and Sudan, respectively. The Nubians who inhabited the areas were forced to resettle in large numbers. During the Arab oil decade of the 1970s, over three million workers migrated from “labor surplus” Arab countries to the Gulf and Libya, making up for labor shortages and helping to sustain development efforts. Most recently, the Gulf crisis and war led to the displacement of several million “third-country nationals”, including 500,000 Palestinians, one million Yemenis, 800,000 Egyptians, and several hundred Sudanese from Kuwait, Iraq, and Saudi Arabia (Shami 1993; Al-Qudsi et al. 1993).

The Population Aging Problem Currently, nearly 21% of the population in advanced countries is 60 years of age or older, which is three times the corresponding rate in developing countries where the ratio is 8.4%. The U.N predicts that globally, the percentage of people aged 65 years or older will double between 2007 and 2050. By 2050, one-third of the population in developed countries will be 60 years or older, while in less-developed countries, one fifth (20%) will be over 60(WEF 2008). MENA countries encounter somewhat of a variant aging issue however: Specifically, the growth rate of the urban population of the elderly is found to exceed the rural growth rate. Indeed, some countries are projected to lose their rural populations in that age segment by 2015. This unexpected trend could stem from factual errors in the data. In fact, with the rapid mortality transition, the absolute number of survivors and therefore, the percentage of the old population are expected to increase. However, owing to the above-mentioned assumption of a constant age structure of the rural population, the elderly segment does not show the change in the percentage of rural population, thereby suppressing the effect of aging on the age structure of the rural population. Moreover, given that the urban population was obtained as the residual of the total projected population, the urban population could be overestimated in the 65+ group, which could account for the high urban

2 Arab Demography and Health Provision

49

growth rate observed for that age segment of the population. However, migrations away from rural areas for the 65+ group could equally stem from a lack of rural infrastructure, particularly in the health and economic sectors. A majority of those engaged in economic activity in old age could lack adequate cover under social security schemes and therefore feel compelled to move to urban areas in search of employment (ESCWA 2007 Population Aging in Arab Countries UN, NY).

Rural-to-Urban Migration According to a study by ESCWA (2007), available evidence suggests a migration from rural to urban areas, particularly in working-age groups, to varying degrees of magnitude across the Arab region. Generally, this phenomenon is supported by the age-structural transition of the urban populations of the eight selected Arab countries and by the analysis of trends in the growth rates of rural and urban populations. A downward and sometimes negative growth rate of rural population in some countries suggests a heavy rural-to-urban shift; and the upward trend in the growth rate of urban populations is expected to continue unabated until 2015. In addition, and in tandem with the pattern in many developing countries, aging of rural populations is now well underway in Arab countries. The phenomenon of aging comprises both population aging and individual aging, which represent macro and micro concepts of aging. The former refers to aging of populations in an aggregate sense whereby the structure of a population by age and gender, which is represented by a pyramid, undergoes a shift as a result of changes in mortality, fertility, and migration flows. Individual aging, on the other hand, is solely influenced by reductions in mortality rates and has not contributed to a significant degree toward rural aging in the Arab region. Utilizing the aforementioned ESCWA study, in Table 2.4 three

Table 2.4 Indices of aging for rural and urban populations of selected Arab countries Country Rural Urban 1980 1980 2000 2015 AI YDR ODR AI YDR ODR AI YDR ODR AI YDR ODR Egypt 8.2 73.0 6.0 10.9 79.2 8.6 20.8 45.0 9.4 45.0 25.4 11.4 Iraq 5.7 98.9 5.6 6.7 92.1 6.2 7.1 69.6 4.9 10.6 46.6 5.0 Jordon 5.9 83.9 5.0 6.5 120.0 7.8 7.2 67.6 4.9 14.2 44.3 6.3 Morocco 18.5 39.9 7.4 4.7 198.0 9.3 11.4 68.5 7.8 23.9 39.8 9.5 Tunisia 15.4 66.9 10.3 4.1 88.3 3.6 22.4 37.9 8.5 46.8 19.6 9.2 Syrian Arab 9.3 42.7 4.0 3.7 88.3 10.7 6.3 37.9 7.4 10.4 19.6 7.1 Republic Somalia 3.3 90.2 3.0 14.1 286.5 10.7 4.9 117.5 7.4 11.3 67.9 7.1 Yemen 7.2 118.8 8.5 6.5 82.1 5.3 NA 54.3 NA 16.5 27.7 4.6 Source: ESCWA 2008 Note: AI, YDR and ODR refer, respectively to aging index, young dependency ratio and old dependency ratio. NA Indicate that data are not available

50

S.S. Al-qudsi

indices of aging are presented for rural and urban populations of selected Arab countries, namely, the aging index (AI), which measures the number of 65+ per 100 persons aged 15 years and under; the young dependency ratio (YDR), which measures the number of persons aged 15 years and under per 100 persons aged 15–64 years; and the old dependency ratio (ODR), which measures the number of 65+ per 100 persons aged 15–64 years. Within the context of the latter, it is important to note that labor force participation is higher among the elderly in Arab countries where more than 38% were still working as against 27% in developed countries (ESCWA 2007). The AI for rural population is highest in Morocco (18.5%), followed by Tunisia (15.4%). In the other countries, the index ranges between 3.3% in Somalia and 9.3% in the Syrian Arab Republic, thereby suggesting that the aging process is considerably slower in the rural populations of Arab countries. However, the AI is expected to rise in the wake of drops in fertility and increases in life expectancy. The rural YDR is comparatively high in all eight selected countries, particularly in Yemen, Iraq, Somalia, and Jordan. This could be attributed to prevailing high fertility in rural areas coupled with shrinking rural populations, owing to migration of economically active age groups.

Health Systems and Health Expenditures The health system of Arab countries tends to be pluralistic and segmented with many different public and private providers and financing agents. In general, financing agents are the public sector, the private sector such as private insurance companies, unions, professional organizations and NGO’s, and finally the household sector. The public sector provides health care through government hospitals and clinics, teaching, and university hospitals. The provision of health in the private sector occurs through a suite of profit and nonprofit providers including medication for service charges and fees, charity hospitals, pharmacies and clinics. Health expenditure has increased markedly over time. Table 2.5 records comparative data on the health expenditures both as shares of each country’s GDP and by private and public sector spending. Expenditure on health in Arab countries was generally in the vicinity of 4.5% of GDP versus globally this ratio was about 8.7% of GDP, with the highest level in the Mashreq (Jordan 9.9%) and the lowest in the GCC (Kuwait 2.2%). This translates to 116 USD per capita on average but varies however from low per capita levels in Syria to US$ 2,753 in Qatar. The provision of health requires the sufficient availability of good-quality staff, that is the number of health workers and their proficiency. Table 2.6 shows health workforce data in a set of Arab countries. Unequivocally, Qatar leads in terms of density (providers per 10,000 populations) in the case of physicians and dentistry providers. Two favorable factors induce these outcomes: small population size and

6.2

37.1 47.6 43.7 72.9

46.4

44.8 25.6 40.4 48.5 78.6

Source: WHO, 2009

41.9

4.2 7.2 6.5 6.8 7.6

77.3 27.5 66.4 75.4 40.7 55.6 72.5 42 78.9 46.8 70.2 35.9 84 16.4 78.1 77.2

73.3 1 67.5 67.8 40.1 37 34.2 46.6 78.1 30 60.7 31.2 83.6 20 68.8 76.4

Algeria Afghanistan Bahrain Djibouti Egypt Iran Iraq Jordan Kuwait Lebanon Libya Morocco Oman Pakistan Qatar Saudi Arabia Somalia Sudan Syria Tunisia United Arab Emirates Yemen

General government expenditure on health as percentage of total government expenditure, 2000 9 1.1 10.2 12 7.5 9.6 1.3 10.3 8.8 7.8 6.9 4.3 7.3 1.8 5 9.2

Gov. expenditure on health(%) of total exp. on health, 2000

Country

Gov. expenditure on health(%) of total exp. on health, 2006

5.6

6.3 5.9 6.5 8.7

General government expenditure on health as percentage of total government expenditure, 2006 9.5 4.4 9.5 13.4 7.3 9.2 3.4 9.5 4.9 11.3 6.5 5.5 5.4 1.3 9.7 8.7

Table 2.5 Health expenditure Indicators in the Mena Region

28

8 8 43 177 478

97 <1.0 478 47 83 135 15 192 391 177 148 56 286 9 381 430

Per capita government expenditure on health (PPP int. $), 2000

38

23 52 214 491

146 8 669 75 129 406 90 257 422 285 189 98 321 8 1,115 468

Per capita government expenditure on health (PPP int. $), 2006

66

18 32 105 365 609

132 11 708 69 207 364 45 413 501 589 243 178 342 44 553 563

Per capita total expenditure on health (PPP int. $), 2000

82

61 109 488 673

188 29 1,008 100 316 731 124 611 535 608 270 273 382 51 1,426 607

Per capita total expenditure on health (PPP int. $), 2006

4.5

2.6 3.1 4.9 5.6 3.1

3.5 3.3 4 5.8 5.6 5.9 1.1 9.4 3.1 11 3.6 4.8 3 2.5 2.3 4

Total expenditure on health as percentage of gross domestic product, 2000

4.6

3.8 3.9 5.3 2.6

3.6 5.4 3.8 6.7 6.3 7.8 3.8 9.9 2.2 8.9 2.9 5.1 2.3 2 4.3 3.4

Total expenditure on health as percentage of gross domestic product, 2006

2 Arab Demography and Health Provision 51

52

S.S. Al-qudsi

Table 2.6 Health workforce, infrastructure, essential medicines Member state Health workforce Physicians Nursing and midwifery personnel Number Density Number Density (Per 10,000 (Per 10,000 Population) Population) 2000–2007 Algeria 35,368 11 Bahrain 1,980 27 Egypt 179,900 24 Iran 61,870 9 Iraq 19,010 7 Jordan 13,460 24 Kuwait 4,840 18 Lebanon 8,440 24 Libya 7,070 13 Morocco 15,991 5 Oman 4,290 17 Qatar 2,150 26 Saudi Arabia 34,261 14 Sudan 11,083 3 Syria 10,342 5 Tunisia 13,330 13 United Arab 4,960 17 Emirates Yemen 6,739 3 Source: WHO Statistics, 2009

2000–2007 69,749 22 3,850 61 248,010 34 98,020 16 36,300 13 16,770 32 9,940 37 4,720 13 27,160 48 24,328 8 9,500 37 4,880 60 74,114 30 33,354 9 27,288 14 28,537 29 10,340 35 13,746

7

Dentistry personnel Number

9,553 300 25,170 13,210 3,460 4,330 810 3,260 850 3,091 460 690 4,235 944 2,306 2,452 850 850

Density (Per 10,000 Population)

2000–2007 3 4 3 2 1 8 3 9 2 1 2 9 2 <1 1 3 3 <1

relative abundance of financial resources yet inadvertently, government’s vision and policy agenda play a significant role as well. The health supply indicators can be examined in terms of the availability of hospital bed, nursing, and physicians per 10,000 populations as shown in Table 2.7. Clearly, differences across Arab countries are substantial. The supply of health workforce critically depends on the presence of effective and rewarding remuneration system that manages to attract and retain capable health workers over their life-cycles. Other supplementary factors include the availability of clinical laboratories, medical research facilities, and medical testing instruments and technologies as well as the supply of paramedical and supporting services, in sufficient quantity and quality that encourage physicians and dentistry workforce to pursue medical career path in Arab countries. Absence of these integrated factors and technological supplies invariably drives out-migration of health workers in search of self-improvement, scientific advancement, and higher living standards. Table 2.8 provides a snapshot of Arab doctors and health workers who are employed in the OECD countries.

2 Arab Demography and Health Provision

53

Table 2.7 Human and physical resources indicators (per 10,000 population) Country Physicians Dentists Pharmacists Nursing and Hospital midwifery beds No Year No Year No Year No Bahrain 27.6 2006 55 2006 4.1 2006 8.3 Egypt 25.1 2006 28.2 06 3.6 2006 13.7 Jordan 24.5 2006 33 06 8.2 2006 12 Kuwait 18 2006 36 06 3 2006 2.0b Lebanon 28.8 2007 17.9 07 10.9 2007 12.1 Libya 17 2006 50 06 2.7 2006 2 Morocco 5.6 2006 10 06 1.1 2006 2.6 Oman 18.2 2007 38.7 07 1.9 2007 3.4 Qatar 27.6 2006 73.8 06 5.8 2006 12.6 Saudi 20 2005 34.6 05 2.1 2005 3.5 Syria 14.8 2007 18.8 07 7.4 2007 6.5 Tunisia 9.4 2007 31.1 07 1.8 2007 2 UAE 16.1 2005 29.1 05 4 2005 5.8 Source: World Health Statistics Database Note: Year ¼ Reference year for data provided NA ¼ Data not available for 2000–2005 or not reported a

Year 2006 2006 2006 2006 2007 2006 2006 2007 2006 2005 2007 2007 2005

No 27.4 21 19 19 34.3 37 8.7 20.2 25.2 22 14.7 17.6 18.8

Year 2006 2006 2006 2006 2007 2006 2006 2007 2006 2005 2007 2007 2005

Primary health care units and centersa No Year 0.3 2006 2.2 2006 2.4 2006 0.4 2006 N.A 2007 2.6 2006 0.9 2006 0.9 2007 2.7 2006 0.8 2007 1 2007 2 2007 4 2005

¼ 2003, b ¼ 2004

Table 2.8 Arab doctor and nurses in OECD Country of Birth

Algeria Bahrain Egypt Iran Iraq Kuwait Lebanon Libya Morocco Oman Qatar Saudi Arabia Sudan Syria Tunisia United Arab Emirates Yemen

Number of persons working in OECD countries 8,796 77 1,128 4,234 415 152 1,400 100 5,730 18 QAT SAU 151 SDN 183 SYR 319 TUN 410 ARE 11 YEM

Source: OECD (2007)

231

Nurses Expatriation rate

12.4 2.5 0.8 4.8 1.3 1.6 25.2 0.6 20.5 0.2 0.2 1 1 1.6 0.1 1.7

Country of birth

Algeria Bahrain Egypt Iran Iraq Kuwait Lebanon Libya Morocco Oman Qatar Saudi Arabia Sudan Syria Tunisia United Arab Emirates Yemen

QAT SAU SDN SYR TUN ARE YEM

Doctors Expatriation Number of rate persons working in OECD countries 10,793 23.4 74 8.4 7,243 15.8 8,991 12.9 3,730 18 465 11.5 4,552 28.3 592 8.5 6,221 28 23 0.6 45 3.3 421 1.2 778 9.3 4,721 16.6 2,415 15.3 44 0.7 248

3.5

54

S.S. Al-qudsi

The Pharmaceutical Market Issues A related issue pertains to the availability of pharmaceutical products and the size of the pharmaceutical markets in the Middle East. Current estimates suggest that the pharmaceutical market in MENA is likely to grow by between 10 and 15% annually over the next 3 years. This rapid growth is driven by economic reform and the policy objective of achieving a greater degree of “self sufficiency” in medicine. Combined with rapid population growth and demographic transition, these factors are attracting huge domestic and foreign investments which are taking place in the private and public health sectors. Turkey, Israel, Saudi Arabia, Egypt, and Iran stand out as the largest markets in terms of projected growth potential and value representing a host of opportunities. Despite this bullish forecast for pharmaceutical and healthcare markets, the Arab market represents just 2% of global pharmaceutical sales. On the downside, continued economic volatility and stressed financial and economic conditions with fluctuations in oil prices, which have historically been highly correlated with the pharmaceutical market growth in the region, are likely to affect the growth of industry adversely. In response to these challenges and to increase the efficiency and meet the escalating demand for medicines to match the rapidly growing population, Arab governments need to encourage domestic production, provide industry incentives including infrastructural investments and fiscal incentives and encourage syndicated industry financing with the objective of reducing reliance on pharmaceutical imports including medicines equipments while promoting medical and pharmaceutical exports. To illustrate, in many Arab economies, production factors including technical expertise, raw materials, quality standards, and production and laboratory equipment currently need to be imported at exorbitant foreign exchange cost. To be sure, the region does contain vibrant domestic pharmaceutical markets such as those of Egypt, Israel, and Turkey; for instance, local pharmaceuticals manufacturing satisfies 90% of consumption requirements in Egypt. Yet and by sheer contrast, Saudi Arabia is a net importer of pharmaceutical products with 85% of pharmaceutical consumption requirements originating from import sources regionally and internationally. The stakeholders, government, industry, and consumers should examine and emulate policies of advanced countries. For instance, recently the Unites State government intends to “save $313 billion over the next 10 years by forcing greater efficiency in Medicare, demanding better prices from drug makers and cutting the number of uninsured Americans”. Table 2.9 shows the Pharmaceuticals trade at Million USD current prices during the period 2000–2007.

Intercountry Inequalities in Health Indicators As shown in Table 2.10, inequality in the health availability, affordability, and in health indicators is quite vivid in Arab countries. Health inequalities result from economic, political, geographic, and cultural forces. Such inequality tends to persist

Table 2.9 Pharmaceuticals trade (exports vs. imports) at million USD current prices Egypt Jordan KSA UAE Israel Year exp imp exp imp exp imp exp imp exp imp 2000 50 338 112 136 22 883 49 316 429 601 2001 50 427 193 158 27 967 51 326 638 657 2002 66 501 218 176 31 1,002 66 373 927 713 2003 51 362 211 209 40 1,387 94 445 959 784 2004 44 362 245 235 57 1,514 164 576 1,359 813 2005 65 401 296 263 119 1,730 138 612 2,068 904 2006 64 316 316 292 112 1,941 163 720 3,164 1,032 2007 92 436 448 350 155 2,230 231 958 3,509 1,113 Source: WTO, various years Turkey exp imp 148 1,344 153 1,345 165 1,718 220 2,302 289 3,035 317 3,184 354 3,343 378 4,084

USA exp imp 13,122 14,855 15,421 18,753 16,149 24,874 19,199 31,739 23,980 35,371 25,946 39,323 29,105 46,222 33,464 54,003

Total MENA exp imp 274 3,037 358 3,379 423 3,898 446 4,564 585 5,263 710 5,396 773 5,742 1,005 6,631

2 Arab Demography and Health Provision 55

na na 97 na na na na na 98 na na na na

na na 95 na na na na na 83 na na na na

na na 1.0 na na na na na 1.2 na na na na

na na 2 na na na na na 15 na na na na

2 na na na 66 na na na na 21 na na 57 na na 96 60 na na na na 88 na na na 50

na na na 49 na na na 53 na na na 27

MDG 4 Measles immunization coverage among 1-year-olds (%) Algeria 2006 na na na na Bahrain na na na na Egypt 2005 97 97 1.0 0 Iraq 2006 60 76 1.3 16 Jordan 2007 na na na na Kuwait na na na na Lebanon na na na na Libya na na na na Morocco 2003–2004 86 94 1.1 8 Oman na na na na Qatar na na na na KSA na na na na Sudan 1990 56 70 1.2 14

1 na na na 3.2 na na na na 1.3 na na 4.3 na na 98 79 na na na na 96 na na na 85

na na na 94 na na na 96 na na na 61 na na 1.0 1.3 na na na na 1.1 na na na 1.7

na na na 1.9 na na na 1.8 na na na 2.3

na na 2 19 na na na na 9 na na na 35

na na na 46 na na na 43 na na na 34

na na 35 17

100 na na na 95 na na na na 99 na na 74

na na 1.6 1.2

98 na na na 30 na na na na 78 na na 17

na na 89 96

na na 54 79

na na 45

na na 96

na na 51

na na 1.9

Education Level of Mother Lowest Highest Ratio Difference highest–lowest highest–lowest

Wealth Quintile Lowest Highest Ratio Difference highest–lowest highest–lowest

Year

Place of residence Rural Urban Ratio Difference urban–rural urban–rural MDG 5 Births attended by skilled health personnel (%) Algeria 2006 92 98 1.1 6 Bahrain na na na Egypt 2005 66 89 1.3 23 Iraq 2006 78 95 1.2 17 Jordan 2007 99 99 1 1 Kuwait na na na na Lebanon na na na na Libya na na na na Morocco 2003–2004 40 85 2.2 46 Oman na na na na Qatar na na na na Saudi na na na na Sudan 1990 59 86 1.4 27 Syria 2006 88 98 1.1 9 Tunisia 2006 na na na na UAE na na na na Yemen 2006 26 62 2.3 35

Member state

Table 2.10 Health inequities in Arab countries

56 S.S. Al-qudsi

1.0 1.0 na 1.4

3 2 na 22

89 na na 52

97 na na 86 na na 50 na 3 na na na 52 na na na na 2 na na 81

2006

94 99 na 80

MDG 4 Under-5 mortality rate (probability of dying by age of five per 1,000 live births) Algeria 2006 na na na na na na na Bahrain na na na na na na na Egypt 2005 56 39 1.4 17 75 25 3.0 Iraq 2006 41 41 1.0 0 na na na Jordan 2007 27 22 1.2 5 30 27 1.1 Kuwait na na na na na na na Lebanon na na na na na na na Libya na na na na na na na Morocco 2003–2004 69 38 1.8 31 78 26 3.0 Oman na na na na na na na Qatar na na na na na na na KSA na na na na na na na Sudan 1990 144 117 1.2 27 na na na Syria 2006 24 19 1.3 5 22 20 1.1 Tunisia 2006 na na na na na na na UAE na na na na na na na Yemen 2006 86 57 1.5 29 118 37 3.2

91 97 na 59

9 na na 33

2006 2006

1.1 na na 1.6

Syria Tunisia UAE Yemen na na 68 49 na na na na 63 na na na 152 na na na na

na na na 60 na na 31 37 na na na na 27 na na na 84 na na na na

na na na 81 na na 2.2 1.3 na na na na 2.3 na na na 1.8 na na na na

na na na 1.4 na na 37 12 na na na na 36 na na na 68 na na na na

na na na 21

2 Arab Demography and Health Provision 57

58

S.S. Al-qudsi

over time even as standards of living rise. To illustrate, infant mortality rate varies among countries. Life expectancy at birth also varies, from 73.4 years in Kuwait to 51.5 years in Yemen, while the number of patients per physician ranged from 5,639 for Yemen to 660 in Saudi Arabia. In several Gulf countries, patients enjoy free health services, while in some other countries inequitable distribution of health services remains a problem. Access to medical services and medical care is often very difficult for some sectors of the population, particularly those living in rural areas. For example, during 1985–1987 the percentage of the population with access to health services was only 35% in Yemen, 51% in Sudan, 74 and 76% in Morocco and Syria, respectively, 81% in Egypt, 90% in the UAE, and 100% in Kuwait (UNDP, 1991/1994). These differences are the result of differences in resource- and non-resourcedependent characteristics. Resource characteristics include income and wealth variations while nonresource characteristics include genetic, psychological, and cultural factors. More specifically, differences in orientation toward smoking, drinking, diet, exercise, and occupational risk in interaction with availability (or lack) of medical goods and health facilities could produce differential health status outcomes. Whatever the underlying reasons are, continued existence of health inequalities across and within countries poses important challenges to policy makers in these countries. With the onset of global financial crisis and the resultant global economic downturns since late 2007, the Arab region, in tandem with other regions must work hard to safeguard the future and maintain good health among its populace. Maintaining precrisis levels of government expenditures on health as a proportion of total government spending is desirable, but by itself does not guarantee that pro-poor services will be protected. Governments should take explicit measures to protect pro-poor expenditures on health. Public spending should target adequate nutrition for the most vulnerable groups, as a fall in the quantity and quality of nutrition is one of the most serious human development consequences of an economic crisis (World Bank 2009). Special mention should be made of the interactions between health and water availability, access, and usage by income and social strata produce dynamic implications for socio-economic transformations. While the region is rich in oil and gas and other energy and nonenergy sources, it is generally plagued by water scarcity. Actual renewable water resources per capita are 1.1 m3 per year, the smallest globally. Roof-top water storage tanks are ubiquitous in Amman and Jordan, where water service lasts only 2 h a day and residents of arid Yemen use only 2% of the water consumed by the average person in other parts of the world. Much of Yemen’s water is mined from rapidly depleting underground aquifers. Yemen and Jordan have the most severe water shortages in the Middle East and North Africa. And even the most casual observer knows water is scarce throughout the entire Middle Eastern region. Most of the countries of the region cannot meet current water demands and the situation is likely to get worse in the future. The World Bank projects that per capita water consumption will fall by half by 2050, with serious consequences for the region’s already stressed aquifers and natural

2 Arab Demography and Health Provision

59

hydrological systems (World Bank 2008). Some 60% of the region’s water flows across international boundaries, further complicating the resource management challenge. Scarcity of fresh water in some countries and degraded quality of water in others cause significant health problems. Over 50% of all the populations in the Middle East and North Africa, excluding the Maghreb, depend either on water from rivers that cross an international boundary before reaching them or on desalinized water and water drawn from deep wells. Millions of people face daily problems in obtaining water for drinking, cooking, bathing, and washing. More than 25% of the population of Egypt, Sudan, Algeria, and Yemen are estimated to be without access to uncontaminated water, and unknown but large proportions have to spend hours daily to collect water. Cholera and typhoid related to contaminated water are common in Egypt, Sudan, and Yemen. Large proportions of the population of some Arab countries do not have access to safe drinking water nor to sanitation. For example, 46% of the population of Morocco, 30% of Tunisians, 21% of the Syrian population, 10% of Egyptians, and 66% of the population in Sudan do not have access to safe drinking water (UNDP 1994, Table A.2). Oil spillage and resultant water pollution are common at the shores of the Gulf countries. The scarcity and contamination of water imply that mother’s milk has a greater effect in promoting child survival in distressed areas where water and sewage facilities are poor (Sirageldin and Diop 1991). Country differences with respect to adult mortality rate are marked. The republic of Yemen has the highest male adult mortality rate, 334 per 100,000 followed by Sudan with 267. Jordan has a relatively low rate of 138, while Algeria and Tunisia have rates of 135 and 166, respectively. In all countries, adult mortality rate is higher for males than for females because of the higher risk factors that men are typically subjected to – for example, occupational risk, industrial accidents, car accidents, smoking-related risks, war, and conflict-related risks. In addition to the role of genetics, falling victim to diseases depends on the age, income, nutrition, and exercise and work habits of individuals. Figure 3.1 displays the relationship between age and expected disability: visual, mental, chronic, and psychological-for males and females separately. Needless to say that some segments of Arab population remain disadvantaged, in fact some are strictly “homeless” as shown in Table 2.11. The prevalence of malnutrition among children under 5 years of age is 13% in Egypt, 10% in Tunisia, and 55% in Sudan (World Bank 1993). The leading reasons for the prevalence of malnutrition are poverty, interhousehold and interregional economic disparities, and the inadequacy of infrastructure to deal with natural disasters. For instance, in Sudan and Yemen, economic hardships including famine situations reoccur. They result in large numbers of deaths and create human and medical hardship. Preschool children and women are typically at greatest nutritional risk. In the case of Egypt, empirical work has demonstrated that household income has pronounced effects during early childhood and that the impact on child malnutrition and mortality persists even when one controls for other socioeconomic forces (Casterline et al. 1989). Results of dietary studies in Egypt have shown that the average diet of low-income, nutritionally vulnerable groups – children under five

60 Table 2.11 Estimates of the homeless and disadvantaged in thousands & percent

S.S. Al-qudsi Year Jordan 2005 UAE 2005 Bahrain 2005 Tunisia 2005 Algeria 2005 Djibouti 2005 Saudi Arabia 2005 Sudan 2005 Syria 2005 Somalia 2005 Iraq 2005 Oman 2005 Palestine 2005 Qatar 2005 Kuwait 2005 Lebanon 2005 Libya 2005 Egypt 2005 Morocco 2005 Mauritania 2005 Yemen 2005 Total 2005 Source: WHO, 2009

No. of homeless 170.7 59.041 18.768 486.307 1,448 143.7 458.587 2,600 412.86 1,065 2,366.952 68.55 194 11.114 27.438 90.744 286.485 2,267 1748.98 191.84 834.057 14,950.123

Homeless (%) 13 2.3 3.4 14.2 15.3 50 6.05 18.5 8.08 24 29.2 7.5 23.5 2 1.67 8.2 17.2 10.7 15.7 22 16.3 15.3

Source

estimate

estimate

estimate

estimate

estimate estimate

estimate estimate estimate

and pregnant and lactating women – provided only 76% of recommended caloric allowances, that the average amount of protein in the diet of these groups was below the recommended allowances, and that only 11% of their protein was from animal sources. Further, about half of rural farm laborers suffer from secondary anemia as a result of heavy iron losses associated with schistosomiasis and hookworm infections (El-Mehairy 1984). The region continues to suffer from tuberculosis; poorer countries have the highest incidence. In Sudan, for example, the annual incidence rate during the period 1985–1990 was 211/100,000 persons. Morocco had an incidence rate of 125; Iraq, 111; and Egypt, 96. Oil-producing countries had substantially lower rates 22 and 12 in Saudi Arabia and Libya, respectively (World Bank 1993). Infections and toxemia are reported to be among the leading causes of maternal deaths. Complications associated with childbirth are common in the region and at times leave residual damage to the kidneys or reproductive organs. Anemia is also a common complication, particularly in Jordan, Egypt, and Morocco, where its prevalence among pregnant women reaches 50, 47, and 46%, respectively (World Bank 1993). Car accidents are, regrettably, responsible for significant mortality. In Bahrain and Kuwait, they cause 3.5 and 3.4% of all deaths, making these countries respectively first and second in the world in terms of the most deaths caused by motor accidents (The Economist 1991). One can only speculate that such high rates are

2 Arab Demography and Health Provision

61

the result of two forces: modern technology and traditional cultural values. That is, the slow-adjusting cultural values are challenged by the fast pace of importation and use of consumer technologies. Regional conflict continues to claim many lives. The Gulf war, for instance, is estimated to have caused over 100,000 deaths in Iraq and over 1,000 in Kuwait (Faour 1993). Scarcity of essential medicine, food shortages, and lack of potable water had a dramatic impact on health: 900,000 Iraqi children, accounting for 29% of all children, were malnourished.

Conclusion Like other regions in our troubled globe, Arab health system has received a lot of attention lately after emerging new diseases such as Swine flu besides rising pandemics of chronic diseases across the world due to more sedentary lifestyles. Deteriorating global economic climate has already caused many of advanced and developing countries to announce major cost reductions in reaction to projected revenue shortfalls. Combined with growing populations, such developments will exert increasing pressures on health services and challenge the Arab health systems where fertility rate remains high compared to developed countries. Economic volatility and stressed financial and economic conditions with fluctuations in oil prices are likely to affect the growth of the pharmaceutical industry adversely. The regional and global economic downturns may also worsen the already high outmigration of Arab health workforce, especially doctors, nurses, and paramedical staff. These developments and associated challenges renew the debate about adequacy, affordability, equity, and efficiency of health system in Arab economies. While demographic transition has been occurring and the supply of health services in terms of coverage and quality has increased substantially, the progress to date has largely been unequal across space and income and social strata. In the GCC countries, there has been a substantial improvement but in other countries, such as Sudan and Yemen, the improvement is much less discernable. The nature of health problems is changing in ways that were only partially anticipated, and at a rate that was wholly unexpected. Aging and the effects of ill-managed urbanization and globalization accelerate worldwide transmission of communicable diseases, and increase the burden of chronic and noncommunicable disorders. Health systems are not insulated from the rapid pace of change and transformation that is an essential part of today’s globalization. Economic and political crises challenge state and institutional roles to ensure access, delivery, and financing. The global economic downturn is imposing big tolls on the Arab governments and economies and will affect the future provision of health services in Arab economies. Regrettably, such cyclical downturns produce adverse income and health effects whose incidence is uneven across geography and income groups within Arab countries.

62

S.S. Al-qudsi

It cannot be emphasized enough that these developments require continuous monitoring by governments and by civil society groups and private sector establishments and by opinion leaders. The Arab region is in critical need of proper action plans and long-term strategies that can help it successfully respond to the emerging challenges. What is at stake is nothing less than the future well-being, health-wise and in terms of living standards, of Arab generations to come.

References Al-Qudsi S (2006) Unemployment Evolution in the GCC Economies: Its Nature and Relationship to Output Gaps Center for Labour Market Research and Information (CLMRI): Dubai, UAE Al-Qudsi S, Abu-Dahesh A (2004) “Potential Output, total factor productivity and institutions in the private Sector of Saudi Arabia” Journal of Development and Economic Policies 6(2):5–49 Al-Qudsi S, Assaad R, Shaban R (1993) Labor markets in the Arab countries: a survey. Paper presented at the World Bank 1st Annual Conference on Development Economics, Cairo, 4–6 June Bolbol A, Fatheldin A (2005) Intra-Arab exports and direct investment: an empirical analysis. AMF, Abu Dhabi Bram L, Dickey NH (1992) Funk & Wagnalls new Encyclopedia. Funk & Wagnalls, New York Casterline JB, Cooksey EC, Ismail AF (1989) Household income and child survival in Egypt. Demography 26(1):15–35 El-Mehairy T (1984) Medical doctors: a study of role, concept and job satisfaction; the Egyptian case. E.J Brill-Leiden, Netherlands Faour M (1993) The Arab World after desert storm. United States Institute of Peace, Washington, DC Fargues P (1994) From demographic explosion to social rupture. Middle East Report, 6–10 September–October For instance, The Middle East Economic Digest (MEED) classified the new trend as “new era of growth” and a period of “unparalleled prosperity”, MEED (2006): “Gulf Economic Review” Hassan AY, Hill DR (1986) Islamic technology: an illustrated History. UNESCO, Paris Held CC (1993) Middle East patterns: places, peoples, and politics. Westview Press, Boulder Lewis B (1993) The Arabs in History, 5th edn. Oxford University Press, Oxford Libya has only imports data for 2003 and 2004, so the total MENA in these two years includes the Libyan imports data .noting that, there is no Libyan exports data for whole the period. Data available for Lebanon is just from (2000–2004), Kuwait (2000–2005) and Syria (2000–2006) so we exclude those values from the total MENA in these years Local Production of Pharmaceuticals: Industrial Policy and Access to Medicines, HNP, Jan (2005) MENA countries: (KSA, Oman, UAE, Kuwait, Qatar, Bahrain, Lebanon, Egypt, Jordan, Syria, Morocco, Algeria, Tunisia, Libya) Raffer K (2007) Macro-economic evaluations of Arab economies: a foundation for structural reforms. OFID Pamphlet Series 36, OPEC Vienna, August Said E (2001) The clash of ignorance. Media Monitors Network October 11 2001. www. mediamonitors.net/edward40 Sanchez-Barricarte J, Veira-Ramos A (2008) Demographic transition in thE Mashreq region “European Population Conference, Barcelona-Spain (September)” Shami S (1993) The social implications of population displacement and resettlement: an Overview with focus on the Arab Middle East. Int Migr Rev 27(1):4–33

2 Arab Demography and Health Provision

63

Sirageldin I, Diop F (1991) Equity and efficiency in health status and health services utilization: a household perspective. Pak Dev Rev 30(4):415–437 The Economist (1991) Pocket world in figures. Hutchison Books, London UNDP (1991/1994) Human development Report. Oxford University Press, New York USAID (2009) How will the global economic crisis impact the health of the world’s poor? USAID Global Health Perspectives Series, April World Bank (1993) World development report 1993. Oxford University Press, New York World Bank (2008) Making the most of scarcity: Accountability for better water management results in MENA, World Bank, Washington, DC World Bank (2009): “Protecting pro-poor health services during financial crises: Lessons and experience” April World Bank, Washington, DC Yousef T (2005) Macroeconomic aspects of the new Demography in the Middle East and North Africa. Georgetown University, Washington, DC

Chapter 3

Influences of Systems’ Resources and Health Risk Factors on Genetic Services Amal A. Saadallah and Ahmad S. Teebi

Newborn screening (NBS) services and genetic testing are contemporary public health preventive population-screening programs present in most developed countries. Advances in laboratory technology and knowledge of metabolism and genetics have led to an increased focus on screening for preventable causes of disability and death in newborn babies. NBS services and genetic testing are examples of health service trends that are extending globally. Currently, they are spreading into several Arab countries (World Atlas, not dated) (Fig. 3.1), not necessarily as national public health services but as supplementary, selective, or pilot formats. As a product of this recent cascading trend, a stressing issue presents itself, and requires close examination. Can national healthcare systems of the Arab nations, most of which are developing, accommodate NBS and genetic testing as a standard equitable national public health service? On the other hand, should this service become only a high-risk approach, or a supplemental testing service? To answer these questions and many others, we need to take a closer look to examine factors that will influence these new or approaching services as they have affected all the other established health services.

Healthcare Systems and Services A healthcare system is an individualized national arrangement by which health care is allotted to a population in a particular country. The health system includes all the institutions, organizations, and resources (human and financial) that are dedicated to producing health actions whose primary intent is to improve health (Alliance for Health Policy and Systems Research, Geneva 2004). The goals for health systems are good health, responsiveness to the expectations of the population, and fair A.A. Saadallah (*) Medical College, Ain Shams University, Cairo, Egypt e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_3, # Springer-Verlag Berlin Heidelberg 2010

65

66

A.A Saadallah and A.S Teebi

Algeria, Bahrain, Comoros, Djibouti , Egypt, Iraq, Jordan, Kuwait, Lebanon, Libya , Mauritania, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, United Arab Emirates, and Yemen.

Fig. 3.1 Names and locations of Arab countries

financial contribution (World Health Organization 2000). Organized health systems in the modern sense evolved less than 100 years ago. First hospitals were built followed by the founding of healthcare systems and the extension of social insurance schemes. Afterwards, primary health care became a route for achieving affordable universal coverage. According to the World Health Organization (WHO, 2000), high-quality health care is defined mostly by the criteria of effectiveness, cost, and social acceptability. Goldman and McGlynn (2005) wrote that the Institute of Medicine (IOM) in the United States of America has defined quality of care by a complex multi-dimensional concept as follows. (1) People receive the care they need; if not, there is underuse of services. (2) People do need the care that is provided for them; if not, there is overuse of services. (3) Care is provided in a safe manner; if not, medical errors exist. (4) Care is provided in a timely manner; if not, there are delays in services. (5) Care is patient-centered; if not, there is unresponsiveness. (6) Care is delivered equitably; if not, there are disparities and inequities. (7) Lastly, care is delivered efficiently, with optimal use of resources, if not, there is waste. Health services including established or proposed screening and genetic services formulate parts of the overall healthcare system, and they thus have and will become influenced by factors that affect it. Countries including Arab nations have noninfinite resources coupled with constant demands that require frequent examination and selective balances. These include weighing scales between healthcare needs and other population needs, providing care access within limitations of resources, reaching a degree of equilibrium between curative and preventative

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

67

care, allotting basic resources for primary care while still adopting new technologies, and assuring stability between private and public service entities. Getting to ground zero, there are additional national pressures that face health systems. Nations have to strive towards abolishment of under-service to certain geographical locations and to certain subpopulations in a country. Health systems have to produce well-trained and equally distributed workforce. Systems have to be in a state of readiness to respond to all types of health threats starting from natural disasters, epidemics, and extending to terrorist health threats. Along the lines of the most recent trend of patient and consumer-centered care, countries need to gain the views and seek consumer involvement in how services are offered. This chapter will focus on some of these elements from the perspective of the Arab part of the globe. This chapter will also shed light on several parameters in an attempt to appraise the foundation and competency of healthcare systems of the Arab nations and their reciprocal influence on the extent and types of services offered including screening and genetic ones. To do so, this chapter displays some graphs of various parameters of health systems of Arab nations and compares them to those of an equal number of developed nations, namely Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Iceland, Italy, Japan, Luxembourg, Netherlands, New Zealand, Norway, Spain, Sweden, Switzerland, United Kingdom (UK), and United States of America (USA). Parameters of the occupied Palestinian Territories of West Bank and Gaza Strip (World Health Organization Regional Office of the Eastern Mediterranean 2005) are included in Table 3.1.

Table 3.1 Parameters of the occupied Palestinian territories Indicator name Physicians’ density (per 1,000 population) Nursing and midwifery personnel (per 10,000 population) Neonatal mortality rate (per 1,000 live births) Infant mortality rate (per 1,000 live births) Under-five mortality rate (per 1,000 live births) Population with sustainable access to improved water source (%) Population with access to improved sanitation (%) Total expenditure on health as % of gross domestic product (GDP) General government expenditure on health as % of total health expenditure Out-of-pocket expenditure as % of total health expenditure General government expenditure on health as % of total general government expenditure Births attended by skilled health personnel (%) One-year-olds immunized with measles vaccine (%) One-year-olds immunized with DPT (%) One-year-olds immunized with Hepatitis B vaccine (%) Antenatal care coverage (%) na: Not available for latest entries http://www.emro.who.int/emrinfo/index.asp?Ctry=pal

Measure 9.7 16 na 20.5 23.8 97 100 13.5 28.3 na na 97 100 99 100 na

68

A.A Saadallah and A.S Teebi

Development Levels Arab countries are 22 in number including, in alphabetical order, Algeria, Bahrain, Comoros, Djibouti, Egypt, Iraq, Jordan, Kuwait, Lebanon, Libya, Mauritania, Morocco, Oman, Occupied Palestinian Territories, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, United Arab Emirates, and Yemen. All these countries are in a developing state and six of them are at a least-developed status. The more developed Arab countries include Algeria, Bahrain, Egypt, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Palestine, Qatar, Saudi Arabia, Syria, Tunisia, and United Arab Emirates. The least-developed Arab countries include Comoros, Djibouti, Mauritania, Somalia, Sudan, and Yemen. They were categorized as leastdeveloped according to specific criteria identified by the Committee for Development Policy (CDP). The CDP is a subsidiary body of the Economic and Social Council (ECOSOC) of the United Nations (UN-Office of High Representative for Least Developed Countries 2008). Currently there are 48 countries worldwide on the list of least-developed nations, which is beyond the scope of this chapter. As six of the Arab nations are least developed, it is important to clarify the criteria for identifying Least-Developed Countries (LDCs). These criteria include (1) an economic vulnerability criterion, (2) a human resource weakness criterion, and (3) a low-income criterion. For more details, refer to the above-cited source. In an attempt to upgrade their developmental statuses, all developing and leastdeveloped Arab countries joined the Group of 77, which came into existence on June 15 1964. It is the largest intergovernmental organization of developing states in the United Nations (The Group of 77 at the United Nations 2008a,b). G-77 has bloomed from its originating 77 members into 130 affiliate countries spanning from the three world regions of Africa, Asia, and Latin America and the Caribbean. Even though G-77 currently encompasses 130 member nations, the organization kept the original name because of its historic significance. G-77 grants capacity for the countries of the South to express and uphold their combined economic interests and augments their mutual negotiating capability on all chief international economic issues within the United Nations system. G-77 also promotes South–South cooperation for purposes of development. G-77 also constructs mutual declarations, action programs, and accords on development issues. Many G-77 countries including the 48 LDCs put health, education, and defense as their most urgent priorities (The Group of 77 at the United Nations 2006). This situation creates challenges for enhancing science, technology, and innovation for the South, which in turn will influence improvement in development statuses.

Health System Resources Before discussing health system resources of Arab countries, it is of value to mention their affiliation with the WHO, as a number of resources of this organization are used to compile graphs and tables for this chapter (WHO, 2006a).

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

69

The countries of Bahrain, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, United Arab Emirates, Djibouti, Yemen, and the Occupied Palestinian Territories of West Bank and Gaza are part of the Eastern Mediterranean Regional Office (EMRO) of the WHO. Algeria, Comoros, and Mauritania belong to the WHO Regional Office for Africa. Several factors affect capabilities of a country to provide health services for its citizens. Also, these same factors can be used to measure or predict the capacity of nations to provide their health functions. The WHO periodically examines the healthcare systems and human resources of nations around the globe (World Health Organization 2007a). By such type of health system inspection, an examiner could gain insight not only into health aspects but also into the social, demographic, and economic architecture of any country. From a health care and economic standpoint, but not in the scope of this chapter, it is important to know the number of population of a nation. This brings attention to the expected burdens and demands that a health system as part of a country’s overall systems will go through. Direct resources required for the establishment of national health services in Arab nations as well as others include two broad factions namely financial and human. Two critical measures of human resource capabilities of health systems used in this chapter include density of physicians and nurses per 1,000 population.

Human Resources National Health needs cannot be met without a well-trained, adequate, and available health workforce (World Health Organization 2006b). It is critical to know that as per the WHO there is a direct relationship between the ratio of health workers and the survival of women during childbirth and children in neonatal period and infancy. As the number of health workers declines, survival declines proportionately. Any country with limited health workforce should examine the types of health services it offers on national basis and those offered at supplemental or high-risk levels. The 2004 Joint Learning Initiative report on human resources for health used three categories to identify the density of health workers as low, medium, or high (World Health Organization 2007a). Low density is less than 2.5 health workers per 1,000 population, medium is 2.5 to less than 5.0, and high density is 5.0 and more health workers per 1,000 population. Most displayed developed countries have high densities in human resources for both physicians and nurses (Figs. 3.2 and 3.3). It is important to note that the LDCs of Comoros, Djibouti, Mauritania, Somalia, Sudan, and Yemen display the lowest levels of densities of physicians and nurses compared to the rest of the Arab countries. The overall density of physicians in all Arab countries is low (less than 2.5 health workers per 1,000 population) with the exception of Lebanon that has a medium density. However, the six Arab states of the Persian Gulf namely Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates have higher levels of physicians than the rest of the Arab

eri

SA nU d me K Ye lan n U itzer da w en Su lia S ed ma a Sw i So tan in uri a Ma Sp ay uti orw bo Dji ros N land a mo Ze nds Co ew rla E N ethe rg UA N u o ia nis emb an x Tu p Lu Ja ia ria Sy Arab i ud Sa taly I d tar lan Qa Ice ary an ug Om co H y roc man r Mo Ge nce ya ra Lib nF no and l ba Le t Fin rk i a wa enm Ku nD rda ada Jo an q C lguim Ira e t B stria yp Eg in Au lia a hra ustr aA Ba

Alg

10

8

6

Per 1000 Population

3

2.5

2

1.5 Per 1000 Populations

A.A Saadallah and A.S Teebi 70

4.5

SA nU d me K lan Ye n U itzer da Su ia Sw eden l Sw ma So tania uri ain Ma ti Sp ay u rw bo No Dji nd os r ala mo Ze nds Co ew rla E N the UA Ne ourg ia mb an nis p Tu Luxe Ja ia ria Sy rab iA ud ly Sa Ita tar nd Qa Icela ry a an ug Om co H y roc man r Mo Ge nce ya ra Lib nF no and l ba Le it Fin ark wa nm e Ku nD rda a Jo ad an im u qC Ira elg tB tria yp us Eg in A a ali hra str Ba a Au eri

Alg

Fig. 3.3 Nurses’ density

Developed Countries Arab Countries

Developed Countries Arab Countries

4

3.5

1

0.5

0

Fig. 3.2 Physicians’ density

16

14

12

4

2

0

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

71

countries in their density category (Fig. 3.2). The density of nurses in many Arab countries is low. However, it is medium (2.5 to less than 5.0 health workers per 1,000 population) in Jordan, Tunis, and the six Arab states of the Persian Gulf (Fig. 3.3). It is important to note that the six Arab states of the Persian Gulf namely Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates have significant revenues from oil and gas and with their small populations have higher per capita incomes in comparison to their neighboring countries. Even though monetary revenues offer these countries the financial capabilities to establish affluent health services, their small population sizes restrict national manpower capabilities, pushing them to complement their deficits from Arab and other in-need nations, producing shortages in human resources and brain drain in the source nations.

Financial Resources The WHO measures financial capabilities extended to national health systems and the financial constraints put on these systems by using several indicators. These include total expenditure on health as percentage of gross domestic product (GDP), general government expenditure on health as percentage of total government expenditure, general government expenditure on health as percentage of total expenditure on health, and private expenditure on health as percentage of total

Fig. 3.4 Total expenditure on health

72

A.A Saadallah and A.S Teebi

expenditure on health. Figure 3.4 demonstrates the total expenditure of Arab nations on health and compares them to an equal number of developed nations. An economic rule is that there is a direct correlation between GDP per capita and the total health care spending per capita at any given point in time (Goldman and McGlynn 2005). The chart displays the drastic differences between developed and Arab countries in these aspects. Total expenditure on health as percentage of GDP and general government expenditure on health as percentage of total government expenditure denote the level of attention health care occupies compared to other national endeavors. Comparing the two categories of general government expenditure on health and private expenditure on health as percentage of total expenditure on health will demonstrate the healthcare environment as market-minimized or marketmaximized. This is a critical factor, as the cost of establishment and maintenance, and prices of testing and treatments need to be assigned as either provided hundred percent free of charge; at a nominal fee; or carried hundred percent by private entities, the parents, or their insurers. As such, each country needs to examine the market location of its health sector and see if it is market-minimized, marketmaximized, or somewhere along Anderson’s continuum.

Risk Factors and Demands Not only the resources discussed in the previous section, namely human and financial resources, but also several other factors influence capabilities of health services. These other factors collectively function as both risk factors for health and health systems, and as demands on health systems. These include mortality rates, national infrastructure, and burden of disease risk factors. Even though burdens of diseases is an important stressor on a national health system, the scope of this chapter does not accommodate its mention. This chapter provides several charts that demonstrate different mortality rates and mortality profiles in Arab nations. These charts demonstrate the following profiles: neonatal mortality rates (Fig. 3.5); infant mortality rates (Fig. 3.6); mortality rates due to preterm births (Fig. 3.7); mortality rates due to congenital anomalies (Fig. 3.8); and mortality rates due to other causes (Fig. 3.9). To highlight the national impact of these measures the same indicators of an equal number of developed countries including the USA and the UK are incorporated in each of these charts. Overall, the different mortality rates, namely neonatal mortality rates and infant mortality rates, are higher in all Arab countries in comparison to the developed countries (Figs. 3.5 and 3.6). But there are variables worth mentioning between different Arab nations as follows. Iraq and the LDCs of Comoros, Djibouti, Mauritania, Somalia, Sudan, and Yemen display the highest levels of neonatal (25–63 deaths per 1,000 live births), infant (35–90 deaths per 1,000 live births), and under five mortality rates (45–145 deaths per 1,000 live births) than the rest of the other Arab countries (figure not included). Neonatal. Neonatal, infant, and under-five mortality rates are lowest (<10 deaths per 1000 live births) in the

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

Fig. 3.5 Neonatal mortality rate

Fig. 3.6 Infant mortality rate

73

74

Fig. 3.7 Neonatal deaths due to preterm births

Fig. 3.8 Neonatal deaths due to congenital anomalies

A.A Saadallah and A.S Teebi

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

75

Fig. 3.9 Neonatal deaths due to other causes

Arab states of the Persian Gulf namely Bahrain, Kuwait, Oman, Qatar, and the United Arab Emirates, approaching the levels of developed nations, with the exception of Saudi Arabia (>10 neonatal and >20 infant and under-five deaths per 100 live births respectively) . This is probably due to the vast geographical size of this country rendering access to health services inequitable. It could be also due to local preference or necessity for home deliveries. The causes of mortality in the first week of life (asphyxia, birth trauma, and infection) relate directly to the birthing process. Interventions that provide for safe delivery have a bigger impact in this period of a newborn’s life (Department of Child and Adolescent Health and Development of the World Health Organization n.d.). After the first week of life, various infections (sepsis, pneumonia, meningitis, diarrhoeal diseases, and tetanus) are the most important contributors to mortality in children in developing countries. Neonatal deaths due to tetanus, severe infections, diarrheal diseases, and birth asphyxia are higher in the majority of Arab countries in comparison to the developed countries. It is worth mentioning that deaths due to tetanus, severe infections, and diarrheal diseases are lowest in the Arab states of the Persian Gulf namely Bahrain, Kuwait, Oman, Qatar, and the United Arab Emirates (10% combined annual estimated neonatal deaths) in comparison to the other Arab countries (18–59%), with the exception of Saudi Arabia (20%). It is evident by examining all these data that prevention of overall mortality of neonates, infants, and children under five will take priority over other activities through enhancing basic maternal and child health services. Especially it is to be borne in mind that the

76

A.A Saadallah and A.S Teebi

main reasons of death are birth asphyxia, tetanus, severe infection, and diarrheal diseases, which supersede other causes of death like congenital anomalies, preterm births, and other factors. It is critical to note that neonatal deaths due to congenital anomalies is the highest in the Arab states of the Persian Gulf with the exception of Saudi Arabia (<20% of the annual estimated neonatal deaths), namely in Bahrain (>40%), Kuwait (>50%) , Oman (>25%), Qatar (45%) , and the United Arab Emirates (>60%) and also in Japan (>45%) in comparison to the other Arab countries and developed countries included in the chart (Fig. 3.8) (World Health Organization 2007b). This probably calls for NBS and genetic services among other measures to be on the primary list of national health services for these nations. The ECOSOC of the United Nations (UN), the WHO, and development aiding banks assess progress in countries by several outcome and process indicators. One category of these indicators involves the measure of extent of access, especially of the poor, to such basic government services as health, education, infrastructure, water, and power at the local level (United Nations 2004). A simple mode for estimating the overall national competencies including the capabilities and resources of healthcare services is by the measuring of the level of access to improved drinking water sources, and improved sanitation. Two charts (Figs. 3.10 and 3.11) demonstrate the percentages of population with sustainable access of both improved drinking water and improved sanitation in the Arab nations. Both these figures demonstrate the level of inequity (if existing) of allocation of water and/or sanitation services between rural and urban areas in each Arab

Fig. 3.10 Sustainable access of improved drinking water in Arab countries

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

77

Fig. 3.11 Sustainable access of improved sanitation in Arab countries

country. This will shed light on probable parallel trends in the existence of other basic infrastructures like electricity, waste disposal, and roads. This will also reflect presence of matching trends in the healthcare services provided. This is because a prerequisite for establishment and proper operation of any health facility is the presence of constant and intact infrastructures. Each country, Arab or otherwise, that displays major disparities between its rural and urban areas is ethically required to examine the health allocation disparities that will definitely arise if it chooses to introduce what it will term a “national” NBS and genetic testing service. This is because, to be effective these services demand the presence of not only intact national infrastructures, but also dedicated and constant financial resources; equipped facilities; modern modes of communication like telephones, faxing, and Internet; prompt and constant delivery of health services; unremitting follow-ups; and experienced workforce. An alternate route for countries facing such type of situation is to provide NBS and genetic testing services as a high-risk approach or as a supplemental testing service, and then nationalize these services as conditions improve. In conclusion, the product of the different mortality rates and profiles in each country, coupled with inadequate rural and in some cases even urban access to both improved drinking water and improved sanitation, highlights the extent of demands on basic infrastructure as well as on primary health services in each Arab country. Bearing in mind that as per the WHO, high-quality health care is defined by the criteria of effectiveness, cost, and social acceptability, assuring primary health care will probably take precedence over services like NBS and genetic testing for a few

78

A.A Saadallah and A.S Teebi

years to come in several of the Arab countries. That is, if countries with such parameters are seeking to satisfy equity, quality, and efficiency of their health services on a national level.

Projection of Health System Performance This section of the chapter will try to provide some insight into a simple mode for directly predicting overall performances of health systems on national levels. It is by examining health services coverages as monitoring (1) the percentages of antenatal care coverage, (2) the percentages of births attended by skilled health professionals, and (3) the percentages of children immunized. Even though monitoring the percentages of antenatal care coverage is a simple mode for directly predicting the overall performances of national health systems of the 22 Arab countries, Bahrain, Morocco, Oman, Saudi Arabia, and UAE did not measure and/or did not report such data to the relevant WHO regional offices. Information available on this performance measure is as follows. There are six data points for “at least one visit of antenatal care coverage”, four of which have less than 80% of their pregnant population receiving at least one antenatal care visit (66.7%). Also, there are 14 data points for “at least four visits of antenatal care coverage,” 11 of which have less than 80% of their pregnant population having at least four antenatal care visits (78.6%). The dual situation of missing data and nonoptimal antenatal care services are not encouraging as these trends could occur with delivering babies or measuring the performance indicators of national NBS programs, as short-term and long-term follow-ups of screened children. Thirteen of the 22 Arab countries are close to 90% or even above in the parameter of the percentages of the births that are attended by skilled health professionals (Fig. 3.12). On the other hand, less than 80% of the births are attended by skilled health professionals in Egypt, Iraq, Morocco, Somalia, Sudan, Yemen, Comorous, and Mauritania. A small percentage of these numbers are due to local customs of preference to home births over births in health centers or hospitals. Another important type of national health services is that of nationwide vaccination coverages. Closer examination of vaccination trends provides some insight for gauging overall performances of health systems on national levels. This is because, for a country to provide vaccination services to all its newborns and children, it needs to solicit participation of several branches of its health system on a national level. This national vaccination service activity parallels what will be needed to establish newborn and genetic testing systems on a national level. But we need to be cautious, as newborn and genetic testing systems are at a more complex and demanding levels. Data on vaccination of 1-year-olds immunized by one dose measles immunization and 1-year-olds immunized by three doses DTP3 (diphtheria, tetanus, pertussis) immunization in most Arab countries are comparable to those in developed countries. It is evident that Comoros, Djibouti, Mauritania, Somalia, Sudan, and Yemen have the lowest immunization rates

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

79

Fig. 3.12 Births attended by skilled health professionals

compared to the rest of the Arab countries. This is expected as these six countries are categorized as least-developed (GNI per capita less than $750, weaknesses in human resources, and economic vulnerability) as per the ECOSOC of the United Nation (UN Office of the High Representative for the Least Developed Countries 2008). The coming section displays available genetic services in the Arab world as to date.

Genetic Services in the Arab World Excluding Gulf Cooperation Council (GCC) countries, Lebanon, Egypt, and Jordan, medical genetic services in Arab countries are generally considered scant. One of the early genetic services offered to the public was in Egypt as part of university research. Late Dr Nemat Hashem of Ain Shams University in Cairo started some genetic service in the early 1960s; later on, other academic institutions in Cairo became involved. In 1966, Dr S. Temtamy earned her Ph.D from John Hopkins University on her work on limb malformations and that formed the basis of the book that was co-authored with Dr McKusick. Following this, she initiated the department of Human Genetics within the National Research Centre in Cairo. Later on, the department expanded remarkably to include a large number of

80

A.A Saadallah and A.S Teebi

researchers and clinical geneticists, many of whom were students of Dr Hashem and Dr Temtamy. Later on, Alexandria University developed genetic counseling services (Dr S. Rushdy). This was followed by the development of services by departments at the Universities of Mansoura, Suez Canal, Assuit, October 6, and other universities. Most of these services remained to be selective. In early 1960s, cytogenetic services became available in Lebanon, offered by the American University of Beirut. Dr V Der Kaloustian was the leading geneticist in Lebanon since his return from USA after he finished his training in Medical genetics in late 1960s. He published his famous book on Genetics of Skin Disease while in Lebanon. After he left for Canada in the 1990s, a new generation of geneticists from different places continued to provide services in Lebanon; however, services remained scattered and not sufficient. In Kuwait, Dr O Alfi initiated a cytogenetic laboratory and a genetic clinic in late 1960s. This continued only for a few years, as he decided to immigrate to the USA. However, comprehensive genetic services started in Kuwait in 1979 led by Dr S. Al-Awadi. A group of geneticists/pediatricians including Dr T Farag, Dr K Naguib, and Dr A Teebi were instrumental in providing high standard of services and research that included neonatal screening. The invasion of Kuwait in 1990 caused delays in the development of more genetic services. They later developed but at a slower pace, in particular with regard to neonatal screening. In Saudi Arabia, King Faisal Specialist Hospital and Research Centre (KFSH & RC) represents the leading comprehensive genetic service since its establishment in late 1970s. Dr N Sakati who had pediatric genetic and endocrinology training in the USA was recruited to be the first geneticist there. The clinical care provided at KFSH & RC covers diagnostic, therapeutic, and preventive interventions with the presence of molecular, biochemical, and cytogenetics laboratories, advanced treatment modalities, and the availability of preventive interventions via prenatal diagnosis, preimplantation genetic diagnosis, and carrier screening, in addition to well established genetic counseling services. Both Dr P Ozand and Dr M Rashed left important landmarks during their service in the metabolic clinics and laboratories. Less comprehensive, genetic services are also provided in other Saudi healthcare institutions as in ministry of Health (MOH) tertiary centers, the National Guard, and Military Hospitals; however, most of the services cluster in the capital, Riyadh, with scattered services offered in other regions. In the mid-1980s, a number of genetic clinics were developed in Bahrain, Oman, and UAE and were supported by cytogenetic facilities; some were noticeably expanded to involve molecular genetics and biochemical genetics laboratories. The large number of genetic publications from UAE (Dr L Al-Gazali) and Oman (Dr Anna Rajab) reflects the richness and diversity of clinical cases as well as the scholarly activities of the physicians involved. Many of such publications are cited elsewhere in this book. In Qatar, the move was fast to include comprehensive genetic services including premarital counseling and expanded neonatal screening, within less than 20 years from the start of small cytogenetic laboratory at the main hospital in Doha in the early 1990s.

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

81

In Tunisia, similar to Egypt and Lebanon, some genetic services were offered as part of research at universities or research centers. The interest in neurogenetic disorders was clear since the 1970s (Dr M Ben Hamida) from the National Neurology Institute and then from Pasteur Institute. The involvement of other groups came with the work of Dr H Chaabouni in the field of pediatrics genetics and genetic counseling since the mid-1980s. Now, several centers across the country offer diagnostic as well as counseling services but are still far from being comprehensive or sufficient. The published work of Dr H Hamamy from Iraq and Dr M Salih from Sudan points to some genetic services including diagnostic facilities that were available in academic centers in their respective countries since the 1980s. However, it remained fragmented because of the political situation or the lack of funding. In Jordan and Morocco, some cytogenetic and molecular diagnostic facilities were available since early 1990s. Clinical genetic services are available in one or two locations in the country based in a university or an academic center. However, such services are far from being able to cover the need of the population. In Syria and Libya, very little diagnostic and clinical genetic services are offered by pediatricians and other nongenetic specialists. Genetic testing is sent abroad on demand basis only. In Comoros, Djibouti, Mauritania, Somalia, and Yemen, such services are virtually not available.

NBS in the Arab World In 2008, the second newborn conference of the Middle East and North Africa NBS initiative was held in Cairo with representatives from most Arab countries excluding Algeria, Comoros, Djibouti, Iraq, Mauritania, Somalia, and Sudan. Representatives were asked to identify the current status of NBS in their countries. According to their responses, the countries were put into three groups (Krotoski et al. 2009). Group 1 included countries that have not begun national NBS. The countries are Libya, Morocco, Syria, and Yemen. Morocco and Syria, however, had developed plans to start some NBS in particular for congenital hypothyroidism. Group 2 included countries that have completed pilot studies for at least one condition and anticipated expansion to national programs. Countries in this group are Jordan, Kuwait, Lebanon, and Tunisia. Group 3 countries included Bahrain, Egypt, the Palestinian Authority, Oman, Qatar, Saudi Arabia, and United Arab Emirates. All countries in this group screen for at least one condition, primarily congenital hypothyroidism, and most screen for two or more conditions. Saudi Arabia and Qatar use tandem mass spectrometry (MS/MS) for a large panel of metabolic conditions. There is growing recognition in the Arab World of the importance of NBS and its role in preventing or ameliorating mental retardation, physical disability, neurological damage, and even death in disorders amenable to NBS, particularly in those conditions in which treatment is simple and relatively inexpensive (Saadallah and Rashed 2007).

82

A.A Saadallah and A.S Teebi

Common barriers for implementing NBS were the need of trained professionals and obtaining financial and political support. Other difficulties included the issue of geographic challenges due to large distances and isolated areas, as well the need for policies to mandate NBS.

Conclusion We have attempted to give a comprehensive preview on both the national and healthcare levels to evaluate some of the resources, burdens, strengths, and weaknesses that affect national health systems in their respective Arab countries. Topics discussed included healthcare systems and services, development levels, health resources including human and financial, risk factors and demands, projection of performance, and genetic services and NBS in the Arab world. This collective view will probably help to answer the questions posed at the beginning of this chapter. Can national healthcare systems of the Arab nations, most of which are developing, accommodate neonatal screening and genetic testing as a standard service? Moreover, could these services prove to become efficient and equitable as part of a national public health service? On the other hand, should these services only become a high-risk approach, or a supplemental testing? Even though the directions of responses to these and other questions could seem evident from the statistics and the charts, the final answers lie mostly in the hands of authorities of each country on the basis of its assigned health goals and priorities. At the end, it is pertinent to add that the goals for national health systems are good health, responsiveness to the expectations of the population, and fair financial contribution (World Health Organization 2000).

References Alliance for Health Policy and Systems Research, Geneva (2004) Strengthening health systems: the role and promise of policy and systems research. http://www.who.int/alliance-hpsr/ resources/Strengthening_complet.pdf Department of Child and Adolescent Health and Development of the World Health Organization (n.d.) (IMCI) Technical seminar on the sick young infant. http://www.who.int/child-adolescenthealth/New_Publications/IMCI/WHO_FCH_CAH_01.10/Young_Infant/TS-Sick_Young_ Infant.doc Goldman DP, McGlynn EA (2005) U.S. health care. Facts about cost, access, and quality. http:// www.rand.org/pubs/corporate_pubs/2005/RAND_CP484.1.pdf Krotoski D, Namaste S, Raouf RK, El Nekhely I, Hindi-Alexander M, Engelson G, Hanson JW, Howell RR, on behalf of the MENA NBS Steering Committee (2009) Conference report: second conference of the Middle East and North Africa newborn screening initiative: partnerships for sustainable newborn screening infrastructure and research opportunities. Genet Med 11(9):663–668

3 Influences of Systems’ Resources and Health Risk Factors on Genetic Services

83

Saadallah A, Rashed M (2007) Newborn screening: experiences in the Middle East and North Africa. J Inherit Metab Dis 30:482–489 The Group of 77 at the United Nations (2006) Conclusions and recommendations of the meeting of ministers of science and technology. Meeting of the ministries of science and technology of the member states of the Group of 77. Angra dos Reis, Rio de Janeiro, Brazil. http://www.g77.org/ mmst/conclusion.html The Group of 77 at the United Nations (2008a) About the group of 77. http://www.g77.org/doc/ The Group of 77 at the United Nations (2008b) Member states of the group of 77. http://www.g77. org/doc/members.html UN Office of the High Representative for the Least Developed Countries, Landlocked Developing Countries, and Small Island Developing States (UN-OHRLLS) (2008, July 17) The criteria for identification of Least Developed Countries. LDCs. http://www.un.org/special-rep/ohrlls/ldc/ ldc%20criteria.htm United Nations (2004) Economic and Social Council. Supplement 13. Committee for Development Policy. Report on the sixth session, 29 March-2 April 2004. http://www.un.org/specialrep/ohrlls/ldc/E-2004-33.pdf World Atlas (n.d.) http://www.worldatlas.com/webimage/countrys/asia/arableag.htm World Health Organization Regional office of the Eastern Mediterranean (2005) Palestine. http:// www.emro.who.int/emrinfo/index.asp?Ctry=pal World Health Organization (2000) The world health report 2000. Health systems: improving performance. http://www.who.int/whr/2000/en/ World Health Organization (2006a) WHO statistical information system. WHOSIS. Core health indicators. http://www.who.int/whosis/database/core/core_select.cfm World Health Organization (2006b) The global shortage of health workers and its impact. Fact sheet N 302. http://www.who.int/mediacentre/factsheets/fs302/en/index.html World Health Organization (2007a) Human resources for health. http://www.who.int/whosis/ indicators/2007HumanResourcesForHealth/en/index.html World Health Organization (2007b) World health statistics 2007. http://www.who.int/whosis/dat abase/core/core_select.cfm?strISO3_select=btn&strIndicator_select=healthpersonnel&int Year_select=latest&language=english

Chapter 4

Endogamy and Consanguineous Marriage in Arab Populations Alan H. Bittles and Hanan A. Hamamy

Introduction Arabs are a Semitic people basically defined as individuals speaking Arabic as their native tongue, although with many different dialects, who self-identify as being of Arab ancestry. The Arab world extends from Iraq and the Gulf States in the east to Morocco and Mauritania on the Atlantic coast of North Africa in the west, and through time it has incorporated many populations with ancestral origins outside the Arabian Peninsula. Large Arab communities are now permanent residents in Western Europe, North and South America, and Australia, and so the global Arab population is estimated to number 300–350 million (Hamamy and Bittles 2009). All Arabs share certain core cultural values and beliefs, with the family accepted as the central structure of society. Marriage is primarily regarded as a family matter and arranged marriage is widespread within all Arab societies. The practice of arranged marriage does not entail a union contracted against the will of the partners but essentially reflects the fact that the marriage has been mutually agreed by both families on familial and traditional grounds.

Traditional and Contemporary Patterns of Endogamy in Arab Societies Although social life and identity traditionally focuses on the family, family ties extend into the structure of clans and tribes, and for this reason an individual’s sense of loyalty continues to be oriented to extended patrilineal kin relations, i.e., the hamula or clan, and more widely to the tribe. Family support is expected in all A.H. Bittles (*) Centre for Comparative Genomics, Murdoch University, South Street, Perth, WA 6150, Australia e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_4, # Springer-Verlag Berlin Heidelberg 2010

85

86

A.H. Bittles and H.A. Hamamy

circumstances, and so “one turns to a member of the family for assistance in almost any area, whether it is a question of health, financial need, employment, or even admission to school” (Khlat 1997). Tribal structure and composition can change through time and for example, a detailed study of the Abbad tribe in Jordan indicated that the present-day grouping coalesced approximately 250 years ago from a number of quite diverse sub-groups, which had previously been affiliated with other older tribal communities (Nabulsi 1995). The Abbad tribe now incorporates some 120,000 individuals and is subdivided into 76 male lineages, ranging in numbers from approximately 250 to 2,000 persons. Some 90% of marriages are contracted within the tribe, and half of all marriages are between members of the same paternal descent line (Nabulsi 1995). Given this complex tribal and clan structure and the quite restricted effective population sizes of many sub-groups, a substantial level of random inbreeding is inevitable within Arab communities and internal genetic differentiation is probable on the basis of tribe and clan membership. However, the degree to which these processes apply will be dependent on the specific history of each tribe and clan, and more particularly on past and present frequencies and patterns of tribal admixture and inter-clan marriage. Marriage within tribal boundaries is largely paralleled by religious endogamy. In multi-faith countries such as Lebanon, with three main religious communities, Sunni and Shia Muslims and Maronite Christians, plus the smaller Druze, Greek Orthodox, Greek Catholic and Armenian communities, denominational endogamy has historically been the norm and is accompanied by a variable level of genetic differentiation (Klat and Khudr 1986).

Consanguineous Marriage Within Arab Societies As previously noted, Arab societies place great emphasis on the role and importance of the family. Thus, in addition to tribal and clan endogamy, consanguineous marriage is customary in most, if not all, Arab communities.

The Prevalence and Preferred Types of Consanguineous Marriage Intra-familial unions between couples related as second cousins or closer (F 0.0156) currently account for approximately 20–50% of all marriages in Arab countries (Table 4.1). Specific inter-country comparisons are often difficult because of the different study populations sampled, for example, through household surveys versus antenatal clinics or maternity wards, and researchers also vary in the level of detail collected, with some studies based on data on first-cousin and nonconsanguineous marriages only.

Table 4.1 Prevalence and types of consanguineous marriage in representative studies on Arab populations Country Study region Consanguinity (%) Marriages studied Mean coefficient of inbreeding (a) Algeria All-Algeria 22.6 1C, 2C – 0.0152 Bahrain Bahrain 31.8 1C, 11/2C, 2C 0.0101 Egypt All-Egypt 24.5 D1C, 1C, 11/2C, 2C Iraq All-Iraq 33.0 D1C, 1C 0.0219 0.0177 Israel Arab Muslim 32.1 D1C, 1C, 11/2C, 2C 0.0142 Jordan Amman 25.5 D1C, 1C, 11/2C, 2C 0.0219 Kuwait All-Kuwait 34.3 D1C, 1C, 11/2C, 2C Lebanon Beirut 25.0 1C,<1C 0.0088 Morocco All-Morocco 19.9 1C, 2C 0.0089 0.0198 Oman All-Oman 35.9 D1C, 1C, 11/2C, 2C Palestinian Territories All-Palestine 27.7 D1C, 1C 0.0186 0.0271 Qatar Doha 44.5 D1C, 1C, 11/2C, 2C Saudi Arabia All-Saudi 40.6 1C, 2C 0.0184 Sudan Khartoum 52.0 1C, 2C 0.0302 0.0181 Tunisia North region 26.9 >1C, 1C, 11/2C, 2C 0.0245 United Arab Emirates Al Ain 37.4 D1C, 1C, 11/2C, 2C 0.0244 Yemen Sana’a 44.7 D1C, 1C, 11/2C, 2C Marriages studied: D1C double first cousin, F ¼ 0.125 1C first cousin, F ¼ 0.0625 11/2C first cousin once removed, F ¼ 0.0313 2C second cousin, F ¼ 0.0156 Source: www.consang.net

Benalle`gue and Kedji (1984) Al Arrayed (1994) Hafez et al. (1983) COSIT (2005) Vardi-Saliternik et al. (2002) Hamamy et al. (2005) Al-Awadi et al. (1985) Khlat (1988) Lamdouar Bouazzaoui (1994) Rajab and Patton (2000) Assaf and Khawaja (2009) Bener and Alali (2006) El-Hazmi et al. (1995) Saha and El Sheikh (1988) Riou et al. (1989) Al-Gazali et al. (1997) Gunaid et al. (2004)

Reference

4 Endogamy and Consanguineous Marriage in Arab Populations 87

88

A.H. Bittles and H.A. Hamamy

It is important to acknowledge that the consanguinity estimates and mean coefficients of inbreeding reproduced in Table 4.1 refer only to relationships that extend back to the grandparental generation. Given the long history and preference for consanguineous marriage in Arab societies and their tradition of tribe and clan endogamy, the cumulative levels of inbreeding and thus the percentage of homozygosity would be substantially higher than suggested by these data. Determination of ancestry in Arab societies and the construction of family pedigrees are greatly advantaged by the precise terminology that exists in Arabic to describe various family relationships. First-cousin unions are especially popular, in particular the paternal parallel subtype ‘Bint amm, i.e., between a man and his father’s brother’s daughter. ‘Bint amm unions are favoured culturally and socially and they are considered to be the usual or expected form of marriage for first cousins whether they have been reared in adjoining or separate households. As indicated in Table 4.2, parallel-cousin marriages (‘Bint amm and ‘Bint khala) predominate in Arab countries, ranging from 59.9% of first-cousin unions in Lebanon (Khlat 1985) to 73.3% in UAE (Al-Gazali et al. 1997). The prevalence of ‘Bint amm marriages varies significantly between populations, with the lowest rates in urban Lebanon (Khlat 1985) and the highest in lower income, rural and Bedouin tribal communities (Khlat et al. 1986; Radovanovic et al. 1999; Raz and Atar 2004; Joseph 2007). However, no hard and fast rule exists, and in communities or extended families with few marriageable offspring, it may be difficult to ensure that a ‘Bint amm, or indeed any other type of first-cousin marriage, is possible within the socially acceptable age differences of the groom and bride. In more traditional Arab societies it is held that a man has the common-law right (urf) to marry his first cousin, and if she marries another male he may be entitled to

Table 4.2 Preferred patterns of first cousin marriage in different Arab societies Country Type I Type II Type III Type IV All first Authors (%) (%) (%) (%) cousin ‘Bint amm ‘Bint khala ‘Bint amma ‘Bint khal unions (%) Lebanon 37.4 22.5 10.4 29.7 14.1 Khlat (1985) Jordan 62.8 9.9 7.7 11.3 32.0 Khoury and Massad (1992) UAE 64.9 8.4 12.2 14.5 26.2 Al-Gazali et al. (1997) Israel 48.2 20.3 13.5 17.7 24.3 Jaber et al. (2000) Yemen 48.9 18.1 14.2 18.8 29.4 Gunaid et al. (2004) Palestinian 47.9 17.6 20.1 14.4 14.4 Assaf and territories Khawaja (2009) Parallel-cousin marriage Type I father’s brother’s daughter, F ¼ 0.0625, Fx ¼ 0 Type II mother’s sister’s daughter, F ¼ 0.0625, Fx ¼ 0.1875 Cross-cousin marriage Type III father’s sister’s daughter, F ¼ 0.0625, Fx ¼ 0 Type IV mother’s brother’s daughter, F ¼ 0.0625, Fx ¼ 0.125

4 Endogamy and Consanguineous Marriage in Arab Populations

89

financial compensation (El-Badramany et al. 1997; Joseph 2007). In practice, the girl’s paternal uncle can agree to forego his son’s right to their marriage (Joseph 2007). If his permission is not granted, practices such as revoking the marriage of a cousin to another man have persisted in some Palestinian villages, even occurring on the marriage night (Assaf and Khawaja 2009). While all four types of first-cousin marriage have the same coefficient of inbreeding at autosomal loci (F ¼ 0.0625), an often understated factor is the difference in the equivalent coefficient of inbreeding at X-chromosome loci (Fx). As shown in Table 4.2, from a theoretical perspective, homozygosity at X-chromosome loci is zero for ‘Bint amm and ‘Bint amma progeny, but Fx ¼ 0.125 for ‘Bint khal and 0.1875 for ‘Bint khala offspring. As a result, it would be expected that the expression of X-chromosome disorders, such as glucose 6-phosphate dehydrogenase deficiency, reflects the proportional prevalence of each first-cousin sub-type in a population.

Religion and Consanguinity It is generally accepted that consanguineous marriage in the Arab world is a preIslamic tradition (Stern 1939). The practice may, however, have been encouraged by the rules of inheritance introduced by the Holy Quran, with daughters entitled to inherit half of the amount received by sons and the wife inheriting a determinate share from her husband (Sura Al-Nisa: 7,11,12). Under Islamic law, a dower (mahr) is specified as part of the marriage arrangement, with these goods transferred to the bride at marriage (Khuri 1970; Tucker 1988). Consanguineous marriage is also common within Christian Arab communities, although usually at a lower prevalence than among their Muslim compatriots (Freundlich and Hino 1984; Khlat 1988). In Arab Christian denominations affiliated with the Roman Catholic Church, and in the Greek Orthodox Church, religious dispensation requirements may apply to marriages contracted between couples related as first cousins or closer, whereas in the Coptic Orthodox Church no such regulation applies to first-cousin unions. The basic guidelines on permitted marital relationships within Islam allow marriages up to and including first-cousin unions (F ¼ 0.0625) to be contracted. Uncle–niece marriage (F ¼ 0.125) is proscribed by the Holy Quran. However, double first-cousin marriage, also F ¼ 0.125, is allowed within Islam and the current prevalence of double first-cousin unions typically ranges from 0.6% to 5.8% (Al-Gazali et al. 1997; Radovanovic et al. 1999). It has been mistakenly assumed that consanguineous marriage is favoured within Islam, when a number of the hadith (oral pronouncements of the Prophet Muhammad) actually encourages marriage between non-relatives (Hussain 1999). In addition, the second Caliph, Omer Ibn Al-Khatab, reputedly advised the Bani Assayib tribe to avoid close-cousin marriage and resultant ill-health by intermarrying with other tribes (Albar 1999). Nonetheless, Fatima, the daughter of the Prophet, married Ali,

90

A.H. Bittles and H.A. Hamamy

the Prophet’s ward and first cousin, so in practice the advice offered on consanguinity appears not to have been intended or regarded as binding.

Demographic, Social and Economic Correlates of Consanguinity Across the Arab world, consanguineous marriage is most prevalent in rural communities following more traditional life styles (Al-Salem and Rawashdeh 1993; Al-Gazali et al. 1997; Radovanovic et al. 1999; Zaoui and Bie´mont 2002; El-Mouzan et al. 2007; Joseph 2007). In general, the highest prevalence of consanguineous marriage is contracted among families with the lowest standard of living (Saedi-Wong et al. 1989; Assaf and Khawaja 2009) and wives in consanguineous marriages mostly have a lower level of education (Al-Thakeb 1985; Khlat 1988; Jurdi and Saxena 2003). As indicated in Table 4.3, in keeping with a more traditional lifestyle, consanguinity is generally associated with younger maternal and paternal ages at marriage and so longer female reproductive spans (Khlat 1988; Assaf and Khawaja 2009). These generalisations are by no means uniform, and historical records from eighteenth and nineteenth century Palestine indicate that cousin marriage was most prevalent in upper-class Arab societies (Tucker 1988). Upper socioeconomic status males in Kuwait favour consanguineous marriage (Al-Thakeb 1985), and males with advanced educational backgrounds express a similar preference for intrafamilial marriage in the UAE (Bener et al. 1996) and Yemen (Jurdi and Saxena 2003). Representative surveys in the Palestinian Territories also showed no significant difference in the prevalence of consanguineous marriage across female educational standards (Assaf and Khawaja 2009). A small number of detailed studies have been conducted into the social outcomes of consanguineous marriage, although they have mainly involved female subjects only. An early report from Sudan indicated greater marital stability in consanguineous unions, irrespective of the type of cousin relationship, with divorce in 3.6% of first-cousin marriages as against 14.6% in other types of marriage (Hussien 1971). This pattern has also been reported in non-Arab populations, possibly because of the highly disruptive effect of marriage failure on the stability of the extended family (Bittles 2005).

Table 4.3 Demographic and social correlates of consanguinity Younger maternal and paternal age at marriage Extended maternal reproductive span Larger completed family sizes Low level of maternal education Rural residence More traditional mode of life

4 Endogamy and Consanguineous Marriage in Arab Populations

91

A higher degree of dissatisfaction may, however, arise when there is a large age differential between consanguineous partners (El-Islam 1976), and in Saudi Arabia there was a positive but statistically non-significant association between the degree of consanguinity and marital discord (Chaleby 1988). More recent investigations have centred on the highly sensitive issue of domestic violence, with no significant advantage or disadvantage reported for consanguineous marriage among lowincome women in Syria (Maziak and Asfar 2003) or Palestinian refugees in Lebanon (Khawaja and Tewtel-Salem 2004).

Contemporary Attitudes Toward Consanguineous Marriage As shown in Table 4.4, when questioned about consanguineous marriages, a number of reasons are commonly advanced for the popularity of intra-familial unions (Hamamy and Bittles 2009). In general, besides various social and economic explanations, women who married a close biological relative or whose family has a tradition of consanguineous unions are more favourably disposed to the practice (Khlat et al. 1986; Jaber et al. 1996). The fact that espoused partners would have met at family gatherings before betrothal is held to be especially helpful, and it is also useful in promoting and achieving harmony between a bride and her future in-laws to whom she is related (Khlat et al. 1986). Some studies have reported a secular decline in the prevalence of consanguineous marriages, for example, in Beirut, Lebanon (Khlat 1985), urban Kuwait (Radovanovic et al. 1999), Saudi Arabia (Al-Abdulkareem and Ballal 1998), Jordan (Hamamy et al. 2005), Israeli Arab communities (Jaber et al. 2000; Zlotogora et al. 2002; Sharkia et al. 2007) and the Palestinian Territories (Assaf and Khawaja 2009). By comparison, in the UAE (Al-Gazali et al. 1997), Yemen (Jurdi and Saxena 2003) and Qatar (Bener and Alali 2006), the overall levels of consanguineous marriage and the prevalence of first-cousin unions have actually increased. The latter observations may reflect the larger family sizes of recent generations and hence the greater availability of potential cousin spouses. But some caution needs to be exercised in interpreting and comparing the prevalence of consanguineous marriages across time, especially given the different study populations sampled,

Table 4.4 Perceived social and economic advantages of consanguineous marriage The assurance of marrying within the family and the strengthening of family ties Simplified premarital negotiations, usually conducted in the partners’ early or late teens Knowledge of one’s spouse prior to marriage Greater social compatibility of the bride with her husband’s family, in particular her mother-in-law Lower risk of undeclared health problems in the intended spouse Reduced requirement for dowry payments, with consequent maintenance of the family goods and monies In land-owning families, maintenance of the integrity of family land-holdings

92

A.H. Bittles and H.A. Hamamy

the variant study protocols employed, and the major economic and educational changes which have occurred in most Arab countries during the second half of the twentieth century (Bittles 2008).

Endogamy, Consanguinity and Genetic Disease in Arab Populations Of the six World Health Organization (WHO) Regions, the highest rate of severe congenital disorders and genetic diseases that are lethal or could potentially cause lifelong impairment was reported in the Eastern Mediterranean Region, with >65 affected children per 1,000 live births as opposed to 52/1,000 live births in Europe, North America and Australia (Alwan and Modell 2003; Christianson et al. 2006). The elevated level of inherited disorders in the Eastern Mediterranean Region can mostly be attributed to higher rates of inherited blood disorders and other autosomal recessive conditions, for example, with carrier rates of 2–15% for b-thalassaemia, 2–50% for a-thalassaemia, and 0.3–30% for sickle cell disease in Arab countries. In addition, G6PD deficiency has been estimated to range from 2.5% to 27% in different Arab countries (Hamamy and Alwan 1994; Alwan and Modell 1997; Al-Gazali et al. 2006), possibly reflecting the elevated levels of homozygosity at X-chromosome loci (Table 4.2). The large sizes of many Arab families, in conjunction with clan/tribe endogamy and high consanguinity rates, facilitate the expression of autosomal recessive disorders, with rare or previously unreported syndromes and metabolic defects especially apparent (Teebi 1994; Al-Gazali et al. 2005; Hamamy et al. 2007a, b). Consanguineous marriages continue to be contracted within the Arab diaspora in Western countries, and so the reported rates of inherited disease in these communities are comparable to those in their countries of origin, including a large proportion of autosomal recessive diseases and developmental disorders (Hoodfar and Teebi 1996; Nelson et al. 1997).

Consanguinity and Reproductive Health Increased numbers of pregnancies have been recorded in a majority of global studies of consanguineous marriages and, in a meta-analysis of 30 populations, on average first cousins had 11.9% more live-born children than non-consanguineous couples (Bittles et al. 2002a). This pattern of higher fertility holds true in most Arab populations (Khlat 1988; al-Abdulkareem and Ballal 1998; Hammami et al. 2005; Kerkeni et al. 2007). The primary reasons are more probably social than biological, with younger parental ages at marriage in consanguineous unions and longer potential reproductive spans as important contributory factors (Table 4.3). In the more traditional rural Arab communities where consanguineous marriage is most prevalent, there may be a lower uptake of contraception with consequent larger family sizes.

4 Endogamy and Consanguineous Marriage in Arab Populations

93

Most studies worldwide have shown that consanguinity is not associated with increased abortion or miscarriage rates (Bittles et al. 2002a). With some exceptions (Mokhtar and Abdel-Fattah 2001; Assaf et al. 2009), there was also no significant association between consanguinity and prenatal losses in a majority of Arab populations (Al-Awadi et al. 1986; Khlat 1988; Saha et al. 1990; Abdulrazzaq et al. 1997; al Husain and al Bunyan 1997; Jaber et al. 1997a; al-Abdulkareem and Ballal 1998; Khoury and Massad 2000; Saad and Jauniaux 2002; Kerkeni et al. 2007), but it has to be acknowledged that data on very early pregnancy terminations are at best partial, and so an unknown proportion of these early losses may be unrecorded. Although information on stillbirths is more reliable, the reported outcomes with respect to consanguinity are varied, with some studies reporting a positive association (Khoury and Massad 2000; Mokhtar and Abdel-Fattah 2001; Assaf et al. 2009) but no significant difference in stillbirth prevalence in consanguineous pregnancies in a majority of cases (Al-Awadi et al. 1986; Khlat 1988; Saha et al. 1990; Abdulrazzaq et al. 1997; al Husain and al Bunyan 1997; Jaber et al. 1997a; Kerkeni et al. 2007). A cross-sectional study which reported an association between consanguinity and apnoea of prematurity in Lebanon awaits confirmation in other populations (Tamim et al. 2003).

Anthropometric Studies at Birth and in Childhood Investigations into the influence of consanguinity on birth measurements, including weight, recumbent length and head circumference, often produce conflicting results. Thus in different Arab populations, a positive association between consanguinity and low birth weight was both reported (Al-Eissa et al. 1991; Jaber et al. 1997a; Mumtaz et al. 2007) and refuted (Khlat 1989; Saedi-Wong and al-Frayh 1989; Wong and Anokute 1990; al-Abdulkareem and Ballal 1998). Possible reasons for these contradictory findings include the variability of the investigative protocols employed, with a common lack of discrimination between different levels of consanguinity, and limited or no control for potential confounding factors, including socioeconomic status, and maternal nutrition, health status and disease. The importance of these factors was demonstrated in a study in Jordan, in which univariate analysis initially indicated a highly significant positive association between consanguinity and low birth weight. However, this relationship disappeared in multivariate analysis when control for age, body mass index, occupation, education, smoking, gravidity, parity, medical problems during pregnancy and a family history of premature deliveries was introduced (Obeidat et al. 2008). Inbreeding depression in stature among school children was observed in Egypt (Abolfotouh et al. 1990). But, as with birth weight, studies with better control for the effect of socioeconomic variables on stature are needed, taking into consideration the rapidly changing socioeconomic and nutritional parameters which have occurred in most Arab countries.

94

A.H. Bittles and H.A. Hamamy

Early Postnatal Mortality In keeping with studies conducted in other major populations (Bittles 2001), almost all data from Arab countries indicate higher postnatal mortality in consanguineous versus non-consanguineous couples, especially during the first year of life (Jaber et al. 1997a). For example, among Palestinian families resident in different Middle Eastern countries, infant mortality among first cousin progeny was on average 15/1,000 live births higher than in non-consanguineous offspring (Pedersen 2002). Given the higher homozygosity that would be expected in the progeny of biologically related couples, the findings are strongly suggestive of deleterious recessive gene expression, although in most published reports on Arab populations no specific causes of death were diagnosed to support this contention. Besides a larger number of pregnancies and live births and despite a higher percentage of infant and childhood deaths, consanguineous couples commonly have more surviving children. In some cases, these findings can be explained in terms of differentials between consanguineous and non-consanguineous couples with respect to factors such as socioeconomic status, religious affiliation and marriage duration (Khlat 1988). Reproductive compensation is a probable additional factor, with families replacing children who have died in infancy or early childhood, either through choice or via cessation of lactational amenorrhoea.

Consanguinity and Childhood Morbidity Studies of childhood deafness (Zakzouk et al. 1993; Al-Gazali 1998; Attias et al. 2006; Khabori and Patton 2008), blindness (Al-Idrissi et al. 1992; Elder and De Cock 1993) and dental anomalies, especially structural defects and malocclusion (Maatouk et al. 1995), all have implicated parental consanguinity in the disease aetiology. The case for a significant recessive gene contribution to deafness is strongest, with 92% and 57% respectively of non-syndromic and syndromic deafness examined in the UAE attributed to autosomal recessive inheritance (Al-Gazali 1998). As in other major populations, a significantly elevated risk of birth defects has been widely recorded in the progeny of Arab first-cousin couples. The actual rates and types of congenital defect reported vary widely between populations, with differing study protocols, highly variable sample sizes and limited control for sociodemographic variables making a detailed summary and overall assessment very difficult. In many instances, attempts to determine the genetic weighting are also hampered by affected individuals being designated only as “consanguineous”, which in Arab populations could range from F ¼ 0.0156 to 0.125, or “nonconsanguineous” (F ¼ 0). Percentage consanguinity rates are often cited for children referred with a major congenital defect and compared with the equivalent cousin marriage rate in the

4 Endogamy and Consanguineous Marriage in Arab Populations

95

“general population”; the implication being that there is a causal relationship between consanguinity and the expression of the defect(s) under investigation. Unfortunately, in Arab populations with restricted effective population sizes and strongly preferential clan and tribal endogamy, this type of comparison may fall far short of the minimum requirement for rigorous case-control studies. Across generations, significant inter-clan, and more especially inter-tribal, genetic differences could have arisen via founder effect and drift, and been amplified by intra-familial marriage. Several studies directly compared the prevalence of major congenital defects in first-cousin and non-consanguineous progeny with, for example, an excess of 7.5% (Jaber et al. 1992) and 6.1% at F ¼ 0.0625 (Bromiker et al. 2004). The frequency of consanguineous marriages was higher among the parents of offspring with congenital malformations compared with the figures for the general population in virtually all studies reported among Arabs, including the UAE (Al-Gazali et al. 1995; Abdulrazzaq et al. 1997; Al Hosani et al. 2005; Dawodu et al. 2005), Kuwait (Madi et al. 2005), Oman (Sawardekar 2005; Patel 2007), Iraq (Hamamy and Al-Hakkak 1989; Mahdi 1992), Jordan (Khoury and Massad 2000; Obeidat et al. 2008), Egypt (Temtamy et al. 1998), Lebanon (Khlat 1988; Bittar 1998), Tunisia (Khrouf et al. 1986) and Saudi Arabia (El Mouzan et al. 2008). Elevated rates of consanguinity have been consistently reported for congenital heart defects, in particular septal defects (Gev et al. 1986; Bassili et al. 2000; Subramanyan et al. 2000; Becker et al. 2001; Nabulsi et al. 2003; Yunis et al. 2006; Seliem et al. 2007; El Mouzan et al. 2008), but for other heart defects such as transposition of the great vessels and coarctation of the aorta, the results varied between study centres, suggesting community-specific causes. Studies of neural tube defects also showed positive associations with consanguinity (Zlotogora 1997; Rajab et al. 1998; Al-Gazali et al. 1999; Murshid 2000; Asindi and Shehri 2001), but for oral and facial clefts, the data were less consistent, with both a positive association (Zlotogora 1997; Kanaan et al. 2008) and no association reported (al-Bustan et al. 2002; Aljohar et al. 2008).

Consanguinity and Chromosome Aberrations Following the initial report of an excess of Kuwaiti children with Down syndrome born to consanguineous parents, a mechanism involving a recessively expressed gene coding for non-disjunction of chromosome 21 was proposed (Alfi et al. 1980). Additional support for this hypothesis was obtained from Kuwait (Naguib et al. 1989) and other non-Arab countries, but a number of subsequent studies in Arab populations have been unable to identify the existence of a predisposing gene for trisomy 21 (Hamamy et al. 1990; Zlotogora 1997; Chaabouni 1999; El Mouzan et al. 2008). Some degree of uncertainty as to the possible predisposing role of consanguinity remains, given the high rates of Down syndrome reported in Gulf

96

A.H. Bittles and H.A. Hamamy

countries (Wahab et al. 2006), with conclusive results of either regional or global application dependent on large-scale epidemiological studies incorporating control for all appropriate non-genetic variables.

Consanguinity and Early Behavioural Disorders Many early studies into possible adverse effects of consanguinity focused on intellectual and developmental disability. In Arab populations, a significant but modest negative association was demonstrated between consanguinity and mean Intelligence Quotient (IQ) scores in children aged 10 years and 12 years, with the lowest mean scores and highest variance in the progeny of double first cousins (Bashi 1977). However, as previously discussed in other contexts, control for variables other than consanguinity was incomplete, and this observation also applies to studies that have reported an increased prevalence of speech disorders (Jaber et al. 1997b), learning and reading difficulties (Eapen et al. 1998; Abu-Rabia and Maroun 2005), hyperactivity (Al-sharbati et al. 2003), intellectual disability (Al-Ansari 1993; Farag et al. 1993; Salem et al. 1994; Temtamy et al. 1994; Abdulrazzaq et al. 1997), and recurrent febrile seizures (al-Eissa 1995) in firstcousin and other consanguineous progeny. Given the high overall rates of consanguineous marriages in Saudi Arabia, the comparatively low level of intellectual disability (8.9/1,000) reported in Saudi children aged 0–18 years was somewhat surprising (El-Hazmi et al. 2003). However, the authors noted that 83.2% of children with intellectual disability were not attending school, which may have resulted in under-enumeration of affected children. It is interesting that 70.9% of affected children were diagnosed with moderate to severe intellectual disability (El-Hazmi et al. 2003), which suggests both a high level of genetic causality and a significantly reduced life expectancy (Bittles et al. 2002b).

Consanguinity and Adult-Onset Disease Limited information has been published on the effects of consanguinity on adultonset disorders among Arabs, with no significant differences in the prevalence or the age of onset of diabetes mellitus, myocardial infarction, bronchial asthma or duodenal ulcer in “consanguineous” and non-consanguineous subjects (Jaber et al. 1997c). As each of these conditions can be categorized as a complex disease, with multiple potential interacting genes and environmental factors, and there was no control for socioeconomic status or clan/tribe endogamy, the outcome is not surprising. Similar caveats apply to the confusing picture reported for adult cancers, with a negative association between consanguinity and the overall risk of cancer (Denic et al. 2007), both a lower breast cancer rate in women with consanguineous parents

4 Endogamy and Consanguineous Marriage in Arab Populations

97

(Denic and Bener 2001) and no effect of parental consanguinity on the risk of breast cancer (Denic et al. 2005), and a hypothetical positive association between consanguinity and cervical cancer (Denic 2003). With life expectancy rapidly increasing in most Arab countries, cancer can clearly be identified as a disease where wellplanned and rigorously conducted epidemiological studies are urgently needed. Additional diagnostic problems may arise with adult behavioural disorders, and until discrete disease phenotypes can be reproducibly demonstrated, the lack of a significant association between consanguinity and schizophrenia reported in Sudan (Ahmed 1979) and Saudi Arabia (Chaleby and Tuma 1987), and the positive association of consanguinity with bipolar disease type 1 in Egypt (Mansour et al. 2009) merit acceptance with due caution. There is, however, convincing evidence of specific predisposing genes for Alzheimer disease in an Israeli Arab village isolate (Farrer et al. 2003), and it may be that studies that concentrate on individual families and discrete communities, rather than surveys organised on a national or regional basis, will prove to be the most rewarding in identifying individuals and communities at high risk of complex diseases.

Genetic Counselling for Consanguineous Couples Consanguinity is linked to ill-health, congenital malformations and intellectual disability in the minds of many lay people in Arab countries. Often there is no clear concept of how such conditions could be inherited, and the parents of affected children may have difficulty in accepting a genetic explanation for diseases that did not affect all of their children at the time of birth. Parents may also cite religious or folk beliefs to account for illness, with denial or resignation to the situation, and with divorce and remarriage accepted as possible solutions (Panter-Brick 1991; Hamamy and Bittles 2009). The belief that inherited disorders can arise only through cousin marriages on the paternal side of the family is also quite common, as Arab societies are patrilineal and in the minds of many people consanguinity may refer only to paternal blood relationships. Thus, during counselling, if a couple indicate that they are not related, it is imperative to specifically inquire about any shared biological relationships on their mothers’ sides of the families. In similar vein, families may opt to avoid cousin marriages when the disease is inherited as an autosomal dominant and are bewildered by the subsequent birth of an affected baby. Through school- and community-based education programmes and with improved, non-invasive diagnostic facilities, younger couples in many Arab countries are becoming increasingly aware of both the existence and the nature of genetic and congenital disorders, and strategies to prevent their occurrence (Hamamy and Alwan 1997; Alwan and Modell 1997). In Saudi Arabia, there is also strong evidence that university students are aware of the availability of premarital screening for genetic disorders (Al-Aama et al. 2008).

98

A.H. Bittles and H.A. Hamamy

Premarital Counselling Premarital genetic counselling is a particularly important strategy in Arab communities. Despite a Fatwa issued by the Islamic Jurisprudence Council of the Islamic World League that allowed abortion up to 120 days after conception in pregnancies involving a foetus with a severe disorder or malformation not amenable to therapy (Alkuraya and Kilani 2001; Albar 2002; Al Aqeel 2007), medical termination of pregnancy is unacceptable on cultural, religious and legal grounds in many Arab countries, Tunisia being an exception (Hessini 2007; Chaabouni-Bouhamed 2008). In part, the reluctance to accept medical termination of pregnancy may reflect the School of Islamic Jurisprudence to which an individual or community belongs (Hamamy and Bittles 2009), besides differences in their cultural background and community organisation (El-Hazmi 2007). In many Arab countries, there are still inadequate numbers of appropriately trained clinicians, midwives and nurses, genetic counsellors and laboratory personnel capable of providing full premarital genetic counselling coverage. In addition, inconsistencies in genetic counselling protocols can arise, and guidelines on premarital counselling for consanguineous couples are not generally available to health care providers (Hamamy and Bittles 2009). Thus, an accurate risk estimate cannot always be provided by a counsellor because of unknown population basal parameters. Premarital counselling is, nevertheless, an effective strategy for the prevention of autosomal recessive conditions and can be of particular help in reducing the numbers of arranged marriages of high-risk couples. Following premarital counselling, even if couples had decided to proceed with marriage to a relative, a large majority reported that the counselling had influenced their final decision to some degree (Shiloh et al. 1995). Given the close structure of Arab families, premarital counselling can also provide educational benefits to other members of the extended family.

Premarital Screening and Carrier Testing Community programmes for premarital screening to detect b-thalassaemia carriers have been initiated in a number of Arab countries, including Jordan, Saudi Arabia, Bahrain, UAE and Tunisia (Al Arrayed 2005; Al-Gazali et al. 2005; Al-Gazali et al. 2006; El-Hazmi 2006). Besides their intended purpose, the programmes have additionally served to increase public awareness about genetic diseases in general and specific disease prevention options, and have helped to reduce the fear that consanguinity is a major risk factor in such disorders. Problems can exist in terms of carrier testing, because of difficulty in diagnosing the condition in the family, including the lack of a molecular diagnosis, the refusal of affected family members to undergo testing, or the death of an affected person

4 Endogamy and Consanguineous Marriage in Arab Populations

99

before sampling could be arranged. In countries with a strong tradition of medical paternalism, there may also be an expectation on the part of counsellees and their families that directive advice will be given on issues such as the choice of a marriage partner, reproductive options and medical termination of pregnancy (WHO 2002; Rantanen et al. 2008; Hamamy and Bittles 2009). Unfortunately, failure to provide such advice may be interpreted by families as a sign of self-doubt and a lack of knowledge on the part of the clinician (Eldahdah et al. 2007). As consanguineous marriage is a strong cultural belief, cousin couples may face specific problems in conveying the diagnosis of their disorder to other family members whose own future marital arrangements may be jeopardised. Some couples also express dissatisfaction when offered a percentage risk estimate rather than a definitive diagnostic opinion (Hamamy and Bittles 2009). Even though a decision not to proceed with an arranged marriage is taken voluntarily by the family on the grounds of a high risk to future offspring, in communities with a strong patrilineal and patrilocal tradition some stigmatisation may be directed at the female partner (Raz and Atar 2004).

Conclusions With increasing urbanisation, improved access to higher education, professional employment and wider social networks, some decline in the occurrence of arranged and consanguineous marriages seems probable, especially in the Arab diaspora. As previously indicated, this trend is underway in many, but by no means all, Arab countries, and in Arab societies in general consanguineous marriage remains culturally and socially respected. Many Arab countries are experiencing demographic transitions, including a substantial reduction in infant mortality rates. Therefore, it is important that action be taken to improve the education and training of Arab health care providers on issues concerning consanguineous marriage. As infant mortality rates decline, the proportion of ill-health and early deaths due to genetic and congenital disorders increases (Bittles 1995, 2001), necessitating robust, comprehensive national programmes for the control of inherited disorders. The need for a better understanding of the potential association between consanguinity and genetic disorders is crucial in Arab countries where up to 50% of all marriages may be intra-familial (Table 4.1). To date, there has been limited appreciation of the very important role and consequences of clan and tribal subdivisions in the transmission of disease genes, resulting in an over-emphasis of the adverse role of consanguinity. In populations that are sub-divided along ethnic, religious, clan and tribal lines, a recessive founder or de novo mutation of chronic effect can rapidly increase in frequency within a particular community. Hence, with the strict patterns of clan and tribe endogamy that still apply in most Arab societies, a child may have inherited a specific recessive disorder irrespective of whether its parents are consanguineous or non-relatives (Zlotogora et al. 2006).

100

A.H. Bittles and H.A. Hamamy

Clear examples of community endogamy are seen in the distribution of tribespecific single-gene disorders in Saudi Arabia, for example, maple syrup urine disease, methylmalonic acidaemia, Sandhoff disease and Canavan disease (Ozand et al. 1990; Ozand et al. 1992; Rashed et al. 1994). Likewise, in an Israeli Arab village of 8,600 inhabitants, 19 mostly chronic autosomal recessive disorders have been identified with a prevalence of known and suspected AR disorders of 1/70 (Zlotogora et al. 2000). Different villages may exhibit quite different disease profiles, and the levels of village endogamy and consanguinity in some Arab communities are such that, even within a single village, it has been possible to identify and plot the origins and expansion patterns of four different b-globin mutations (Zlotogora et al. 2005), with no suggestion that this situation is unique to the study community. There is also a significantly increased chance that more than one detrimental recessive gene may be expressed in a family (Gordon et al. 1990), which can cause major difficulties in the provision of genetic counselling. Failure to recognise the significant role of population stratification in the prevalence and distribution patterns of genetic disorders has serious implications for genetic education and genetic counselling programmes. Subject to ethical considerations, in many cases the clan or tribe may be the most logical unit of population for interventions based on population screening and genetic counselling, since in effect each acts as a separate and largely discrete gene pool (Bittles 2008). This opinion is exemplified by the distribution pattern of b-thalassaemia in Oman. Of the estimated 185 major Omani tribes and sub-tribes, only some 10% of tribes are affected by b-thalassaemia and over 50% of all cases were diagnosed in a single tribe (Rajab and Patton 1997, 1999). Under these circumstances, the selection of subjects for case–control studies, association studies and clinical trials becomes critical. More specifically, in the investigation of consanguinity outcomes, comparisons drawn between the progeny of couples selected solely in terms of their current marital relationships will be of dubious validity unless they are members of the same tribe and clan (Bittles 2008). Conversely, where there is evidence of both consanguinity and family clustering, as in a study of male factor infertility in Lebanon (Inhorn et al. 2008), the associations drawn become much more persuasive. Given their particular family, clan and tribal structures, high rates of consanguineous marriage, large kindred size, and in many countries access to rapidly advancing health facilities, it can be expected that Arab populations will continue to be a major focus for research in medical and community genetics. The Arab Genetic Disease Database (Teebi et al. 2002) and the Catalogue of Transmission Genetics in Arabs established by the Centre for Arab Genomic Studies (Tadmouri et al. 2006) will greatly assist this progress and improve our knowledge of the underlying disease genomics and phenotypes. It is essential that equivalent emphasis be devoted to the investigation of the cultural, social and economic attributes of consanguineous unions, and the advantages that make them attractive marital options to families. With socioeconomic progress, the balance between the advantages and disadvantages of consanguinity is changing, and many infants with a genetic disorder who in earlier generations

4 Endogamy and Consanguineous Marriage in Arab Populations

101

would have died at a young age will survive into adulthood (Bittles 2001). A radical shift in disease impact of this nature places parents and the extended family in an invidious position with respect to future family marriage prospects and arrangements. There is evidence of the difficulties faced by families in arranging marriages with non-relatives, when multiple family members are affected by a serious inherited health disorder (Jalili and Smith 1988; Basel-Vanagaite et al. 2007). For such families, the only realistic option may be to resort to even higher rates of intrafamilial marriage, with the probability that equivalently increased numbers of affected offspring will be born. Against this background, the importance of genetic education and premarital genetic counselling programmes becomes increasingly obvious and effective in social, economic and health terms. Especially since it is probable that endogamy and consanguinity will be shown to play significant roles in the aetiology of many complex diseases, including common major disorders of adult-onset. It is imperative that programmes of this type, appropriate in design, structure and content to meet the needs of Arab communities, be developed and introduced as an issue of high priority.

References Abdulrazzaq YM, Bener A, Al-Gazali LI, Al-Khayat AI, Micallef R, Gaber T (1997) A study of possible deleterious effects of consanguinity. Clin Genet 51:167–173 Abolfotouh MA, Nofal LM, Safwat H (1990) Growth and nutritional status of preschool children attending the well-baby clinics. J Egypt Public Health Assoc 65:485–507 Abu-Rabia S, Maroun L (2005) The effect of consanguineous marriage on reading disability in the Arab community. Dyslexia 11:1–21 Ahmed AH (1979) Consanguinity and schizophrenia in Sudan. Brit J Psychiat 134:635–636 Al Aqeel A (2007) Islamic ethical framework for research into and prevention of genetic diseases. Nat Gen 39:1293–1298 Al Arrayed S (1994) Consanguinity in the state of Bahrain. In: El-Hazmi MAF (ed) Medical genetics in the setting of Middle Eastern populations. King Abdul Aziz City for Science and Technology, Riyadh, pp 97–101 Al Arrayed S (2005) Campaign to control genetic blood diseases in Bahrain. Community Genet 8:52–55 Al Hosani H, Salah M, Abu-Zeid H, Farag HM, Saade D (2005) The national congenital anomalies register in the United Arab Emirates. East Mediterr Health J 11:690–699 al Husain M, al Bunyan M (1997) Consanguineous marriages in a Saudi population and the effect of inbreeding on prenatal and postnatal mortality. Ann Trop Paediatr 17:155–160 Al-Aama JY, Al-Nabulsi BK, Alyousef MA, Asiri NA, Al-Blewi M (2008) Knowledge regarding the national premarital screening program among university students in western Saudi Arabia. Saudi Med J 29:1649–1653 al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse health effects on the offspring. J Commun Health 23:75–83 al-Ansari A (1993) Etiology of mild mental retardation among Bahraini children: a communitybased case control study. Ment Retard 31:140–143 Al-Awadi S, Moussa MA, Naguib KK, Farag TI, Teebi AS, el-Khalifa M, el-Dossary L (1985) Consanguinity among the Kuwaiti population. Clin Genet 27:483–486

102

A.H. Bittles and H.A. Hamamy

Al-Awadi SA, Naguib KK, Moussa MA, Farag TI, Teebi AS, el-Khalifa MY (1986) The effect of consanguineous marriages on reproductive wastage. Clin Genet 29:384–388 Albar M (1999) Counselling about genetic disease: an Islamic perspective. East Mediterr Health J 5:1129–1133 Albar M (2002) Ethical considerations in the prevention and management of genetic disorders with special emphasis on religious considerations. Saudi Med J 23:627–632 al-Bustan SA, el-Zawahri MM, al-Adsani AM, Bang RL, Ghunaim I, Maher BS, Weinberg S, Marazita ML (2002) Epidemiological and genetic study of 121 cases of oral clefts in Kuwait. Orthod Craniofac Res 5:154–160 al-Eissa YA (1995) Febrile seizures: rate and risk factors of recurrence. J Child Neurol 10:315–319 al-Eissa YA, Ba’Aqeel HS, Haque KN (1991) Low birthweight in Riyadh, Saudi Arabia: incidence and risk factors. Ann Trop Paediatr 11:75–82 Alfi O, Chang R, Azen S (1980) Evidence for genetic control of nondisjunction in man. Am J Hum Genet 32:477–483 Al-Gazali LI (1998) A genetic aetiological survey of severe childhood deafness in the United Arab Emirates. J Trop Ped 44:157–160 Al-Gazali LI, Dawodu AH, Sabarinathan K, Varghese M (1995) The profile of major congenital abnormalities in the United Arab Emirates (UAE) population. J Med Genet 32:7–13 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micaleff R, Al-Khayat GT (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali LI, Sztriha L, Dawodu A, Bakir M, Varghese M, Varady E, Scorer J, Abdulrazzaq YM, Bener A, Padmanabhan R (1999) Pattern of central nervous system anomalies in a population with a high rate of consanguineous marriages. Clin Genet 55:95–102 Al-Gazali LI, Alwash R, Abdulrazzaq YM (2005) United Arab Emirates: communities and community genetics. Community Genet 8:186–196 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. Brit Med J 333:831–834 Al-Idrissi I, Al-Kaff AS, Senft SH (1992) Cumulative incidence of retinoblastoma in Riyadh, Saudi Arabia. Ophthal Paediat Genet 13:9–12 Aljohar A, Ravichandran K, Subhani S (2008) Pattern of cleft lip and palate in hospital-based population in Saudi Arabia: retrospective study. Cleft Palate Craniofac J 45:592–596 Alkuraya FS, Kilani RA (2001) Attitude of Saudi families affected with hemoglobinopathies towards prenatal screening and abortion and the influence of religious ruling (Fatwa). Prenat Diagn 21:448–461 Al-Salem M, Rawashdeh N (1993) Consanguinity in North Jordan: prevalence and pattern. J Biosoc Sci 25:553–556 Al-sharbati MM, Al-Hussaini AA, Anthony SX (2003) Profile of child and adolescent psychiatry in Oman. Saudi Med J 24:391–395 Al-Thakeb FT (1985) The Arab family and modernity: evidence from Kuwait. Curr Anthropol 26:575–580 Alwan A, Modell B (1997) Community control of genetic and congenital disorders, EMRO Technical Publications 24. World Health Organization, Alexandra Alwan A, Modell B (2003) Recommendations for introducing genetics services in developing countries. Nat Rev Genet 4:61–68 Asindi A, Shehri A (2001) Neural tube defects in the Asir region of Saudi Arabia. Ann Saudi Med 21:26–29 Assaf S, Khawaja M (2009) Consanguinity trends and correlates in the Palestinian Territories. J Biosoc Sci 41:107–124 Assaf S, Khawaja M, DeJong J, Mahfoud Z, Yunis K (2009) Consanguinity and reproductive wastage in the Palestinian territories. Paediatr Perinat Epidemiol 23:107–115 Attias J, Al-Masri M, Abukader L, Cohen G, Merlov P, Pratt H, Othman-Jebara R, Aber P, Raad F, Noyek A (2006) The prevalence of congenital and early-onset hearing loss in Jordanian and Israeli infants. Int J Audiol 45:528–536

4 Endogamy and Consanguineous Marriage in Arab Populations

103

Basel-Vanagaite L, Taub E, Halpern GJ, Drasinover V, Magal N, Davodov B, Zlotogora J, Shohat M (2007) Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel. Eur J Hum Genet 15:250–253 Bashi J (1977) Effects of inbreeding on cognitive performance. Nature 266:440–442 Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A (2000) Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol 16:805–814 Becker SM, Al Halees Z, Molina C, Paterson RM (2001) Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet 99:8–13 Benalle`gue A, Kedji F (1984) Consanguinite´ et sante´ publique: Etude alge´rienne. Arch Fr Pediatr 41:435–440 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatari population. J Biosoc Sci 38:239–246 Bener A, Abdulrazzaq YM, Al-Gazali LI, Micallef R, Al-Khayat AI, Gaber T (1996) Consanguinoity and associated socio-demographic factors in the United Arab Emirates. Hum Hered 46:256–264 Bittar Z (1998) Major congenital malformations presenting in the first 24 hours of life in 3865 consecutive births in south of Beirut. Incidence and pattern. J Med Liban 46:256–260 Bittles AH (1995) When cousins marry: consanguineous marriage in the Middle East. Perspect Hum Biol 1:71–83 Bittles AH (2001) Consanguinity and its relevance to clinical genetics. Clin Genet 60:89–98 Bittles AH (2005) Endogamy, consanguinity and community disease profiles. Commun Genet 8:17–20 Bittles AH (2008) A community genetics perspective on consanguineous marriage. Commun Genet 11:324–330 Bittles AH, Grant JC, Sullivan S, Hussain R (2002a) Does inbreeding lead to decreased human fertility? Ann Hum Biol 29:111–131 Bittles AH, Petterson BA, Sullivan S, Hussain R, Glasson EJ, Montgomery PD (2002b) The influence of intellectual disability on life expectancy. J Gerontol A: Biol Sci Med Sci 57A:M470–M472 Bromiker R, Glam-Baruch M, Gofin R, Hammerman C, Amitai Y (2004) Association of parental consanguinity with congenital malformations among Arab newborns in Jerusalem. Clin Genet 66:63–66 Chaabouni H (1999) E´tude epidemiologique et genetique de la trisomie 21 en Tunisie. Tunisie Me´ 77:407–414 Chaabouni-Bouhamed H (2008) Tunisia: communities and community genetics. Community Genet 11:313–323 Chaleby K (1988) Traditional Arabian marriages and mental health in a group of outpatient Saudis. Acta Psychiatr Scand 77:139–142 Chaleby K, Tuma TA (1987) Cousin marriages and schizophrenia in Saudi Arabia. Brit J Psychiatr 150:547–549 Christianson A, Howson C, Modell B (2006) Global report on birth defects. The hidden toll of dying and disabled children. March of Dimes Birth Defects Foundation, White Plains, NY COSIT, Central Organization for Statistics and Information Technology (2005) Iraq living conditions survey 2004, vol. II: Analytical Report. Ministry of Planning and Development Cooperation, Baghdad Dawodu A, Al-Gazali L, Varady E, Varghese M, Nath K, Rajan V (2005) Genetic contribution to high neonatally lethal malformation rate in the United Arab Emirates. Community Genet 8:31–34 Denic S (2003) Consanguinity as a risk factor for cervical carcinoma. Med Hypoth 60:321–324 Denic S, Bener A (2001) Consanguinity decreases risk of breast cancer – cervical cancer unaffected. Brit J Cancer 85:1675–1679 Denic S, Bener A, Sabri S, Khatib F, Milenkovic J (2005) Parental consanguinity and risk of breast cancer: a population-based case-control study. Med Sci Monit 11:CR415–CR419

104

A.H. Bittles and H.A. Hamamy

Denic S, Frampton C, Nicholls MG (2007) Risk of cancer in an inbred population. Cancer Detect Prev 31:263–269 Eapen V, Al-Gazali L, Bin-Othman S, Abou-Saleh M (1998) Mental health problems among schoolchildren in United Arab Emirates: prevalence and risk factors. J Am Acad Child Adolesc Psychiatr 37:880–886 El Mouzan MI, Al Salloum AA, Al Herbish AS, Qurachi MM, Al Omar AA (2008) Consanguinity and major genetic disorders in Saudi children: a community-based cross-sectional study. Ann Saudi Med 28:169–173 El-Badramany MH, Farag TI, Al-Awadi SA, Teebi AS (1997) Psychosocial and medical aspects of genetic counseling among Arabs: the example of Kuwait. In: Teebi AS, Farag TI (eds) Genetic disorders among Arab populations, vol 1. Oxford University Press, New York, pp 474–486 Eldahdah L, Ormond K, Nassar A, Khalil T, Zahed L (2007) Outcome of chromosomally abnormal pregnancies in Lebanon: obstetricians’ roles during and after prenatal diagnosis. Prenat Diagn 27:525–534 Elder MJ, De Cock R (1993) Childhood blindness in the West Bank and the Gaza Strip: prevalence, aetiology and hereditary factors. Eye 7:580–583 El-Hazmi MA (2006) Pre-marital examination as a method of prevention from blood genetic disorders. Community views. Saudi Med J 27:1291–1295 El-Hazmi M (2007) Islamic teachings of bioethics in relation to the practice of medical genetics. Saudi Med J 28:1781–1787 El-Hazmi M, Al-Swailem AA, Warsy A, Al-Swailem AM, Sulaimani R, Al-Meshari A (1995) Consanguinity among the Saudi Arabian population. J Med Genet 32:623–626 El-Hazmi M, Al-Swailem AA, Al-Mosa NA, Al-Jarallah AA (2003) Prevalence of mental retardation among children in Saudi Arabia. East Mediterr Health J 9:6–11 El-Islam MF (1976) Intergenerational conflict and the young Qatari neurotic. Ethos 4:45–56 El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Qurachi MM, Al-Omar AA (2007) Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi Med J 28:1881–1884 Farag TI, Al-Awadi SA, el-Badramany MH, Aref MA, Kasrawi B, Krishna Murthy DS et al (1993) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44:329–334 Farrer LA, Bowirrat A, Friedland RP, Waraska K, Korczyn AD, Baldwin CT (2003) Identification of multiple loci for Alzheimer loci in a consanguineous Israeli-Arab community. Hum Mol Genet 12:415–422 Freundlich E, Hino N (1984) Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci 20:1035–1038 Gev D, Roguin N, Freundlich E (1986) Consanguinity and congenital heart disease in the rural Arab population in northern Israel. Hum Hered 36:213–217 Gordon CR, Bar-Ziv Y, Frydman M, Zlotogora J, Gadoth N (1990) Mucolipidosis III and BardetBiedl syndrome in the same family: diagnostic pitfalls. Brain Dev 12:403–407 Gunaid AA, Ali Hummad N, Tamim KA (2004) Consanguineous marriage in the capital city Sana’a, Yemen. J Biosoc Sci 36:111–121 Hafez M, El-Tahan H, Awadalla M, El-Khayat H, Abdel-Gafar A, Ghoneim M (1983) Consanguineous matings in the Egyptian population. J Med Genet 20:58–60 Hamamy H, Al-Hakkak Z (1989) Consanguinity and reproductive health in Iraq. Hum Hered 39:271–275 Hamamy H, Alwan A (1994) Hereditary disorders in the Eastern Mediterranean Region. Bull World Health Organ 72:45–154 Hamamy H, Alwan A (1997) Genetic disorders and congenital abnormalities: strategies for reducing the burden in the region. East Mediterr Health J 3:123–132 Hamamy H, Bittles AH (2009) Genetic clinics in Arab communities: meeting individual, family and community needs. Public Health Genomics 12:30–40 Hamamy HA, al-Hakkak ZS, al-Taha S (1990) Consanguinity and the genetic control of Down syndrome. Clin Genet 37:24–29

4 Endogamy and Consanguineous Marriage in Arab Populations

105

Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Hamamy H, Al-Hait S, Alwan A, Ajlouni K (2007a) Jordan: communities and community genetics. Commun Genet 10:52–60 Hamamy HA, Masri AT, Al-Hadidy AM, Ajlouni KM (2007b) Consanguinity and genetic disorders. Profile from Jordan. Saudi Med J 28:1015–1017 Hammami A, Chalbi N, Ben Abdallah M, Elgazzeh M (2005) Effects of consanguinity and social factors on mortality and fertility in Mauritania. Tunis Me´d 83:221–226 Hessini L (2007) Abortion and Islam: policies and practice in the Middle East and North Africa. Reprod Health Matters 15:1–10 Hoodfar E, Teebi AS (1996) Genetic referrals of Middle Eastern origin in a western city: inbreeding and disease profile. J Med Genet 33:212–215 Hussain R (1999) Community perceptions of reasons for preference for consanguineous marriages in Pakistan. J Biosoc Sci 31:449–461 Hussien FH (1971) Endogamy in Egyptian Nubia. J Biosoc Sci 3:251–257 Inhorn MC, Kobeissi L, Nassar Z, Lakkis D, Fakih MH (2008) Consanguinity and family clustering of male factor infertility in Lebanon. Fertil Steril (Epub ahead of print) Jaber L, Merlob P, Bu X, Rotter JI, Shohat M (1992) Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community. Am J Med Genet 44:1–6 Jaber L, Shohat T, Halpern GJ (1996) Demographic characteristics of the Israeli Arab community in connection with consanguinity. Isr J Med Sci 32:1286–1289 Jaber L, Merlob P, Gabriel R, Shohat M (1997a) Effects of consanguineous marriage on reproductive outcome in an Arab community in Israel. J Med Genet 34:1000–1002 Jaber L, Nahmani A, Shohat M (1997b) Speech disorders in Israeli Arab children. Isr J Med Sci 33:663–665 Jaber L, Shohat T, Rotter JI, Shohat M (1997c) Consanguinity and common adult diseases in Israeli Arab communities. Am J Med Genet 70:346–348 Jaber L, Halpern GJ, Shohat T (2000) Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin Genet 58:106–110 Jalili IK, Smith NJD (1988) A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet 25:738–740 Joseph SE (2007) “Kissing coins”: consanguineous marriage and early mortality in a reproductive isolate. Curr Anthropol 48:756–764 Jurdi R, Saxena PC (2003) The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries. J Biosoc Sci 35:1–13 Kanaan ZM, Mahfouz R, Tamim H (2008) The prevalence of consanguineous marriages in an underserved area in Lebanon and its association with congenital anomalies. Genet Test 12:367–372 Kerkeni E, Kerkeni E, Monastiri K, Saket B, Guediche MN, Ben Cheikh H (2007) Interplay of socio-economic factors, consanguinity, fertility, and offspring mortality in Monastir, Tunisia. Croat Med J 48:701–707 Khabori MA, Patton MA (2008) Consanguinity and deafness in Omani children. Int J Audiol 47:30–33 Khawaja M, Tewtel-Salem M (2004) Agreement between husband and wife reports of domestic violence: evidence from poor refugee communities in Lebanon. Int J Epidemiol 33:526–533 Khlat M (1985) Consanguineous marriages in Beirut: time trends, spatial distribution. Soc Biol 35:324–330 Khlat M (1988) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Khlat M (1989) Inbreeding effects on fetal growth in Beirut, Lebanon. Am J Phys Anthropol 80:481–484 Khlat M (1997) Endogamy in the Arab world. In: Teebi AS, Farag TI (eds) Genetic disorders among Arab populations, 1st edn. Oxford University Press, New York, pp 63–80

106

A.H. Bittles and H.A. Hamamy

Khlat M, Halabi S, Khudr A, Der Kaloustian VM (1986) Perception of consanguineous marriages and their genetic effects among a sample of couples from Beirut. Am J Med Genet 25:299–306 Khoury SA, Massad D (1992) Consanguineous marriage in Jordan. Am J Med Genet 43:769–775 Khoury SA, Massad D (2000) Consanguinity, fertility, reproductive wastage, infant mortality and congential malformations in Jordan. Saudi Med J 21:150–154 Khrouf N, Spang R, Podgorna T, Miled SB, Moussaoui M, Chibani M (1986) Malformations in 10, 000 consecutive births in Tunis. Acta Pediatr Scand 75:534–539 Khuri FI (1970) Parallel cousin marriage reconsidered: a Middle Eastern practice that nullifies the effects of marriage on the intensity of familial relationships. Man 5:597–618 Klat M, Khudr A (1986) Religious endogamy and consanguinity in marriage patterns in Beirut, Lebanon. Soc Biol 33:138–145 Lamdouar Bouazzaoui N (1994) Consanguinite´ et sante´ publique au Maroc. Bull Acad Natl Me´d 178:1013–1027 Maatouk F, Laamri D, Argoubi K, Ghedra H (1995) Dental manifestations of inbreeding. J Clin Pediatr Dent 19:305–306 Madi SA, Al-Naggar RL, Al-Awadi SA, Bastaki LA (2005) Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait. East Mediterr Health J 11:700–706 Mahdi A (1992) Consanguinity and its effect on major congenital malformations. Iraqi Med J 40–42:70–176 Mansour H, Klei L, Wood J, Talkowski M, Chowdari K, Fathi W et al (2009) Consanguinity associated with increased risk for bipolar 1 disorder in Egypt. Am J Med Genet Part B: Neuropsychiatr Genet 150:879–885 Maziak W, Asfar T (2003) Physical abuse in low-income women in Aleppo, Syria. Health Care Women Int 24:313–326 Mokhtar MM, Abdel-Fattah MM (2001) Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 17:559–565 Mumtaz G, Tamim H, Kanaan M, Khawaga M, Khogali M, Wakim G, Yunis K (2007) Effect of consanguinity on birth weight for gestational age in a developing country. Am J Epidemiol 165:742–752 Murshid WR (2000) Spina bifida in Saudi Arabia: is consanguinity among the parents a risk factor? Pediatr Neurosurg 32:10–12 Nabulsi A (1995) Mating patterns of the Abbad tribe in Jordan. Soc Biol 42:162–174 Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, Bitar FF (2003) Parental consanguinity and congenital heart malformations in a developing country. Am J Med Genet A 116A:342–347 Naguib K, Al-Awai S, Moussa M, Farag T, Teebi A (1989) Effect of parental age, birth order and consanguinity on nondisjunction in the population of Kuwait. J Kuwait Med Assoc 23:37–43 Nelson J, Smith M, Bittles AH (1997) Consanguineous marriage and its clinical consequences in migrants to Australia. Clin Genet 52:142–146 Obeidat BR, Khader YS, Amarin ZO, Kassawneh M, Al Omari M (2008) Consanguinity and adverse pregnancy outcomes: the north of Jordan experience. Matern Child Health J [E-publication] Ozand PT, Gascon GC, al Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inherit Dis 13:849–861 Ozand PT, Devol EB, Gascon GC (1992) Neuro-metabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Panter-Brick C (1991) Parental responses to consanguinity and genetic disease in Saudi Arabia. Soc Sci Med 33:1295–1302 Patel PK (2007) Profile of major congenital anomalies in the Dhahira region, Oman. Ann Saudi Med 27:106–111

4 Endogamy and Consanguineous Marriage in Arab Populations

107

Pedersen J (2002) The influence of consanguineous marriage on infant and child mortality among Palestinians in the West Bank and Gaza, Jordan, Lebanon and Syria. Community Genet 5:178–181 Radovanovic Z, Shah N, Behbehani J (1999) Prevalence and social correlates of consanguinity in Kuwait. Ann Saudi Med 19:206–210 Rajab A, Patton MA (1997) Major factors determining the frequencies of hemoglobinopathies in Oman. Am J Med Genet 71:240–242 Rajab A, Patton MA (1999) Analysis of the population structure in Oman. Community Genet 2:23–25 Rajab A, Patton MA (2000) A study of consanguinity in the Sultanate of Oman. Ann Hum Biol 27:321–326 Rajab A, Vaishnav A, Freeman NV, Patton MA (1998) Neural tube defects and congenital hydrocephalus in the Sultanate of Oman. J Trop Pediatr 44:300–303 Rantanen E, Hietala M, Kristoffersson U, Nippert I, Schmidtke J, Swequeiros J, K€a€ari€ainen H (2008) What is ideal genetic counselling? A survey of current international guidelines. Eur J Hum Genet 16:445–452 Rashed M, Ozand PT, Al Aqeel A, Gascon GG (1994) Experience of King Faisal Hospital and Research Centre with Saudi organic acid disorders. Brain Dev 16(Suppl):1–6 Raz AE, Atar M (2004) Cousin marriage and premarital carrier matching in a Bedouin community in Israel: attitudes, service development and educational intervention. J Fam Plann Reprod Health Care 30:49–51 Riou SE, Younsi C, Chaabouni H (1989) Consanguinite´ dans la population du Nord de la Tunisie. Tunis Me´d 67:167–172 Saad FA, Jauniaux E (2002) Recurrent early pregnancy loss and consanguinity. Reprod Biomed Online 5:167–170 Saedi-Wong S, al-Frayh AR (1989) Effects of consanguineous matings on anthropometric measurements of Saudi newborn infants. Fam Pract 6:217–220 Saedi-Wong S, al-Frayh AR, Wong HYH (1989) Socio-economic epidemiology of consanguineous mating in the Saudi Arabian population. J Asian Afr Stud 24:247–251 Saha N, El Sheikh FS (1988) Inbreeding levels in Khartoum. J Biosoc Sci 20:333–336 Saha N, Hamad RE, Mohamed S (1990) Inbreeding effects on reproductive outcome in a Sudanese population. Hum Hered 40:208–212 Salem K, Lashin S, El Dib A (1994) Consanguinity and mental retardation. Med J Cairo Univ 62 (Suppl):177–186 Sawardekar KP (2005) Profile of major congenital malformations at Nizwa Hospital, Oman: 10-year review. J Paediatr Child Health 41:323–330 Seliem MA, Bou-Holaigah IH, Al-Sannaa N (2007) Influence of consanguinity on the pattern of familial aggregation of congenital cardiovascular anomalies in an outpatient population: studies from the eastern province of Saudi Arabia. Community Genet 10:27–31 Sharkia R, Zaid M, Athamna A, Cohen D, Azem A, Zalan A (2007) The changing pattern of consanguinity in a selected region of the Israeli Arab community. Am J Hum Biol 20:72–77 Shiloh S, Reznik H, Bat-Miriam-Katznelson M, Goldman B (1995) Pre-marital genetic counselling to consanguineous couples: attitudes, beliefs and decisions among counselled, noncounselled and unrelated couples in Israel. Soc Sci Med 41:1301–1310 Stern GH (1939) Marriage in early Islam. London, The Royal Asiatic Society, pp 165–166 Subramanyan R, Joy J, Venugopalan SA, Al Khusaiby SM (2000) Incidence and spectrum of congenital heart disease in Oman. Ann Trop Paediatr 20:337–340 Tadmouri GO, Al Ali MT, Al-Haj Ali S, Al Khaja N (2006) CTGA: the database for genetic disorders in Arab populations. Nucleic Acids Res 34(Database issue):D602–606 Tamim H, Khogali M, Beydoun H, Melki I, Yunis K (2003) Consanguinity and apnea of prematurity. Am J Epidemiol 158:942–946 Teebi A (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233

108

A.H. Bittles and H.A. Hamamy

Teebi AS, Teebi SA, Porter CJ, Cuticchia AJ (2002) Arab genetic disease database (AGDDB): a population-specific clinical and mutation database. Hum Mutat 19:615–621 Temtamy SA, Kandil MR, Demerdash AM, Hassan WA, Meguid NA, Afifi HH (1994) An epidemiological/genetic study of mental subnormality in Assiut Governorate, Egypt. Clin Genet 46:347–351 Temtamy S, Abdel Meguid N, Mazen I, Ismail S, Kassem N, Bassiouni R (1998) A genetic epidemiological study of malformations at birth in Egypt. East Mediterr Health J 4:252–259 Tucker JE (1988) Marriage and family in Nablus, 1720–1856: toward a history of Arab marriage. J Fam Hist 13:165–179 Vardi-Saliternik R, Friedlander Y, Cohen T (2002) Consanguinity in a population sample of Israeli Muslim Arabs, Christian Arabs and Druze. Ann Hum Biol 29:422–431 Wahab AA, Bener A, Teebi AS (2006) The incidence patterns of Down syndrome in Qatar. Clin Genet 69:360–362 WHO (2002) Advisory committee on health research, genomics and world health. World Health Organization, Geneva Wong SS, Anokute CC (1990) The effect of consanguinity on pregnancy outcome in Saudi Arabia. J R Soc Health 110:146–147 Yunis K, Mumtaz G, Bitar F, Chamseddine F, Kassar M, Rashkidi J et al (2006) Consanguineous marriage and congenital heart defects: a case-control study in the neonatal period. Am J Med Genet A 140:1524–1530 Zakzouk S, El-Sayed Y, Bafaqeeh SA (1993) Consanguinity and hereditary hearing impairment among Saudi population. Ann Saudi Med 13:447–450 Zaoui S, Bie´mont C (2002) Fre´quence et structure des mariages consanguins dans le re´gion de Tlemcen (Ouest alge´rien). Cahiers Sante´ 12:289–295 Zlotogora J (1997) Genetic disorders among Palestinian Arabs: 1. Effects of consanguinity. Am J Med Genet 68:472–475 Zlotogora J, Shalev S, Habiballah H, Barjes S (2000) Genetic disorders among Palestinian Arabs: 3. Autosomal recessive in a single village. Am J Med Genet 92:343–345 Zlotogora J, Habiballa H, Odatalla A, Barges S (2002) Changing family structure in a modernizing society: a study of marriage patterns in a single Muslim village in Israel. Am J Hum Biol 14:680–682 Zlotogora J, Hujerat Y, Zalman L, Barges S, Filon D, Koren A, Shalev SA, Chakravarti A (2005) The origin and expansion of four different beta globin mutations in a single Arab village. Am J Hum Biol 17:659–661 Zlotogora J, Hujerat Y, Barges S, Shalev SA, Chakravti A (2006) The fate of 12 recessive mutations in a single village. Ann Hum Genet 71:202–208

Part III Selected Disease Entities Prevalent Among the Arabs

Chapter 5

Familial Mediterranean Fever and Other Autoinflammatory Disorders Hatem El-Shanti and Hasan Abdel Majeed

Autoinflammatory diseases are a group of disorders characterized by seemingly unprovoked inflammation in the absence of high-titer autoantibodies or antigenspecific T-cells (Stojanov and Kastner 2005). The autoinflammatory diseases include the hereditary periodic fever syndromes and are thought to be due to disturbances in the regulation of the innate immunity (Kastner 2005). Familial Mediterranean Fever (FMF) is the archetypal hereditary periodic fever syndrome and autoinflammatory disease. Other disorders include tumor necrosis factor receptorassociated periodic syndrome (TRAPS); hyperimmunoglobulinemia D with periodic fever syndrome (Hyper-IgD); pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; the cryopyrinopathies: familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous and articular syndrome, or CINCA syndrome); and chronic recurrent multifocal osteomyelitis (McGonagle and McDermott 2006; Milhavet et al. 2008).

Familial Mediterranean Fever (FMF, MIM 249100; MEFV, MIM 608107) FMF is characterized by recurrent self-limiting episodes of fever and painful polyserositis affecting mainly the peritoneum, pleura, and synovium. It was first described as a distinct disease entity, under the name of benign paroxysmal peritonitis, in 1945 (Siegal 1945). The international medical community adopted the name FMF, as suggested by the team led by Heller (Sohar et al. 1961), although the disorder had several other names including recurrent polyserositis, recurrent H. El-Shanti (*) Director, Shafallah Medical Genetics Center, Doha, Qatar Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA email: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_5, # Springer-Verlag Berlin Heidelberg 2010

111

112

H. El-Shanti and H.A. Majeed

hereditary polyserositis, periodic disease and periodic peritonitis. FMF is an autosomal recessive disorder (Sohar et al. 1961), with considerable prevalence in specific ethnic groups, namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs. The impact of FMF on patients is determined mainly by the presence or absence of its most deleterious complication, amyloidosis (Heller et al. 1961). However, the burden of the febrile and painful episodes as manifested in loss of school or work days, repetitive suffering, and unnecessary hospitalization, and surgery (Kasifoglu et al. 2009) is also substantial.

Clinical Aspects The classic clinical picture consists of recurrent febrile episodes that are usually of acute onset, variable frequency, sometimes without a recognized triggering factor but often occurring with menstruation, emotional stress, or strenuous physical activity (Samuels et al. 1998). These febrile episodes are short-lived, lasting 1–3 days but may last 4 days or longer, and usually abort abruptly. The episodes are often accompanied by pain due to peritonitis, pleuritis, or acute synovitis of large joints. The frequency of the attacks varies from once per week to long periods of remission. Over the course of the lifelong illness, an affected individual will probably experience several forms of the febrile and painful episodes, but the recurrence of one type over many years is common (Sohar et al. 1967). During the attack there is neutrophilia and a brisk acute-phase response, and histologically there is a massive sterile influx of polymorphonuclear leukocytes (PMNs) into the affected site (Sohar et al. 1967). Between attacks, patients feel well, although biochemical evidence for inflammation may persist (Kastner 2005). The episodes start, most commonly during childhood, with more than 80% of patients presenting before the age of 20 years and a very few after the age of 40 years (Barakat et al. 1986; Padeh 2005; Sohar et al. 1967). The painful abdominal (peritoneal) attack is the most frequent association with the febrile episode. It is experienced by the majority of patients (Padeh 2005) and is reported in about 50% of patients as the first symptom (Sohar et al. 1967). The abdominal pain can be diffuse or localized, ranging in intensity from mild bloating to real peritonitis with guarding, rigidity, tenderness, and rebound tenderness (Padeh 2005; Samuels et al. 1998). The organization of the peritoneal inflammatory exudate may result in fibrous adhesions and may give rise to mechanical intestinal obstruction (Michaeli et al. 1966). These adhesions are probably the cause of sterility in some women affected by FMF (Ehrenfeld et al. 1987; Ismajovich et al. 1973; Mijatovic et al. 2003; Rabinovitch et al. 1992). The articular involvement in FMF episodes is the second-most common association with the fever. The articular inflammation presents as an abrupt onset of acute arthritis, accompanied by high fever, redness, warmth, tenderness, and swelling (Barakat et al. 1986; Majeed and Rawashdeh 1997; Ozer et al. 1971; Schwabe and Peters 1974). It is often monoarticular and commonly affects the large joints of the

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

113

lower limbs. It usually lasts longer than other FMF manifestations and subsides gradually rather than abruptly and leaves no residual damage (Padeh 2005). The synovial fluid is sterile but contains large numbers of neutrophils (Heller et al. 1966; Sohar et al. 1967). Rarely, FMF patients develop protracted arthritis, synovitis, muscle atrophy, erosions, and juxta-articular osteoporosis (Heller et al. 1966; Salai et al. 1997; Sneh et al. 1977; Yalcinkaya et al. 1997). Non-steroidal antiinflammatory drugs (NSAIDs) are generally effective in FMF arthritis. Pleural attacks occur in 15–30% of FMF patients (Saatci et al. 1997). Usually, the attacks present as an acute one-sided febrile pleuritis resembling the peritoneal attacks in their abrupt onset, unpredictable occurrence, and abrupt and rapid resolution (Majeed et al. 1999; Ozer et al. 1971; Sohar et al. 1967). Breathing may be painful, there may be diminished breath sounds on auscultation, and there may be radiological evidence of pleural effusion or lung collapse. The characteristic skin lesion is the erysipelas-like erythema which may sometimes accompany the arthritis (Azizi and Fisher 1976; Sohar et al. 1967). Histological examination of the lesions reveals edema of the dermis, sparse perivascular infiltrate without vasculitis and C3 deposits seen by immunofluorescence (Barzilai et al. 2000). Muscle pain occurs in about 10% of FMF patients and is usually mild and confined to the lower extremities (Padeh 2005). It may be precipitated by physical exertion or prolonged standing, lasts few hours to 1 day and subsides with rest or NSAIDs (Majeed et al. 2000a). Rarely, a syndrome of protracted febrile myalgia may develop (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi et al. 2000). It is characterized by severe debilitating myalgia, prolonged fever, abdominal pain without peritoneal involvement, a high erythrocyte sedimentation rate (ESR), and hyperglobulinemia. If treated with NSAIDs alone, the syndrome may last for up to 8 weeks, but it will subside promptly if treated with corticosteroids (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi et al. 2000). Acute inflammation of the tunica vaginalis in FMF patients may mimic torsion of the testis and will present as a unilateral tender scrotal swelling (Eshel et al. 1988, 1994; Majeed et al. 2000c). This is not surprising as the tunica vaginalis is structurally part of the peritoneum. However, these episodes usually do not occur with an acute peritoneal attack and are usually unilateral (Majeed et al. 1999). Fever and pain are always present with these self-limiting and short-lived acute scrotum episodes. Uncommon manifestations include headache (Buskila et al. 1997; Gedalia and Zamir 1993), meningeal irritation and increased CSF proteins and cells (Barakat et al. 1988; Gedalia and Zamir 1993; Karachaliou et al. 2005; Schwabe and Monroe 1988; Vilaseca et al. 1982), impaired female fertility (Ehrenfeld et al. 1987; Ismajovich et al. 1973; Mijatovic et al. 2003), pericarditis (Kees et al. 1997), and transient microscopic hematuria. Vasculitides are found in FMF at a higher frequency than in the general population. Henoch–Schonlein purpura (HSP) has been reported in 3–11 % of FMF patients (Flatau et al. 1982; Gershoni-Baruch et al. 2003; Majeed et al. 1990; Schlesinger et al. 1985). A study identified more than expected homozygous and

114

H. El-Shanti and H.A. Majeed

heterozygous FMF mutations among children presenting with HSP (GershoniBaruch et al. 2003). Polyarteritis nodosa also occurs more commonly in patients with FMF (Sachs et al. 1987). Various types of glomerulonephritis have been reported in FMF (Said et al. 1992), but the data are insufficient to draw conclusions about its higher prevalence in FMF patients when compared to the general population even within the same ethnic group. The most significant complication of FMF is amyloidosis, which mainly affects the kidneys causing proteinuria and leading to renal failure (Heller et al. 1961). Chemically, it is the same type of reactive amyloidosis, with amyloid A deposits, which takes place with chronic infectious and non-infectious inflammatory conditions, such as tuberculosis, bronchiectasis, and rheumatoid arthritis (Pras et al. 1982). Family history of amyloidosis and consanguinity are factors causing a higher risk of development of amyloidosis in FMF patients (Saatci et al. 1993, 1997). Colchicine treatment greatly influenced the occurrence of amyloidosis as a complication of FMF. In a group of patients, clinically designated as phenotype II FMF patients, renal amyloidosis develops without being preceded by typical attacks of the disease (Balci et al. 2002; Konstantopoulos et al. 2001; Melikoglu et al. 2000; Tunca et al. 2005). A daily regimen of 1–2 mg of oral colchicine remains the recommended treatment since its introduction in 1972 (Ben-Chetrit and Levy 1998; Goldfinger 1972; Ozkan et al. 1972). Adherence to a daily dose of colchicine produces significant decrease in the frequency and severity of the attacks or even cessation of the attacks all together in about 95% of FMF patients (Zemer et al. 1974). Continuous prophylactic treatment with colchicine in FMF patients inhibits the development of amyloidosis (Cabili et al. 1985), even in the patients who do not experience a decrease in the frequency or severity of the attacks (Ben-Chetrit and Levy 1991). The diagnosis of FMF remains a clinical bedside diagnosis with well-outlined validated diagnostic criteria (Livneh et al. 1997); however, a positive response to colchicine is supportive of the diagnosis. An attempt at the revision of the diagnostic criteria, especially as it applies to children, produced a newer set of clinical diagnostic criteria although this set awaits independent validation (Yalcinkaya et al. 2009). There is slight predominance of males affected with FMF, because of either reduced penetrance in females (Shohat et al. 1992b) or more probably because of underestimation of the disease in females (Medlej-Hashim et al. 2005).

The Genetics The gene responsible for FMF, MEFV, is located on the short arm of human chromosome 16 (Gruberg et al. 1992; Pras et al. 1992, 1994; Shohat et al. 1992a), and was independently identified by two positional cloning consortia (French FMF Consortium 1997; International FMF Consortium 1997). With the cloning of the gene, four missense mutations in exon 10, namely M694V, V726A, M694I,

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

115

and M680I, were identified (French FMF Consortium 1997; International FMF Consortium 1997). These four mutations and E148Q in exon 2 are the most common MEFV mutations among the putative mutations identified to date (Bernot et al. 1998; Booth et al. 1998; Touitou 2001). Exon 10 remains the major site of mutations, with a smaller cluster in exon 2 (available at http://fmf.igh.cnrs.fr/ infevers) (Fig. 5.1) (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004). The FMF carrier rate can be as high as 1 in 3 in the commonly affected ethnic groups, raising the possibility of selective heterozygote advantage (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Kogan et al. 2001; Stoffman et al. 2000; Touitou 2001; Yilmaz et al. 2001). Although FMF is an autosomal recessive disease, pseudodominance is frequently observed, because of the high mutation frequency and also because of consanguinity, which is practiced frequently in the ethnic groups commonly affected by FMF (Aksentijevich et al. 1999; Yuval et al. 1995). Consistent with the biology of FMF, MEFV is expressed predominantly in granulocytes, monocytes, dendritic cells, and in fibroblasts derived from skin, peritoneum, and synovium (Centola et al. 2000; Diaz et al. 2004; Matzner et al. 2000). MEFV encodes a full-length 781 amino acid protein named pyrin (International FMF Consortium 1997) or marenostrin (French FMF Consortium 1997). Native pyrin protein is localized in different subcellular compartments in different cell types (Diaz et al. 2004). Wild-type pyrin is cytoplasmic, co-localizes with MEFV NM

000243.1(16p13.3)

DNA: 14600bp, mRNA: 3499bp, Protein: 781aa P180R N99N G196W D102D R202Q D103D S208Afs S108R A457V L110P G219G G632S V469L P221P L110L I640M Y688X Y471X E225D G111G I692del I641F E474E E230K G112fs M694del P646L E474K Y232H P124P P646P M694I Q476Q G236V E125E M694L L649P H478Y N130_13line S242S T309M M694V R652R F479L R314R S242R C>G G138G R653H K695M V487M S141I S242R C>A R314H K695R E656A Q489Q E319K E251K R143P K695N D66IN R501G N256Dfs E148Q V328A A701A S675N 1759+8C>T R501H R329H I259V E148V S702C G678E 1760–30A>T R501R T267I R151S S339F M680L S703S 1760–28T>A I506I R348H A268V E163A M680IG>A V704I 1760–4G>A I506V C352C A165A R278P M680IG>C P705S 1423V D510D –792C>T E167D P283L R354W P706P T68II P588P 1610+47A>T Q440E I513T –751A>T P175H P283R S363S S683S R708C I591T 1610+96C>T G514E –740C>T P369S 1260+10C>T T177I A289V L709R Y688C G592G –614C>G Q383K 1260+18C>G 1587+18C>T F299G L9L S179I A595V –382C>G 1587+29G>T G304R 910+29C>T P393P 1260+92G>A R42W P180P 1727-587>C 1792+39 G>A –330G>A Y65Y 1587+33C>G 911-22T>G R408Q 1261–11T>G T577S 1792+57 C>T –12C>G A89T 911-78T>C V415V 1261–28A>G 1356+44A>G 1540+69G>A L559F M582L 1793–14A>G

5’flanking Sizes (bp)

1 317

11 1520

2 633

12 4377

3 350

13 426

4 96

14 1662

5 231

15

16

468

1936

6 23

17

18

7 8 9 186 361 116 33 33

19

10

165

R717S I720M F721F V722M D723D V726A F743F F743L A744S S749C Q753Q I755V P758S R761H 1772V G779G P780T *9C>T *12T>C *21C>G

3’flanking

1667

CDS joints Positions Codons

277/278 93

910/911 304

1260/1261 420/421

1356/1357 452/453

1587/1588 529/530

This graph shows the variant usual name (i.e. as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

Fig. 5.1 MEFV and its variations

1610/1611 537

1726/1727 576

1759/1760 587

1792/1793 598

INFEVERS: May 25,2009 N Sequence variants:181

116

H. El-Shanti and H.A. Majeed

microtubules, and it is proposed that it regulates inflammatory responses at the level of the cytoskeletal organization (Mansfield et al. 2001; Papin et al. 2000). However, nuclear localization of full-length pyrin in synovial fibroblasts, dendritic cells and granulocytes has been demonstrated (Diaz et al. 2004). Several alternatively spliced forms have been described (Diaz et al. 2004; Papin et al. 2000). In addition, it appears that pyrin acts as an upstream regulator of interleukin (IL)-1b activation (Chae et al. 2003; Yu et al. 2005), having both inhibitory and potentiating effects on IL-1b production. There is also evidence that pyrin plays a role in regulating nuclear factor (NF)-kB activation and apoptosis (Chae et al. 2003; Dowds et al. 2003; Masumoto et al. 2003; Stehlik and Reed 2004; Yu et al. 2005).

Genotype/Phenotype Correlation Patterns The Tel Hashomer severity score (Pras et al. 1998), has been used to facilitate comparison of FMF phenotype severity among the different ethnic groups. Several studies have examined the correlation between certain mutations and phenotype severity in the different affected ethnic groups. Most studies showed correlation between M694V and severity of the disease or the presence of amyloidosis across all affected ethnic groups with the exception of the Turkish FMF patients (Brik et al. 1999; Cazeneuve et al. 1999; Dewalle et al. 1998; Livneh et al. 1999; Majeed et al. 2002; Mansour et al. 2001; Shinar et al. 2000; Shohat et al. 1999; Sidi et al. 2000; Yalcinkaya et al. 2000). The results of selected studies are summarized in Table 5.1. Upon reviewing the FMF genotype/phenotype correlation literature, we can conclude that there is no consistency in the correlation between a specific MEFV mutation and amyloidosis or other phenotypic feature across all populations, with the exception of M694V and amyloidosis or severity of the FMF symptoms. However, there is a specific pattern of severity or amyloidosis within the same population, such as in homozygosity for M694V in the North African Jews and M694V homozygosity in the protracted febrile myalgia syndrome in the Arabs. Overall, the studies that explored the reasons accounting for the fact that only a subset of FMF patients develops amyloidosis did not lead to definitive conclusions. These studies tested a limited number of variables in often small series. In addition the studies had variable designs which do not allow comparisons or meta-analytic approaches. A web-based project denoted “metaFMF” emerged with the goal of resolving discrepant published conclusions related to genotype/phenotype correlation patterns in FMF (Milhavet et al. 2008; Pugnere et al. 2003; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004, 2007). This project that utilizes a standardized mode of data collection represents an international effort with significant contribution from the Arabic FMF investigator teams. The project evolved into an online mutation registry for autoinflammatory disorders (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004) (available at http://fmf.igh.cnrs.fr/infevers).

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders Table 5.1 Summary of selected genotype/phenotype correlation studies Mutation Ethnic group Phenotype assessed 1 M694V/M694V Non-Ashkenazi Arthritis & Pleuritis Jews Amyloidosis 2 M694V/M694V Armenians Arthritis

3

M694V/M694V

4

M694V/M694V

5

Others M694V/M694V

6

M694V/M694V

Non-Ashkenazi Jews Arabs North African Jews, Armenians & Turks Non-Ashkenazi Jews Mixed Jewish

7

M694V/M694V

Mixed Jewish

8

M694V/M694V

Turks

9

M694V/M694V M680I/M680I M694V/M694V

M694I/M694I M694V/M694I 10 M694V/M694V

Arabs

Arabs

M694V/V726A

Amyloidosis Severity (no specific index) Amyloidosis Amyloidosis Severity Amyloidosis Tel Hashomer Severity Score Protracted febrile myalgia Severity (12 parameters) Amyloidosis Arthritis Amyloidosis Amyloidosis Amyloidosis Severity (modified score) Protracted febrile myalgia

117

Relation Increased 2X Dewalle et al. (1998) Increased Increased Cazeneuve et al. (1999) Increased Increased Brik et al. (1999) Increased Increased Shohat et al. (1999) No relation Increased Livneh et al. (1999) Increased Shinar et al. (2000) Increased Sidi et al. (2000) No relation Yalcinkaya et al. (2000) No relation Decreased Increased Mansour et al. (2001) Increased Increased Increased Majeed et al. (2002) Increased

FMF in the Arabs Currently, FMF is established as a common genetic disease among the Arabs and in the early 1980s it became recognized as a public health concern in some Arabic countries (Barakat et al. 1984a, b, 1986; Majeed and Barakat 1989). Since then, it became increasingly notable that FMF has a considerable impact on the health and welfare of children and adults in the Arabic countries (El-Shanti et al. 2006). FMF may be complicated by amyloidosis which leads to renal failure and it is associated with loss of school days or work hours and unnecessary hospitalizations and surgeries. In addition, the painful and febrile episodes are extremely uncomfortable for FMF patients. However, similar to other ethnic groups commonly affected by FMF, the mortality and morbidity associated with FMF are preventable with early identification of affected individuals followed by appropriate treatment and prophylaxis. Clinical and molecular studies involving a variety of Arabic subpopulations demonstrate the high prevalence of FMF and high MEFV mutation-carrier

118

H. El-Shanti and H.A. Majeed

frequency (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Rawashdeh and Majeed 1996). However, the clinical and particularly the molecular aspects FMF have not been adequately studied in the Arabs when compared to other ethnic groups commonly affected by FMF.

Clinical Aspects The studies that elaborate on the clinical features of Arabic patients were carried out either prior to the identification of the MEFV as the gene responsible for FMF or did not incorporate molecular data in the analyzes (Barakat et al. 1986; Majeed 2000; Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1990, 1999, 2000a, c; 2002, 2005a; Rawashdeh and Majeed 1996; Said and Hamzeh 1990; Said et al. 1988, 1989, 1992). The majority of these studies employed the original diagnostic criteria (short attacks of fever and abdominal pain recurring at varying intervals in the absence of any causative factor) proposed by Heller and coworkers (1958). However, more recent studies employed the validated diagnostic criteria of Livneh and coworkers (1997) as a standard for the diagnosis (Majeed 2000; Majeed et al. 1999; Majeed et al. 2000a, 2000c, 2002, 2005a). In addition, most of these studies were done after the establishment of colchicine as an effective treatment and this may have influenced the reported phenotype. We conclude that different diagnostic standards and colchicine therapy are the primary confounding factors that may have contributed to the reported clinical peculiarities of the FMF phenotype in the Arabs. In addition, several other confounding factors may have contributed to the difference in phenotype, such as under-reporting of symptoms, criteria for patient selection, reliance on family history, chance variations, and the lack of a definitive diagnostic test. About 80% of Arabic FMF patients present before the age of 10 years and abdominal pain is the most commonly reported presenting feature (Majeed et al. 1999). This earlier age at onset is probably explained by the skewed patient selection in the reported case series which is influenced by the clarity of symptoms and the presence of family history. Unlike the higher prevalence in men in other ethnic groups commonly affected by FMF, the male to female ratio in Arabs is almost equal (Majeed et al. 1999; Rawashdeh and Majeed 1996). This is probably due to the accurate estimation of the number of affected women, also influenced by patient selection. In addition, this finding does not support the suggestion that FMF may have incomplete penetrance in females (Shohat et al. 1992b). Arthritis is less common in the Arabic FMF children and adults (Barakat et al. 1986; Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1999), as compared to that in Jews (Sohar et al. 1967; Zemer et al. 1991); however, it is similar to arthritis in Turks (Ozdemir and Sokmen 1969; Sayarlioglu et al. 2005) and Armenians (Cazeneuve et al. 1999; Schwabe and Peters 1974). The decreased frequency of arthritis in Arabs, Turks, and Armenians may be due to under-reporting of the symptoms, as well as due to delay in the diagnosis.

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

119

The pleural attacks (Majeed et al. 1999), peritoneal attacks (Barakat et al. 1986; Majeed and Barakat 1989; Rawashdeh and Majeed 1996), and myalgia (Majeed et al. 2000a) are not different from those in other ethnic groups commonly affected by FMF. About 20% of Jewish and Arab children with functional abdominal pain were homozygous for an MEFV mutation (Brik et al. 2001). In one early report, non-specific purpuric rash was reported more commonly than erysipelas-like erythema in Arabic FMF patients (Majeed et al. 1990), while erysipelas-like erythema is the most common in other ethnic groups commonly affected by FMF. This unusual finding is probably due to the small number in that series and the differences were probably not statistically significant. In addition, the erysipelas-like erythema was noted to be a common cutaneous manifestation of FMF in Arabs in a later case series (Majeed et al. 1999). The acute scrotal swelling reported in Arabic FMF patients sometimes occurred in the absence of peritonitis (Majeed et al. 1999) and is associated with a high rate of decreased favorable response to colchicine therapy in Arabic and Jewish FMF patients (Eshel et al. 1994, 1988; Majeed et al. 1999, 2000c). This therapy failure rate is alarming due to a report of testicular necrosis following recurrent scrotal attacks in the latter ethnic group (Livneh et al. 1994). Recurrent hyperbilirubinemia has been described in the early FMF literature but very few patients were clinically icteric (Priest and Nixon 1959). This probably explains why this feature is not mentioned in the large clinical series reported from all ethnic groups commonly affected by FMF. Recurrent hyperbilirubinemia has been described in two Arabic patients in 1994 (Neequaye and Jelly 1994) and in 1998 (Majeed et al. 1998). In these two reports, the hyperbilirubinemia was transient, occurring only during a peritoneal attack and clinical jaundice was mild with only a minimal rise in serum bilirubin (mainly conjugated) (Majeed et al. 1999). The etiology of the hyperbilirubinemia is unclear, but seems to be a benign process as no cases of acute or chronic liver failure have been reported. It has been noted that amyloidosis and chronic renal disease are less common in the Arabic FMF patients when compared to the other ethnic groups commonly affected by FMF (Bakir and Murtadha 1975; Barakat et al. 1986; Majeed and Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed 1996). The frequency of amyloidosis ranged from 0.4% in Jordanian FMF patients (Majeed et al. 1999) to 2% in a mixed Arabic population residing in Kuwait (Majeed and Barakat 1989). The frequency of amyloidosis in Sephardic Jews ranges from 26 to 42% (Gafni et al. 1968; Sohar et al. 1967), while in Armenians it is about 24% (Aivazian et al. 1977) and in Turks about 60% (Ozdemir and Sokmen 1969; Saatci et al. 1993). The low rate of occurrence of FMF-related amyloidosis in the Arabic patients is probably due to the fact that these figures were obtained after the worldwide establishment of colchicine as the standard of care for FMF patients (Barakat et al. 1986; Majeed and Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed 1996). In two studies from Lebanon, the frequency of amyloidosis was about 10% (Armenian and Khachadurian 1973; Khachadurian and Armenian 1974). This higher figure can be explained by the conduction of the two studies prior to the establishment of colchicine therapy in Lebanon and that some of the Lebanese FMF

120

H. El-Shanti and H.A. Majeed

patients in the studied cohorts were Armenian in origin. The frequency of amyloidosis in the Arabic FMF patients and the factors influencing its occurrence have been studied together with specific MEFV mutations and examination of genotype/ phenotype correlation patterns and is discussed in detail below. Besides amyloidosis, kidney involvement in the form of IgM nephropathy, IgA nephropathy, or rapid progressive glomerulonephritis has been described in Arabic FMF patients (Said and Hamzeh 1990, Said et al. 1988, 1989, 1992). However, the numbers in these case series are small to draw firm conclusions but may point to the higher prevalence of vasculitis or glomerulonephritis in FMF patients.

MEFV Mutations The mutation analysis studies that include a substantial number of Arabic FMF patients are limited in number and in methodology (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000; GershoniBaruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008). All of these studies examined for the five common mutations (E148Q, M680I, M694V, M694I, and V726A) using a combination of restriction endonuclease-based test, ARMS (Amplification Refractory Mutation System) test, DGGE (denaturing gradient gel electrophoresis), and selective exonic sequencing. A few studies examined for additional mutations but also in a selective manner (Ayesh et al. 2005; Chaabouni et al. 2007; Dode et al. 2000; Jarjour 2010; MedlejHashim et al. 2000, 2005; Sabbagh et al. 2008). A summary of selected MEFV mutation analysis studies that included Arabic FMF patients is provided in Table 5.2. However, despite their limitations, these studies point to the high MEFV mutation carrier frequency among the Arabs, which is similar to that among the other ethnic groups commonly affected by FMF (1 in 3–6 individuals). The most common MEFV mutation is the M694V (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Dode et al. 2000; Gershoni-Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, Majeed et al. 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008), although it is less common than in other ethnic groups commonly affected by FMF (Cazeneuve et al. 1999; Medlej-Hashim et al. 2005; Padeh et al. 2003; Yalcinkaya et al. 2000). The V726A is the second most common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Dode et al. 2000; Gershoni-Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005; Sabbagh et al. 2008) similar to the findings in Armenians, Turks, and Jews (Cazeneuve et al. 1999; Padeh et al. 2003; Yalcinkaya et al. 2000). M694I is the third most common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Gershoni-Baruch et al. 2002a; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2005; Sabbagh

Table 5.2 Summary of selected MEFV mutational analysis studies that included Arabic patients with FMF Proportion (%) mutant alleles identified (n/N) Method of analysis Arabs Jews Armenians Turks 96% (47/49)a ns ns Brik et al. (1999) Restriction endonuclease digestion 90% (28/31)a Dode et al. (2000) Sequencing of exon 10, restriction endonuclease 49% (48/98) 70% (131/186) 90% (56/62) 75% (36/48) digestion & DGGE Medlej-Hashim et al. (2000) Restriction endonuclease digestion & ARMS 56% (47/84) ns ns ns Mansour et al. (2001) Sequencing of exon 10, restriction endonuclease 67% (97/143) ns ns ns digestion, DGGE & ARMS Gershoni-Baruch et al. (2001) Restriction endonuclease digestion 85% (121/142) 96% (144/150) ns ns Majeed et al. (2002) Sequencing of exon 10, restriction endonuclease 32% (176/556) ns ns ns digestion & ARMS Al-Alami et al. (2003) Sequencing of exon 10, restriction endonuclease 54% (31/58) ns ns ns digestion & ARMS Majeed et al. (2005a) Restriction endonuclease digestion & ARMS 47% (387/814) ns ns ns Ayesh et al. (2005) Sequencing of exon 10 & ARMS 49% (504/1022) ns ns ns Medlej-Hashim et al. (2005) Sequencing of exon 10, restriction endonuclease 50% (553/1116) ns ns ns digestion, SSCP & resequencing exons 1–9 Chaabouni et al. (2007) Restriction endonuclease digestion & ARMS 38% (105/278) ns ns ns Sabbagh et al. (2008) Strip assay 38.5% (205/532) ns ns ns Jarjour (2010) Strip assay 49% (150/306) ns ns ns ARMS Amplification refractory mutation system; DGGE Denaturing gradient gel electrophoresis; ns population not studied a Proportion of patients identified to have one or two mutations and not proportion of identified alleles

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 121

122

H. El-Shanti and H.A. Majeed

et al. 2008) and appears to be found mainly in this ethnic group (Aksentijevich et al. 1999; Ben-Chetrit et al. 2002; Booth et al. 1998; French FMF Consortium 1997; Samuels et al. 1998). The M680I mutation found mostly in Armenians and Turks (Cazeneuve et al. 1999; Yalcinkaya et al. 2000) is the fourth common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Gershoni-Baruch et al. 2002a; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). There are few studies that show that in Arabic patient series M680I is more common than M694I (GershoniBaruch et al. 2002a; Gershoni-Baruch et al. 2001; Jarjour 2010; Medlej-Hashim et al. 2000) or even the most common mutation among the population studied (Chaabouni et al. 2007). The E148Q mutation is the least penetrant and might be a polymorphism (Ben-Chetrit et al. 2000; Chaabouni et al. 2007; Jarjour 2010; Mattit et al. 2006; Medlej-Hashim et al. 2005; Sabbagh et al. 2008; Touitou 2001). It has been identified in Arabic FMF patients alone or in a complex allele with other exon ten mutations (Majeed et al. 2002, 2005a; Mansour et al. 2001; Medlej-Hashim et al. 2000, 2002), but is more commonly identified in healthy carriers (Al-Alami et al. 2003; Mattit et al. 2006). Table 5.3 provides a summary of the distribution of the five common MEFV mutations in the Arabic FMF patients in selected studies that provided clear mutant allele frequencies. The distribution of the five common MEFV mutations among healthy Arabic individuals has been the subject of two studies to date (Al-Alami et al. 2003; Mattit et al. 2006). In the first study, healthy cohorts from Jordan, Egypt, Syria, Saudi Arabia, and Iraq were examined for the five common MEFV mutations. The distribution of each mutation in each Arabic population and the collective distribution are shown in Table 5.4. This study concludes that E148Q has reduced penetrance in the Arabic population and thus, a proportion of the genetically affected individuals remain asymptomatic. It is of note that utilizing the restriction endonuclease digestion test for the detection of the E148Q mutation can lead to misdiagnosis in presence of the E148V mutation (Medlej-Hashim et al. 2002), which may have increased the number of E148Q identified in healthy Arabic cohorts (Al-Alami et al. 2003). M694I and M680I are more prevalent in affected individuals when compared to the healthy individuals, which points to their higher

Table 5.3 The distribution of the five common MEFV mutations in the Arabic FMF patients in selected studies Mutation M694V (%) V726A (%) M694I (%) M680I (%) E148Q (%) Medlej-Hashim et al. (2000) 20.2 14.3 1.2 9.5 7.1 Dode et al. (2000) 36 0 55.4 4.3 4.3 Gershoni-Baruch et al. (2001) 17.4 34.7 9.9 21.5 16.5 Gershoni-Baruch et al. (2002a) 16.7 26.7 13.3 22.5 5.8 Al-Alami et al. (2003) 35.5 29 16 9.7 0 Majeed et al. (2005a) 37.5 26 14 10 12.5 Ayesh et al. (2005) 49 16.7 11.9 4 8.5 The percentage value is the contribution of the mutation to the pool of the identified mutant alleles

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

123

Table 5.4 Distribution of the five common mutations, allele frequencies, and carrier rates among the healthy adult cohort from five Arabic countries Saudies Total Nationality and Egyptians Syrians Jordaniansa Iraqies (200) (176) (107) (939) number (231) (225) Number of 462 450 400 352 214 1,878 chromosomes M694V 2 6 13 0 0 21 V726A 8 5 14 9 1 37 M694I 4 0 2 0 0 6 M680I 0 1 1 0 0 2 E148Q 29 30 23 29 12 123 Total 43 42 53 38 13 189 Wild-type allele 0.907 0.907 0.8675 0.892 0.939 0.899 frequency “p” Mutant allele 0.093 0.093 0.1325 0.108 0.061 0.101 frequency “q” Calculated carriers 39(16.87%) 38(16.92%) 46(23%) 34(19.26%) 12(11.4%) 170 (rate) Observed number 43 42 37 38 13 173 of carriers a The calculations of the carrier rate and allele frequency are done under the assumption that there are no complex alleles

penetrance. The overall carrier rate for the five common MEFV mutations from this study is 1 in 5 which is very similar to the calculated carrier rate. Despite the high carrier rate, the heterozygote advantage for the MEFV mutations could not be demonstrated in the study probably because of the relatively small sample size. In the second study, examination of healthy Syrian controls for the five common mutations revealed a carrier status of 17.5% (1:5.8) (Mattit et al. 2006). One of the remarkable conclusions from these studies is that the percentage of unidentified disease-causing MEFV alleles is highest in the Arabic population when compared to the other ethnic groups commonly affected by FMF (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000; Gershoni-Baruch et al. 2001; Jarjour 2010; Majeed et al. 2002, 2005b; Mansour et al. 2001; Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). This is clearly shown in one study that used a combination of methods including direct sequencing of exon 10, DGGE, and restriction endonuclease digestion in a cohort of well characterized FMF patients from the four commonly affected ethnic groups (Dode et al. 2000). While 51% of the alleles in Arabic FMF patients were not identified in this study, only 30, 25, and 9% of the alleles were not identified in nonAshkenazi Jews, Turks, and Armenians, respectively. A recent study that employed methods that detect 24 previously described mutations (ARMS test followed by resequencing of exon 10 and exploration of five other mutations in exons 2, 3, 4, 5, and 6) in Palestinians failed to detect 51% of the alleles, which is quite high considering the detailed methodology (Ayesh et al. 2005). It is unlikely that the diagnosis of FMF in these studies is inaccurate, as all published reports follow the validated diagnostic criteria (Livneh et al. 1997). In a recently published study on

124

H. El-Shanti and H.A. Majeed

83 FMF patients from Syria, 76% of mutant alleles were identified by testing for the five common mutations followed by resequencing of exon 10 in patients with one or no mutation (Mattit et al. 2006). This is the highest reported percentage of identifiable mutation in an Arabic cohort. However, an independent study on 153 patients from Syria who were screened for a similar number of mutations albeit utilizing a different technical approach identified only 49% of mutant alleles and 51% of the alleles remained undetermined (Jarjour 2010). The summary of selected studies shown in Table 5.2 indicates the high percentage of unidentifiable alleles in Arabic FMF patients, which suggests the presence of other mutations not identified by the applied methods.

Genotype/Phenotype Correlation Patterns There are a few genotype/phenotype correlation pattern studies involving Arabic FMF patients (Brik et al. 1999; Gershoni-Baruch et al. 2002a; Jarjour 2010; Majeed et al. 2002; Mansour et al. 2001; Medlej-Hashim et al. 2004). One study that included mixed Arabic and Jewish FMF patients denoted that in Arabic patients FMF tends to run a milder course and carries a better prognosis (Brik et al. 1999). This was attributed to the fact that M694V is less common among the Arabic FMF patient cohort. Another study concluded that Arabic FMF patients with the genotypes M694V/M694V or M694V/V726A tend to have a severe clinical course (Majeed et al. 2002). The genotype M694I/M694I is common in Arabic FMF patients and seems to be associated with milder disease. However, this study used a severity score modified from the Tel Hashomer severity score and both have not been statistically validated. Homozygosity of M694V or the complex allele V726A/E148Q was associated with most severe course and highest risk for amyloidosis in mixed Arabic, Ashkenazi, and Non-Ashkenazi Jewish FMF patients (Gershoni-Baruch et al. 2002a). In Lebanese patients, M694V and M694I were associated with higher risk of amyloidosis (Mansour et al. 2001; Medlej-Hashim et al. 2004). It appears that the phenotype associated with the M694I mutation is not consistent in the limited number of studies. The genotype/ phenotype correlation pattern studies performed in Arabic FMF patients are mentioned in Table 5.1. A new and simple severity score has recently been developed and has been statistically validated (Mor et al. 2005). It was utilized on one cohort from Syria to outline a genotype/phenotype correlation pattern (Jarjour 2010). There was a statistically significant higher severity score in patients homozygous for the M694V mutations, although the numbers are still small. It would be of interest to apply this severity score to large cohorts of Arabic FMF patients to outline the specific genotype/phenotype correlation patterns. As this severity score reflects on the actual burden of FMF, it will also be of interest to measure the burden of FMF on Arabic communities utilizing this tool.

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

125

Needs and Goals for the Future As a considerable proportion of the disease-causing MEFV alleles in the Arabic FMF patients remain unidentified, the need arises to perform extensive studies that take a comprehensive approach to the identification of MEFV mutations. These studies should explore regulatory sequences and conserved intronic sequences for disease-causing mutations. The exploration of other non-traditional mutation mechanisms should also be examined, such as analysis for large deletions or duplication. Furthermore, the exploration of the role of already described and potential modifier genes and polymorphisms within these genes should be carried out in conjunction with the appropriate genotype/phenotype relationship studies. It is of paramount importance to identify if there is a distinctive pattern of the relationship between MEFV and modifier gene genotypes on one hand and the phenotype in the Arabic FMF patient population on the other hand. It is of equal importance to identify if there is a correlation between the severity of the disease, its burden, and its common complications with any of the mutations in Arabic FMF patients. The severity of the disease should be a practical and actual measure of the disease burden and should not be affected by colchicine therapy, which is the standard of care for diagnosed patients. The achievement of these goals will lead to the establishment of adequate population screening protocols for early and presymptomatic identification of patients and the provision of prophylactic colchicine therapy. There is a paucity of the studies that measure and evaluate FMF as a public health consideration in the Arabic countries, and the need for such crosssectional studies cannot be overstated. There is a need to establish collaborative and standardized study protocols across the Arabic countries with substantial numbers of FMF patients to facilitate comparisons and allow the aggregation of data for robust statistical analysis. These protocols will also provide the guidelines for the appropriate screening approaches and the instatement of public policies that provide adequate preventive measures. The establishment of educational resources parallels the establishment of diagnostic laboratory testing and increases the awareness of physicians and medical personnel to FMF and its complications. As diagnostic laboratory testing is not specific and the molecular diagnosis is still limited, the clarity of the clinical diagnostic criteria is the hallmark for making an accurate and precise diagnosis. The development of these diagnostic skills among physicians requires the appropriate and continued medical educational resources to be available to health care providers. There is a need for the utilization of clinically well-characterized FMF patients in research endeavors that aim at exploring the pathogenesis of the disorder. The understanding of the pathogenesis of the disorder will serve all ethnic groups commonly affected by FMF and will promote the understanding of inflammation and the molecular correlates to the innate immunity.

126

H. El-Shanti and H.A. Majeed

TNF Receptor Associated Periodic Syndrome (TRAPS) (FPF, MIM 142680) TRAPS is a newly recognized autoinflammatory disease that actually subsumes several older diagnoses that were consolidated with the recent recognition that all are caused by mutations in the extracellular domain of the 55 kDa TNF receptor (TNFRSF1A) (McDermott et al. 1999), Figure 5.2 (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003; Touitou et al. 2004). Before the discovery of TNFRSF1A mutations, the dominant periodic fevers included a poorly understood, ethnically diverse group of illnesses, most of which had been described in case reports of single families. The most thoroughly characterized was a large pedigree of Irish and Scottish ancestry ascertained in Nottingham, England, whose illness was denoted familial Hibernian fever (McDermott et al. 1997; Williamson et al. 1982). A second large Australian family of Scottish ancestry with similar clinical findings was denoted as benign autosomal dominant familial periodic fever because of uncertainty over whether this family had the same condition as the first (Mulley et al. 1998). Although amyloidosis was observed in only 1 of 21 affected members of the first family and in none of the eight affected members of the second family,

TNFRSFIA NM 001065.2 (12p13.2) DNA: 13231bp, mRNA: 2096bp, Protein: 455aa G36E C55Y T371 F60L(I>C) Y38C F60V L39F F60S D42del F60L(C>A) C43R T6II D12E C43Y T6IN S86P Y20H C43S N65I C88R Y20D P46L H66Y C88Y H22Y G47G L67P R92W H22R T50M H69fs R92P H22Q T50K C70R R92Q S27S C52R C70S T94T C29F C52F C70G V95M C29Y C52Y C70Y C96Y C30R E54E C73R C98Y 472+1G>A C30S C55R C73W R104Q 472+6C>T K157K C30Y C55S S74C H105P 472+64C>T L167 G175del C30F E109A 473–72G>A ll70N C33G194–29G>A F112I 473–33C>T V173D –609 G/T 36 A>G C33Y 194–18 -17del 625+10G>A N116S 473–16 G>A –580 A/G 194–15C>T –383 A/C 39+1899(GT) (GA) 194–14G>A 740–97>C 323–32A>G 552–89A>T SI97S

5’flanking Sizes (bp)

1

11 7531

229

12

2

3

225 154

129

13 220

4 150

14 219

5 79

15 2142

6

16 141

74

17

7 302 8 114

18

200 29

Y331X

9

19 155

289

3’flanking

10 849

CDS joints 39/40 Positions Codons(- Leader Seq.) (+ Leader Seq.) 13/14

193/194 322/323 472/473 36 79 129 65 158 108

551/552 625/626 739/740 768/769 155 180 218 227/228 184 247 256/257 209

This graph shows the variant usual name (i.e. as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

Fig. 5.2 TNFRSF1A and its variations

1057/1058 324 353

INFEVERS: April 19, 2009 N Sequencevariants: 91

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

127

amyloidosis was a prominent feature in several other reported families of various ethnic backgrounds (Gertz et al. 1987). As is generally the case in the hereditary periodic fevers, patients experience febrile episodes accompanied by peritoneal or pleural inflammation, arthralgia or arthritis, and skin rash. However, in TRAPS, the attacks tend to be longer than in FMF. Many attacks last more than 1 week and some TRAPS patients have episodes lasting more than 1 month or experience nearly continuous inflammation. Conjunctival involvement and/or periorbital edema, as well as localized myalgia, are also much more frequent in TRAPS than in FMF. Another distinguishing feature in TRAPS, although it is not observed in all patients, is a rash that progresses centrifugally on the limbs. Finally, most patients with TRAPS respond poorly to colchicine, which is quite effective in FMF, but show significant improvement on corticosteroids, which are usually ineffective in FMF. Patients with traps TRAPS respond quite well to etanercept (TNF-alpha blocker) (Arostegui et al. 2005; Jesus et al. 2008; Morbach et al. 2009). TRAPS has not been reported in Arabs, probably because of lack of the diagnostic tools and for the decreased suspicion as it is an autosomal dominant disease. In addition, several instances in which autosomal dominant periodic fever syndrome was suspected in an Arabic family turned out to be FMF exhibiting pseudodominant transmission because of the high consanguinity rate and the high of frequency of mutation carriers. One report was of an Israeli Arab who had a de novo mutation in TNFRSF1A (Aganna et al. 2002). Mutations in TNFRSF1A should be always sought in Arab patients with atypical FMF or without identifiable mutations within MEFV.

Chronic Recurrent Multifocal Osteomyelitis (CRMO, MIM 259680; 609628) CRMO is a relatively rare childhood disease that presents with bone pain with or without associated fever (Giedion et al. 1972; Schultz et al. 1999). The disease course often lasts several years and is characterized by remissions and exacerbations. The inflammatory bone lesions are typically located at the metaphyses of tubular long bones, but they can occur at other sites including the mandible, sternum, clavicle, and vertebrae (Bjorksten and Boquist 1980; El-Shanti and Ferguson 2007; Ferguson and El-Shanti 2007; Girschick et al. 2005; Huber et al. 2002; Jansson et al. 2007; Jurik 2004; Schultz et al. 1999). Plain films reveal lytic bone lesions surrounded by sclerosis (Bjorksten and Boquist 1980; Jurik 2004). Bone histology reveals neutrophils early in the disease course, accompanied by multinucleated giant cells, scattered granulomatous foci, and osteoclastic bone resorption. Later, new bone formation, fibrosis, and lymphocytes predominate (Bjorksten and Boquist 1980). Cultures and stains for pathogens are negative, and treatment with antibiotics is rarely associated with clinical improvement (Bjorksten and Boquist

128

H. El-Shanti and H.A. Majeed

1980; Girschick et al. 1999; Schultz et al. 1999). Not long after the initial description of CRMO, its association with other chronic inflammatory disorders began to be reported. Disease associations included palmar–plantar pustulosis, psoriasis vulgaris, and inflammatory bowel disease, which suggested that an inflammatory pathway common to skin, bone, and gut is dysregulated in these disorders (Bergdahl et al. 1979; Bjorksten et al. 1978; Bognar et al. 1998; Laxer et al. 1988; Schultz et al. 1999). There is evidence that the etiology of sporadic CRMO has a genetic component, including several reports of affected siblings, affected parent and child, concordant monozygotic twins, and a report of a susceptibility locus on chromosome 18q21.3–18q22 (Ben Becher et al. 1991; Festen et al. 1985; Golla et al. 2002; Jansson et al. 2007). In addition, as many as half the patients have a first-degree or second-degree family member who is affected by a chronic inflammatory disorder, most often psoriasis (Jansson et al. 2007). In our cohort of 45 CRMO patients, 47% of first-degree relatives have a chronic inflammatory disorder (family history of psoriasis in 18%, inflammatory bowel disease in 13%, inflammatory arthritis in 11%, and severe acne in 7%; unpublished data). A syndromic form of CRMO was first described by Dr. Hasan Abdel Majeed and his colleagues in 1989 (Majeed et al. 1989) and was subsequently named after him as Majeed syndrome. Affected individuals present with periodic fevers, early-onset CRMO (age range 3 weeks to 19 months), a microcytic congenital dyserythropoietic anemia, and often a transiently occurring inflammatory dermatosis (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The congenital dyserythropoietic anemia presents during the first year of life and the resultant anemia varies in severity from mild to transfusion-dependent (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The dermatosis is most often Sweet syndrome. Hepatomegaly, neutropenia, and transient cholestatic jaundice may occur during the neonatal period (Al-Mosawi et al. 2007). The bone marrow exhibits increased erythropoiesis associated with evidence of dyserythropoiesis, including binucleated normoblasts (Majeed et al. 2001). The CRMO in Majeed syndrome is persistent with a few short remissions, frequent exacerbations, and prolonged duration. Like sporadic CRMO, there is a predilection for the metaphyses of the long bones, and radiographs demonstrate extensive lytic lesions with areas of sclerosis (Majeed et al. 2001). Cultures of the bone lesions are negative and prolonged antibiotic administration provides no benefit (Al-Mosawi et al. 2007; Majeed et al. 2001). Permanent joint deformities and growth disturbance may occur after years of continued inflammation (Majeed et al. 2001). Uniformly, there is marked clinical improvement with corticosteroids (AlMosawi et al. 2007; Majeed et al. 1989). Nonsteroidal anti-inflammatory drugs provide a moderate degree of improvement (Al-Mosawi et al. 2007; Majeed et al. 2001). Majeed syndrome is an autosomal-recessive disorder caused by mutations in LPIN2 (Ferguson et al. 2005). The gene responsible for Majeed syndrome was localized to the short arm of chromosome 18 using homozygosity mapping, because the first two described families were inbred. To date, three different

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

129

LPIN2 NM 014646.2(18p11.31) DNA: 94953 bp, mRNA: 6228 bp, protein: 896 aa

A331S P348L K387E

T180fs

L504F

E601K

S734L

R776S

5’flanking

3’flanking

11

12

13

14

15

16

17

18

19 110 111 112 113 114 115 116 117 118 119

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

779 916 1354 677 536 1575 399 651 340 Sizes (bp) 50868 6049 3147 10342 1001 1442 3241 2907 2097 404 100 188 94 153 115 104 302 108 124 346 70 90 83 145 149 87 230 201 96 CDS joints Positions

Codons

20 3443

2546/2547 -10/-9 698/699 1168/1169 1456/1457 1620/1621 1793/1794 2087/2088 2327/2328 288/289 192/193 590/591 822/823 1268/1269 1550/1551 1710/1711 1938/1939 2174/2175 2442/2443 96/97 64/65

233 197

390 274/275

486 423

517

540/541 598 570/571

This graph shows the variant usual name (i.e as first published). Please refer to the variant detail by clicking on its name for possible edited nomenclature.

696 646/647

776 725

849 814/815

INFEVERS: April 19, 2009 N Sequence variants:8

Fig. 5.3 LPIN2 and its variations

homozygous mutations in LPIN2 have been found in each of the reported families with Majeed syndrome, all of whom are Arabic (Al-Mosawi et al. 2007; Ferguson et al. 2005) (available at http://fmf.igh.cnrs.fr/infevers) (Figure 5.3) (Milhavet et al. 2008). There are two murine models of CRMO. The first model to be described is a spontaneous mutant mouse named the cmo (chronic multifocal osteomyelitis) mouse (Byrd et al. 1991; Ferguson et al. 2006; Hentunen et al. 2000). The cmo mouse develops tail kinks and hind foot deformities, which are the results of a robust mixed inflammatory infiltrate in the bone composed of PMNs, macrophages, lymphocytes, plasma cells, and osteoclasts (Ferguson et al. 2006; Hentunen et al. 2000). Later, there is presence of osteosclerosis as the inflammatory infiltrate is replaced by new bone and fibrosis (Ferguson et al. 2006; Hentunen et al. 2000). Subsequently, the mouse develops inflammation of the ears involving the dermis, epidermis, and cartilage (Ferguson et al. 2006). A second autosomal-recessive mouse model of CRMO was produced by chemical (N-ethyl-N-nitrosourea) mutagenesis; it was noted to have a similar but somewhat more severe phenotype than the cmo mouse and was named the Lupo mouse (Grosse et al. 2006). The gene defect was identified in both cmo and Lupo mice utilizing similar genetic approaches as two different missense mutations in pstpip2/Mayp (Ferguson et al. 2006; Grosse et al. 2006).

130

H. El-Shanti and H.A. Majeed

Hyperimmunoglobulinemia D with Periodic Fever Syndrome (Hyper-IgD) HIDS, MIM 260920) The hyper-IgD syndrome was recognized as a separate clinical entity in 1984 (van der Meer et al. 1984). Patients with the hyper-IgD syndrome have recurrent attacks of fever that usually start before the end of the first year of life (Drenth et al. 1994b). An attack is heralded by chills, followed by a sharp rise in body temperature, and lasts for 4–6 days, with gradual defervescence. It can be provoked by vaccination, minor trauma, surgery, or stress. Cervical lymphadenopathy and abdominal pain with vomiting, diarrhea, or both almost always accompany the attack. Symptoms that are common include hepatosplenomegaly, headache, arthralgias, arthritis of large joints, erythematous macules and papules, and even petechia and purpura (Drenth et al. 1994a). After an attack, patients are free of symptoms, although skin and joint symptoms disappear slowly. The attacks generally recur every 4–6 weeks, but the interval between them can vary substantially in an individual patient and from one patient to another. The hyper-IgD syndrome is inherited as an autosomal recessive trait (Drenth et al. 1994c). Most patients with the hyper-IgD syndrome are white and are from western European countries; some 60% are either Dutch or French. Although hyper-IgD syndrome is autosomal recessive, there has been no report from Arabic countries thus far. The hyper-IgD syndrome is diagnosed on the basis of characteristic clinical findings and continuously high IgD values (more than 100 IU per mL). During an attack, there is a brisk acute-phase response, with leukocytosis, high levels of serum C-reactive protein and serum amyloid A, and activation of the cytokine network (Drenth et al. 1995). A genome-wide search established the linkage of the susceptibility gene for the hyper-IgD syndrome to the long arm of chromosome 12 (Drenth et al. 1999; Houten et al. 1999a). This information, along with the fortuitous detection of mevalonic acid in a urine sample obtained during a febrile attack in a patient with the hyperIgD syndrome, led to the identification of mutations in the gene for mevalonate kinase as the cause of the syndrome (Drenth et al. 1999; Houten et al. 1999a). In patients with the hyper-IgD syndrome, the activity of mevalonate kinase is reduced to 5–15% of normal; as a result, serum cholesterol levels are slightly reduced, and during attacks, urinary excretion of mevalonic acid is slightly elevated. Less than 1% of patients have a complete deficiency of mevalonate kinase, which is associated with mevalonic aciduria, a rare inherited disorder characterized by developmental delay, failure to thrive, hypotonia, ataxia, myopathy, and cataracts. In mevalonic aciduria, the disease-associated mutations are mainly clustered within a specific region of the protein (Houten et al. 1999b). No uniformly successful treatment of the hyper-IgD syndrome is available. Patients with the hyper-IgD syndrome have febrile attacks throughout their lives, although the frequency of attacks is highest in childhood and adolescence. Patients may be free of attacks for months or even years. Amyloidosis has not been reported in association with the hyper-IgD syndrome.

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

131

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome (PAPA, MIM 604416) This syndrome, first described in 1997, is a rare autoinflammatory disease mainly involving the joints and the skin (Lindor et al. 1997). It is inherited in an autosomal dominant pattern and the disease gene was mapped to chromosome 15 (Yeon et al. 2000). Subsequently, the CD2-binding protein 1, CD2BP1, also called the proline/ serine/thronine phosphatase interacting protein 1, PSTPIP1, was reported as the PAPA syndrome susceptibility gene (Wise et al. 2002). The CD2BP1 protein appears to interact with pyrin where PAPA-associated mutations lead to increased binding to pyrin (Shoham et al. 2003). As a result, CD2BP1 may sequester pyrin and therefore reduce pyrin’s inhibitory role in regulation of the IL-1b pathway and the innate immune response. Individuals with PAPA syndrome typically develop cystic acne, sterile abscesses, and cutaneous ulcers, including pyoderma gangrenosum-like lesions. They may also develop sterile abscesses at injection sites (Lindor et al. 1997). Histologic examination of skin shows a superficial and deep perivascular, interstitial, periadnexal infiltrate predominantly consisting of lymphocytic and neutrophilic leukocytes. At a young age, patients with PAPA syndrome develop a severe sterile, pyogenic, destructive arthritis that affects the non-axial skeleton (Lindor et al. 1997). Corticosteroids can provide relief for patients with PAPA syndrome but their adverse effects often limit their use. Biologic therapies provide a possible new avenue for treatment, such as the TNF-a inhibitor etanercept (Cortis et al. 2004).

The Cryopyrinopathies Familial cold autoinflammatory syndrome (FCAS, MIM 120100), Muckle–Wells syndrome (MWS, MIM 191900), and neonatal-onset multisystem inflammatory disease (NOMID, MIM 607115), also called chronic infantile neurologic cutaneous and articular syndrome, or CINCA syndrome, represent unique disease entities, which are also known as the cryopyrinopathies. The cryopyrinopathies share a number of similar phenotypic features and appear to represent a continuum of disease, with FCAS at the mild end and NOMID/CINCA syndrome representing the severe end of the spectrum. Genetic studies using linkage analysis of large families with FCAS and MWS identified the susceptibility loci for these two disorders at chromosome 1q44.4 (Hoffman et al. 2000). In 2001, it was shown that both FCAS and MWS were associated with mutations in the same gene, CIAS1 (Dode et al. 2002; Hoffman et al. 2001a). CIAS1 encodes for cryopyrin (also called PYPAF1, NALP3, and CATERPILLER 1.1). Subsequently, it was shown that mutations in CIAS1 are also associated with NOMID/CINCA syndrome

132

H. El-Shanti and H.A. Majeed

(Aksentijevich et al. 2002; Feldmann et al. 2002). To date, more than 50 mutations in CIAS1 have been identified. Almost all of these mutations, except three, are missense mutations that are localized to exon 3 of CIAS1, which encodes for the NACHT domain. These findings suggest that the mutated cryopyrin may have a dominant negative or gain-of-function effect over the wild-type product (Neven et al. 2004). FCAS, also known as familial cold urticaria and MWS are rare autosomal dominant disorders that are characterized by fever, urticarial-like eruption, and limb pain (Hawkins et al. 2004; Muckle and Wellsm 1962). Erythematous and edematous papules and plaques are the most common dermatologic manifestations of FCAS and MCS. They are present in almost all patients in the first 6 months of life (Hoffman et al. 2001b). In addition to skin findings during attacks, patients with FCAS also have fever, headache, nausea, sweating, drowsiness, extreme thirst, conjunctivitis, blurred vision, ocular pain, and polyarthralgia. Progressive sensorineural hearing impairment, nephropathy, and amyloidosis are reported in MWS (Muckle 1979; Muckle and Wellsm 1962). In the past, aside from avoidance of cold exposure, there was no effective treatment for patients with FCAS or MWS. Nonsteroidal anti-inflammatory drugs are often used for relief of arthralgias. Therapy with high dose corticosteroids is effective, but adverse effects usually limit long term use. Anakinra, an IL-1 receptor antagonist, has been shown not only to prevent a recurrence of episodes but also to decrease a chronic inflammatory response that can lead to systemic amyloidosis (Hawkins et al. 2003, 2004; Hoffman et al. 2004). NOMID/CINCA syndrome is a rare inflammatory disease that is characterized by the triad of disabling arthropathy, skin eruption, and central nervous system inflammation. Patients have progressively worsening visual, auditory, and nervous system manifestations. Only a few cases of NOMID/CINCA syndrome have been reported with autosomal dominant transmission, but most cases seem sporadic (Aksentijevich et al. 2002; Feldmann et al. 2002). Nonpruritic, migratory eruption of edematous papules and plaques, which fluctuates in intensity, arises in a large percentage of patients with NOMID/CINCA syndrome (Prieur 2001) About twothirds of affected newborns have the “urticaria-like eruption” at birth, and most develop it in the first 6 months of life. Patients with NOMID/CINCA syndrome commonly have short episodes of recurrent fevers. They also develop an assortment of neurologic abnormalities, including headaches, macrocephaly, cerebral atrophy, chronic aseptic meningitis, high-frequency hearing loss, and developmental delay (Mallouh et al. 1987). Arthropathy, varying greatly in severity between patients, may develop (Mallouh et al. 1987). High-dose steroids have been effective in attenuating pain and inflammation, but in general do not alleviate the other manifestations of disease. Recently, there have been several reports of patients with NOMID who had a dramatic response to treatment with the IL-1 receptor antagonist, anakinra (Goldbach-Mansky et al. 2006, 2008).

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

133

References Aganna E, Zeharia A, Hitman GA, Basel-Vanagaite L, Allotey RA, Booth DR, Hawkins PN, Thacker C, Syndercombe-Court D, McDermott MF (2002) An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 46(1):245–249 Aivazian AA, Zavgorodniaia AM, Abramian MK, Pashinian SA, Bagdasarian GB (1977) Immunogenesis of periodic disease. Klin Med (Mosk) 55(2):91–97 Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G et al (1999) Mutation and haplotype studies of Familial Mediterranean Fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64(4):949–962 Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P et al (2002) De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 46(12):3340–3348 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean Fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56(3):960–964 Armenian HK, Khachadurian AK (1973) Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26(6):605–614 Arostegui JI, Solis P, Aldea A, Cantero T, Rius J, Bahillo P, Plaza S, Vives J, Gomez S, Yague J (2005) Etanercept plus colchicine treatment in a child with tumour necrosis factor receptorassociated periodic syndrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response. Eur J Pediatr 164(1):13–16 Ayesh SK, Nassar SM, Al-Sharef WA, Abu-Libdeh BY, Darwish HM (2005) Genetic screening of Familial Mediterranean Fever mutations in the Palestinian population. Saudi Med J 26(5):732–737 Azizi E, Fisher BK (1976) Cutaneous manifestations of Familial Mediterranean Fever. Arch Dermatol 112(3):364–366 Bakir F, Murtadha M (1975) Periodic peritonitis. Report of 41 cases without amyloidosis. Trans R Soc Trop Med Hyg 69(1):111–117 Balci B, Tinaztepe K, Yilmaz E, Gucer S, Ozen S, Topaloglu R, Besbas N, Ozguc M, Bakkaloglu A (2002) MEFV gene mutations in Familial Mediterranean Fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant 17(11):1921–1923 Barakat MH, El-Khawad AO, Gumaa KA, El-Sobki NI, Fenech FF (1984a) Metaraminol provocative test: a specific diagnostic test for Familial Mediterranean Fever. Lancet 1(8378):656–657 Barakat MH, El-Sobki NI, El-Khawad AO, Gumma KA, Fenech FF (1984b) Diagnosing Familial Mediterranean Fever letter. Lancet 2(8393):41–42 Barakat MH, Karnik AM, Majeed HW, El-Sobki NI, Fenech FF (1986) Familial Mediterranean Fever (recurrent hereditary polyserositis) in Arabs–a study of 175 patients and review of the literature. Q J Med 60(233):837–847 Barakat MH, Mustafa HT, Shakir RA (1988) Mollaret’s meningitis. A variant of recurrent hereditary polyserositis, both provoked by metaraminol. Arch Neurol 45(8):926–927 Barzilai A, Langevitz P, Goldberg I, Kopolovic J, Livneh A, Pras M, Trau H (2000) Erysipelaslike erythema of Familial Mediterranean Fever: clinicopathologic correlation. J Am Acad Dermatol 42(5 Pt 1):791–795

134

H. El-Shanti and H.A. Majeed

Ben Becher S, Essaddam H, Nahali N, Ben Hamadi F, Mouelhi MH, Hammou A, Hadj Romdhane L, Ben Cheikh M, Boudhina T, Dargouth M (1991) Recurrent multifocal periostosis in children. Report of a familial form. Ann Pediatr (Paris) 38(5):345–349 Ben-Chetrit E, Levy M (1991) Colchicine prophylaxis in Familial Mediterranean Fever: reappraisal after 15 years. Semin Arthritis Rheum 20(4):241–246 Ben-Chetrit E, Levy M (1998) Colchicine: 1998 update. Semin Arthritis Rheum 28(1):48–59 Ben-Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D (2000) The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum Mutat 15(4):385–386 Ben-Chetrit E, Urieli-Shoval S, Calko S, Abeliovich D, Matzner Y (2002) Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals. Clin Exp Rheumatol 20(4 suppl 26): S25–S29 Bergdahl K, Bjorksten B, Gustavson KH, Liden S, Probst F (1979) Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica 159(1):37–45 Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet V, Ahmed-Arab M, Dross C, Dupont M, Cattan D et al (1998) Non-founder mutations in the MEFV gene establish this gene as the cause of Familial Mediterranean Fever (FMF). Hum Mol Genet 7(8):1317–1325 Bjorksten B, Boquist L (1980) Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg [Br] 62(3):376–380 Bjorksten B, Gustavson KH, Eriksson B, Lindholm A, Nordstrom S (1978) Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr 93(2):227–231 Bognar M, Blake W, Agudelo C (1998) Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci 315(2):133–135 Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN (1998) Pyrin/marenostrin mutations in Familial Mediterranean Fever. QJM 91(9):603–606 Brik R, Shinawi M, Kepten I, Berant M, Gershoni-Baruch R (1999) Familial Mediterranean Fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics 103(5):e70 Brik R, Litmanovitz D, Berkowitz D, Shamir R, Rosenthal E, Shinawi M, Gershoni-Baruch R (2001) Incidence of Familial Mediterranean Fever (FMF) mutations among children of Mediterranean extraction with functional abdominal pain. J Pediatr 138(5):759–762 Buskila D, Zaks N, Neumann L, Livneh A, Greenberg S, Pras M, Langevitz P (1997) Quality of life of patients with Familial Mediterranean Fever. Clin Exp Rheumatol 15(4):355–360 Byrd L, Grossmann M, Potter M, Shen-Ong GL (1991) Chronic multifocal osteomyelitis, a new recessive mutation on chromosome 18 of the mouse. Genomics 11(4):794–798 Cabili S, Zemer D, Pras M, Aviram A, Sohar E, Gafni J (1985) The prevention of amyloidosis in Familial Mediterranean Fever with colchicine. Proc Eur Dial Transplant Assoc Eur Ren Assoc 21:709–711 Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, Ayvazyan A, Kouyoumdjian JC, Ajrapetyan H, Delpech M et al (1999) MEFV-Gene analysis in armenian patients with Familial Mediterranean Fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet 65(1):88–97 Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM et al (2000) The gene for Familial Mediterranean Fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95(10):3223–3231 Chaabouni HB, Ksantini M, M’Rad R, Kharrat M, Chaabouni M, Maazoul F, Bahloul Z, Ben Jemaa L, Ben Moussa F, Ben Chaabane T et al (2007) MEFV mutations in Tunisian patients suffering from Familial Mediterranean Fever. Semin Arthritis Rheum 36(6):397–401 Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, Kastner DL (2003) Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell 11(3):591–604

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

135

Cortis E, De Benedetti F, Insalaco A, Cioschi S, Muratori F, D’Urbano LE, Ugazio AG (2004) Abnormal production of tumor necrosis factor (TNF) – alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected]. J Pediatr 145(6):851–855 Dewalle M, Domingo C, Rozenbaum M, Ben-Chetrit E, Cattan D, Bernot A, Dross C, Dupont M, Notarnicola C, Levy M et al (1998) Phenotype-genotype correlation in Jewish patients suffering from Familial Mediterranean Fever (FMF). Eur J Hum Genet 6(1):95–97 Diaz A, Hu C, Kastner DL, Schaner P, Reginato AM, Richards N, Gumucio DL (2004) Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-terminal domain that is highly mutated in Familial Mediterranean Fever. Arthritis Rheum 50(11):3679–3689 Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G (2000) Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of Familial Mediterranean Fever. Am J Med Genet 92(4):241–246 Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A et al (2002) New mutations of CIAS1 that are responsible for Muckle–Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet 70(6):1498–1506 Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Nunez G (2003) Regulation of cryopyrin/ Pypaf1 signaling by pyrin, the Familial Mediterranean Fever gene product. Biochem Biophys Res Commun 302(3):575–580 Drenth JP, Boom BW, Toonstra J, Van der Meer JW (1994a) Cutaneous manifestations and histologic findings in the hyperimmunoglobulinemia D syndrome International Hyper IgD Study Group. Arch Dermatol 130(1):59–65 Drenth JP, Haagsma CJ, van der Meer JW (1994b) Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 73(3):133–144 Drenth JP, Mariman EC, Van der Velde-Visser SD, Ropers HH, Van der Meer JW (1994c) Location of the gene causing hyperimmunoglobulinemia D and periodic fever syndrome differs from that for Familial Mediterranean Fever. International Hyper-IgD Study Group. Hum Genet 94(6):616–620 Drenth JP, van Deuren M, van der Ven-Jongekrijg J, Schalkwijk CG, van der Meer JW (1995) Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Blood 85(12):3586–3593 Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD, de Jong JG, Beckmann JS, van der Meer JW, Delpech M (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22(2):178–181 Ehrenfeld M, Brzezinski A, Levy M, Eliakim M (1987) Fertility and obstetric history in patients with Familial Mediterranean Fever on long-term colchicine therapy. Br J Obstet Gynaecol 94 (12):1186–1191 El-Shanti HI, Ferguson PJ (2007) Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–19 El-Shanti H, Majeed HA, El-Khateeb M (2006) Familial Mediterranean Fever in Arabs. Lancet 367(9515):1016–1024 Eshel G, Zemer D, Bar-Yochai A (1988) Acute orchitis in Familial Mediterranean Fever. Ann Intern Med 109(2):164–165 Eshel G, Vinograd I, Barr J, Zemer D (1994) Acute scrotal pain complicating Familial Mediterranean Fever in children. Br J Surg 81(6):894–896 Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint BG (2002) Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71(1):198–203

136

H. El-Shanti and H.A. Majeed

Ferguson PJ, El-Shanti HI (2007) Autoinflammatory bone disorders. Curr Opin Rheumatol 19(5):492–498 Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42(7):551–557 Ferguson PJ, Bing X, Vasef MA, Ochoa LA, Mahgoub A, Waldschmidt TJ, Tygrett LT, Schlueter AJ, El-Shanti H (2006) A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. Bone 38(1):41–47 Festen JJ, Kuipers FC, Schaars AH (1985) Multifocal recurrent periostitis responsive to colchicine. Scand J Rheumatol 14(1):8–14 Flatau E, Kohn D, Schiller D, Lurie M, Levy E (1982) Schonlein–Henoch syndrome in patients with Familial Mediterranean Fever. Arthritis Rheum 25(1):42–47 French FMF Consortium (1997) A candidate gene for Familial Mediterranean Fever. Nat Genet 17:25–31 Gafni J, Ravid M, Sohar E (1968) The role of amyloidosis in Familial Mediterranean Fever. A population study. Isr J Med Sci 4(5):995–999 Gedalia A, Zamir S (1993) Neurologic manifestations in Familial Mediterranean Fever. Pediatr Neurol 9(4):301–302 Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean Fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9(8):634–637 Gershoni-Baruch R, Brik R, Shinawi M, Livneh A (2002a) The differential contribution of MEFV mutant alleles to the clinical profile of Familial Mediterranean Fever. Eur J Hum Genet 10(2):145–149 Gershoni-Baruch R, Shinawi M, Shamaly H, Katsinetz L, Brik R (2002b) Familial Mediterranean Fever: the segregation of four different mutations in 13 individuals from one inbred family: genotype-phenotype correlation and intrafamilial variability. Am J Med Genet 109 (3):198–201 Gershoni-Baruch R, Broza Y, Brik R (2003) Prevalence and significance of mutations in the Familial Mediterranean Fever gene in Henoch–Schonlein purpura. J Pediatr 143 (5):658–661 Gertz MA, Petitt RM, Perrault J, Kyle RA (1987) Autosomal dominant Familial Mediterranean Fever-like syndrome with amyloidosis. Mayo Clin Proc 62(12):1095–1100 Giedion A, Holthusen W, Masel LF, Vischer D (1972) Subacute and chronic “symmetrical” osteomyelitis. Ann Radiol (Paris) 15(3):329–342 Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, Muller-Hermelink HK, Papadopoulos T (1999) Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 30(1):59–65 Girschick HJ, Raab P, Surbaum S, Trusen A, Kirschner S, Schneider P, Papadopoulos T, MullerHermelink HK, Lipsky PE (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64(2):279–285 Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355(6):581–592 Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH et al (2008) A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 58(8):2432–2442 Goldfinger SE (1972) Colchicine for Familial Mediterranean Fever. N Engl J Med 287 (25):1302 Golla A, Jansson A, Ramser J, Hellebrand H, Zahn R, Meitinger T, Belohradsky BH, Meindl A (2002) Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3–18q22. Eur J Hum Genet 10(3):217–221

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

137

Grosse J, Chitu V, Marquardt A, Hanke P, Schmittwolf C, Zeitlmann L, Schropp P, Barth B, Yu P, Paffenholz R et al (2006) Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease. Blood 107(8):3350–3358 Gruberg L, Aksentijevich I, Pras E, Kastner DL, Pras M (1992) Mapping of the Familial Mediterranean Fever gene to chromosome 16. Am J Reprod Immunol 28(3–4):241–242 Hawkins PN, Lachmann HJ, McDermott MF (2003) Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N Engl J Med 348(25):2583–2584 Hawkins PN, Lachmann HJ, Aganna E, McDermott MF (2004) Spectrum of clinical features in Muckle–Wells syndrome and response to anakinra. Arthritis Rheum 50(2):607–612 Heller H, Sohar E, Sherf L (1958) Familial Mediterranean Fever. AMA Arch Intern Med 102 (1):50–71 Heller H, Sohar E, Gafni J, Heller J (1961) Amyloidosis in Familial Mediterranean Fever. Arch Intern Med 107:539–550 Heller H, Gafni J, Michaeli D, Shahin N, Sohar E, Ehrlich G, Karten I, Sokoloff L (1966) The arthritis of Familial Mediterranean Fever (FMF). Arthritis Rheum 9(1):1–17 Hentunen TA, Choi SJ, Boyce BF, Dallas MR, Dallas SL, Shen-Ong GL, Roodman GD (2000) A murine model of inflammatory bone disease. Bone 26(2):183–188 Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD (2000) Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet 66(5):1693–1698 Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD (2001a) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29(3):301–305 Hoffman HM, Wanderer AA, Broide DH (2001b) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108(4):615–620 Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, Anderson JP, Wanderer AA, Firestein GS (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364(9447):1779–1785 Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA et al (1999a) Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet 22 (2):175–177 Houten SM, Romeijn GJ, Koster J, Gray RG, Darbyshire P, Smit GP, de Klerk JB, Duran M, Gibson KM, Wanders RJ et al (1999b) Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. Hum Mol Genet 8(8):1523–1528 Huber AM, Lam PY, Duffy CM, Yeung RS, Ditchfield M, Laxer D, Cole WG, Kerr Graham H, Allen RC, Laxer RM (2002) Chronic recurrent multifocal osteomyelitis: clinical outcomes after more than five years of follow-up. J Pediatr 141(2):198–203 International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause Familial Mediterranean Fever. Cell 90:797–807 Ismajovich B, Zemer D, Revach M, Serr DM, Sohar E (1973) The causes of sterility in females with Familial Mediterranean Fever. Fertil Steril 24(11):844–847 Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, Grote V, Diebold J, Jansson V, Schneider K et al (2007) Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 46(1):154–160 Jarjour RA (2010) Familial Mediterranean fever in Syrian patients: MEFV gene mutations and genotype-phenotype correlation. Mol Bio Rep 37(1):1–5 Jesus AA, Oliveira JB, Aksentijevich I, Fujihira E, Carneiro-Sampaio MM, Duarte AJ, Silva CA (2008) TNF receptor-associated periodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept. Eur J Pediatr 167(12):1421–1425 Jurik AG (2004) Chronic recurrent multifocal osteomyelitis. Semin Musculoskelet Radiol 8(3):243–253

138

H. El-Shanti and H.A. Majeed

Karachaliou I, Karachalios G, Charalabopoulos A, Charalabopoulos K (2005) Meningitis associated with Familial Mediterranean Fever. Int J Clin Pract Suppl 147:60–61 Kasifoglu T, Cansu DU, Korkmaz C (2009) Frequency of abdominal surgery in patients with Familial Mediterranean Fever. Intern Med 48(7):523–526 Kastner DL (2005) Hereditary periodic Fever syndromes. Hematology Am Soc Hematol Educ Program 2005:74–81 Kees S, Langevitz P, Zemer D, Padeh S, Pras M, Livneh A (1997) Attacks of pericarditis as a manifestation of Familial Mediterranean Fever (FMF). QJM 90(10):643–647 Khachadurian AK, Armenian HK (1974) Familial paroxysmal polyserositis (Familial Mediterranean Fever); incidence of amyloidosis and mode of inheritance. Birth Defects Orig Artic Ser 10 (4):62–66 Kogan A, Shinar Y, Lidar M, Revivo A, Langevitz P, Padeh S, Pras M, Livneh A (2001) Common MEFV mutations among Jewish ethnic groups in Israel: high frequency of carrier and phenotype III states and absence of a perceptible biological advantage for the carrier state. Am J Med Genet 102(3):272–276 Konstantopoulos K, Kanta A, Tzoulianos M, Dimou S, Sotsiou F, Politou M, Loukopoulos D (2001) Familial Mediterranean Fever phenotype II in Greece. Isr Med Assoc J 3(11):862–863 Kotevoglu N, Sahin F, Ozkiris SO, Bankaoglu M, Sakiz D, Kuran B (2004) Protracted febrile myalgia of Familial Mediterranean Fever. Clin Exp Rheumatol 22(4 Suppl 34):S69–S70 Langevitz P, Zemer D, Livneh A, Shemer J, Pras M (1994) Protracted febrile myalgia in patients with Familial Mediterranean Fever. J Rheumatol 21(9):1708–1709 Laxer RM, Shore AD, Manson D, King S, Silverman ED, Wilmot DM (1988) Chronic recurrent multifocal osteomyelitis and psoriasis–a report of a new association and review of related disorders. Semin Arthritis Rheum 17(4):260–270 Lindor NM, Arsenault TM, Solomon H, Seidman CE, McEvoy MT (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72(7):611–615 Livneh A, Madgar I, Langevitz P, Zemer D (1994) Recurrent episodes of acute scrotum with ischemic testicular necrosis in a patient with Familial Mediterranean Fever. J Urol 151 (2):431–432 Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of Familial Mediterranean Fever. Arthritis Rheum 40 (10):1879–1885 Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E (1999) MEFV mutation analysis in patients suffering from amyloidosis of Familial Mediterranean Fever. Amyloid 6(1):1–6 Majeed HA (2000) Differential diagnosis of fever of unknown origin in children. Curr Opin Rheumatol 12(5):439–444 Majeed HA, Barakat M (1989) Familial Mediterranean Fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 148:636–641 Majeed HA, Rawashdeh M (1997) The clinical patterns of arthritis in children with Familial Mediterranean Fever. QJM 90(1):37–43 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115(5 Pt 1):730–734 Majeed HA, Quabazard Z, Hijazi Z, Farwana S, Harshani F (1990) The cutaneous manifestations in children with Familial Mediterranean Fever (recurrent hereditary polyserositis). A six-year study. Q J Med 75(278):607–616 Majeed HA, Halabi I, al-Taleb O (1998) Recurrent hyperbilirubinaemia, a feature of Familial Mediterranean Fever: report of a child and review of the literature. Ann Trop Paediatr 18(1):13–15

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

139

Majeed HA, Rawashdeh M, El-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM (1999) Familial Mediterranean Fever in children: the expanded clinical profile. QJM 92(6):309–318 Majeed HA, Al-Qudah AK, Qubain H, Shahin HM (2000a) The clinical patterns of myalgia in children with Familial Mediterranean Fever. Semin Arthritis Rheum 30(2):138–143 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N (2000b) On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 137(3):441–442 Majeed HA, Ghandour K, Shahin HM (2000c) The acute scrotum in Arab children with Familial Mediterranean Fever. Pediatr Surg Int 16(1–2):72–74 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160(12):705–710 Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA (2002) Genotype/phenotype correlations in Arab patients with Familial Mediterranean Fever. Semin Arthritis Rheum 31(6):371–376 Majeed HA, El-Khateeb M, El-Shanti H, Abu Rabaiha Z, Tayeh M, Najib D (2005a) The spectrum of Familial Mediterranean Fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–818 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005b) The spectrum of Familial Mediterranean Fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–818 Mallouh A, Abu-Osba YK, Talab Y (1987) Infantile-onset arthritis and multisystem inflammatory disease: “a new syndrome”. J Pediatr Orthop 7(2):227–230 Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL (2001) The Familial Mediterranean Fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98(3):851–859 Mansour I, Delague V, Cazeneuve C, Dode C, Chouery E, Pecheux C, Medlej-Hashim M, Salem N, El Zein L, Levan-Petit I et al (2001) Familial Mediterranean Fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations. Eur J Hum Genet 9(1):51–55 Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S et al (2003) ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun 303(1):69–73 Mattit H, Joma M, Al-Cheikh S, El-Khateeb M, Medlej-Hashim M, Salem N, Delague V, Megarbane A (2006) Familial Mediterranean Fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. Eur J Med Genet 49 (6):481–486 Matzner Y, Abedat S, Shapiro E, Eisenberg S, Bar-Gil-Shitrit A, Stepensky P, Calco S, Azar Y, Urieli-Shoval S (2000) Expression of the Familial Mediterranean Fever gene and activity of the C5a inhibitor in human primary fibroblast cultures. Blood 96(2):727–731 McDermott EM, Smillie DM, Powell RJ (1997) Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc 72 (9):806–817 McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T et al (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97(1):133–144 McGonagle D, McDermott MF (2006) A proposed classification of the immunological diseases. PLoS Med 3(8):e297 Medlej-Hashim M, Rawashdeh M, Chouery E, Mansour I, Delague V, Lefranc G, Naman R, Loiselet J, Megarbane A (2000) Genetic screening of fourteen mutations in Jordanian Familial Mediterranean Fever patients. Hum Mutat 15(4):384

140

H. El-Shanti and H.A. Majeed

Medlej-Hashim M, Petit I, Adib S, Chouery E, Salem N, Delague V, Rawashdeh M, Mansour I, Lefranc G, Naman R et al (2001) Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations. Eur J Hum Genet 9(11):849–854 Medlej-Hashim M, Salem N, Chouery E, Rawashdeh M, Delague V, Haffar M, Mansour I, Naman R, Lefranc G, Loiselet J et al (2002) Familial Mediterranean Fever: the potential for misdiagnosis of E148V using the E148Q usual RFLP detection method. Clin Genet 61(1):71–73 Medlej-Hashim M, Delague V, Chouery E, Salem N, Rawashdeh M, Lefranc G, Loiselet J, Megarbane A (2004) Amyloidosis in Familial Mediterranean Fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 5(1):4 Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G et al (2005) Familial Mediterranean Fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48 (4):412–420 Melikoglu M, Ozdogan H, Korkmaz C, Kasapcopur O, Arisoy N, Akkus S, Fresko Z, Yazici H (2000) A survey of phenotype II in Familial Mediterranean Fever. Ann Rheum Dis 59 (11):910–913 Michaeli D, Pras M, Rozen N (1966) Intestinal strangulation complicating Familial Mediterranean Fever. BMJ 2:30–31 Mijatovic V, Hompes PG, Wouters MG (2003) Familial Mediterranean Fever and its implications for fertility and pregnancy. Eur J Obstet Gynecol Reprod Biol 108(2):171–176 Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, Sarrauste de Menthiere C et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29(6):803–808 Mor A, Shinar Y, Zaks N, Langevitz P, Chetrit A, Shtrasburg S, Rabinovitz E, Livneh A (2005) Evaluation of disease severity in Familial Mediterranean Fever. Semin Arthritis Rheum 35 (1):57–64 Morbach H, Richl P, Stojanov S, Lohse P, Girschick HJ (2009) Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment. Rheumatol Int Muckle TJ (1979) The ‘Muckle–Wells’ syndrome. Br J Dermatol 100(1):87–92 Muckle TJ, Wellsm (1962) Urticaria, deafness, and amyloidosis: a new heredo-familial syndrome. Q J Med 31:235–248 Mulley J, Saar K, Hewitt G, Ruschendorf F, Phillips H, Colley A, Sillence D, Reis A, Wilson M (1998) Gene localization for an autosomal dominant familial periodic fever to 12p13. Am J Hum Genet 62(4):884–889 Neequaye J, Jelly AE (1994) Acute hepatitis in recurrent hereditary polyserositis (Familial Mediterranean Fever). J Trop Pediatr 40(4):243–245 Neven B, Callebaut I, Prieur AM, Feldmann J, Bodemer C, Lepore L, Derfalvi B, Benjaponpitak S, Vesely R, Sauvain MJ et al (2004) Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/ NOMID, MWS, and FCU. Blood 103(7):2809–2815 Ozdemir AI, Sokmen C (1969) Familial Mediterranean Fever among the Turkish people. Am J Gastroenterol 51(4):311–316 Ozer FL, Kaplaman E, Zileli S (1971) Familial Mediterranean Fever in Turkey. A report of twenty cases. Am J Med 50(3):336–339 Ozkan E, Okur O, Ekmekci A, Ozcan R, Tag T (1972) A new approach to the treatment of periodic fever. Med Bull Istanbul 5:44–49 Padeh S (2005) Periodic fever syndromes. Pediatr Clin North Am 52(2):577–609, vii Padeh S, Shinar Y, Pras E, Zemer D, Langevitz P, Pras M, Livneh A (2003) Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean Fever. J Rheumatol 30(1):185–190

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

141

Papin S, Duquesnoy P, Cazeneuve C, Pantel J, Coppey-Moisan M, Dargemont C, Amselem S (2000) Alternative splicing at the MEFV locus involved in Familial Mediterranean Fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Hum Mol Genet 9(20):3001–3009 Pras M, Bronshpigel N, Zemer D, Gafni J (1982) Variable incidence of amyloidosis in Familial Mediterranean Fever among different ethnic groups. Johns Hopkins Med J 150(1):22–26 Pras E, Aksentijevich I, Gruberg L, Balow JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing Familial Mediterranean Fever to the short arm of chromosome 16. N Engl J Med 326(23):1509–1513 Pras E, Aksentijevich I, Levy E, Gruberg L, Prosen L, Dean M, Pras M, Kastner DL (1994) The gene causing Familial Mediterranean Fever maps to the short arm of chromosome 16 in Druze and Moslem Arab families. Hum Genet 94(5):576–577 Pras E, Livneh A, Balow JE Jr, Kastner DL, Pras M, Langevitz P (1998) Clinical differences between North African and Iraqi Jews with Familial Mediterranean Fever. Am J Med Genet 75(2):216–219 Priest RJ, Nixon RK (1959) Familial recurring polyserositis: a disease entity. Ann Intern Med 51:1253–1274 Prieur AM (2001) A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy. Clin Exp Rheumatol 19(1):103–106 Pugnere D, Ruiz M, Sarrauste de Menthiere C, Masdoua B, Demaille J, Touitou I (2003) The MetaFMF website: a high quality tool for meta-analysis of FMF. Nucleic Acids Res 31(1):286–290 Rabinovitch O, Zemer D, Kukia E, Sohar E, Mashiach S (1992) Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with Familial Mediterranean Fever. Am J Reprod Immunol 28(3–4):245–246 Rawashdeh MO, Majeed HA (1996) Familial Mediterranean Fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr 155(7):540–544 Saatci U, Bakkaloglu A, Ozen S, Besbas N (1993) Familial Mediterranean Fever and amyloidosis in children. Acta Paediatr 82(8):705–706 Saatci U, Ozen S, Ozdemir S, Bakkaloglu A, Besbas N, Topaloglu R, Arslan S (1997) Familial Mediterranean Fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr 156(8):619–623 Sabbagh AS, Ghasham M, Abdel Khalek R, Greije L, Shammaa DM, Zaatari GS, Mahfouz RA (2008) MEFV gene mutations spectrum among Lebanese patients referred for Familial Mediterranean Fever work-up: experience of a major tertiary care center. Mol Biol Rep 35(3):447–451 Sachs D, Langevitz P, Morag B, Pras M (1987) Polyarteritis nodosa and Familial Mediterranean Fever. Br J Rheumatol 26(2):139–141 Said R, Hamzeh Y (1990) IgM nephropathy associated with Familial Mediterranean Fever. Clin Nephrol 33(5):227–231 Said R, Nasrallah N, Hamzah Y, Tarawneh M, al-Khatib M (1988) IgA nephropathy in patients with Familial Mediterranean Fever. Am J Nephrol 8(5):417–420 Said R, Hamzeh Y, Tarawneh M, el-Khateeb M, Abdeen M, Shaheen A (1989) Rapid progressive glomerulonephritis in patients with Familial Mediterranean Fever. Am J Kidney Dis 14 (5):412–416 Said R, Hamzeh Y, Said S, Tarawneh M, al-Khateeb M (1992) Spectrum of renal involvement in Familial Mediterranean Fever. Kidney Int 41(2):414–419 Salai M, Zemmer D, Segal E, Corat A, Heyman Z, Davidson B, Langevitz P, Livneh A (1997) Chronic massive knee effusion in Familial Mediterranean Fever. Semin Arthritis Rheum 27(3):169–172 Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL (1998) Familial Mediterranean Fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 77(4):268–297

142

H. El-Shanti and H.A. Majeed

Sarrauste de Menthiere C, Terriere S, Pugnere D, Ruiz M, Demaille J, Touitou I (2003) INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res 31(1):282–285 Sayarlioglu M, Cefle A, Inanc M, Kamali S, Dalkilic E, Gul A, Ocal L, Aral O, Konice M (2005) Characteristics of patients with adult-onset Familial Mediterranean Fever in Turkey: analysis of 401 cases. Int J Clin Pract 59(2):202–205 Schlesinger M, Rubinow A, Vardy PA (1985) Henoch-Schonlein purpura and Familial Mediterranean Fever. Isr J Med Sci 21(1):83–85 Schultz C, Holterhus PM, Seidel A, Jonas S, Barthel M, Kruse K, Bucsky P (1999) Chronic recurrent multifocal osteomyelitis in children. Pediatr Infect Dis J 18(11):1008–1013 Schwabe AD, Monroe JB (1988) Meningitis in Familial Mediterranean Fever. Am J Med 85(5):715–717 Schwabe AD, Peters RS (1974) Familial Mediterranean Fever in Armenians. Analysis of 100 cases. Medicine (Baltimore) 53(6):453–462 Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, Kastner DL, Pras M, Pras E (2000) Genotype-phenotype assessment of common genotypes among patients with Familial Mediterranean Fever. J Rheumatol 27(7):1703–1707 Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL (2003) Pyrin binds the PSTPIP1/CD2BP1 protein, defining Familial Mediterranean Fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci USA 100 (23):13501–13506 Shohat M, Bu X, Shohat T, Fischel-Ghodsian N, Magal N, Nakamura Y, Schwabe AD, Schlezinger M, Danon Y, Rotter JI (1992a) The gene for Familial Mediterranean Fever in both Armenians and non-Ashkenazi Jews is linked to the alpha-globin complex on 16p: evidence for locus homogeneity. Am J Hum Genet 51(6):1349–1354 Shohat M, Danon YL, Rotter JI (1992b) Familial Mediterranean Fever: analysis of inheritance and current linkage data. Am J Med Genet 44(2):183–188 Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A et al (1999) Phenotype-genotype correlation in Familial Mediterranean Fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 7(3):287–292 Sidi G, Shinar Y, Livneh A, Langevitz P, Pras M, Pras E (2000) Protracted febrile myalgia of Familial Mediterranean Fever. Mutation analysis and clinical correlations. Scand J Rheumatol 29(3):174–176 Siegal S (1945) Benign paroxysmal peritonitis. Ann Intern Med 23:1–21 Sneh E, Pras M, Michaeli D, Shanin N, Gafni J (1977) Protracted arthritis in Familial Mediterranean Fever. Rheumatol Rehabil 16(2):102–106 Sohar E, Pras M, Heller J, Heller H (1961) Genetics of Familial Mediterranean Fever. Arch Intern Med 107:529–538 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean Fever. A survey of 470 cases and review of the literature. Am J Med 43(2):227–253 Stehlik C, Reed JC (2004) The PYRIN connection: novel players in innate immunity and inflammation. J Exp Med 200(5):551–558 Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, Danon Y, Halpern GJ, Lifshitz Y, Shohat M (2000) Higher than expected carrier rates for Familial Mediterranean Fever in various Jewish ethnic groups. Eur J Hum Genet 8(4):307–310 Stojanov S, Kastner DL (2005) Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 17(5):586–599 Touitou I (2001) The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9(7):473–483 Touitou I, Lesage S, McDermott M, Cuisset L, Hoffman H, Dode C, Shoham N, Aganna E, Hugot JP, Wise C et al (2004) Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 24(3):194–198

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders

143

Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalcinkaya F, Ozen S, Majeed H, Ozdogan H et al (2007) Country as the primary risk factor for renal amyloidosis in Familial Mediterranean Fever. Arthritis Rheum 56(5):1706–1712 Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, Tutar E, Ozen S, Topaloglu R, Yilmaz E et al (2005) Familial Mediterranean Fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84(1):1–11 van der Meer JW, Vossen JM, Radl J, van Nieuwkoop JA, Meyer CJ, Lobatto S, van Furth R (1984) Hyperimmunoglobulinaemia D and periodic fever: a new syndrome. Lancet 1 (8386):1087–1090 Vilaseca J, Tor J, Guardia J, Bacardi R (1982) Periodic meningitis and Familial Mediterranean Fever. Arch Intern Med 142(2):378–379 Williamson LM, Hull D, Mehta R, Reeves WG, Robinson BH, Toghill PJ (1982) Familial Hibernian fever. Q J Med 51(204):469–480 Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, Lovett M (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11(8):961–969 Yalcinkaya F, Tekin M, Tumer N, Ozkaya N (1997) Protracted arthritis of Familial Mediterranean Fever (an unusual complication). Br J Rheumatol 36(11):1228–1230 Yalcinkaya F, Cakar N, Misirlioglu M, Tumer N, Akar N, Tekin M, Tastan H, Kocak H, Ozkaya N, Elhan AH (2000) Genotype-phenotype correlation in a large group of Turkish patients with Familial Mediterranean Fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford) 39(1):67–72 Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N, Cakar N, Duzova A, Kasapcopur O, Elhan AH, Doganay B, Ekim M et al (2009) A new set of criteria for the diagnosis of Familial Mediterranean Fever in childhood. Rheumatology (Oxford) 48(4):395–398 Yeon HB, Lindor NM, Seidman JG, Seidman CE (2000) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 66(4):1443–1448 Yilmaz E, Ozen S, Balci B, Duzova A, Topaloglu R, Besbas N, Saatci U, Bakkaloglu A, Ozguc M (2001) Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 9(7):553–555 Yu JW, Wu J, Zhang Z, Datta P, Ibrahimi I, Taniguchi S, Sagara J, Fernandes-Alnemri T, Alnemri ES (2005) Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ 13(2):236–249 Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M (1995) Dominant inheritance in two families with Familial Mediterranean Fever (FMF). Am J Med Genet 57(3):455–457 Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, Gafni J (1974) A controlled trial of colchicine in preventing attacks of Familial Mediterranean Fever. N Engl J Med 291 (18):932–934 Zemer D, Livneh A, Danon YL, Pras M, Sohar E (1991) Long-term colchicine treatment in children with Familial Mediterranean Fever. Arthritis Rheum 34(8):973–977

Chapter 6

Muscular Dystrophies and Myopathies in Arab Populations Mustafa A.M. Salih

Interest in neuromuscular disorders has grown rapidly in recent years as knowledge of their molecular basis has advanced and the search for potential treatment by gene or cell therapy has begun. (Allamand et al. 2000; Cordier et al. 2000; Dressman et al. 2002; Yakota et al. 2009). This chapter gives an overview of the epidemiologic, clinical, and laboratory studies of muscular dystrophies (MDs) and myopathies reported in Arab communities.

Epidemiology The data presented here, though scarce, came mainly from retrospective surveys of medical records in secondary- and tertiary-care hospitals, or from smaller prospective series of selected neuromuscular disorders. One of these was a 3-year search (January 1983–December 1985) for certain conditions in the sole neurology center in the Benghazi region of Libya (Radhakrishnan et al. 1987). This study included 34 patients with Duchenne muscular dystrophy (DMD): 25 were index cases; 19 MD (13 index cases); 4 had fascioscapulohumeral MD (3 index cases); 3 had opthamoplegia plus (all index cases); and 41 were index cases of hereditary motor and sensory neuropathy (HMSN). The estimated overall prevalence of MDs was 132/106 (1,000,000), DMD being the most common of them (60/106). The overall prevalence is less than half the figure (286/106) estimated by Emery (1991) in a world survey, whereas the prevalence of DMD was about twice as high (Table 6.1). This might have resulted from the inherent problems of ascertainment in the study from Benghazi, since histopathological confirmation (using light microscopy) was possible in about half of the cases, whereas facilities for electron microscopy and enzyme histochemistry were not available. M.A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_6, # Springer-Verlag Berlin Heidelberg 2010

145

146

M.A.M. Salih

Table 6.1 Prevalence rate (per million population) of selected muscular dystrophies among Arabs compared to a world survey prevalence Muscular dystrophies Study Location/ Overall Duchenne Limb“DuchenneMyotonic country prevalence girdle like” dystrophy Benghazi, 132 60 37 – – Radhakrishnan Libya et al. (1987)a 44 – – 88 Al-Rajeh et al. Thugbah, 265b (1993) Saudi Arabia Romdhane et al. Kelibia, 315 – – – – (1993) Tunisia Emery (1991) World survey 286 32 <40 5 50 a Age-adjusted prevalence b Refers to “primary muscle disorders”

A total population survey of the Thugbah community in the eastern province of Saudi Arabia (Al Rajeh et al. 1993) estimated a prevalence of 265/106 for “primary muscle disease.” Ascertained conditions were confined to myotonic disorders which had a high prevalence of 88/106 and DMD (44/106). This might also have resulted from lack of ancillary investigations (for example, enzyme, histochemistry, and electron microscopy). In a similar study in Kelibia, Tunisia, that screened 34,874 persons (Romdhane et al. 1993), a prevalence of 315/106 was recorded for MDs. No attempt was made in this study to subclassify these into the various forms of MD. In a study (Salih et al. 1996a) that described the pattern of childhood neuromuscular disorders seen in a decade (1982–1992) at a tertiary-care hospital (King Khalid University Hospital, KKUH) in Riyadh, Saudi Arabia, MDs and myotonic disorders constituted 48% of cases.

Muscular Dystrophies Severe Childhood Autosomal Recessive Muscular Dystrophy In the late 1970s, studies were independently conducted in Sudan (Salih 1980, 1982) and Tunisia (Ben-Hamida and Marrakchi 1980a, b) on a form of MD that resembled clinically the Duchenne type but affected both sexes, indicating an autosomal recessive mode of inheritance. The Sudanese family in which the disease was described lived in a village about 160 km to the south of Khartoum and consisted of 176 individuals in 8 generations. Fifteen members (seven boys and eight girls) were affected and eight (four boys and four girls) died of the disease. Onset occurred before the age of 5 years in both sexes and was characterized by weakness that progressed steadily until the child was unable to walk at a mean age of 10.7 years in boys and in girls, significantly later, at

6 Muscular Dystrophies and Myopathies in Arab Populations

147

Fig. 6.1 Phenotype of the Sudanese family with severe childhood autosomal recessive muscular dystrophy (SCARMD) which was later found to be caused by b-sarcoglycan gene mutation. (a) An 8-year and 4-month-old boy, in the ninth generation, showing calf hypertrophy. Historic clinical photographs taken in 1980 showing; (b) equinovarus deformity with preserved calf muscles in a 16-year-old girl; (c) Gowers’ sign, winging of scapula and calf hypertrophy in a 10-year-old girl; and (d) tongue enlargement in a 15-year-old boy

12.7 years. Both sexes became completely dependent by 16 years and died at or before 20 years of age of a respiratory illness of short duration (Salih et al. 1983, 1984). The selective muscle weakness in the upper and lower limbs had the same pattern as that seen in classical DMD. The facial muscles were involved in three patients, pseudohypertrophy was remarkable in many muscles, and muscular enlargement also involved the tongue (Fig. 6.1). Deformities started with equinovarus at the age of 10 years in males and progressed in a way similar to that seen in Duchenne cases. Females developed contractures about 3 years later than the males in the case of the hip, knee, and elbow joints. Similarly, equinovarus was observed at the age of 13½ years and wrist contractures were not evident until the age of 16 years. Serum creatine kinase (CK) was raised in affected individuals up to five times the upper normal limit. Electrocardiography (ECG) showed ST-segment and T-wave changes involving leads II, III and AVF in most patients, suggesting basal myocardial involvement with the dystrophic process, but none of the tall right precordial R waves in the lateral and left leads that are characteristic of DMD (Perloff et al. 1967). Muscle biopsy showed dystrophic features with multiple foci of necrosis and regeneration and numerous rounded hyaline fibers. Histochemistry revealed type I fiber predominance. Myofibrillar ATPase preparations at pH 9.5 showed good differentiation of the major fiber types in contrast to the poor differentiation of the fiber types in Duchnne MD. Descriptions in earlier publications (Salih 1980, 1982) suggested that the disease described in the Sudanese family constituted an “unusual” form of MD. It could also be distinguished from cases of childhood MD with autosomal recessive

148

M.A.M. Salih

inheritance that have, hitherto, been reported in Europe, North America, and Australia (Salih et al. 1983; Salih 1985). The clinical features of these differed from those seen in the Sudanese family in that the age of onset was relatively later (mean ¼ 6–9 years) and affected patients were still ambulant after 14 years (Stern 1972; Ionasescu and Zellweger 1974; Shokeir and Kobrinsky 1976). The mean loss of ambulation was 24 years in the kindred reported by Jackson and Strehler (1968), whereas the age of death ranged between 41 and 67 years. In a national survey of the disease in the United Kingdom, Gardner-Medwin and Johnson (1984) studied 14 cases (12 girls and 2 boys) and outlined the salient features of autosomal recessive MD of childhood, as observed in Europe. Five other documented cases were added in a later update (Gardner-Medwin and Sharples 1989). Clinical features that served to distinguish it from the Duchenne type included the pattern of onset, which is characterized by early toe walking at a mean age of 3.8 years (range: 11 months to 7 years), followed by a tendency to show an obvious waddle or to fall (between 5 and 15 years). Muscular involvement is relatively milder and the ability to walk is retained longer (11 to >17 years) than in DMD (<11 years in 75% of cases). Intelligence and ECG are within the normal range, in contrast to the intellectual impairment and characteristic ECG usually apparent in the latter disease (Perloff et al. 1967; Billard et al. 1992). Severe autosomal recessive MD, with a remarkable similarity to that seen in Sudan, has been simultaneously and independently described in Tunisia by Ben Hamida and his associates (Ben Hamida and Fardeau 1980; Ben-Hamida and Marrakchi 1980a). The first cases were reported under the title “DMD in Tunisia: 31 cases in 13 families with Autosomal Recessive Inheritance” (Ben-Hamida and Marrakchi 1980a). In the same year (Ben Hamida and Fardeau 1980), a group of 49 patients belonging to 17 families were described under the title “Severe, Autosomal Recessive, Limb-Girdle Muscular Dystrophies Frequent in Tunisia.” The prevalence of this form of MD seems to be equivalent to that of Duchenne dystrophy; and Ben-Hamida and Marrakchi (1980b) observed 23 (33%) affected with what they called “Duchenne-like autosomal recessive MD” among 73 investigated cases. The number of patients with “classical” Duchenne dystrophy was 24 (32%). In a contemporary report, Dubowitz (1980) described similar cases: a girl from Libya and another from Qatar, the latter having had two affected brothers. Onset of the disease in these North African and other Arabian children was relatively delayed (7–11½ years) compared to the Sudanese cases. However, observable weakness in a chronic disease depends on the astuteness of the parents, which is culturally influenced. Hence, this discrepancy may not be genuine. However, these cases share the features of rapidity and steady progression of the disease. Eight of the Tunisian cases lost ambulation at 11 years and another seven between 11 and 24 years. The Libyan girl was still walking at the age of 14 years but the girl and two boys from Qatar lost the ability to walk by the age of 11 years. The age of death, reported in five Tunisian cases, ranged from 13 to 25 years, which was comparable to that seen in the Sudanese series (Ben Hamida and Fardeau 1980; Salih et al. 1983). Electrocardiograms were reported to be normal in these studies and CK was up to 24–116 times the upper normal limit. Muscle biopsy in Tunisian

6 Muscular Dystrophies and Myopathies in Arab Populations

149

cases revealed – like the Sudanese – a marked tendency to hyalinization and type I fiber predominance but the degree of fiber differentiation (whether clear or poor) has not been commented on (Ben Hamida and Fardeau 1980). In the cases reported by Dubowitz (1980), hyaline fibers were not a feature and histochemical preparations showed a normal distribution of fiber types. On the basis of a comparative analysis of the previous reports, the author stated: “the forms of autosomal recessive MD of childhood seen in Sudan, in North Africa and in Arabia have many features in common and may constitute a single entity” (Salih 1985). Subsequently, a larger study of the disease was reported by Ben-Hamida et al. (1983) under the title “Severe Childhood Muscular Dystrophy Affecting Both Sexes and Frequent in Tunisia.” This consisted of 93 children (75 of whom belonged to 17 families) with affected individuals of both sexes. The first clinical symptoms were noticed between 3 and 12 years but the progression of weakness was severe, often similar to that of the Duchenne type. The study emphasized the marked variability of the disease course between families and from one sibling to another. It also emphasized normal intellectual function of these patients and pointed to the “frequent” ECG changes that showed signs related to respiratory involvement and in some cases, partial right or left atrioventricular heart blocks or anomalies of repolarization. Muscle biopsies revealed dystrophic fatures and histochemistry showed type I fiber predominance. The quality of differentiation (whether good or poor) of the major fiber types was not commented on but the muscle biopsy was depicted in the study (Ben-Hamida et al. 1983). Figures 6C, 7A, and C of that study show clear districtions between the fiber types in the routine ATPase (pH 9.4) similar to the finding in Sudanese children (Salih et al. 1983). Neurophathological examination of the central nervous system of a patient who died at the age of 21 years from “Tunisian severe childhood muscular dystrophy” showed normal anterior horns of spinal cord, particularly at the level of the cervical and lumbar regions (Ben Hamida and Hentati 1989). The study affirmed that the disease was a primary MD without any involvement of the nervous system. In 1989, Farag and his associates reported the first Kuwaiti family with “automosomal recessive Duchenne-like muscular dystrophy” and reviewed the relevant literature (Farag et al. 1989). Subsequently, Farag and Teebi (1990) drew attention to the relatively high prevalence of the disease in Kuwait. At community genetic clinics that served about 50% of the entire Kuwait population, they found 22 families with Duchenne or Duchenne- like MD. Using pedigree analysis and DNA studies, they estimated the proportion of families with severe MD inherited as an autosomal recessive trait to be at least 36.3% (8/22) as against a frequency of 5% in North America and Britain (Emery 1987) and 6.7% in Brazil (Zatz et al. 1989).

Molecular Biology The cloning of the DMD gene and identification of its protein product (dystrophin) paved the way for delineating the pathogenesis of MDs (Hoffman et al. 1987; Hoffman et al. 1988). Dystrophin is a component of the membrane skeleton of

150

M.A.M. Salih

muscle cells. Its absence at the inner face of the plasma membrane leads to membrane instability and ultimately results in myofiber destruction. Dystrophin is absent in patients with DMD, whereas it is present in an abnormal amount or is of abnormal molecular weight in Becker MD (Specht and Kunkel 1993). Confirmation that SCARMD was different from Duchenne/Becker MD was shown in a study in Tunisia (Ben Jelloun-Dellagi et al. 1990) where all the 20 cases of SCARMD examined were found to have normal quantity and quality of dystrophin. Identification of dystrophin has led to the discovery of a large oligomeric complex of sarcolemmal glycoproteins that were associated with dystrophin (Matsumura and Campbell 1993). In skeletal muscle, the dystrophin–glycoprotein complex (DGC) spans the sarcolemma to provide a linkage between the subcarcolemmal cystoskelton and the exracellular matrix (Ervasti and Campbell 1991; Ibrahimov-Beskrovnaya et al. 1992). In these pioneering studies, the DGC was identified to consist of two cystoskeletal proteins – namely, dystrophin and a 59-kDa protein (59-kDa dystrophinassociated protein or syntrophin). These are linked to three transmembrane dystrophin-associated glycoproteins (DAGs) of 50 kDa (50 DAG), 43 kDa (43 DAG or dystroglycan), and 35 kDA (35 DAG). The transmembrane glycoproteins are linked to another transmembrane protein of 25 kDa (25-kDa-dystrophin-associated protein) and to an extracellular glycoprotein of 156 kDa which binds the extracellular matrix protein, laminin (Ibrahimov-Beskrovnaya et al. 1992). In DMD, the absence of dystrophin leads to a 90% reduction in all the dystrophin-associated proteins within the sarcolemma (Ohlendieck et al. 1993). Following the identification of SCARMD in other countries of the Maghreb – namely, Algeria and Morocco (Azibi et al. 1991, 1993) – the disease acquired another name: Maghrebian autosomal recessive myopathy: (MIM #253700) in McKusick (1994). In Algeria, Azibi et al. (1993) identified 57 patients belonging to 34 families (29 of whom had more than one affected individual) including some large inbred pedigrees. Three patients in this series were shown to be deficient in the 50 DAG (Matsumura et al. 1992). This breakthrough documented for the first time the association of a phenotype of MD with the deficient components of the sarcolemmal DAG. However, Ben Othmane et al. (1992) analyzed the DNA of 52 members in three highly inbred Tunisian families afflicted with SCARMD and documented linkage of the disease to the pericentromeric region of chromosome 13q. The families demonstrated no evidence of linkage to 6q (D6S87), which contains the dystrophin-related gene, to 15q in the region where the autosomal recessive limb-girdle muscular dystrophy (LGMD) locus has been localized, or to 5q22.3–31.3, where autosomal dominant LGMD has been localized. Investigating 13 selected Algerian families with SCARMD who showed a sarcolemmal deficiency of 50 DAG, Azibi et al. (1993) demonstrated linkage of the disease to markers of the proximal region of chromosome 13 (13q12). This work confirmed the homogeneity of SCARMD in Algeria and Tunisia. It also showed, for the first time, that the genetic defect responsible, either directly or indirectly, for 50 DAG deficiency in muscle from SCARMD patients is localized to 13q.

6 Muscular Dystrophies and Myopathies in Arab Populations

151

Similarly, linkage analysis was also performed in six families from Morocco (El Kerch et al. 1994). In one family, the 50 DAG was tested and found to be negative in a muscle biopsy. The results showed similar linkage in this country, with statistical tests indicating genetic homogeneity between the three Maghrebian countries. Conversely, other non-Arab families with SCARMD and 50 DAG deficiency have been excluded from linkage to markers on chromosome 13q12 (Passos-Bueno et al. 1993; Romero et al. 1994). Of ten Brazilian patients who had SCARMD and belonged to nine unrelated families, 50 DAG was detected in six of them, while the others had normal DAG, suggesting genetic heterogeneity at the protein level for SCARMD (Passos-Bueno et al. 1993). Linkage analysis in four of these families showed that three of them were unlinked to the 13q markers although they were deficient for 50 DAG, while one family was positive for this glycoprotein. The authors (Passos-Bueno et al. 1993) concluded that the SCARMD phenotype may be caused by more than one gene and that a gene not located to 13q causes deficiency of 50 DAG as a primary or secondary defect. The other non-Arab family was of French origin and included one male and three females (Romero et al. 1994). Onset of weakness was at 9 and 11 years in two patients, whereas the other two were “almost” clinically asymptomatic at 5 and 6 years. Both patients had a mild form of the disease, with less rapid progression than most cases of SCARMD, whereas all the four affected individuals had calf muscle hypertrophy. Immunoreactivity with dystrophin antibodies revealed normal staining of sarcolemma in all patients but was completely absent with 50 DAG. Since DNA analysis excluded linkage to the 13q12 band, the authors speculated that a “new” locus might account for the sporadic cases of MD with 50 DAG deficiency that had been reported in Europe (Fardeau et al. 1993). Another phenotypic variant of SCARMD was described in two Asian male cousins born in Britain (Sewry et al. 1994). They were the result of consanguineous marriages, and their parents originated from Pakistan. Onset in the older patient was at 2½ years of age, when he was noticed to be walking on his toes and to have a waddling gait, whereas it was at 8 years in the other. Progress of the disease was relatively mild and the patients were still able to walk at 13 and 12 years, respectively. Neither of the patients had calf muscle hypertrophy, scoliosis, or cardiac abnormalities. Serum CK was 58 and 43 times the upper normal limit, respectively. Muscle biopsy showed dystrophic picture in both patients with a slight predominance of type I fiber in one. Immunolabeling for dystrophin and b-spectrin was normal. However, both patients showed a deficiency of 50 DAG and an abnormal expression of utrophin. The utrophin (dystrophin-related protein) was observed on the surface of several nonregenerating muscle fibers, with less intense immunolabeling in the clinically more affected child. It is noteworthy that utrophin is confined in normal male adult to the neuromuscular and myotendinous junctions and blood vessels. Extrajunctional sarcolemmal expression was detected in immature and regenerating fibers and mature fibers in Duchenne and Becker MDs and inflammatory myopathies (Khurana et al. 1991; Helliwell et al. 1992).

152

M.A.M. Salih

“Adhalin”: Primary Structure and Muscle Specific Expression One of the pioneering researches on DAG was done at the Howard Hughes Institute and Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa. Researchers there successfully cloned the cDNA encoding 50 DAG from rabbit skeletal muscle. The authors (Roberds et al. 1993a) proposed 50 DAG be named “adhalin,” derived from the Arabic word “adhal” for muscle, “because the 50 kDA dystrophin-associated glucoprotein was first implicated in the pathogenesis of SCARMD, which is prevalent in Arab countries.” Researchers from the same institute have also successfully cloned and sequenced human adhalin cDNA and large portions of the gene, which is mapped to the long arm of chromosome 17 (Roberds et al. 1993a, 1994). They also sequenced adhalin cDNA and genomic DNA from the affected children of the French kindred studied by Romero et al. (1994). This led to the identification of two missence mutations, one in each allele of the 50 DAG adhalin in these patients. They postulated that the deficiency of adhalin observed in North African patients linked to arm 13q is due to a defect in an as-yet-unidentified gene that may be responsible for encoding a physiological ligand for adhalin. Absence or perturbation in this ligand may lead to instability of adhalin and hence, to disruption of the DGC. Within the following 2 years (1995 and 1996), g- and d-sarcoglycan genes were cloned by the groups of Ozawa-Kunkel (Noguchi et al. 1995) and Nigro-Zatz (Nigro et al. 1996a, b), respectively. The b-sarcoglycan gene was independently cloned by the Campbell-Beckmann (Lim et al. 1995) and Kunkel-Ozawa (Bonnemann et al. 1995) groups. Studying families with childhood-onset progressive proximal MD revealed phenotypic heterogeneity with adult-onset cases (i.e., LGMD) described in the same families (Bushby 1999). Also several independent gene loci started to emerge. A consortium meeting (Bushby and Beckmann 1995), under the auspices of the European Neuromuscular Centre, proposed a locus-based classification. The designation “SCARMD” was incorporated into this LGMD classification. The dominant-LGMD loci were designated LGMD1A, B, C, etc. and the recessive forms as LGMD2A, B etc. in the order of their identification. Also “adhalin” was subsequently renamed “a-sarcoglycan” and “adhalinopathies” became known as “sarcoglyconopathies” (Jeanpierre et al. 1996). Nevertheless, most patients with SCARMD have defects in one of the four sarcoglycan genes (a, b, g, or d) and the synonyms “SCARMD” and “adhalin” are still in active use (see: http://www.medlink.com).

SCARMD in Saudi Arabia SCARMD was reported from Saudi Arabia (Bohlega et al. 1992; Salih et al. 1992). Of 84 children found (over a decade, 1982–1992 at the KKUH in Riyadh) to have had a disorder of voluntary muscle, MD contributed to 40 cases. Within the group that had MD, SCARMD was more prevalent (30%) than the Duchenne type (25%) (Salih et al. 1996a).

6 Muscular Dystrophies and Myopathies in Arab Populations

153

The other report of Bohlega et al. (1992) described a Saudi family where three (one girl and two boys) of ten siblings were afflicted with SCARMD. Parents were consanguineous. They had progressive proximal weakness by the age of 7 years, and their examination showed contracture of shoulders, hips, and ankles; kyphoscoliosis (two of three); proximal atrophy and weakness; and calf muscle hypertrophy (one of three). CK values were >10 times normal. Electromyography (EMG) showed myopathic features, whereas muscle biopsy was consistent with MD and also revealed type I fiber predominance (>75%) and normal dystrophin staining. Another series of 14 patients (nine females (F) and five males (M)) with SCARMD were also studied at KKUH, Riyadh (Salih et al. 1996b). Six of these (three M and three F) were siblings of two Saudi families, whereas another Syrian family had an affected boy and girl. Two other Saudi girls had positive family history, including three males and three females, one of whom died of the disease at 15 years. The remaining four patients were isolated cases and included three Saudis (one M and two F) and one Yemeni girl. Close parental consanguinity was found in five (63%) of the eight pairs of parents. Onset was between 3 and 9 years (median 3 years) and all of those aged >12 years lost ambulation except one male. The mean serum CK was 20 times the upper normal limit. In a remarkable similarity to what has been observed in Sudanese patients (Salih et al. 1983), ECG showed ST-segment depression and T-wave changes that tended to occur in fixed leads, pointing to the possibility of myocardial involvement with the dystrophic process (Armstrong 1985). Changes in QRS configuration, which suggested intraventricular conduction delay, were seen in four patients, similar to what has been reported in Tunisian SCARMD patients (Ben-Hamida et al. 1983). It is noteworthy that a specific deficiency of adhalin has been observed in skeletal muscle of the cardiomyopathic hamster, whereas a deficiency of multiple DAGs, including adhalin, was found in its cardiac muscle (Roberds et al. 1993b). These animals suffer from both myopathy and cardiomyopaty, with death occurring because of the latter. Muscle biopsy showed dystrophic features in all patients associated with type I fiber predominance, which agreed with findings in Tunisian and Sudanese series (Ben-Hamida et al. 1983; Salih et al. 1983). There was also good differentiation of the major fiber types in the routine ATPase (pH 9.4), similar to findings in Sudanese children (Salih et al. 1983) and to what appears in the muscle photomicrographs that were published in one of the Tunisian series (Ben-Hamida et al. 1983). Dystrophin was positive in all of the six cases that were tested (Fig. 6.2), whereas a specific deficiency of adhalin was detected in three of four patients (two girls and one boy). The adhalin deficient boy was an isolated case (aged 13 years) with rapidly progressing disease. Having identified SCARMD in Saudis, Syrians, and Yemenis, such studies provided further evidence that cases reported previously in the Arabian Peninsula (Dubowitz 1980; Farag and Teebi 1990), northwestern Africa (Ben Hamida and Fardeau 1980; Ben-Hamida et al. 1983), and Sudan (Salih 1980, 1982; Salih et al. 1983) belong to the same disease entity. In fact, historic data on the Sudanese kindred that had several patients affected with SCARMD revealed that it belonged

154

M.A.M. Salih

Fig. 6.2 A 13-year-old girl from the Central Region of Saudi Arabia who had SCARMD. (a) There is remarkable muscle hypertrophy, especially of the calf muscles associated with equinovarus deformity. Cautery marks (a form of alternative medicine) are evident. (b) Immunohistochemical staining of vastus lateralis (biopsied in 1992) showed normal sarcolemma dystrophin distribution (400). Staining for adhalin (a-sarcoglycan) was negative (not shown)

to the Kawahla tribe. This Sudanese tribe is known to descend from Kahil Ibn Asad Ibn Khuzaima and to have migrated from the central region of Saudi Arabia to Sudan after crossing the Read Sea during the twelfth and thirteenth centuries (Fig. 6.3) (Mohamed 1956; MacMichael 1967).

Limb-Girdle Muscular Dystrophy 2B (LG-MD 2B) This form of LGMD is associated with defects in the DYSF gene that encodes the protein dysferlin. The initial linkage of this subtype to chromosome 2q was reported by Bashir et al. (1994) in two unrelated consanguineous families, one Palestinian and one of Sicilian origin, manifesting autosomal recessive inheritance. Two other allelic phenotypes of dysferlin deficiency were later recognized. These are Miyoshi myopathy (MM), which is characterized by weakness affecting initially the gastrocnemius muscle from the late teens or early adulthood (Miyoshi et al. 1986), and distal anterior compartment myopathy characterized by anterior compartment (tibi alis anterior) myopathy (Salani et al. 2004). The term “dysferlinopathy” was coined by Bushby (1999) after MM and LGMD 2B were found to be allelic disorders. The co-existence of MM phenotype with LGMD in the same family had been reported earlier by Mahjneh et al. (1992) in a large kindred from Palestine. Cupler et al. (1998) described MM in a Saudi family with five siblings aged 3–25 years and in an 18-year-old woman and a 40-year-old man who were unrelated. The two sporadic and two of the familial cases showed classic findings of MM, including early adult onset, preferential involvement of gastrocnemius muscles,

6 Muscular Dystrophies and Myopathies in Arab Populations

155

Fig. 6.3 Map showing the migration of the ancestors of the family in whom SCARMD was initially described in Sudan. Three settlement areas (1, 2, 3) of the Kawahla tribe in the Sudan, to whom the family belongs, are shown. This tribe migrated from central Saudi Arabia (Mohamed 1956; MacMichael 1967). The village of the SCARMD family is marked (dots) in area 3

markedly elevated serum CK, and dystrophic appearing muscle without vacuoles. Interestingly, the three familial cases had elevated serum CK and only two of these also had early myopathic findings by EMG. In a study involving researchers from Saudi Arabia and Tunisia, Lui et al. (1998) identified a novel mutation in a skeletal muscle gene, dysferlin, at the locus 2p12–14 and documented that dysferlin mutations cause MM and LGMD 2B. An international collaborative study (Aoki et al. 2001), including patients from Sudi Arabia, described the exon–intron structure of the dysferlin gene and identified nine novel mutations associated with MM. The study also confirmed that dysferlin gene is mutated in both MM and LGMD 2B. It is noteworthy that no mutational hot spots have been reported, as yet, in any of the three Maghrebian countries (Morocco, Algeria, and Tunisia) despite the high prevalence of primary dysferlinopathy in this area (Urtizberea et al. 2008).

Limb-Girdle Muscular Dystrophy, Type 2C (LGMD2C) In an extension of the studies that demonstrated linkage homogeneity to 13q patients with SCARMD (DMD-like) phenotype from Morocco, Tunisia, and

156

M.A.M. Salih

Algeria (Ben Othmane et al. 1992; Azibi et al. 1993; El Kerch et al. 1994), Ben Othmane et al. (1995) also identified six Tunisian and one Egyptian families who showed linkage to the pericentromeric region of chromosome 13q. Ben Hamida et al. (1996) further highlighted the clinical features of the LGMD2C linked to chromosome 13q and realted to a 35 kDa DAG deficiency. They described the disease to be characterized by a variability of the age of onset, the severity of the evolution, and the severity of the myopathic changes at the muscle biopsy. This variability was also present in the expression of the a-sarcoglycan (adhalin) between the same sibships and between different families. The study of Kefi et al. (2003) emphasized the previous observations that all Tunisian patients were homozygous for del521T mutation in the g-sarcoglycan gene, and carried the same allele 122-bp of D13S232 marker indicating a founder effect. All the studied 132 LGMD2C patients had the same homozygous del521-T mutation in the g-sarcoglycan gene. However, this identical mutation was found to lead to mild, intermediate and severe phenotypes in different families. Immunohistochemical studies of muscle biopsy showed a total absence of g-sarcoglycan and a normal or slightly reduced a- and d-sarcoglycans, whereas the expression of b-sarcoglycan was variable. They accounted for this phenotypic variability by the possible involvement of a modifying gene controlling the course of the disease. Fendri et al. (2006) reported on three Tunisian patients belonging to the same consanguineous family and sharing similar SCARMD phenotype but heterogenous sarcoglycans immunohistochemical patterns. One patient had del521T homozygous mutation in exon 6 of the g-sarcoglycan gene (LGMD2C), and two had a 157G>A homozygous mutation in exon 2 of the adhalin (a-sarcoglycan) gene (LGMD2D). The authors highlighted the complexity of genetic counseling in inbred populations. It is noteworthy that the same del521T mutation was found in patients from Western India (Khadilkar and Benny 2008) and in Towareg tribe from Niger (A. Urtizberea, personal communication), possibly relating to the pattern of human migration. Piccolo et al. (1996) identified a different founder g-sarcoglycan gene mutation (C283Y) in the Romany Gypsies of Europe. These are believed to have originated from Northern Indian populations that arrived in Europe around 1,100 A.D. Another novel nonsense mutation: 93G > A (Trp31X) on exon 2 of the d-sarcoglycan gene was identified in a Moroccan patient who presented with progressive walking disturbances for several years, exercise intolerance, and leg pains (Vermeer et al. 2004).

Primary Adhalinopathy (a-sarcoglycanopathy, LGMD2D) Following the discovery of adhalin (a-sarcoglycan) gene in a French kindred (Roberds et al. 1994), an international collaborative study (Piccolo et al. 1995) examined 12 cases of autosomal recessive MD from various origins (France, Italy, Germany, Algeria, and Morocco). The authors first emphasized the fact that there are two types of myopathies with adhalin (a-sarcoglycan) deficiency: one with primary

6 Muscular Dystrophies and Myopathies in Arab Populations

157

defect of adhalin (primary adhalinopathy), and one in which absence of adhalin is secondary to a separate gene defect of chromosome 13. Both of the Algerian and Moroccan patients had SCARMD phenotype and revealed negative lodscores with the markers of the 17q21 region including the intragenic adhalin microsatellite. Mutations in the adhalin gene were detected in 10 new cases and the most severe clinical course was observed in patients who had homozygous null mutations. In three patients belonging to the same consanguineous family, Fendri et al. (2006) described two siblings with LGMD2D (a-sarcoglycanopathy). Onset was at 5 years and both patients became wheelchair-bound by the age of 18 years. A homozygous mutation (157G>A) in exon 2 of the a-sarcoglycan gene was found in the two siblings. A second-degree cousin of these patients had g-sarcoglycan gene mutation (LGMD2C). Adhalin (a-sarcoglycan) gene mutations were also found in Saudi Arabia in four families (M.A.M. Salih, unpublished work). Three of these were Saudi, whereas the other originated from Yemen. b-Sarcoglycanopathy (LGMD2E) Following the cloning of b-sarcoglycan gene in 1995 (Lim et al. 1995; Bonnemann et al. 1995), the first Tunisian family with b-sarcoglycanopathy (LGMD2E) was described, adding to the genetic heterogeneity of autosomal recessive LGMD in this population (Bonnemann et al. 1998). The family had SCARMD phenotype and immunohistochemical analysis showed absence of the sarcoglycan complex components. A homozygous mutation (G272 ! T, Arg 91Leu) was identified in exon 3 of the b-sarcoglycan gene. The Sudanese kindred with SCARMD phenotype that were first studied in 1977 (Salih 1980; Salih et al. 1983) were re-investigated applying molecular genetic tools (Salih et al. 2007). By the year 2007, a total of 17 individuals in 8 generations were ascertained to have died of the disease at a mean age of 21.65 + 9.96 years (range 12–39 years). In the ninth generation, an affected boy was evaluated at the age of 9 years and 4 months. Onset was at the age of 3 years and he was wheelchairbound at 8 years and 8 months. Apart from proximal muscle weakness and wasting, he showed tongue enlargement and calf muscle hypertrophy (Fig. 6.1a). Serum CK was 9.5 times normal and the histology of muscle biopsy showed dystrophic features. Re-examination of the stored muscle biopsy of one of the patients in the eight generation revealed negative staining for the sarcoglycans a (adhalin), b, g, and d. Molecular analysis showed mutation in the b–sarcoglycan gene (homozygous 2bp deletion at 112bp, changing Ser 38 to a Stop codon in exon 2). Genomic DNA analysis of the young boy in the ninth generation also showed a b–sarcoglycan gene deletion (2 bases (AG) in exon 2, creating a stop codon in position 48). The parents were heterozygous for the mutation. The phenotypic differences reported in the 1980s between the Sudanese and Tunisian families (Salih et al. 1983) seem to have been a reflection of the different sarcoglycans (b versus g) involved in the pathogenesis of the disease.

158

M.A.M. Salih

LGMD2I Type 2I of LGMD was originally described in a large consanguineous Tunisian family and linked to 19q (Driss et al. 2000). The disease is caused by mutations in Fukutin-related protein gene (FKRP). The phenotype is characterized by calf hypertrophy, marked elevation of creative kinase, and frequent cardiac and respiratory involvement (Poppe et al. 2003). Three Saudi families were found to be LGMD2I and harbor FKRP mutations (M.A.M. Salih, unpublished data).

Advances in the Molecular and Cell Biology of the Dystrophin-Associated Proteins Further studies in the characterization of the dystrophin associated proteins (DAPs) classified them into three groups (Ozawa et al. 2005): an intracellular peripheral membrane complex composed of dystrophin with dystrobrevins and the syntrophins and their associated molecules, and two transmembrane complexes, dystroglycan and sarcoglycan-sarcospan complex. The sub-sarcolemmal action filaments are connected to laminin, one of the main components of the extracellular matrix, through dystrophin and dystroglycan. This system seems to play an important role in protecting the sarcolemma during contraction and relaxation of muscle fibers. Dystroglycan is composed of two sub-units, a- and b-dystroglycan, both of which are transcribed from the same gene in chromosome 3p25 and are generated by posttranslational processing. a-dystroglycan is a heavily glycosylated protein and appears as a broad smeared band on western blots with an aberrant molecular weight of 156 kDa in skeletal muscle. Defects in the glycosylation of a-dystroglycan result in several forms of congenital MDas well as some types of LGMD. No naturally occurring mutations of the dystroglycan gene have been described so far. Nevertheless, a mild form of MD associated with b-dystroglycan deficiency has been described in a 4-year-old Saudi boy (Salih et al. 1996c). This patient had a myopathy starting at 1½ years of age that mainly affected the girdle and the proximal limb muscles. Investigations revealed normal findings on electrocardiogram (ECG), echocardiogram, and nerve conduction studies. Serum CK, measured on two occasions, was marginally raised at 248 and 255 IU/L (normal <232). Magnetic resonance imaging (MRI) of the brain showed no evidence of brain malformation or increased signal intensities in the white matter on T2-weighted images. The muscle biopsy samples showed dystrophic features with type 1 fiber predominance but no evidence of grouping. The normal dystrophin immunostaining excluded typical DMD or Becker’s MD, and no deficiency of a (adhalin)-, b-, g-sarcoglycan also excluded sarcoglycanopathy, which encompasses the SCARMD phenotype. Laminin a2 – negative congenital muscular dystrophy (CMD) was ruled out by the normal immunostaining of laminin a2 chain. Instead, there was selective deficiency of b-sarcoglycan with normal expression of a-dystroglycan on both

6 Muscular Dystrophies and Myopathies in Arab Populations

159

immunostaining and immunoblot analysis. The findings in this single case provided a clue to understanding the molecular organization of the DGC.

Congenital Muscular Dystrophy This category embraces a number of disorders that are characterized by muscle weakness, are recognized at birth, and associated with hypotonia and/or multiplejoint contractures and delayed motor development. Muscle biopsy shows features of dystrophy (Leyten et al. 1989). The nosology of the various types of CM evolved over time (Dubowitz 1994). However, certain distinct forms were initially categorized on clinical basis. These include the Fukuyama type, in which CMD and high serum CK are associated with mental retardation, seizures, and brain dysgenesis characterized by atrophy, large ventricles, and dysmyelination (Fukuyama et al. 1981). Another type is Santavouri CMD (muscle-eye-brain disease), comprising those cases with motor and intellectual disabilities, progressive myopia, and retinal disease (Santavouri et al. 1977). A third type is Walker-Warburg syndrome (WWS) (cerebral-ocular CMD) characterized by major eye malformations, severe mental and motor dysfunction, and poor prognosis (Dobyns et al. 1989). A fourth type was identified and labeled as the “Occidental type” of CMD (Topaloglu et al. 1991). This comprises those children with normal intelligence but diffuse abnormal myelination on radiographic studies. In Saudi Arabia, CMD seems to be common (Salih et al. 1992, 1996a). It constituted 30% of 84 biopsy-proven cases of MD seen at KKUH (Riyadh) during a decade (1982–1992); it was equal in prevalence to SCARMD and more common than DMD (25%). Reviewing 37 patients with a history of weakness before 1 year of age and muscle biopsy consistent with dystrophy, Cook et al. (1992) highlighted the relatively high prevalence of “Occidental-type” CMD in Saudi Arabia. They identified 11 children with a homogeneous clinical syndrome affecting both sexes, characterized by weakness at birth, slowly improving course, weakness of all muscle groups, areflexia, and elevated serum CK (2.1–8.5 times upper normal limit in eight and 28–51 times in another three siblings). Other features included normal nerve conduction velocity, dystrophic changes on muscle biopsy, and diffuse periventricular cortical white-matter abnormalities. The white-matter abnormalities spared the corpus callosum, internal capsule, and brainstem. These 11 children (7 girls and 4 boys, aged 1–10 years) came from five families and five of the seven sets of parents were first cousins, suggesting an autosomal recessive mode of inheritance. The study compared this group of patients with 48 other previously reported similar cases, as well as to the other accepted phenotypes of CMD. The authors (Cook et al. 1992) postulated that the different phenotypes of CMD are alleles of the same gene, which regulates or expresses a structural protein required for muscle integrity, myelination, and formation of the cerebral cortex.

160

M.A.M. Salih

A study by Hentati and associates from Tunisia (abstracted in Dubowitz 1994) included 25 patients with CMD, eight of whom came from four inbred families, whereas the remaining 17 were isolated cases with frequent parental consanguinity. The disease presented with congenital hypotonia in 22 patients and with delayed milestones in the others. The course was relatively benign with apparent improvement in six, whereas it was static in 15. Four had progressively deteriorating course. Serum CK was grossly evleated in six, moderately elevated in ten, and normal in nine. Cranial CT scan revealed an abnormal pattern in nine patients and was normal in another nine. However, there was no correlation between the presence of CT abnormality and intelligence, mental retardation, or other evidence of cerebral abnormality. Phenotypic variation of the disease was evident in one of the studied families: Typical CMD with severe muscle weakness was seen in one patient; another had mild dystrophic changes in the muscle; a third patient had a deficient intelligence quotient but no weakness. Following the rapid increase of separate variants of CMD in the molecular era, a classification of CMD based on the primary biochemical defect has been proposed (Muntoni and Voit 2004). As of 2009, identified genetic defects in CMD involve: a. Proteins of the extracellular matrix or peripheral membrane. These include collagen VI, which causes Ullrich CMD, and laminin-a2 chain (or merosin), which results in MD congenital type 1A (MDC1A, or merosin-deficient (MD) and integrin a7. b. Putative or demonstrated glycosyltransferases, which affect the glycosylation of a-dystroglycan. These include protein O-mannosyltransferase 1 and 2 (POMT1 and POMT2, respectively), O-mannose b-1, 2-N-acetylglucosaminyltransferase (POMGnT1), fukutin, fukutin-related protein (FKRP), and LARGE. c. Seleprotein 1, which encodes an endoplasmic reticulum protein of unknown function and causes, when mutated, rigid spine MD 1. LARGE gene was established for the first time as causative of WWS in a Saudi family (Van Reeuwijk et al. 2007). The proband was a newborn male who had a homozygous 63-kb intragenic deletion in LARGE. He showed classical features of WWS and died at the age of 2 months. His elder sister was similarly affected and died at the age of 6 months. Mutations in LARGE has previously been identified in a patient with relatively mild CMD associated with severe mental retardation (MDC1D; MIM No. 608840). The compound heterozygous mutations which this patient had do not seem to abolish the activity of the LARGE protein completely, as western blot analysis of skeletal muscle indicated in this patient residual functional glycosylation and laminin binding activity for a-dystroglycan (Longman et al. 2003). It is noteworthy that mice that carry a spontaneous deletion in large gene resemble two severe forms of CMD, namely Fukuyama CMD and MEB disease (Grewal et al. 2001; Longman et al. 2003; Michele et al. 2002). Another remarkable finding highlighted by this study is the therapeutic potential of LARGE, demonstrated by the recovery of dystroglycan processing and functioning in WWS/MEB fibroblasts by overexpression of the LARGE gene (Barresi et al. 2004).

6 Muscular Dystrophies and Myopathies in Arab Populations

161

In an international collaborative work, a mild form of CMD, affecting two Saudi Arabian siblings from a consanguineous family, was characterized (Allamand et al. 1997). A novel mutation in the laminin a2-chain which leads to the expression of an internally deleted protein, was identified in the two CMD siblings. The predicted protein lacks 63 aminoacids in domain IVa which forms a globular structure on the short arm of the a2-chain. Immunofluorescence analysis of muscle from two siblings, with antibodies recognizing different domains of the laminin a2-chain, revealed striking results. Antibodies recognizing the G-domain of the protein detected a near-normal level of expression of the protein with only a few fibers showing patchy pattern. Conversely, the use of antibodies recognizing N-terminal region of the laminin a2-chain revealed a more obvious reduction in the protein, consistent with deletion in domain Iva of the protein. These results demonstrated for the first time that use of more than one antibody can provide valuable indications as to what domain(s) of the laminin a2-chain may be affected in CMD patients. Thereafter, this procedure became the standard method for staining muscle of patients with CMD and has also been used for prenatal diagnosis. (Campbell et al. 2000). A new variant of CMD (MIM No. 601170) associated with brain malformation was reported in two Saudi babies of first-degree cousin parents (Seidahmed et al. 1996). Both patients were born with severe hypotnia, arthrogryposis multiplex congenita (AMC), and dysmorphic features consistent with fetal akinesia / hypokinesia sequence. Both needed assisted ventilation and died at the age of 5 months. Both had type II lissencephaly (cobblestone lissencephaly), which was visualized by MRI in the proband. Ophthalmic evaluation showed no ocular malformations in either of them, findings dissimilar to those seen in Fukuyama CMD, WWS, and MEB disease. Brain auditory-evoked potentials (BAEP) revealed bilateral severe sensorineural haring loss, whereas an MRI-guided open muscle biopsy of the sartorious muscle (the only remaining thigh muscle) showed features of MD. Immunofluorescence of muscle showed normal dystrophin and its associated protein, including adhalin (a-sarcoglycan), g-sarcoglycan, laminin a2, b-dystroglycan, and syntrophins. Sztriha et al. (1999) also described later a very similar phenotype in two female infants born to consanguineous parents in an inbred Arab family of United Arab Emirates (UAE) origin. They had microcephaly with simplified gyral pattern, abnormal myelin formation, and arthrogryposis. Both infants had dysmorphic features consistent with fetal akinesia/hypokinesia sequence. In both cases muscle biopsy showed increased variation of fiber size. CK was normal.

Duchenne and Becker Muscular Dystrophies DMD (MIM No. 310200) and Becker muscular dystrophy (BMD, MIM No. 300376) are common inherited disorders of muscle. Both are transmitted as X-linked recessive traits and are caused by mutatiosn of the dystrophin gene, and

162

M.A.M. Salih

are therefore named dystrophinopathies (Hoffman and Kunkel 1989). Affecting 1 in every 3,500 boys, DMD is one of the most common lethal heritable childhood diseases (van Essen et al. 1992). Al-Qudah et al. (1990) prospectively studied four DMD patients by clinical examination, intelligence testing, cranial MRI, and DNA deletion analysis. Other than mild atrophy in two patients, these first MRI studies of DMD did not reveal any significant anatomic brain alteration. A study (Salih et al. 1996a) of the pattern of childhood neuromuscular disorders seen in a decade (1982–1992) at KKUH, King Saud University, Riyadh, Saudi Arabia, identified 40 (48%) of 84 ascertained cases to have different forms of MD. Both SCARMD (30%) and congenital MD (30%) were more prevalent than DMD (25%). This was accounted for by the high rate of consanguinity (55%) which resulted in having the autosomal recessively inherited diseases (SCARMD and DMD) to be more prevalent than the X-linked DMD. All of the ten DMD patients (eight of whom were Saudis) were isolated and half were the product of consanguineous marriages. Their median serum CK was 36 times normal (range: 12–85). One patient was investigated abroad and found to have dystrophin deletion. Becker MD was diagnosed in three children who were also isolated cases and consanguinity was evident in one of them. The patients when first seen were relatively older than Duchenne cases (mean: 13.7 years) and elevation of their serum CK ranged from 5.6- to 36-fold (median: 21) above normal. It is noteworthy that the relatively lower prevalence of DMD compared with other autosomal recessively inherited forms of MD was later reported in Jordan (Al Qudah and Tarawneh 1998). Of 55 MD patients, seen at Jordan University Hospital in the period from January 1990 to February 1997, CMD was the most prevalent (50.9%), followed by DMD (20%) and BMD (16.4%).

Screening for Dystrophin Gene The first study of deletion of the dystrophin gene in Arab populations was done in Kuwait (Haider et al. 1998). Using three different multiplex polymerase chain reaction (PCR) sets, intragenic deletions were investigated in 26 Kuwaiti and 16 Egyptian DMD patients. The overall deletion detection rate (36 of 42 patients, 86%) was one of the highest in DMD. The investigators attributed this high rate to screening of additional exons, in their study, between the two hot spots regions (multiplex III). Another explanation was genetic/racial factors characteristics of this particular population group. Later on, multiplex PCR using 18 pairs of specific primers was used for screening of deletion mutations within the dystrophin gene in 100 Egyptian families (Effat et al. 2000). A frequency of 55% among families was detected with 60% of deletions involving multiple exons spanning the major or the minor hot spots of the dystrophin gene. The remaining 40% mainly involved exon 45. The study

6 Muscular Dystrophies and Myopathies in Arab Populations

163

concluded that employment of the 18 exon analysis is cost effective and highly accurate (97%) to justify launching a nationwide program. Al-Jumah et al. (2002) explored deletion mutations in the dystrophin gene in a cohort of Saudi patients. These included 26 who had DMD and one patient with BMD (confirmed by muscle biopsy and dystrophin staining), and 14 patients with clinical suspicion of DMD but without confirmatory biopsy. A total of 25 exons around the deletion prone regions (hot spots) of the dystrophin gene were amplified. The deletion of one or more exons was found in 21 of 27 (78%) DMD/BMD patients confirmed by muscle biopsy. The deletion of the gene was detected in 5 of 14 with DMD phenotype which has not been confirmed by dystrophin staining of muscle biopsy. The overall figure for intragenic dystrophin gene deletions (63%) in Saudi patients with DMD/BMD phenotypes was similar to that reported in other ethnic groups. Multiplex PCR technology was also utilized to demonstrate the frequency of the most commonly found deletion in a limited group (n ¼ 8) of Saudi DMD/BMD patients (Chaudhary et al. 2008). The study analyzed 26 exons of the dystrophin gene and the deletion detection rate (5 of 8, 62.5%) was in accordance with studies from elsewhere. A study in Egypt (El-Harouni et al. 2003) aimed to examine the genotype/ phenotype correlation in 250 DMD/BMD patients with double-deletion (Ddel) mutations in comparison with those having single deletions (Sdel). Comparing 10 Ddel patients with 20 Sdel subjects of the same age and disease duration, patients with double-deletion mutations within the dystrophin gene were found to have milder phenothype than patients who had single deletions at either major or minor hot spots of the gene. A recent study by Effat et al. (2008) explored the impact of prenatal diagnosis on Egyptian families with DMA. The study characterized the deletion patterns in 85 Egyptian patients with DMD and 32 fetuses from 27 mothers with a previous history of DMD deletion mutations. Multiplex PCR amplification of 18 exons covering the two hot spots within the dystrophin gene was used to detect deletions in the probands. Detection in the fetal DNA was performed by using targeted multiplex containing the deleted exons. Deletion mutations were detected in 48 of 85 (55%) probands, 24 of these 46 (52%) had multiple exon deletions, whereas 22 (48%) showed single exon deletion. Of the 32 amniotic fetal samples, 14 fetuses were found to have inherited the same deletions present in the index cases, while 18 were normal. The study noted an emerging awareness of the importance of genetic counseling and prenatal diagnosis in this population. Also, there were observed changes of attitude in favor of termination of pregnancy in situations where the fetus is affected.

Schwartz-Jampel Syndrome Schwartz-Jampel syndrome (SJS) is a rare myotonic syndrome of unknown pathogenesis characterized by mask-like facies, narrow palpebral fissures, microstomia,

164

M.A.M. Salih

generalized myotonia, muscular hypertrophy, osteochondro-dysplasia, and growth retardation (Schwartz and Jampel 1962; Aberfeld et al. 1965). Inheritance is presumed to be autosomal recessive, although cases with autosomal dominant inheritance have been described (Pavone et al. 1978; Ferrannini et al. 1982). In Kuwait, an Iraqi girl of first-cousin parents was reported (Bessiso et al. 1986). Electromyographic studies including single-fiber EMG have shown distinct paramyotonia-like spontaneous activity. In Saudi Arabia, Jamil et al. (1992) reported on four cases of SJS in two sisters (aged 3½ and 16 months) and two boys (aged 30 months and 4 years). In each case, the parents were first cousins. Some of the syndrome manifestations were seen early (during the first few months of life); the full-blown clinical spectrum was evident by the age of 8–14 months. Investigations showed minimal increase in serum CK; typical continous and spontaneous myotonic discharges (Dive-Bomber type); normal NCV, brain auditory-evoked responses, and visual evoked response; and abnormal somatosensoryevoked potentials (SEP). Electroencephalography was nonspecific and CT brain showed minimal cerebral atrophy in one case. ECG and echocardiography showed dilated cardiomyopathy in one case and biventricular hypertrophy in another. Muscle biopsies did not reveal any specific histologic changes. The authors drew attneiton to the constantly abnormal SEP, which could be diagnostically helpful, in the presence of other clinical features. Another five patients (three M and two F) from four Saudi families were described at KKUH (Al-Husain et al. 1994). These included a pair of 6-year-old male twins; the others were aged between 2 and 6 years. Consanguinity was evident in three of the four families. The age of onset of symptoms ranged between 3 and 9 months. Apart from the cardinal clinical features of SJS, one child had umbilical and two inguinal hernias. Serum CK ranged between two and ten times the upper normal limit, whereas myotonia was detected by clinical examination and/or EMG in all patients. From the UAE, Al-Gazali (1993) reported on three siblings of unrelated parents with severe manifestations of SJS. All died because of respiratory problems. A more recent study in UAE showed that the neonatal form of SJS is fairly common in this country (Al-Gazali et al. 1996). A study from Tunisia investigated the pattern of expression of both the myofibrillar and cytoskeletal protein in muscle biopsies of four cases of SJS (SoussiYanicostas et al. 1991). The four patients were members of the same family, the offspring of two first-cousing marriages. Their histology and histochemistry showed variation in fiber size (the presence of both hypertrophic and atrophic muscle fibers), presence of fiber type grouping, internal nuclei, fiber splitting and necrosis, subsarcolemmal accumulation of mitochondrial activity, and targetoid muscle fibers. The muscle specimens revealed familial heterogeneity in the expression of SJS that could not just be explained by an age-dependent progression of the disease. There was also a predominance of slow type I fibers in the oldest cases, in agreement with the hypothesis that a progressive alteration in motoneuron innervation may occur in this syndrome

6 Muscular Dystrophies and Myopathies in Arab Populations

165

(Fariello et al. 1978). Moreover, two classes of small clusters of atrophic type IIC fibers were observed. The first class corresponded to fibers that coexpressed embryonic, fetal, and fast, but not slow, MHC isoforms. These fibers also displayed an abnormal distribution of desmin, vimentin, and titin. The second class was composed of fibers coexpressing embryonic, fetal, fast and slow MHC isoforms. Fibers in the second class displayed a normal pattern of expression of desmin, vimentin, and titin, in contrast to that observed for the first class. This modification in the expression of both the contractile and cytoskeletal proteins suggested that both regeneration and reinnervation may occur in this syndrome. Alternatively, they might have resulted from myotonia, which could cause focal damage because of the continued contraction of muscle fibers. A study in Oman (Rajab et al. 2005) estimated the prevalence of commonly diagnosed autosomal diseases from a hospital-based register in the years 1993–2002. Fifteen cases of SJS were diagnosed, with an observed incidence of 1 in 30,000 births. Similarly, Sawardekar (2005) studied the prevalence of major congenital malformations in children born during a 10-year period in an Omani hospital in Nizwa. Out of 21,988 births in this hospital, one child was born with the neonatal variant of SJS.

Advances in Phenotype Characterization, Mapping, and Molecular Genetics Most SJS are of type 1A, characterized by childhood onset with moderate skeletal dysplasia. Type 1B of SJS is recognized at birth with more pronounced skeletal dysplasia (Giedion et al. 1997). SJS type 2 is similar to type 1B, with more severe leg bowing and myotonia from birth, but has recently been re-categorized as StuveWiedemann syndrome (MIM 601559). Using homozygosity mapping, Nicole et al. (1995) located the SJS locus to chromosome 1p36.1-p34 in families belonging to different ethnic backgrounds (Algeria, Tunisia, and South Africa). Brown et al. (1997) excluded linkage to this locus in two well-documented families from the UAE, manifesting the severe form of neonatal SJS. They suggested that a second locus is responsible for the latter type. Following localization of SJS1 gene, responsible for type 1A and 1B, CDC42 gene (which has been within the SJS1 critical interval) was explored as a candidate gene in an international collaborative study (Nicole et al. 1999). Screening of 16 SJS1 patients from ten unrelated consanguineous families, including families from Saudi Arabia and Tunisia previously linked to the SJS1 locus, revealed no mutations and excluded CDC42 as the SJS1 gene. Interestingly, further molecular analysis demonstrated that a CDC42-like transcript gene located on chromosome 4 does not contain introns and is similar to the placental form, suggesting that it is a processed peudogene. In the year 2000, SJS1 was reported to be caused by mutation in the gene encoding perlecan (HSPG2) on chromosome 1p36 (Nicole et al. 2000). Perlecan

166

M.A.M. Salih

(heparin sulfate proteglycan type 2, HSPG2) gene is the major component of basement membranes. On the other hand, Stuve-Wiedemann (SJS type 2) syndrome was mapped to chromosome 5p13.1 in 19 affected families and null mutations were identified in the leukemia inhibitory factor receptor (LIFR) (Dagoneau et al. 2004). These 19 families included Palestinian, as well as Yemeni and Omani children (living in the UAE [Al-Gazali et al. 1996, 2003]). The spectrum of HSPG2 (perlecan) mutations was explored in 23 families (35 patients) with SJS (Stum et al. 2006). Unreported polymorphisms and 22 new HSPG2 mutations were identified in this study. The cohort included four families from Tunisia and one Saudi Arabian family. Interestingly, the Saudi family and one Tunisian patient had the same splicing mutation located within intron 81 (c.11108-7G>A). However, the analysis of polymorphisms segregating with the mutation did not suggest that the recurrence of this mutation resulted from a founder effect (S. Nicole and B. Fontaine, personal communication).

Congenital Myopathies Congenital myopathies are a group of muscle disorders which are caused by genetic defects in the contractile apparatus of muscle. They have been defined by distinctive static histochemical or ultrastructural changes on muscle biopsy (Ryan and North 2006; Cardomone et al. 2008). They usually present at birth or in childhood, with hypotonia and muscle weakness (Sewry et al. 2008). Central nuclei are the characteristic feature of the X-linked myotubular myoapthy, caused by mutations in the MTM1 gene, which encodes myotubulation (Laporte et al. 1996). This condition was reported by Tanner et al. (1999) in a 39-year-old Yemenese woman with histologic and clinical phenotype consistent with X-linked myotubular myopathy. The proband was found to be a carrier of the most common MTM1 gene mutation, which is associated with a severe phenotype in males. The patient had an extremely skewed X-inactivation pattern, thus explaining her abnormal phenotype, while her mother was a nonmanifesting carrier with extremely skewed X-inactivation pattern in the opposite direction. Another report on this disease came from Oman, describing one female newborn affected by X-linked myotubular myopathy (Menon et al. 2002). Myofibrillar myopathies include a group of neuromuscular disorders, characterized by structural changes in the myofibril, resulting from intracellular accumulation of proteins such as desmins (Cardomone et al. 2008). Being inherited as autosomal dominant or autosomal recessive, the phenotype is characterized by the development of proximal, distal, or generalized weakness. Additional features include the development of cardiomyopathy, cardiac conduction defects, and peripheral neuropathy (Cardomone et al. 2008). El-Menyar et al. (2004) reported a Qatari family with myofibrillar myopathy. The proband, a 22-year-old male, had been diagnosed 6 years earlier with tachybrady syndrome and had been on a permanent pacemaker since then. His parents were second cousins and he had three sisters.

6 Muscular Dystrophies and Myopathies in Arab Populations

167

One of these underwent heart transplantation for severe obstructive cardiomyopathy, while the other had a permanent pacemaker for complete heart block. El-Menyar et al. (2004) suggested that the clinical heterogeneity in the family could be explained by mutations in the desmin gene. Further analysis of data of all patients (<50 years) who were hospitalized between 1996 and 2003 with cardiomyopathy identified a 16-year-old Qatari male who died of restrictive cardiomyopathy associated with myofibrillar myopathy (El-Menyar et al. 2006). He had distal muscle wasting and his ECG suggested restrictive cardiomyopathy. EMG supported the diagnosis of chronic myopathy, while desmin stain was negative.

Myopathy, Early-Onset, with Fatal Cardiomyopathy (EOMFC, MIM 611705, Salih Myopathy) In a first-degree consanguineous Sudanese family, two siblings presented with neonatal hypotonia and delayed motor development (Salih et al. 1998). They acquired independent gait at 26 months and 4 years, respectively. On examination, they mainly had proximal muscle weakness and wasting involving the upper and lower limbs, associated with mild facial weakness and calf muscle hypertrophy. The younger sibling also had ptosis but otherwise had normal external ocular muscles. Investigations revealed mildly elevated CK levels (300 and 824 IU/L; N 210). Muscle biopsies (at the age of 4 years) showed minimal change myopathy and no neurogenic atrophy but remarkable type 1 fiber predominance (up to 85.5%) but without fiber type disproportion. Immunohistochemistry reveled normal expression of dystrophin, b-dystroglycan, a-(adhalin), b, and g-sarcoglycans, laminin a2, integrin a7, and syntrophin. Both patients could walk independently and managed to maintain walking after 13 years of age. Progressive dilated cardiomyopathy with rhythm disturbance developed at about 12 years of age. The authors (Salih et al. 1998) suggested that this phenotype represents a novel form of CMD. Subahi (2001) studied the cardiac features of this phenotype which distinguish it from those reported in DMD.BMD, SCARMD due to sarcoglycan deficiency (sarcoglycanopathies), and laminin a2-deficient CMD. He designated the name “Salih CMD” to this phenotype. Both siblings suddenly died at 19.5 and 17.5 years. The two Sudanese siblings were re-investigated together with a group of three male siblings (living in France) born to Moroccan first-degree consanguineous parents (Carmignac et al. 2007). Their distribution of muscle weakness resembled closely that observed in the Sudanese family. Ptosis, sometimes asymmetric, was a constant finding. Remarkably, the poor muscle bulk in the upper limbs contrasted with the relative pseudohyperthrophy in the lower limbs, particularly in thighs and calves. Progressive dilated cardiomyopathy developed in all the patients from the ages 5 to 12 years, simultaneously with rhythm disturbances. Heart failure associated with ventricular or supraventricular arrhythmias led to sudden death of the two eldest siblings at 8 and 17 years of age. The third sibling had heart

168

M.A.M. Salih

transplantation at 15 years, with good results, but died 2 years later because of postoperative complications after spinal fusion. Skeletal muscle biopsies showed abundant centrally located nuclei, type 1 fiber predominance, and minicore-like lesions. Dystrophic lesions of variable severity were more conspicuous in the second decade. The minicore-like lesions were also apparent in the biopsy of muscle taken from one of the Sudanese patients at 14 years of age. Ultrastructural examination in this biopsy, as well as that done for one of the Moroccan patients, confirmed the presence of multiple foci of sarcomeric disruption and mitochondria depletion. Noticeably, some M-lines looked to be pulled apart and contrasted with comparatively preserved Z-lines. In the most informative Moroccan family, a whole-genome scan identified two potential regions of homozygosity by descent in chromosomes 2 and 3. Analysis of the DNA from the Sudanese family confirmed homozygous linkage to a 4.63 Mb region in 2q31.1–q31.3 for both families. Candidate gene sequencing identified two different homozygous deletions in the titin gene in affected members of the two families. The deletions resulted in truncation of the C terminus of the protein, absence of which had been expected to be lethal, and distruption of the sarcomeric M-line protein complex. The consanguineous parents of each family were heterozygous for the respective deletions and were clinically unaffected. The study (Carmignac et al. 2007) constituted the first congenital and purely recessive titinopathy, in which both the cardiac and skeletal muscles are involved. This entity of titinopathy is currently referred to as “Salih myopathy” (Fukuzawa et al. 2008, Pernigo et al. 2010).

Mitochondial Disorders Since the 1990s, mitochondrial myopathies (cytopathies) have received growing interest (Morgan-Hughes 1992; DiMauro 1993; DiMauro et al. 2004; Zeviani and Di Donato 2004; Taylor and Turnbull 2005). They are a heterogeneous group of disorders with variable clinical expression and multisystem manifestations (Egger et al. 1981). However, brain and muscle seem to be particularly affected and the disease frequently presents in the form of encephalopathy (Tulinius et al. 1991; DiMauro et al. 2004; Scaglia et al. 2004; Salih et al. 2006). The diagnosis is based mainly on morphological abnormalities and/or biochemical changes detected in the mitochondria of skeletal muscle (DiMauro 1993) followed by screening for molecular or mitochondrial DNA (mtDNA) mutations (Bernier et al. 2002; Wong and Boles 2005). One of the mitochondrial syndromes is Kearns-Sayre syndrome, which is characterized by ophthalmoplegia, retinal degeneration, heart block, ataxia, and/or dementia (Berenberg et al. 1977). Bohlega et al. (1993) reported two isolated Saudi cases with Kearns-Sayre syndrome. Both were males (aged 25 and 19 years) who presented with progressive ptosis, proximal weakness, intellectual deterioration, and growth retardation. One of them (the 19-year-old) had muscle fatiguability and cramps. Examination of both

6 Muscular Dystrophies and Myopathies in Arab Populations

169

showed bilateral ptosis, external ophthalmoplegia, and pigmentary retinal changes. They had elevated serum lactate, pyruvate, and CSF proteins. Imaging studies of the brain showed scattered bilateral white matter and basal ganglia lesions in one and moderate brain atrophy in the other. A study in Saudi Arabia (Salih et al. 1994b) focused on a series of children with mitochondrial myopathy and/or encephalopathy and highlighted those who required intensive care management during the course of the disease. The group consisted of ten children belonging to five families, who were managed at KKUH during the period 1992–1994 (six M and four F). The symptoms started within the first week of life in four children who presented with profound hypotonia and feeding and breathing difficulties and who remained ventilator-dependent until they died within a period of 8 months. A fifth presented with floppiness and recurrent (life-threatening) chest infections and died suddenly at 30 months. The other five, who belonged to two families, had exercise-induced muscle fatigue with onset between 6 months and 6 years. Both families had a history of intrauterine fetal deaths and loss of other children early in infancy. Muscle specimens showed features suggestive of mitochondrial myopathy on histochemistry and/or electron microscopy. Biochemical studies of muscles from six patients revealed b-oxidation defect in one and combined deficiencies involving pyruvate dehydrogenase complex, succinate-ubiquinone: cytochrome c oxidoreductase, and cytochrome c oxidase in the other five. Examination of mitochondrial DNA revealed no abnormalities. Bohlega et al. (1996) reported on six patients in two unrelated families from the eastern Arabian Peninsula who presented with childhood-onset progressive external ophthalmoplegia (PEO), mild facial and proximal limb weakness, and severe cardiomyopathy requiring cardiac transplantation. Ragged red and cytochrome c oxidase-negative fibers were seen on muscle histochemistry. The activities of several complexes in the electron transport chain were decreased and Southern blot analysis showed multiple mtDNA deletions. This autosomal recessive form of PEO became known as “autosomal recessive cardiomyopathy and ophthalmoplegia (ARCO)” (DiMauro et al. 2004). It is postulated to be due to mutations in nuclear genes encoding factors needed for mtDNA integrity and replication (DiMauro et al. 2004). Abba (2006) described a 15-year-old Saudi boy who presented with communityacquired pneumonia and rapidly progressed to respiratory failure. He developed difficulty in walking 10 years of age earlier and became blind at 13 years, with immature cataracts detected in both eyes. His sister and brother, aged 18 and 2 years, respectively, had difficulty in walking but were independent. Biochemical investigations showed lactic acidosis. ECG revealed sinus tachycardia and right bundle branch block. Muscle biopsy revealed the characteristic ragged red fibers. He subsequently developed malignant arrhythmia and died 4 months later. An 11-year-old boy who had encephalopathy suggestive of mitonchondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) was reported by Abu-Amero et al. (2006). He developed frequent recurrent attacks of headache and abdominal pain with vomiting at 5 years of age, and ataxia at 10 years associated with alternating prolonged seizures. His parents are double first cousins with three normal siblings and one infant who died suddenly (cause unknown). Serum lactate

170

M.A.M. Salih

was slightly raised at 2.7 mmol/L (normal <2), whereas cerebrospinal fluid (CSF) lactate was significantly higher at 9.1 mmol/L. Pyruvate level in CSF was also high, 192 mmol/L (normal <100) and CSF proteins were elevated at 0.65 g/L. Muscle biopsy showed an excess of neutral lipid, minimal denervation, and type 2 fiber muscle atrophy with marked subsarcolemmal accumulation of nonlysosomal glycogen. Neither mitochondrial abnormalities nor ragged red fibers were noted. Assay of respiratory activity levels showed significant decrease in complex 1 activity in cultured skin fibroblasts. Over the next 2 years, his condition deteriorated and he died of aspiration pneumonia at 12 years of age. Screening the entire mtDNA coding region detected a novel mtDNA transversion mutation in transfer ribonucleic acid for leucine 2 (CUN). Mutations in mtDNA-encoded cytochrome c oxidase (COX) genes are associated with a range of phenotypes, including MELAS, pure myopathy, encephalopathy, and a motor neuron disease-like presentation (Barrientos et al. 2002). Mutations of the nucleus-encoded structural subunits had been sought for but never found in COX-deficient patients, leading to the assumption that they may be incompatible with extra-uterine survival. Massa et al. (2008) reported a diseaseassociated mutation in one such subunit affecting two brothers in a family composed of five sibs from third-degree cousin parents of Saudi Arabian origin. The first of these brothers was admitted at 6 years because of muscle weakness and pain. During a subsequent hospitalization at 10 years, he was found to suffer from muscle weakness, growth retardation, cognitive deterioration, and visual loss. Several brain MRI examinations showed progressive, diffuse leukodystrophic changes. He died at 10 years of rapidly progressive neurological deterioration after recurrent generalized convulsions and severe metabolic acidosis with very high serum lactate. The second patient had a clinical course similar to, but milder than, that of his elder brother. The histochemical reaction to COX was diffusely low in skeletal muscle biopsy from the elder patient. Linkage analysis followed by sequencing of candidate genes revealed the presence of a missense mutation in the COX6B1 gene. Acknowledgments I express my appreciation for the members of the Department of Pathology, College of Medicine, King Saud University, for the help they offered throughout the various stages of this study. Thanks are due to Vir Salvador and Babiker Faragab for medical illustration and for Rowena Fajardo and Loida M. Sese for typing the manuscript.

References Abba AA (2006) Mitochondrial encephalomyopathy presenting with respiratory failure in an adult. J Med Sci 6:704–708 Aberfeld DC, Hinterbuchner LP, Schneider M (1965) Myotonia, dwarfism, diffuse bone disease and unusual ocular and facial abnormalities (a new syndrome). Brain 88:1313–1321 Abu-Amero KK, Ozand PT, Al-Dhalaan H (2006) Novel mitochondrial DNA transversion mutation in transfer ribonucleic acid for leucine 2 (CUN) in a patient with the clinical features of MELAS. J Child Neurol 21:971–972

6 Muscular Dystrophies and Myopathies in Arab Populations

171

Al-Gazali LI (1993) The Schwartz-Jampel syndrome. Clin Dysmorphol 2:47–54 Al-Gazali LI, Varghese M, Varady E, Al Talabin J, Scorer J, Bakalinova D (1996) Neonatal Schwartz-Jampel syndrome in the United Arab Emirates. J Med Genet 33:203–211 Al-Gazali LI, Ravenscroft A, Feng A, Shubbar A, Al-Saggaf A, Haas D (2003) Stuve-Wiedemann syndrome in children surving infancy: clinical and radiological features. Clin Dysmorphol 12:1–8 Al-Husain MA, Al-Eissa YA, Al-Sohaibani MO, Al-Omair AO, Al-Nasser MN (1994) SchwartzJampel syndrome in Saudi children. Ann Saudi Med 14:152–156 Al-Jumah M, Majumdar R, Al-Rajeh S, Chaves-Carballo E, Salih MM, Awada A, Al-Shahwan S, Al-Uthaim S (2002) Deletion mutations in the dystrophin gene of Saudi patients with Duchenne and Becker muscular dystrophy. Suadi Med J 23:1478–1482 Allamand V, Sunada Y, Salih MA, Straub V, Ozo CO, Al-Turaiki MH, Akbar M, Kolo T, Colognato H, Zhang X et al (1997) Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain. Hum Mol Genet 6:747–752 Allamand V, Donahue KM, Straub V, Davisson RL, Davidson BL, Campbell KP (2000) Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alphasarcoglycan-deficient mice. Gene Ther 16:1385–1391 Al-Qudah AA, Kobayashi J, Chuang S, Dennis M, Ray P (1990) Etiology of intellectual impairment in Duchenne muscular dystrophy. Pediatr Neurol 6:57–59 Al-Qudah AA, Tarawneh M (1998) Congenital muscular dystrophy in Jordanian children. J Child Neurol 13:383–386 Al-Rajeh S, Bademosi O, Ismail H, Awada A, Dawodu A, Al-Freihi H, Assuhaime S, Borollosi M, Al-Shammasi S (1993) A community survey of neurological disorders in Saudi Arabia: the Thugban study. Neuroepidemiology 12:164–178 Aoki M, Lui J, Richard I, Bashir R, Britton S, Keers SM, Oeltjen J, Brown HEV, Marchand S, Bourg N et al (2001) Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy. Neurology 57:271–278 Armstrong ML (1985) Electrocardiograms. A systemic method of reading them. Wright, Bristol Azibi K, Chaouch M, Reghis A, Vinet MC, Vignal A, Becuwe N, Beckmann JC, Seboun E, Nguyen S, Cometto M, Fardeau M, Tome F, Leturcq F, Chafey P, Bachner L, Kaplan JC (1991) Linkage analysis of 19 families with autosomal recessive (Duchenne-like) muscular dystrophy from Algeria. Cytogenet Cell Genet 58:1907 Azibi K, Bachner L, Beckman JS, Matsumara K, Hamouda E, Chaouch M, Chaouch A, Ait-Quarab R, Vignal A, Weissenbach J, Vinet M-C, Leturcq F, Collin H, Tome FMS, Reghis A, Fardeau M, Kampbell KP, Kaplan JC (1993) Severe childhood autosomal recessive muscular dystrophy with the deficiency of 50 kDA dystrophin-associated glycoprotein maps to chromosome 13q12. Hum Mol Genet 2:1423–1428 Barresi R, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz JS, Moore SA, Zhang W, Schachter M, Dumanski JP (2004) LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 10:696–703 Barrientos A, Barros MH, Valnot I, Rotig A, Rustin P, Tzagaloff A (2002) Cytochrome oxidase in health and disease. Gene 286:53–63 Bashir R, Strachan T, Keers S, Stephenson A, Mahjneh I, Marcone G, Nashef L, Nushby KMD (1994) A gene for autosomal recessive limb girdle muscular dystrophy maps to chromosome 2p. Hum Mol Genet 3:455–457 Ben Hamida M, Fardeau M (1980) Severe autosomal recessive limb-girdle muscular dystrophies frequent in Tunisia. In: Angelini C, Danieli GA, Fontanari D (eds) Muscular dystrophy research: advances and new trends. Excerpta Medica, Amsterdam, pp 143–146 Ben Hamida M, Hentati F (1989) Tunisian severe childhood muscular dystrophy: a normal spinal cord and anterior horn neurons. Muscle Nerve 12:156 Ben Hamida M, Ben Hamida C, Zouari M, Belal S, Hentati F (1996) Limb-girldle muscular dystrophy 2C: clinical aspects. Neuromuscul Disord 6:493–494

172

M.A.M. Salih

Ben Jelloun-Dellagi S, Chaffey P, Hentati F, Ben-Hamida C, Tome FMS, Collin H, Dellagi K, Kaplan J-C, Fardeau M, Benm Hamida M (1990) Presence of normal dystrophin in Tunisian severe childhood autosomal recessive muscular dystrophy. Neurology 40:1903 Ben Othmane K, Ben Hamida M, Pericak-Vance M, Ben Hamida C, Blel S, Carte SC, Bowcock AM, Pertruhkin K, Gilliam TC, Roses AD (1992) Linkage of Tunisian autosomal recessive Duchnne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nat Genet 2:315–317 Ben Othmane K, Speer MC, Stauffer S, Blel S, Middleton L, Ben Hamida C, Etribi A, Loeb D, Hentati F, Roses AD et al (1995) Evidence of linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy (LGMD2C). Am J Hum Genet 57:732–734 Ben-Hamida M, Marrakchi D (1980a) Etude genetique des myopathies en Tunisie. Tire a part de I’Union Medical 109:1–8 Ben-Hamida M, Marrakchi D (1980b) Dystrophie musculaire progressive de type Duchenne et Tunisie: a propos de 13 families et 31 cas d’une forme en apparence recessive autosomique. J Genet Hum 28:1–9 Ben-Hamida M, Fardeau M, Attia N (1983) Severe childhood muscular dystrophy affecting both sexes and frequent in Tunisia. Muscle Nerve 6:469–480 Berenberg RA, Pellock JM, DiMauro S, Schotand DL, Bonilla E, Eastwood A, Hays A, Vicale CT, Sehrens M, Chutorian A, Rowland LP (1977) Lumping or splitting? “Ophthalmoplegia plus” or Kearns-Sayre syndrome? Ann Neurol 1:37–54 Bernier FP, Boneh A, Dennet X, Chow CW, Cleary MA, Thornbum DA (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411 Bessiso MS, Teebi AS, Al-Awadi SA, Al-Rashied AA (1986) Schwartz-Jamp syndrome. A case study and electromyographic finding. J Kuwait Med Assoc 20:195–199 Billard C, Gillet P, Signoret JL, Uicaut E, Bertrand P, Fardeau M, Sartho Carpentier MA, Santini JI (1992) Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy. Neuromuscul Disord 2:371–378 Bohlega SA, Cook J, Haider A, Al-Kawi MZ, Sitgsby B (1992) Childhood autosomal recessive muscular dystrophy: a study of Saudi family. Ann Saudi Med 12:600 [Abstract] Bohlega S, Al-Kawi MZ, Chavis P, Haider A, Omer S (1993) Mitochondrial DNA deletion in Kearns-Sayre syndrome: a review and illustrating cases. Ann Saudi Med 13:197–202 Bohlega S, Tanji K, Santorelli FM, Hirano M, Al-Jishi A, DiMauro S (1996) Multiple mitochondrial DNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy. Neurology 46:1329–1334 Bonnemann CG, Modi R, Noguchi S, Mizuno Y, Yoshida M, Gussoni E, McNally EM, Duggan DJ, Angelini C, Hoffman EP (1995) Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of sarcoglycan complex. Nat Genet 1995:266–273 Bonnemann CG, Wong J, Ben Hamida C, Hamida MB, Hentati F, Kunkel LM (1998) LGMD 2E in Tunisia is caused by a homozygous missence mutation in beta-sarcolgycan exon 3. Neuromuscul Disord 8:193–197 Brown KA, Al-Gazali LI, Moynihan LM, Lench NJ, Markham AF, Mueller RF (1997) Genetic heterogeneity in Schwartz-Jampel syndrome: two families with neonatal Schwartz-Jampel syndrome do not map to human chromosome 1p34-p36.1. J Med Genet 54:685–687 Bushby KMD (1999) Making sense of the limb-girdle muscular dystrophies. Brain 122:1403–1420 Bushby KMD, Beckmann JS (1995) Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC workshop on limb-girdle muscular dystrophies. Neuromuscul Disord 5:71–74 Campbell K, Allamand V, Sunada Y, Straub V, Salih M (2000) Method for aiding in the diagnosis of in-frame deletion type congenital muscular dystrophy. US Patent 6,136,546. http://www. freepatentsonline.com/6136546.html Cardomone M, Darras BT, Ryan MM (2008) Inherited myopathies and muscular dystrophies. Semin Neurol 28:250–259

6 Muscular Dystrophies and Myopathies in Arab Populations

173

Carmignac V, Salih MAM, Quijano-Roy S, Marchand S, Marchand S, Al Rayess MM, Mukhtar MM, Ja U, Labeit S, Guicheney P et al (2007) G terminal titin deletions cause a novel earlyonset myopathy with fatal cardiomyopathy. Ann Neurol 61:340–351 Chaudhary AG, Alqahtani MH, Abusenadah A, Gari M, Al-Sofyani AA, Al-Aama JY, Lary SA, Elaimi AH (2008) Mutation analysis in Saudi Duchenne and Becker muscular dystrophy patients using multiplex PCR. Arch Med Sci 4:16–21 Cook JD, Gascon GG, Haider A, Coates R, Stigbsby B, Ozand PT, Banna M (1992) Congenital muscular dystrophy with abnormal radiographic myelin pattern. J Child Neurol 7(Suppl):S51–S63 Cordier L, Hack AA, Scott MO et al (2000) Rescue of skeletal muscles of gamma-sarcoglycandeficient mice with adeno-associated virus-mediated gene transfer. Mol Ther 1(2):119–129 Cupler EJ, Bohlega S, Hesslen R, McLean d, Stigsby B, Ahmad J (1998) Miyoshi myopathy in Saudi Arabia: clinical, electrophysiological, histopathological and radiological features. Neuromuscul Disord 8:321–326 Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Martinovic J, Raas-Rothschild A, Sigaudy S, Unger S (2004) Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am J Hum Genet 74:298–306 DiMauro S (1993) Mitochondrial disorders. In: Rosenberg RN, Prusiner SB, Di Mauro S, Barchi RL, Kunkel LM (eds) Molecular and genetic basis of neurological disease. ButterwothHeinemann, Boston, pp 665–694 DiMauro S, Bonilla E, Mancuso M, Filosto M, Sacconi S, Salviati L, Hirano M (2004) Mitochondrial myopathies. Basic Appl Myol 13:145–155 Dobyns WB, Pagon RA, Armstrong d, Curry CJR, Greenberg F, Grix A, Holmes LB, Laxova R, Michels W, Robinow M, Zimmerman RL (1989) Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet 32:195–210 Dressman D, Araishi K, Imamura M, Sasaoka T, Liue LA, Engvall E, Hoffman EP (2002) Delivery of alpha- and beta-sarcoglycan by recombinant adeno-associated virus: efficient rescue of muscle, but differential toxicity. Hum Gene Ther 13:1631–1646 Driss A, Amari R, Ben Hamida C, Souilem S, Govider-Khorija N, Ben Hamida M, Hentati F (2000) A new locus of autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. Neuromuscul Disord 10:240–246 Dubowitz V (1980) Rapidly progressive limb girdle muscular dystrophy in childhood. In: Angelini D, Danieli GA, Fontanari D (eds) Muscular dystrophy research: advances and new trends. Exceprta Medica, Amsterdam, pp 129–133 Dubowitz V (1994) Workshop report: 22nd ENMC sponsored workshop on congenital muscular dystrophy held in Baarn, The Netherlands, 14–16 May 1993. Neuromuscul Disord 4:75–81 Effat LK, El-Harouni AA, Amr KS, El-Minisi TI, Abdel Meguid N, El-Awady M (2000) Screening of dystrophin gene deletions in Egyptian patients with DMD/BMC muscular dystrophies. Dis Markers 16:125–129 Effat LK, Amr KS, El-Horouni AA, Gaber KR (2008) The impact of prenatal diagnosis in Egyptian families with Duchenne muscular dystrophy. Egypt J Med Hum Genet 9:105–110 Egger J, Lake BD, Wilson J (1981) Mitochondrial cytopathy: a multisystem disorder with ragged red fibres on muscle biopsy. Arch Dis Child 56:741–752 El Kerch F, Sefiani A, Azibi K, Boutaleb N, Yahyaoui M, Bentahila A, Vinet M-C, Leturcq F, Bachner L, Beckmann J, Campbell KP, Tome FMS, Fardeau M, Kaplan J-C (1994) Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in North Africa. J Med Genet 31:342–343 El-Harouni AA, Amr KS, Effat LK, Easawi ML, Ismail S, Gad YZ, E-Awady MK (2003) The milder phenotype of the dystrophin gene double deletions. Acta Neurol Scand 107:400–404 El-Menyar AA, Al-Suwaidi J, Gehani AA, Bener A (2004) Clinical and histologic studies of a Qatani family with myofibrillar myopathy. Saudi Med J 25:1723–1726 El-Menyar AA, Bener A, Numan MT, Morcos S, Taha RY, Al-Suwaidi J (2006) Epidemiology of idiopathic cardiomyopathy in Qatar during 1996-2003. Med Princ Pract 15:56–61 Emery AEH (1987) Duchenne muscular dystrophy. Oxford University Press, New York

174

M.A.M. Salih

Emery AEH (1991) Population frequencies of inherited neuromuscular diseases- a world survey. Neuromuscul Disord 1:19–29 Ervasti JM, Campbell KP (1991) Membrane organization of the dystrophin-glycoprotein complex. Cell 66:1121–1131 Farag TI, Teebi AS (1990) Duchenne-like muscular dystrophy in the Arabs. Am J Med Genet 37:290 Farag TI, Rao VK, El-Khalifa MY, Sundareshan TS, Marafie JM, Voncina D, Simsek M, Mady SA, Al-Othman SA, Al-Awadi SA (1989) Autosomal recessive Duchenne-like muscular dystrophy in Arabs: report of a Kuwaiti family and literature review. Med Princ Pract 1:96–101 Fardeau M, Matsumura K, Tome FMS, Collin LH, Leturcq F, Kaplan J-C, Campbell KP (1993) Deficiency of the 50 kDa dystrophin-associated glycoprotein (adhalin) in severe autosomal recessive muscular dystrophy in children native from European countries. C R Acad Sci Paris III 316:799–804 Fariello R, Meloff K, Murphy EG, Reilly B, Armstrong D (1978) A case of Schwartz-Jampel syndrome with unusual muscle biopsy finding. Ann Neurol 3:93–96 Fendri K, Kefi M, Hentati F, Amouri R (2006) Genetic heterogeneity within a consanguineous family involving the LGMD 2D and the LGMD 2C genes. Neuromuscul Disord 16:316–320 Ferrannini E, Perniola T, Krajewska G, Serlenga L, Trizio M (1982) Schwartz-Jampel syndrome with autosomal-dominant inheritance. Eur Neurol 21:137–146 Fukuyama Y, Osama M, Suzuki H (1981) Congenital progressive muscular dystrophy of the Fukuyama type: clinical, genetic and pathological considerations. Brain Dev 3:1–29 Fukuzawa A, Lange S, Holt M, Vichola A, Carmignac V, Ferreiro A, Udd B, Gautel M (2008) Interchains with titin and myomesin target obscuring and obscuring-like 1 to the M-band-implication for hereditary myopathies. J Cell Sci 121:1841–1851 Gardner-Medwin D, Johnston HM (1984) Severe muscular dystrophy in girls. J Neurol Sci 64:79–87 Gardner-Medwin D, Sharples P (1989) Some studies of the Duchenne and autosomal recessive types of muscular dystrophy. Brain Dev 11:91–97 Giedion A, Boltshauser E, Briner J, Eich G, Exner G, Fendel H, Kaufmann L, Steinmann B, Spranger J, Superti-Furga A (1997) Heterogeneity in Schwartz-Jampel chondrodystrophic myotonia. Eur J Pediatr 156:214–223 Grewal PK, Holzfeind PJ, Bittner RE, Hewitt JE (2001) Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse. Nat Genet 28:151–154 Haider MZ, Bastaki L, Habib Y, Moosa A (1998) Screening 25 dystrophin gene exons for deletions in Arab children with Duchenne muscular dystrophy. Hum Hered 48:61–66 Helliwell TR, Nguyen thi Man, Morris GE, Davies KE (1992) The dystrophin-related protein, utrophin, is expressed in the sarcolemma of regenerating human skeletal muscle fibres in dystrophies and inflammatory myopathies. Neuromuscul Disord 2:177–184 Hoffman EP, Brown RH, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919–928 Hoffman EP, Fischbeck KH, Brown RH, Johnson M, Medori R, Loike JD, Harris JB, Waterson R, Brook M, Specht L, Kupsky W, Chamberlain J, Caskey T, Shapiro F, Kunkel LM (1988) Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne’s or Becker’s muscular dystrophy. N Engl J Med 318:1363–1368 Hoffman EP, Kunkel LM. (1989) Dystrophin abnormalities in Duchenne/Becker muscular dystrophy. Neuron 2:1019–1029 Ibrahimov-Beskrovnaya O, Ervasti JM, Leveille CJ, Slaughter CA, Sernett SW, Campbell KP (1992) Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355:696–702 Ionasescu V, Zellweger H (1974) Duchenne muscular dystrophy in young girls. Acta Neurol Scand 50:619–630 Jackson CE, Strehler DA (1968) Limb-girdle muscular dystrophy: clinical manifestations and detection of preclinical disease. Pediatrics 41:495–502

6 Muscular Dystrophies and Myopathies in Arab Populations

175

Jamil AA, Singh B, Al-sowailem AM, Al-Deeb S, Shahwan S, Omar FZ (1992) SchwartzJampel syndrome: a rare disorder studied in two Saudi families. Ann Saudi Med 12:595 [Abstract] Jeanpierre M, Carrie A, Piccolo F, Leturcq F, Azibi K, De Toma C, Beldjord C, Merlini L, Voit T, Romero N, Sunada Y, Tome FMS, Fardeau M, Campbell KP, Kaplan J-C (1996) From adhalinopathies to alpha-sarcoglycanopathies: an overview. Neuromuscul Disord 6:463–465 Kefi M, Amouri R, Driss A, Ben Hamida C, Ben Hamida M, Kunkel LM, Hentati F (2003) Phenotype and sarcolgycan expression in Tunisian LGMD 2C patients sharing the same del521-T mutation. Neurmuscul Disord 13:779–878 Khadilkar SV, Benny R (2008) Muscle disease in India. ACNR 8:13–14 Khurana TS, Watkins SC, Chafey P, Chelley J, Tome FM, Fardeau M, Kaplan JC, Kunkel LM (1991) Immunolocalisation and developmental expression of dystrophin-related protein in skeletal muscle. Neuromuscul Disord 1:185–194 Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, Klauck SM, Dahl N (1996) Agene mutated in x-linked myotubular myopathy defines a new putative tyrotine phosphatase family conserved in yeast. Nat Genet 13:175–182 Leyten QH, Babreel FJM, Reneir WO, Ter-Laak HJ, Sengers RC, Mullaart RA (1989) Congenital muscular dystrophy. J Pediatr 115:214–221 Lim LE, Duclos F, Broux O, Bourg N, Sunada Y (1995) Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Nat Genet 11:257–265 Longman C, Brockington M, Torelli S, Jimenez-Mallebrea C, Kennedy C, Khalil N, Feng L, Saran RK, Voit T, Merlini L et al (2003) Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 12:2853–2861 Lui J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, Serrano C, Urtizberea JA, Hentati F, Hamida MB et al (1998) Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20:31–36 MacMichael HA (1967) A history of the Arabs in the Sudan, 1st edn. Frank Cass, London, pp 324–329 Mahjneh I, Vannelli G, Bushby K, Marcone GP (1992) A large imbred Palestinian family with two forms of muscular dystrophy. Neuromuscul Disord 2:277–283 Massa V, Fernandez-Vizarra E, Al Shahwan S, Bakhsh E, Goffrini P, Ferrero I, Mereghetti P, D’Adamo P, Gasparini P, Zeviani M (2008) Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet 82:1281–1289 Matsumura K, Campbell KP (1993) Deficiency of dystrophin-associated proteins. A common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. Neuromuscul Disord 3:109–118 Matsumura K, Tome FMS, Collin H, Azibi K, Chaouch M, Kaplan J-C, Fardeau M, Campbell KP (1992) Deficiency of the 50k dystrophin-associated glycol-protein in severe childhood autosomal recessive muscular dystrophy. Nature 359:320–322 McKusick VA (1994) Mendelian inheritance in man: a catalog of human genes and genetic disorders, 11th edn. Johns Hopkins University Press, Baltimore Menon K, Rao TV, Bhat BA, El Amin EO (2002) X-linked myotubular myopathy with probable germline mosaicism. Clin Neuropathol 21:265–268 Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JZ, Dollar J, Nishino I, Kelly RI, Somer H et al (2002) Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417–422 Miyoshi K, Kawai H, Iwasa M, Kusaka K, Nistrino H (1986) Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Seventeen cases in eight families including an autopsied case. Brain 109:31–54 Mohamed MA (1956) Northern Sudan: population and tribes (in Arabic). Writing, Translation and Publication Committee, Cairo, pp 143–153 Morgan-Hughes JA (1992) Mitochondrial diseases. In: Mastaglia FL, LordWalton of Detchant (eds) Skeletal muscle pathology. Churchill Livingstone, London, pp 367–424

176

M.A.M. Salih

Muntoni F, Voit T (2004) The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 14:635–645 Nicole S, Ben Hamida C, Baghton P, Bakouni S, Belal S, Romero N, Viljoen D, Ponsot G, Sammoud A, Weissenbach J et al (1995) Localization of the Schwartz-Jampel syndrome (SLS) locus to chromosome 1p34-p36.1 by homozygosity mapping. Hum Mol Genet 4:1633–1636 Nicole S, White PS, Topaloglu H, Beigthon P, Salih M, Hentati F, Fontaine B (1999) The human CDC42 gene: genomic organization, evidence for the existence of a putative pseudogene and exclusion as a SJS1 candidate gene. Hum Genet 105:98–103 Nicole S, Davoine C-S, Topaloglu H, Cattolico L, Barral D, Beighton P, Ben Hamida C, Hammouda H, Cruaud C, White PS et al (2000) Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nat Genet 26:480–483 Nigro V, Piluso G, Belsito A, Politano L, Puca AA, Papparella S, Rossi E, Viglietto G, Esposito MG, Abbondanza C et al (1996a) Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein. Hum Mol Genet 5:1179–1186 Nigro V, Moreira ES, Piluso G, Vainzof M, Belsito A, Poltano L, Pucca AA, Passos-Bueno MR, Zatz M (1996b) Autosomal recessive limb-girdle muscular dystrophy, LGMD2F, is caused by a mutation in the delta-sarcoglycan gene. Nature 13:195–198 Noguchi S, McNally EM, Ben Othmane K, Hagiwara Y, Mizuno Y, Yoshida M, Yamamoto H, Bo¨nnemann CG, Gussoni E, Denton PH et al (1995) Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science 270:819–822 Ohlendieck K, Matsumura K, Ionasescu VV, Towbin JA, Bosch EP, Weinstein SL, Sernett SW, Campbell KP (1993) Duchenne muscular dystrophy: deficiency of dystrophin-associated proteins n the sarcolemma. Neurology 43:795–800 Ozawa E, Mizuno Y, Hagiwara Y, Sasaoka T, Yoshida M (2005) Molecular and cell biology of the sarcoglycan complex. Muscle Nerve 32:563–576 Passos-Bueno MR, Oliveira JR, Bakker E, Anderson RD, Marie SK, Vainzof M, Roberds S, Campbell KP, Zatz M (1993) Genetic heterogeneity for duchenne-like muscular dystrophy (DLMD) based on linkage and50 DAG analysis. Hum Mol Genet 2:1945–1947 Pavone L, Mollica F, Grasso A, Cao A, Gullota F (1978) Schwartz-Jampel syndrome in two daughters of first cousins. J Neurol Neurosurg Psychiatry 41:161–169 Perloff JK, Roberts WC, de Leon AC, O’Doherty D (1967) The distinctive electrocardiogram of Duchenne’s progressive muscular dystrophy. Am J Med 42:179–188 Pernigo S, Fukuzawa A, Bertz M, Holt M, Reif M, Steiner RA, Gautel M (2010) Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex. Proc Natl Acad Sci USA 107:2908–2913 Piccolo F, Roberds SL, Jeanpierre M, Leturcq F, Azibi K, Beldjord C, Carrie´ A, Re´can D, Chaouch M, Reghis A et al (1995) Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity. Nat Genet 10:243–245 Piccolo F, Jeanpierre M, Leturcq F, Dode C, Azibi K, Toutain A, Merlini L, Jarre L, Navarro C, Krishnamoorthy R et al (1996) A founder mutation in the gamma-sarcoglycan gene of Gypsies possibly predating their migration out of India. Hum Mol Genet 5:2019–2022 Poppe M, Cree L, Bourke J, Bourk J, Eagle M, Anderson LV, Burchall D (2003) The phenotype of limb-girdle muscular dystrophy type 21. Neurology 60:1230–1231 Radhakrishnan K, El-Mangoush MA, Se G (1987) Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 75:95–100 Rajab A, Bappol B, Al-Shaikh H, Al-Khusaibi S, Mohammaed AJ (2005) Common autosomal recessive diseases in Oman derived from a hospital-based registry. Community Genet 8:27–30 Roberds SL, Anderson RD, Ibraghimov-Beskrovanya O, Campbell KP (1993a) Primary structure and muscle-specific expression of the 50-kDA dystrophin-associated glycoprotein (Adhalin). J Biol Chem 268:23739–23742

6 Muscular Dystrophies and Myopathies in Arab Populations

177

Roberds SL, Ervasti JM, Anderson RD, Ohlendieck K, Kahl SD, Zoloto D, Campbell KP (1993b) Disruption of the dystrophin-glycoprotein complex in the cardiomyopathic hamster. J Biol Chem 268:11496–11499 Roberds SL, Leturcq F, Allamand V, Piccolo F, Jean Pierre M, Anderson RD, Lim LE, Lee JC, Tome FMS, Romero NB, Fardeau M, Beckmann JS, Kaplan J-C, Campbell KP (1994) Missence mutations in the adhalin gene linked to autosomal recessive muscular dystrophy. Cell 78:625–633 Romdhane NA, Ben Hamida M, Mrabet A, Larnaout A, Samoud S, Ben Hamda A, Ben Hamda M, Oueslati S (1993) Prevalence study of neurologic disorders in Kelibia (Tunisia). Neuroepidemiology 12:285–299 Romero NB, Tome FMS, Leturcq F, El Kerch F, Azibi K, Bachner L, Anderson RD, Roberds SL, Campbell KP, Fardeau M, Kaplan J-C (1994) Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDA dystrophin-associated glycoprotein) deficiency. C R Acad Sci Paris Sci vie/Life Sci 317:70–76 Ryan MM, North KN (2006) Congenital myopathies. In: No Serorthy J (ed) Neurological therapeutics: principles and practice. Martin Dunitz, Rochester, NY, pp 2607–2618 Salani S, Lucchiari S, Fortunato F, Crimi M, Corti S, Locatelli F, Bossolasco P, Bresolin N, Comi GP (2004) Developmental and tissue - specific regulation of a novel dysferlin isoform. Muscle Nerve 30:366–374 Salih MAM (1980) Unusual muscular dystrophy in an extended Sudanese kindred. M.P.C.H. thesis, University of Khartoum Salih MAM (1982) Unusual muscular dystrophy in an extended Sudanese kindred. M.D. thesis, University of Khartoum Salih MAM (1985) Childhood muscular dystrophy: an African review. Ann Trop Paediatr 4:45–48 Salih M, Urtizberea JA, Leturq F, Mukhtar M, Anderson L, Bushby K (2007) Molecular characterization and clinical update on one of the earliest described families with severe childhood autosomal recessive muscular dystrophy (SCARMD). Neuromuscl Disord 17:813 [Abstract] Salih MAM, Omer MIA, Bayoumi RA, Karrar O, Johnson M (1983) Severe autosomal recessive muscular dystrophy in an extended Sudanese kindred. Dev Med Child Neurol 25:43–52 Salih MAM, Ekmejian A, Omer MIA (1984) Respiratory insufficiency in a severe autosomal recessive form of muscular dystrophy. Ann Trop Paediatr 4:45–48 Salih MAM, Mahdi AH, Al-Jarallah AA, Al-Jarallah AS, Al-Saadi M, Hafeez MA, Aziz SA (1992) Childhood neuromuscular disorders in Saudi Arabia: a decade’s experience in a tertiary hospital. In: Proceedings of the First Congress of the Saudi Benevolent Association for Disabled Children, Riyadh [Abstract] Salih MAM, Ruitenbeek W, Dincsoy MY, van Oost BA, Abo-Hassan H, Ozo C, Al-Rikabi AC (1994b) Familial childhood mitochondrial disease in Saudi Arabia: defective energy metabolism presenting as an emergency. In: Proceedings of the 7th Paediatric Symposium, Riyadh, Saudi Arabia [Abstract] Salih MAM, Mahdi AH, Al-Jarallah AA, Al-Jarallah AS, Al-Saadi M, Hafeez MA, Aziz SA (1996a) Childhood neuromuscular disorders in Saudi Arabia: a decade’s experience in a tertiary hospital. Ann Trop Paediatr 16:271–280 Salih MAM, Mahdi A, Al-Rikabi AC, Al-Bunyan M, Roberds SL, Anderson RD, Campbell KP (1996b) Clinical and molecular pathological features of childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 38(3):262–270 Salih MA, Sunada Y, Al-Nasser M, Ozo CO, Al-Turaiki MH, Akbar M, Campbell KP (1996c) Muscular dystrophy associated with beta-dystroglycan deficiency. Ann Neurol 40:925–928 Salih MA, Al Rayesi M, Cutshall S, Urtizberca JA, Al-Turaiki MH, CO OZO, Straub V, Akbar M, Abid M, Andeejani A et al (1998) A novel form of familial congenital muscular dystrophy in two adolescents. Neuropediatrics 29:289–293 Salih MA, Abdel-Gader AG, Zahraa JN, Al-Rayess MM, Alorainy IA, Hassan HH, Ruitenbeek W, Zeviani M (2006) Stroke due to mitochondrial disorders in Saudi children. Saudi Med J 27 (Suppl 1):S81–S90

178

M.A.M. Salih

Santavouri P, Leisto J, Kruus S (1977) Muscle, eye and brain disease: a new syndrome. Neuropadiatrie 8(Suppl):553–558 Sawardekar KP (2005) Profile of major congenital malfomartions at Nizwa Hospital, Oman: 10 year review. J Pediatr Child Health 41:323–330 Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutin GD et al (2004) Clinical spectrum, morbidity, mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 114:925–931 Schwartz O, Jampel RS (1962) Congenital blepharophimosis associated with a unique generalized myopathy. Arch Opthlamol 68:82–87 Seidahmed MZ, Sunada Y, Ozo CO, Hamid F, Campbell KP, Salih MAM (1996) Lethal congenital muscular dystrophy in two sibs with orthrogryposis multiplex: new entity or variant of cobblestone lissencephaly syndrome? Neuropediatrics 27:305–310 Sewry CA, Sansome A, Matsumura K, Campbell KP, Dubowitz V (1994) Deficiency of the 50 kDA dystrophin-associated glycoprotein and abnormal expression of utrophin in two South Asian cousins with variable expression of severe childhood autosomal recessive muscular dystrophy. Neuromuscul Disord 4:121–129 Sewry CA, Jimenez-Mallebrea C, Muntoni F (2008) Congenital myopathies. Curr Opin Neurol 21:569–575 Shokeir MH, Kobrinsky NL (1976) Autosomal recessive muscular dystrophy in Manitoba Hutterites. Clin Genet 9:197–202 Soussi-Yanicostas N, Ben Hamida C, Butler-Browne GS, Hentati F, Bejaoui K, Ben Hamida M (1991) Modification in the expression and localization of contractile and cytoskeletal proteins in Schwartz-Jampel syndrome. J Neurol Sci 104:64–73 Specht LA, Kunkel LM (1993) Duchenne and Becker muscular dystrophies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM (eds) The molecular and genetic basis of neurological disease. Butterworth-Heinemann, Boston, pp 613–631 Stern LM (1972) Four cases of Duchenne-type muscular dystrophy in girls. Med J Aust 2:1066–1069 Stum M, Davone CS, Vicart S, Guillot-Noel, Topaloglu H, Carod-Artal FJ, Kayserili H, Hentati F, Merlini L, Urtizberea JA, et al (2006) Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz – Jampel syndrome. Hum Mutat 27:1082–1091 Sztriha L, Al-Gazali LI, Varady E, Goebel HH, Nork M (1999) Autosomal recessive micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediatrics 30:141–145 Tanner SM, Orstavik KH, Kristiansen M, Lev D, Lerman-Sagie T, Sadeh M, Liechti-Gallati S (1999) Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting camir mother. Hum Genet 104:249–253 Taylor R, Turnbull D (2005) Mitochondrial DNA mutation in human disease. Nat Rev Genet 6:389–402 Topalog˘lu H, Yalaz K, Renda Y, Cag˘lar M, Go¨g˘€ us S, Kale G, G€ uc€ uyener K, Nurlu G (1991) Occidental type cerebromuscular dystrophy: a report of eleven cases. J Neurol Neurosurg Psychiatry 54:226–229 Tulinius MJ, Holme E, Kristianssonn B, Larsson NG, Oldfors A (1991) Mitochondrial encephalopathies in childhood. II. Clinical manifestation and syndromes. J Pediatr 119:242–250 Urtizberea Ja, Bassez G, Letureq F, Nguyen K, Kraln M, Levy N (2008) Dysferlinopathies. Neurol India 56:289–297 Van Essen AJ, Busch HF, te Meerman GJ, ten Kate LP (1992) Birth and population prevalence of Duchenne muscular dystrophies in the Netherlands. Hum Genet 88:258–266 Van Reeuwijk J, Gerwald PK, Salih MAM, Daniel Beltran-Valero de Bernabe, McLaughlan JM, Michielse CB, Herrman R, Hewitt JE, Steinbrecher A, Seidahmed MZ, et al (2007) Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome. Hum Genet 121:685–690

6 Muscular Dystrophies and Myopathies in Arab Populations

179

Vermeer S, Verrips A, Willemsen MA, ter Laak HJ, Ginjaar IB, Hamel BC (2004) Novel mutations in three patients with LGMD2C with phenotypic differences. Pediatr Neurol 30:291–294 Wong L-J C, Boles RG (2005) Mitochondrial DNA analysis in clinical laboratory diagnostics. Clin Chem Acta 354:1–20 Yakota T, Lu Q, Partridge, Kobayashi M, Nakamura A, Takeda S, Hoffman E (2009) Effficiency of systemic mrpholine exon-shipping in Duchenne dystrophy dogs. Ann Neurol 65:667–676 Zatz M, Passos-Bueno MR, Rapaport D (1989) Estimate of the proportion of Duchenne muscular dystrophy with autosomal recessive inheritance. Am J Med Genet 32:407–410 Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127:2153–2172

Chapter 7

New Syndromes First Reported Among Arabs Ahmad S. Teebi

Introduction In the last three decades, there has been a considerable increase in the number of reports describing new syndromes and variants from Arab populations. Many of such reports included data related to the molecular genetic basis of the disease in question. They continue to come from countries with established genetic services including Lebanon, Israel, Saudi Arabia, Kuwait, UAE, Oman and Qatar. The number of syndromes included in this chapter is close to 160 syndromes, the majority of which are autosomal recessive. However, the list is by no means thoroughly inclusive and many others were not included for various reason.

A.S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_7, # Springer-Verlag Berlin Heidelberg 2010

181

Iraqi

American American (black) German –

10(4 generations)

16(3 generations)

6 2

137130

145420

603642

Gastric sneezing

Hypertolerism, Teebi type or Teebi hypertolerism syndrome

Atrial septal defect with various cardiac and noncardiac anomalies

2 12 individuals with vertical transmission and male to male transmission

32(4 generations) 20(6 generations)

Kuwaiti

Lebanese Lebanese

113900 125630

Bundle branch block Dermodistortive urticaria

2

102490

Family Origin Egyptian

Acro–reno–ocular syndrome

No. of affected

MIM No.

Disorder

Table 7.1 New autosomal dominant (AD) disorders first described among Arabsa

–

Cardiac abnormalities include EKG abnormalities, QRS, bundle branch block, atrial fibrillation, Wolf–Parkinson–White syndrome aortic stenosis, mitral stenosis, Ebestein anomaly, non-cardiac hypertelorism, cleft lip, pectus deformity

Stratton (1991) Toriello and Delp (1994) Konig (2006) Megarbane et al. (1999)

Teebi and Al-Saleh (1989) Teebi (1987)

Ste´phan (1954, 1978) Epstein and Kidd (1981), Epstein et al. (1981)

Temtamy et al. (1975), Temtamy (1986)

Thumb hypoplasia/aplasia, preaxial polydactyl, radial defects, thenar hypoplasia, renal malformations, eye colobomas, ptosis, Duane anomaly, abnormal dermatoglyphics Syncopal episodes, slow pulse Pruritic erythematous, edematous, cutaneous swelling confined to areas exposed to vibratory or stretching stimulation (develops within minutes and disappear within an hour). Extensive stimulation may cause faintness, headache, facial erythema Multiple sneezing after fullness of stomach Hypertolerism, mild antimongoloid slant of palpebral fissures, prominent forehead, broad and heavy eyebrows, short nose, slightly small and broad hands, shawl scrotum, normal intelligence

References

Consanguinity Manifestations

182 A.S. Teebi

608637

607812

Pontocerebellar hypoplasia type 3, PCH3

608027

Diabetes mellitus, neonatal, 610199 with congenital hypothyroidism Or NDH syndrome

Craniolenticulosutural dysplasia; CLSD Or Boyadjiev-JabsEyaid syndrome

Microcephaly with 603802 simplified gyral pattern

Spondyloepiphyseal dysplasia, Omani type

Omani

Saudi Arabian and French

+

Other 2 families 3

Saudi Arabian

Kuwaiti

3 (2 males, 1 female)

3

Saudi Arabian

Omani

Omani

6 (5 males, 1 female)

4

8 in 2 sibships (1 male, 7 females)

+ +

+

+

+

+

+

+

Progressive microcephaly, cerebelar atrophy, brachcephaly, prominent eyes, low-set ears, truncal hypotonia at birth, seizures in the first year of life, severe developmental delay Linkage to 7 q11-q21

Short stature, short upper segment with progressive kyphoscoliosis, severe arthritic changes, joint dislocations, rhizomelia, camptodactyly, mild brachydactyly, microdontia, normal intelligence Mutation in CHST3 gene Congenital primary microcephaly, simplified gyral pattern, thin corpus callosum, brain stem and cerebellar hypoplasia, seizures, hypotonia, apnea, and early death (microcephaly, Amish type was excluded) Wide calvarial sutures, late closing anterior fontanelle, frontal bossing, hypertelorsim, broad and prominent nose, Y shaped sutural cataract Missense mutation in SEC23A gene in the Saudi family In addition: minor facial abnormalities, intrauterine growth retardation, cholestasis, congenital glaucoma, polycystic kidneys, liver disease progresesses to hepatic fibrosismanifestations variable. Mutations in the GLIS3 gene

(continued )

Rajab et al. (2003)

Senee et al. (2006)

Taha et al. (2003)

Teebi (Unpublished)

Boyadjiev et al. (2003, 2006)

Rajab et al. (2007a)

Rajab et al. (2004), Thiele et al. (2004)

7 New Syndromes First Reported Among Arabs 183

MIM No.

–

150900

609166

608156 4 Mb microdeletion

Generalised lipodystrophy

Lentigines

Branchiogenic-deafness syndrome

Nablus mask-like facial syndrome

Lipodystophy, generalised 608154 with mental retardation and deafness or Lipodystrophy, Rajab type – Microcephaly and brain calcification, developmental delay and small stature

Disorder

Table 7.1 (continued)

Sporadic

Palestinian

MalteseLebanese 2 sibs and their father and Lebanese his sister and half brother

8 (3 generations)

4 in 2 sibships

Omani

Omani

8 children in 2 unrelated families

3

Family Origin Omani

No. of affected

+

+

+

+

Pipkin and Pipkin (1950) Megarbane et al. (2003b)

Rajab et al. (2002), Heathcote et al. (2002)

Rajab et al. (2009)

Rajab et al. (2003a, b)

References

Congenital hearing loss, meatal atravia, preauricular tags and pit, bronchial cysts or fistulae, difficulty in opening mouth wide, short stature, patchy skin pigmentation, hearing disability (variable manifestation). EYA1 gene: normal Teebi (2000), Tight glistening facial skin, upswept Raas-Rothschild et al. frontal hairline, high arched and (2009) sparse eyebrows, scant eyelashes, blepharphimosis, hypertelorism, everted lower lip, cheek dimples, abnormal ears, camptodactyly, contractures, developmental delay, happy demeanor

In addition: low birth weight slender bones with progressive bone changes and dense metaphyseal striations in adolescence. No lipid abnormalities or hepatosplenomegaly Extensive scattered calcifications of basal ganglia and cortex. Resemblance to Aicardi-Goutieres syndrome or Coats’ plus syndrome Novel linkage to chromosome 2 locus In addition: reduced exercise tolerance, hypertophic pyloric stenosis, hypertrophy of ureters, esophaus, and myocardium Lentigines, nystagmus

Consanguinity Manifestations

184 A.S. Teebi

Polish Palestinian

1 16 (2 families)

2

185750

188770b

Symphalangism with multiple anomalies of hands and feet

Tibia, hypoplasia of, with polydactyly

b

MIM based on the Online Mendelian Inheritance in Man Possible autosomal recessive also

a

Algerian

5

184253

Spondylometaphyseal dysplasia, Algerian type

Kuwaiti

Saudi Arabian

7 (3 generations)

175860

Porokeratosis punctata palmaris and plantaris

Omani

Large family

Renal-coloboma– arthrogrposis syndrome

+

–

–

–

+

Rybak et al. (1991) Learman et al. (1981) Proximal symphalangism, syndactyly, clinodactyly, hypoplasia of thenar and hypothenar eminences, distinctive dermatoglypic pattern Al-Awadi et al. (1987), Hypoplastic bowed tibiae, postaxial Naguib and polysyndactyly. Sixteen of their Al-Awadi (1990) relatives have either bilateral syndactyly or postaxial polyndactyly

Al-Gazali et al. (2000) Variable manifestations and lax joints, sequencing of 12 exons of PAX2 gene was negative Lestringant and Berge Spinous keratosis limited to the volar (1989) aspects of the hands and feet (appears in the early 20s). Histology shows columnar parakeratosis resembling the cornoid lamella of porokeratosis Severe spondylometaphyseal dysplasia Kozlowski et al. (1988)

7 New Syndromes First Reported Among Arabs 185

MIM No.

2

210550

211770

3

208870

CAHMR

2 sibships

208850

Ataxia-deafness-retardation syndrome Ataxia-microcephaly-cataract syndrome Biliary malformations with renal tubular insufficiency

2

Egyptian

Lebanese

Palestinian

Kuwaiti

USA Arab

201300

Acroosteolysis, neurogenic

1 4

200700

Grebe-like chondro-dysplasia

Arab Arab Palestinian

1 3

200440

+

+

+

+

+

+ +

+

+

Bedouin Palestinian Lebanese

+

Al-Saleh and Teebi (1990)

References

Finger clubbing, acroosteolysis, profuse hyperhidrosis of the hands and feet, thickening of soft tissues around the knees and ankles giving a cylindrical appearance to the legs (no periosteal changes), joint and leg pain, osteoporosis Ataxia, progressive sensorineural deafness, mental retardation, infantile onset Ataxia, hypotonia, mental retardation, microcephaly Proximal renal tubular insufficiency, cholestatic jaundice, predisposition to infection, and multiple congenital anomalies Congenital lamellar, cataract, generalized hypertrichosis, mental retardation

Temtamy and Sinbawy (1974)

Mikati et al. (1984)

Ziv et al. (1992)

Reardon et al. (1993)

Giaccai (1952) Sirinavin et al. (1982)

Frydman and Cohen (1993) Tetralogy of Fallot and pulmonary atresia Der Kaloustian et al. (1985b) Infantile achalasia, deficient tear production Efrati and Mares (1985) Haverkamp et al. (1989) Severe short-limb dwarfism, peculiar facies, Teebi et al. (1986b) severe shortness and distortion of long bones, irregularity and asymmetry of bone changes, rib anomalies, deafness, normal intelligence

White nails

Palmoplantar, keratoderma, eczema, raised IgE levels

Consanguinity Manifestations

Kuwaiti

Family Origin

1

2

(187500)

Tetralogy of Fallot and pulmonary atresia Achalasia–alacrimia syndrome

2

(151600)

No. of affected 2

Leukonychia

AR epidermolytic palmoplantar (144200) keratoderma

Disorder

Table 7.2 New autosomal recessive (AR) Arabs

186 A.S. Teebi

?Lebanese Egyptian

1

29

8 (3 sibships)

3 3

215518

217080 Cone-rod dystrophy and amelogenesis imperfecta or Jalili syndrome

Convulsive disorder, familial, 217200 with prenatal or early onset

Corneal dystrophy and 217400 perceptive deafness Craniofacial dysmorphism with 218340 ocular coloboma, absent corpus callosum, and aortic dilatation

+

5 other non-Arab families Egyptian

+

+

+

+

?

+

+ +

+

+

Palestinian from Gaza

Lebanese

Bedouin Egyptian

1 2

212550

Cataract, microphthalmia, and nystagmus Ciliary discoordination due to random ciliary orientation

Kuwaiti

2 1

212135

Cardioskeletal syndrome, Kuwaiti type

Lebanese

2? 3

212120

Cardiogenital syndrome or Najjar syndrome

Lebanese

2

212112

Cardiomyopathy-congestive with hypergonadotropic hypogonadism or Malouf syndrome

Reardon et al. (1990)

Najjar et al. (1973, 1984)

Malouf et al. (1985)

(continued )

Badr El-Din (1960) Convulsions of intrauterine onset, MR, hypertonia, myoclonus, death in the first year Corneal dystrophy, corneal opacities, Harboyan et al. (1971) perceptive deafness Temtamy et al. (1991) Coloboma of iris, retina, and choroid; upward dislocated lens; myopia; hypertelorism; macrodolicocephaly; arched eyebrows; antimongoloid eye slant; beaked nose; low-set simple ears; long philtrum; absent corpus callosum; MR; aortic regurgitation/dilatation. Histology of gingival suggests a connective tissue abnormality

Cataract, microphthalmia, miosis, Temtamy and Shalash nystagmus (1974) Recurrent pulmonary infections dating from Rutland and de Longh (1990), de Longh the first weeks of life. Lab: random and Rutland (1989) ciliary orientation Cone-rod retinal dystrophy, photo-phobia, Jalili and Smith (1988) nystagmus, achromatopsia, amelogenesis imperfecta/discoloured/ abnormal teeth. Onset is infantile Parry et al. (2009)

Short stature, short limbs, coronal clefting of vertebral bodies, congenital heart disease

Cardiomyopathy, genital anomalies, MR

Same as in the title: females had ovarian dysgenesis

7 New Syndromes First Reported Among Arabs 187

221950

223400

224800

Dextrocardia with unusual facies and micropthalmia

Duodenal atresia, pyloric

Alopecia, deafness camptodactyly

2

4 (common ancestor)

2 (2 unrelated families)

55

220290

221745

2 families

219721

Cystic fibrosis with helicobacter gastritis megaloblastic anemia, and subnormal mentality Deafness, neurosensory Autosomal recessive, I

Deafness, sensorineural Autosomal-mitochondrial

No. of affected 2

MIM No.

Disorder

Table 7.2 (continued)

Lebanese

+

+

+

Palestinian Lebanese

+

+

+

+

Lubani et al. (1991)

References

Guilford et al. (1994a, Profound, fully penetrant, and prelingual 1994b) neurosensory deafness. Linkage to 13q (D13S175) in the same region for severe childhood autosomal muscular dystrophy Jaber et al. (1992), Progressive sensorineural deafness with Prezant et al. (1992) onset in infancy or childhood (no mitochondrial deletions, duplications or heteroplasmy) Dextrocardia, sloping forehead, prominent Aughton (1990) nose, large ear pinnae, microphthalmia/ anophthalmia, micrognathia, cleft palate, vertebral fusion defects, supernumerary nipples, MR, choreoathetosis, unusual folding of the plantar aspect of the foot Nachlieli and GershoniBaruch (1992) Pyloroduodenal atresia Mishalany et al. (1970, 1971), Der Kaloustian et al. (1974) Mikaelian et al. (1970) Late and sparse scalp-hair growth, sensorineural deafness, camptodactyly of fifth fingers, kyphoscoliosis

Cystic fibrosis with helicobacter gastritis megaloblastic anemia, and subnormal mentality

Consanguinity Manifestations

Jordanian

Palestinian

Tunisian

Kuwaiti Bedouin

Family Origin

188 A.S. Teebi

227330

Faciodigitogenital syndrome, Kuwait type

17 (4 unrelated families)

227320

+ (in three Omani, Turkish families) Pakistani, Turkish Cypriot Arab +

2

226735 Epidermolysis bullosa with diaphragmatic hernia or Dudin–Thalji syndrome Erythroderma, lethal congenital 227090

Faciothoracogenital syndrome

Palestinian

13

14 (5 sibships)

1

Kuwaiti Bedouin

Sudanese

+

+

+

+

226670

Palestinian

Epidermolysis bullosa simplex lethalis, Salih type

8 (2 sibships)

+

226300

Lebanese

Enteropathy, protein losing

2

225360

Ehlers–Danlos syndrome, type IV-D

Dudin and Thalji (1991)

Salih et al. (1985b)

Sheba et al. (1968), Shani et al. (1974)

Sulh et al. (1984)

(continued )

Shield et al. (1992) Congenital exfoliative erythroderma, hyperalbuminemia, failure to thrive, infantile death Wilf-Miron and Microphthalmia, anteverted nostrils, long Goodman (1987) flat philtrum, thin upper lip, micrognathia, pectus excavatum, widely spaced nipples, shawl scrotum, hypospadias, wide thumbs/great toes, hypoplastic nails Teebi et al. (1988b), Short stature, hypertelorism, short nose, Teebi and posteriorly angulated ears, lax hand Al-Awadi (1991) joints, mild interdigital webbing, shawl scrotum, normal intelligence

Marked bruisability, minimal skin hyperextensibility, thin skin with prominent cutaneous venous network, interphalangeal joint laxity, proneness to contractures and rupture of bowel and great vessels, heart defects (ASD, pulmonic stenosis). Production of type III pro-collagen production by fibroblast is normal. Abnormal type III collagen Growth retardation, clubbing, diarrhoea, ascites, abdominal pain, edema, hypoproteinemia, hepatic vein stenosis, Budd –Chiari syndrome Epidermolytic epidermolysis bullosa similar to the simplex type known as an autosomal dominant condition, early lethality Epidermolysis/blistering, congenital diaphragmatic hernia, neonatal death

7 New Syndromes First Reported Among Arabs 189

Arab Palestinian

1 7

1

4 (2 sibships) 2 (1 family)

228980

234060

235300

236410

Fleck retina, familial benign

Infertility associated with multitailed spermatozoa and excessive DNA Split hand/split foot autosomal recessive Humeroradial syntosis with craniofacial anomalies

Hypertelorism, hypospadias, tetralogy of Fallot Hypertrichosis, congenital anterior cervical, with peripheral sensory and motor neuropathy Woodhouse–Sakati syndrome

Turkish

3

228930

7 (in 2 families) Saudi Arabian

241080

Arab

3

239840

Palestinian

4 (2 sibships)

239711

Saudi Arabian

Palestinian

Libyan

Lebanese

228400

Fever, familial lifelong, persistent Fibular aplasia or hypoplasia, femoral bowing and poly/ syn/ and oligodactyly

Family Origin

No. of affected 2 twin brothers

MIM No.

Disorder

Table 7.2 (continued)

+

+

+

+

+

+

+

+

References

Fleck retina, multiple yellow ocular fundus Sabel Aish and Dajani (1980) lesions. Macula is spared and there is no night blindness German et al. (1981) Infertility, large spermatozoa, irregularly shaped sperm heads, polyploidy sperm heads, multitailed spermatozoa Split hand/split foot Zlotogora and Nubani (1989) Al-Hassnan and Teebi Craniofacial anomalia, hypertelorism, (2007) capillary hemangiomas, malformed ears, humeroradial syntosis with rhizomelic shortness of upper limbs Hypertelorism, hypospadias, tetralogy of Farag and Teebi (1990) Fallot Trattner et al. (1991) Hypertrichosis in the anterior cervical region, peripheral sensory and motor neuropathy, painless foot ulcer, osteomyelitis Partial alopecia, diabetes mellitus, MR, Woodhouse and Sakati deafness, ECG abnormalities (1983)

Persistent fever without diurnal variation Herman et al. (1969) (over 102 F) Bowing of femurs, aplasia and hypoplasia Fuhrmann et al. (1980, 1981) of fibulae, poly/syn/oligodactyly, pelvic hypoplasia, hip dislocation, joint contractures, absent/coalescent tarsals, hypoplastic fingers/finger nails, cleft lip/palate, CNS anomalies

Consanguinity Manifestations

190 A.S. Teebi

241090

French

2 5 (3 sibships)

Intestinal atresia, multiple level 243150

Canadian

Bedouin Palestinian Bedouin Palestinian Lebanese

8 4

241750

Hypospadias

6 Palestinian (2 families) Palestinian

6 (2 families) 6

Saudi Arabian & Qatari

Kuwaiti Lebanese

2 2 8 (7 families)

Jordanian

2

Hypophosphatemic rickets with 241530 hypocalciuria

Hypoparathyroidism with short 241410 stature, mental retardation, and seizures or Sanjad–Sakati syndrome

Hypogonadism, primary and partial alopecia

+

+

+ +

+

+

+

Al-Awadi et al. (1985a)

Multiple intestinal atresia, intraluminal calcifications

Uncomplicated hypospadias

Rickets, short stature, increased renal clearance of phosphate, hypercalcicuria, normocalcemia, increased intestinal absorption of calcium and phosphorous, elevated serum concentration of 1,25-dehydroxy vitamin D and suppressed parathyroid production. Study of 50 additional asymptomatic members of the same tribe showed that 40% have hypercalciuria as well as a pattern of biochemical abnormalities similar to their relatives

(continued )

Mishalany and Der Kaloustian (1971) Dallaire and Perreault (1974)

Frydman et al. (1985) Tsur et al. (1987)

Tieder et al. (1985, 1987)

Teebi et al. (1986a) Megarbane et al. (2003a, b) Richardson and Kirk Congenital hypoparathyroidism, growth (1990), Sanjad et al. and mental retardation, seizures, deep(1991), Kalam and set eyes, depressed nasal bridge, beaked Hafeez (1992), nose, large earlobes, skeletal defects, Hershkovitz et al. hypocalcemia, and hyperphosphatemia (1995)

Partial bitemporal alopecia, hypergonadotropic hypogonadism, m€ullerian dysgenesis

7 New Syndromes First Reported Among Arabs 191

5

5 2

2

2

4

245552

246200

248110

249240

249660

250450

251200

Lambotte syndrome

Insulin resistanceleprechaunism-like syndrome

Macrosomia, microphthalmia, lethal Megalencephaly with dysmyelination

Microcephaly – hypogonadism syndrome or Mikati syndrome

Mesangial sclerosis, diffuse renal, with ocular abnormalities Metaphyseal dysplasia, anetoderma, and optic atropy

Saudi Arabian Palestinian Moroccan

2 4 4

Lebanese

Egyptian

Lebanese

Iraqi

Palestinian

Yemeni

Lebanese

243600

Jejunal atresia, apple peel

Family Origin

No. of affected 4

MIM No.

Disorder

Table 7.2 (continued)

+

+

+

+

+

+

+ +

+

References

Megalencephaly, spasticity, ataxia, seizures, onset of manifestation between 2–3 years, progressive in nature. CT scan shows diffuse white matter hypodensity, EEG: posterior discharges and an unusual photoparoxymal response. Nephrosis, renal failure, nystagmus, optic atrophy, narrow retinal vessels, abnormal macula, MR Anetoderma (macular atropy of the skin), marked metaphyseal dysplasia resembling Pyle’s disease, cranial nerve compression, optic atropy Microcephaly, hypergonadotropic hypogonadism, short stature, minor facial and skeletal anomalies

Mikati et al. (1985)

Temtamy et al. (1974a)

Barakat et al. (1982)

Habord et al. (1990)

Because of agenesis of the mesentery, the Mishalany and Najjar (1968), Al-Awadi distal small bowel comes straight off the et al. (1981) cecum and twists around the marginal artery, suggesting an apple peel or Christmas tree Farag and Teebi (1989) Farag et al. (1993a) Verloes et al. (1990) IUGR, microcephaly, holoprosencephaly, facial anomalies, large/soft ears, early lethality Al-Gazali et al. (1993), Milder than classical leprechaunism with Hone et al. (1994) normal subcutaneous tissue and normal growth. Children were found to be homozygous for a novel mutation in the insulin receptor gene In addition, cleft palate was found in 3 cases Teebi et al. (1989a)

Consanguinity Manifestations

192 A.S. Teebi

4 (2 sibships)

3

5 (2 related families)

251455

256020

256370

256851

257850

Micromelic dysplasia, congenital with dislocation of radius Nail-patella-like renal disease

Nephrotic syndrome, early onset with diffuse mesangial sclerosis

Neuropathy, giant axonal, Tunisian form

Occulodentoosseous dysplasia, recessive

1

6 (4 sibships)

8

251260

Microcephaly with normal intelligence

Lebanese

Tunisian

Palestinian

Palestinian

Palestinian

Palestinian

+

+

+

+

+

+

Microcephaly, low receding forehead, prominent eyes, epicanthic folds, receding chin, normal intelligence Severe short-limb dwarfism, dislocated radius, depressed nasal bridge, broad nasal base, long philtrum Nephropathy, glomerulodysplasia, renal failure (normal bones and nails); renal biopsy EM shows glomerular basement membrane changes like nail-patella syndrome Nephritic syndrome, renal failure, asymptomatic proteinuria during infancy. Renal histopathology shows diffuse mesangial sclerosis Chronic polyneuropathy, multisystem degeneration including motor neuron syndrome, distal amyotrophy of limbs, diffuse fasciculations, brisk reflexes, bulbar signs. No hair abnormality. Ultrastructurally: axons are greatly enlarged and packed with masses of tightly woven neurofilaments Long, narrow nose with hypoplastic alae nasi, telecanthus, epicanthal folds, micropthalmia, microcornea, malformed teeth with abnormal enamel, syndactyly of fingers 4–5, clinodactyly of 5th fingers, soft-tissue syndactyly of 2, 3, 4 toes. Skeletal: markedly obtuse mandibular angle, widening of long bones, wide diahyses of bones of hands and feet

(continued )

Traboulsi et al. (1986)

Ben Hamida et al. (1990)

Mendelsohn et al. (1982), Habib and Bois (1973)

Salcedo (1984)

Borochowitz et al. (1991)

Teebi et al. (1987)

7 New Syndromes First Reported Among Arabs 193

260650

264480

Pellagra-like syndrome

Pseudotrisomy 13 syndrome

Saudi Arabian

Sudanese

10 (several sibships) 2

+

+

+

+

Omani

Palestinian

+

+

+

+

Fadhil et al. (1983)

References

Cleft lip/palate, flat nose, hypotelorism, dysgenesis of corpus callosum, short limbs, radiolucent tibial notch, digital anomalies, ambiguous genitalia, hypopituatarism

Dincsoy et al. (1995)

Visual impairment, cataracts, psychomotor Teebi et al. (1988a) retardation, hypotonia, joint laxity, and ventricular septal defect – skeletal survey shows severe osteoporosis and platyspondyly Freundich et al. (1981) Pellagra-like rash and neurologic manifestations (confusion, diplopia, dysarthria, ataxia) improving with nicotinamide. No aminoaciduria or indicanuria and no evidence of tryptophan malabsorption. Cataracts and developmental retardation and early death are additional findings in the Sudanese family Salih et al. (1985a)

Megarbane et al. (2004a, b, c) Early onset of nodulosis, arthropathy, distal Al-Mayouf et al. (2000) osteolysis, deformed painful pads, other deformities, ankylosis, characteristic facies MMP2 mutations Al-Gazali et al. (2000)

Ectodermal dysplasia with erythematous face lesions, thick palms and soles, hyperhidrosis, dystrophic nails, pegshaped incisors, misshapen teeth, dry and sparse hair and thin eyebrows

Consanguinity Manifestations

Saudi Arabian

Saudi Arabian

4

(2 in one family) 3

MMP2 mutations 259770

Osteoporosis-pseudoglioma with congenital heart disease, a variant

10 (6 families)

259600

Lebanese

3

NOA (Nodulosis Osteolysis, Arthropathy) syndrome or Al-Aqeel–Sewairi syndrome

Lebanese

257980

Odontoonychodermal dysplasia

Family Origin

No. of affected 7 (3 sibships)

MIM No.

Disorder

Table 7.2 (continued)

194 A.S. Teebi

Sideroblastic anemia autosomal 269950 recessive 270300 Skin peeling, familial continuous or keratolysis exfoliative congenita Lebanese

4

3 (in 2 sibships) Kuwaiti

South African Libyan

3 4

+

+

+

+

268250

Rhizomelic syndrome

?

Bedouin Palestinian

4

268200

Rhabdomyolysis, acute recurrent

Hungarian

Sudanese

+

3

1

268130 Revesz syndrome or retinopathy, aplastic anemia, CNS abnormalities and IUGR

Palestinian

+

+

2

267500

Phosphorylase kinase deficiency of liver and muscle

Palestinian

Kuwaiti

2

266265

Rambam–Hasharon syndrome

Continuous skin peeling

Sideroblastic anemia, hepatosplenomegaly

Short stature, rhizomelia, dislocated hips, digitalization of thumb, bifid distal phalanx of thumb, microcephaly, large anterior fontanelle, micrognathia, pulmonic stenosis

Rhabdomyolysis, muscle pain/weakness, muscle paralysis, acute renal failure. Attacks triggered by inter-current illness. Lab: myoglobinuria, hyperkalemia, and defective muscle lipid metabolism

(continued )

Abdel-Hafez et al. (1983)

Kurban and Azar (1969)

Viljoen et al. (1987) Kasturi et al. (1982)

Urbach et al. (1986)

Kajtar and Mehes (1994) Ramesh and GardnerMedwin (1992)

Unusual facial appearance, microcephaly, Frydman et al. (1992) severe MR, cortical atrophy, seizures, hypotonia, dwarfism, recurrent infections and neutrophilia with decreased neutrophil opsonophagocytic activity Hepatomegaly, diarrhoea, stunted growth, Bashan et al. (1981) hypotonia, mild weakness, phosphorylase kinase deficiency in the liver and muscle, glycogen accumulation in the liver and muscle Revesz et al. (1992) Same as in the title: The severe vascular changes in the retina are similar to Coats’s retinopathy

7 New Syndromes First Reported Among Arabs 195

MIM No.

270750

271310

271320

271322

271640

272450

272950

273150

Disorder

Spastic paraparesis, vitiligo, premature graying, characteristic facies or Abdallat syndrome

Spinocerebellar degeneration and corneal dystrophy

Spastic ataxia syndrome, Bedouin type

Spinocerebellar degeneration with slow eye movement

Spondyloepimetaphyseal dysplasia, a new variant

Syndesmodysplastic dwarfism

Teebi–Shaltout syndrome

Testes, rudimentary

Table 7.2 (continued)

Kuwaiti

Tunisian Qatari Bedouin Pakistani Lebanese

1

4 4 (3 sibship) 2 5

Bedouin Algerian (Berber)

Jordanian Jordanian Syrian

2 4 (2 sibships) 3

2

+

Bedouin Palestinian

6 (2 sibships)

+ + + +

+

+ + +

+

+

+

+

Farag et al. (1987)

Najjar et al. (1974)

Severe dwarfism, progressive joint stiffness Laplane et al. (1972) including spine and hips Teebi and Shaltout Craniofacial anomalies, abnormal hair, (1989) campptodactyly, caudal appendage, kidney anomalies Additional features: very long big toe Froster et al. (1993) (Unpublished)

Rhizomelic shortness of limbs, dwarfism, disk-like facies, cleft palate, deafness, camptodactyly. Radiological changes resemble Kniest disease

Al-Din et al. (1990, Progressive intellectual impairment, 1994a) spinocerebellar dysfunction, peripheral neuropathy. Muscle biopsy shows nonspecific mitochondrial changes

Lison et al. (1981) Mukamel et al. (1985) Der Kaloustian et al. (1985a)

Abdallat et al. (1980)

References

Subnormal mentality, bilateral corneal opacification (epithelial), slowly progressive spinocerebellar abnormalities Spastic ataxia, congenital cataract, macular Mousa et al. (1986) and stromal corneal dystrophy, nonaxial myopia, normal intelligence

Spastic paraparesis, vitiligo, premature graying, microcephaly, characteristic facies, cafe´ au lait spots

Consanguinity Manifestations

Kuwaiti

Palestinian Palestinian Lebanese

3 4 2

22 (large kindred)

Jordanian

Family Origin

No. of affected 2

196 A.S. Teebi

273395

277350

Ataxia with selective vitamin E 277460 deficiency (AVED)

Vitamin A metabolic defect

Trigonobrachycephaly, bulbous 275590 bifid nose, micrognathia, and abnormalities of the hands and feet 276820 Limb/pelvis-hypoplasia/ aplasia syndrome or AlAwadi-Raas-Rothschild syndrome Mutations in WNT7A

Tetra-amelia with pulmonary hypoplasia

Palestinian

Palestinian

Bedouin Iranian Jews Italian Brazilian United Arab Emirates Lebanese

2

1 3 2 1

5 (2 families)

Tunisian

Palestinian

2 5 (2 sibships) 5 2

1

Palestinian

3

+

+

+ +

+

+

+

+ + + +

Raas-Rothschild et al. (1988) Camera et al. (1993) Richieri-Costa (1987) Woods et al. (2006)

Farag et al. (1993b)

Al-Awadi et al. (1985b)

Teebi (1991)

Zlotogora et al. (1993)

Rosenak et al. (1991)

(continued )

Night blindness, hyperkeratosis follicularis, McLaren and Zekian (1971) Bitot spots of the conjunctiva, very low plasma levels of vitamin A, defective intestinal enzymatic conversion of beta carotene to retinol, growth retardation, clubbing, diarrhea, ascites, abdominal pain, edema, hypoproteinemia, hepatic vein stenosis, Budd–Chiari syndrome Friedreich-like ataxia and selective vitamin Ben Hamida et al. E deficiency (1993)

Severe deficiency of the 4 limbs, hypoplastic femur, absent ulna/fibula, pelvic deformity, unusual facies, m€ullerian hypoplasia/aplasia

Trigonobrachycephaly, bulbous bifid nose, micrognathia, and abnormalities of the hands and feet

Small external genitalia, small testes, hypergonadotropic hypogonadism Tetra-amelia, lung hypoplasia, peripheral pulmonary vessel aplasia, low-set ears, micrognathia, hyprocephalus, cleft lip

7 New Syndromes First Reported Among Arabs 197

10 (5 families)

4 (2 sibships)

9 individuals in Saudi Arabian 5 families

225750

600146

601536

Pseudo-TORCH syndrome or Aicardi–Goutieres syndrome

Spastic paraplegia – 5B autosomal recessive

Athabaskan brain stem dysgenesis syndrome or Bosley–Salih–Alorainy syndrome

Hox Al Mutations

2

277590

Weaver-like syndrome

+

Bedouin European Tunisian

Turkish

+ +

Bedouin Kuwaiti

+

+

+

References

Progressive paraplegia affecting primarily the lower limbs. Four of five families studied showed linkage of the disease locus to markers in the centromeric region of chromosome 8 (SPG5A, McKusick #270800); one family was not linked (SPG5B) Bilatral Duane anomaly senorineural deafness, external ear defects, delayed psychomotor development autism spectrum

Tischfield et al. (2005)

Bosley et al. (2008)

Hentati et al. (1994)

Reardon et al. (1994) Microcephaly, intracranial calcification, psychomotor retardation. Hepatomegaly, abnormal liver function tests, petechial rash, and thrombocytopenia are additional findings

Progressive vitiligo (from age 12), retarded Labrune et al. (1992) psychomotor development, distal urethral duplication, beaked nose, high/ narrow palate, retarded growth. No chromosomal breakage Teebi et al. (1989b) Accelerated growth of prenatal onset, hypotonia, variable psychomotor retardation, excess loose skin, dental dysplasia, serrated gums, joint laxity, peculiar facies, digital anomalies, hoarse, low-pitched cry

Consanguinity Manifestations

Iraqi

Algerian

277465

Family Origin

Vitiligo, progressive with mental retardation and urethral duplication

No. of affected 1

MIM No.

Disorder

Table 7.2 (continued)

198 A.S. Teebi

2 (males)

2

605685

606220

Spinocerebellar ataxia, autosomal recessive 5; SCAR5

606937

5

5 Pallidopyramidal degeneration, 606693 superanuclear upgaze paresis, and dementia or Kufor-Rakeb syndrome Homozygous mutation in ATP13A2 gene (Brazilian)

Megarbane syndrome

2

2

605282

606527

4

603802

Microcephaly with simplified gyral pattern and early lethality Temtamy preaxial polydactyl syndrome

Cutis verticis gyrata, retinits pigmentosa and senorineural deafness Mental retardation, short stature, facial anomalies and joint dislocations

10 (4 sibships)

602401

Ectodermal dysplasia, hidrotic, autosomal recessive

+

Chilean

Brazilian Lebanese

Druze

+

+

+

+

+

+

Palestinian/ Jordanian

Iraqi

Lebanese

Lebanese

Egyptian

Oman

Lebanese

Megarbane et al. (1998)

Williams et al. (2005)

Al-Din et al. (1994b)

Megarbane et al. (2008)

Megarbane and Cormier-Daire (2001)

Megarbane et al. (2001c)

Temtamy et al. (1998)

(continued )

Spinocerebellar ataxia, autosomal recessive Megarbane et al. (2001a, b, c) 5; SCAR5, optic atrophy, microcephaly, skin abnormalities, severe MR Delague et al. (2002)

Bilateral digital anomalies with hyperphalangism of 1–3 talon cusp of upper central incisors, senorineural deafness, growth and mental retardation Cutis verticis, gyrata, retinitis pigmentosa and sensorineural deafness, cataract, MR Short stature, obesity, bulbous nose, microretrognathia, brachydactyly, joint dislocations, radiological abnormalities, MR Short stature, flat face, beaked nose, ptosis of eye lids, joint laxity and dislocations, psycho-motor retardation (severe) Severe parkinsonism, corticospinal tract disease, supranuclear upgaze paresis, dementia

+ Severe apnea and central hypoventilation Rajab et al. (2007a) in early live

Teeth, hair and nails are involved.

7 New Syndromes First Reported Among Arabs 199

1 4 (1 family)

608980

Bifid nose, renal agenesis and anorectal malformations Mental retardation with optic atrophy, facial dysmorphism, microcephaly and short stature Skeletal dysplasia, rhizomelic, with retinitis pigmentosa 1

5

608509

Alopecia universalis, microcephaly, and XY gonadal dysgenesis/ El-Shanti syndrome

609047

23 (Kindred)

607598

2 (male) (Cousins)

Palestinian

4

607239

Deafness, autosomal recessive 33; DFNB33 Lethal congenital contracture syndrome

609037

Jordanian

4 in 2 sibships

607131

Macrocephaly, mutiple epiphyseal dysplasia and distinctive facies

Lebanese

Lebanese

Bedouin

Jordanian

Oman

+

+

+

+

+

+

+

+

6

607084

Palestinian Malaysian Palestinian

Deafness, autosomal recessive 31, DFNB31

+

References

El-Shanti et al. (2003)

Medlej-Hashim et al. (2002) Landau et al. (2003)

Al-Gazali and Bakalinova (1998) Bayoumi et al. (2001)

Teebi et al. (2004) Bifid nose, renal agenesis, variable degrees Al-Gazali et al. (2002) of anorectal malformations Mental retardation with optic atrophy, facial Megarbane (2003) dysmorphism, microcephaly and short stature, elongated face, hypertelorism, ptosis absent earlobes, thin upper lips, seizures, severe MR Megarbane et al. Short stature, platyspondyly, rhizomelic (2004a, b, c) shortness of long bones, hip subluxation, normal intelligence and retinitis pigmentosa

Profound hearing loss, gene encoding, a novel PD2 protein (Whirlin) on 9q32-134 Dysmorphic features, macrocephaly, short neck, swelling of the joints, geu valgum, agenesis of corpus callosum in some Early childhood onset of severe deafness. Locua on 10p11.23-q21.1 Limb contractures hydramnios, distended bladder, early lethality with some exceptions Alopecia congenital, total, microcephaly, laryngomalasia, X-Ygonadal digenesis, ambiguous genitalia

Al-Gazali et al. (1999) Thong et al. (2005) Mustapha et al. (2002)

Anterior segment defects of the eye, clefts, Al-Gazali et al. (1994) heart defect, arachnodactyly, growth retardation, early lethality

Consanguinity Manifestations

Sudanese

609465

Family Origin

Eye, anterior segment defects, clefting and skeletal anomalies or Al-Gazali syndrome

No. of affected 6 (3 families)

MIM No.

Disorder

Table 7.2 (continued)

200 A.S. Teebi

4 (2 related families)

United Arab Emirates

Sudanese

2

612379

Saudi Arabian

4 (1 family)

Coloboma, ocular, and ichthyosis, brain malformations, and endocrine abnormalities

Jordanian

2 (1 family)

Lebanese

Palestinian

611174 Severe hypertelorism with midface prominence, myopia, mild MR and bone abnormality 611555 Renal tubular acidosis distal, nephrocalcinosis, short stature, MR and distinctive facies Myopathy, early-onset, with 611705 fatal cardiomyopathy or Salih myopathy

2

LPIN2 mutations

Palestinian

2 (Cousins)

4

609623

Majeed syndrome or chronic recurrent multifocal osteomyelitis, congenital dyserthropoietic anemia and neutrophilic dermatitis

Lebanese

Rhizomelic dysplasia, scoliosis 610319 and retinitis pigmentosa

4 (Sibs)

609654

Short stature and facioauriculothoracic malformations

+

+

+

+

+

+

+

Hamamy et al. (2007)

(continued )

Salih et al. (1998), Hypotonia, delayed motor development, Subahi (2001) proximal muscle weakness and wasting, mildly elevated CK levels, muscle biopsy with minimal change myopathy, progressive dilated cardiomyopathy at about 12 years of age leads to death before 20. Al-Gazali et al. (2008) Ocular coloboma, ichthyosis, endocrine abnormalities in midline brain malformations, MR

Distal renal tubular acidosis, small kidneys, Faqeih et al. (2007) neurobehavioural impairment, short stature, distinctive facies

Characteristic radiological findings with prominent deltoid tuberosities of humeri, short and wide ribs and clavicles bi-concave vertebral bodies, normal bone age and normal intelligence Severe hypertelorism, prominent simple ears, severe myopia, deafness, borderline/mild MR, fractures

El-Shanti and Ferguson (2007) Megarbane et al. (2006)

Ferguson et al. (2005)

Megarbane et al. Short stature and facioauriculothoracic (2004a, b, c) malformations, pectus malformation, cleft lip, VSD, vertebral anomalies, seizures Majeed et al. (1989) Periodic fevers, early onset of chronic recurrent multifocal osteomyelitis, bone pains, anemia, inflammatory dermatosis

7 New Syndromes First Reported Among Arabs 201

–

–

Dislocated elbows, scoliosis and bowed tibiae

4

3 (2 sibships)

3

–

Chondrodysplasia, Temtamy type

2

–

2

Craniosysnostosis, scalp hair abnormalities and deafness Chondrodysplasia, Khaldi type

612785

Megarbane-Jalkh syndrome

3

612406

Dystonia 17, torsion, autosoml recessive DYT17

No. of affected 3

Agyria – pachygyria and – agencies of corpus callosum

MIM No.

Disorder

Table 7.2 (continued)

Lebanese

Egyptian

Tunisian

Lebanese

Palestinian

Lebanese

Lebanese

Family Origin

+

+

+

?

+

+

+

Primary torsion dystonia in torticollis in the teen age progressing to segmental dystonia with severe dysphonia and dysarthria Locus 20p11.22-q13.12 Dysmorphic features (hypertelorism, prominent eyes, telecanthus, gum hypertrophy and pointed chin), wrinkled skin, neonatal spontaneous fractures, hepatic failure and developmental delay Agyria – pachygyria and agencies of corpus callosum, microcephaly and arthrogryposis mutlitplex Craniosynostosis, scalp hair abnormalities and deafness, deafness, cataract Unusual chondrodysplasia, growth retardation, retinitis pigmentosa, sensorineural hearing loss. Radiographs: osteoporosis, scoliosis, tall vertebral bodies, retarded bone age, dislocated hips, and dysplasia of femoral heads Recurrent bone fractures, short stature, failure to thrive, leucoderma, hearing loss. Radiographs: The lower ends of long bones are widened and splayed with coarse trabiculation and pseudocyst formation. Abnormalities in epiphyses and metaphyses are noted Dislocated elbows, scoliosis and bowed tibiae, deafness, cataract

Consanguinity Manifestations

Megarbane et al. (1998a, b)

Temtamy et al. (1974b)

Khaldi et al. (1989)

Megarbane et al. (2002)

Sztriha et al. (2005)

Megarbane et al. (2008)

Choury et al. (2008)

References

202 A.S. Teebi

Palestinian

2

2

– Microcencephaly with simplified gyral pattern with abnormal myelination and arthrogryposis MR, short stature, ptosis, pectus – excavatum and camptodactyly or Khaldi syndrome Multiple congenital anomalies, – MR, and happy nature

Pancytopenia with multiple congenital anomalies

1

+

Tunisian

2

–

–

+

United Arab Emirates

3

Saudi Arabian

United Arab Emirates

Palestinian

+

+

+

+

+

–

Hypogonadotropic hypogonadism, MR, obesity, and minor skeletal abnormalities Leukonychia totalis and skin changes

Lebanese

2

+

Hypogonadotropic – hypogonadism and alopecia

Palestinian

3

–

Fanconi anemia-like dysmorphic syndrome

Brachcephaly, catis aplasia congenital, hypertelorism, blue sclerae, failure to thrive, MR Pancytopenia, small stature, short webbed neck, broad nasal bridge, prominent epicanthic folds, posteriorly angulated/ large ears, VSD, proximally implanted thumbs, normal development

Same as in the title + hypertelorism, microphthalmia, seizures, short phalanges, MR

White nails, excessive sweating and eruption evolving mainly the upper trunk, neck, abdomen, and thighs consisting of small keratinous papules Variable manifestations

Microcephaly, short stature, slow growth, beaked nose, micrognathia, skin dyspigmentation, forearm and thumb hypoplasia. Normal haematology, normal mental development, normal response to diepoxybutane and mitomycin C. No linkage to 20q (locus for Fanconi’s anemia) Frontoparietal alopecia and hypogonadotropic hypogonadism: proximal renal tubular insufficiency, cholestatic jaundice, predisposition to infection and multiple congenital anomalies Hypogonadotropic hypogonadism, MR, obesity, and minor skeletal abnormalities

(continued )

Sackey et al. (1985)

Teebi and Druker (2000)

Khaldi et al. (1988)

Sztriha et al. (1999)

Galadari and Mohsen (1993)

Teebi et al. (1986a)

Salti and Salem (1979)

Milner et al. (1993)

7 New Syndromes First Reported Among Arabs 203

MIM No.

Large kindred

2

–

–

Spastic cerebral palsy with microcephaly and mental retardation Ulnar hypoplasia, club feet, and mental retardation +

+

Bedouin Omani

Palestinian

+

+

References

Spastic cerebal palsy with microcephaly and mental retardation, senorineural deafness, severe MR and autism Short ulnae, bowed and dislocated radii, hypoplasia or aplasia of all nails, club feet, severe psychomotor retardation

Kohn et al. (1995)

Megarbane et al. (2002)

Scalp-ear-nipple like syndrome, dysarthria Rajab et al. (2006) in some variability Spastic ataxia, profound mental retardation, Farag et al. (1996) retinitis pigmentosa, high arched palate

Consanguinity Manifestations

United Arab Emirates Kuwaiti

Family Origin

CAHMR Cataract, hypertrichosis, mental retardation MR Mental retardation VSD Ventricular septal defect ASD Atrial septal defect CNS Central nervous system ECG Electrocardiogram EEG Electroencephalogram IUGR Intrauterine growth retardation CT Computerized axial tomography MIM number within parenthesis indicates that the entity is included under an autosomal dominant entry in the Online Mendelian Inheritance in Man

3

–

No. of affected 2

Spastic ataxia, Bedouin type 2

Scalp-ear-nipple like syndrome –

Disorder

Table 7.2 (continued)

204 A.S. Teebi

3 males

–

Possible autosomal recessive also

a

55 (5 generations)

4 males

–

Nephrotic syndrome, minimal change, Xlinked Thrombocytopenia, Xlinked

561000

1 +3 (males)

243110a

Interleukin-1, defective T-cell response to

Ribosomal RNA, mitochondrial, 12S

7 (3 sibships)

301090

Amelia, X-linked

No. of affected

MIM No.

Disorder

Palestinian +

Saudi Arabian

Syrian

Lebanese

Recurrent pneumonia, recurrent otitis media and other infections, growth retardation, severe herpes zoster, delayed hypersensitivity, delayed growth. Circulating T-cell subset distribution normal, leukocyte proliferative response to phytohemoaggultinin low, leukocyte proliferative response to antigen absent, T-cell response to interleukin-1 (IL1) defective Patients are steroid responders and frequent relapsers, Renal biopsy shows finding of minimal change nephrosis Early childhood thrombocytopenia, large and normal sized platelets, increased mean platelet volume, hypermegakaryocytic bone marrow Nonsyndromic deafness family (McKusick #221745) found to have an A-to-G transition at nucleotide 1555 in the 12S rRNA, a site implicated in aminoglycoside activity by analogy to the evolutionary related bacterial ribosome

Family Consanguinity Manifestations Origin Palestinian + Tetra-amelia, facial clefts, absent ears, absent nose, anal atresia

Table 7.3 New X-linked (XL) and mitochondrial disorders first described among Arabs

Prezant et al. (1993) Jaber et al. (1992)

Knox-Macaulay et al. (1993)

Awadalla et al. (1989)

Zimmer et al. (1985) Gershoni-Baruch et al. (1990) Chu et al. (1984)

References

7 New Syndromes First Reported Among Arabs 205

206

A.S. Teebi

References Abdallat A, Davis SM, Farrage J, McDonald WI (1980) Disordered pigmentation, spastic paraparesis and peripheral neuropathy in three sibling; a new neurocutaneous syndrome. J Neurol Neurosurg Psychiat 43:962–966 Abdel-Hafez K, Safer AM, Selim MM, Rehak A (1983) Familial continual skin peeling. Dermatologica 166:23–31 Al-Awadi SA, Farag TI, Naguib K, Cuschieri A, Issa M (1981) Familial jejunal atresia with “apple peel” variant. J Roy Soc Med 74:499–501 Al-Awadi SA, Farag TI, Teebi AS, Naguib KK, El-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN (1985a) Primary hypogonadism and partial alopecia in three sibs with m€ ullerian hypoplasia in the affected females. Am J Med Genet 22:619–622 Al-Awadi SA, Teebi AS, Farag TI, Naguib KM, El-Khalifa MY (1985b) Profound limb deficiency, thoracic dystrophy, unusual facies and normal intelligence: a new syndrome. J Med Genet 22:36–38 Al-Awadi SA, Naguib KK, Farag TI, Teebi AS (1987) Hypoplastic tibiae with post-axial polysyndactyly: a new dominant syndrome? J Med Genet 24:369–372 Al-Din ASN, Al-Kurdi A, Al-Salem MK, AL-Nasser KE, Al-Zuhair A, Rudwan MA, Khafaji S, Barghouti S, Hamawi T (1990) Autosomal recessive ataxia, slow eye movements, dementia and extrapyramidal disturbances. J Neurol Sci 96:91–205 Al-Din ASN, Al-Kurdi A, Dasouki M, Wreikat A, Al-Khateeb M, Mubaidin A, Al-Hiari M (1994a) Autosomal recessive ataxia, slow eye movements and psychomotor retardation. J Neurol Sci 124:61–66 Al-Din ASN, Wreikat A, Mubaidin A, Dasouki M, Hiari M (1994b) Pallidopyramidal degeneration, supra-nuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand 89:347–352 Al-Gazali LI, Bakalinova D (1998) Autsomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Clin Dysmorphol 7:177–184 Al-Gazali LI, Khalil M, Devadas K (1993) A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J Med Genet 30:470–475 Al-Gazali LI, Al Talabani J, Mosawi A, Lytle W (1994) Anterior segment anomalies of the eye, clefting and skeletal abnormalities in two sibs of consanguineous parents: Michels syndrome or new syndrome? Clin Dysmorphol 3:238–244 Al-Gazali LI, Bakir M, Hamid ZM, Nair DK, Haas D, Amirlak I, Rushdi A (2000) A new syndrome of optic nerve colobomas and renal abnormalities associated with arthrogryposis multiplex. Clin Dysmorphol 9(3):183–18 Al-Gazali LI, Bakir M, Hamud OA, Gerami S (2002) An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations. Clin Dysmorphol 11(1): 33–38 Al-Gazali L, Hertecant J, Algawi K, El Teraifi H, Dattani M (2008) A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred emirati family. Am J Med Genet 146:813–819 Al-Hassnan ZN, Teebi AS (2007) Craniola anomalies, humero-radial synosostosis, rhizomelic limb shortness: previously unrecognized automosal recessive syndrome. Am J Med Genet 143:521–527 Al-Mayouf S, Majeed M, Hugosson C, Bahabri S (2000) New form of idiopathic nodulosis, arthropathy, and osteolysis (NAO) syndrome. Am J Med Genet 93:5–10 Al-Saleh QA, Teebi AS (1990) Autosomal recessive epidermolytic palmoplantar keratoderma. J Med Genet 27:519–522 Aughton DJ (1990) New syndrome? Clinical anopthalmia, dextrocardia and skeletal anomalies in an infant born to consanguineous parents. Am J Med Genet 37:178–181

7 New Syndromes First Reported Among Arabs

207

Awadalla NB, Teebi AS, Elzouki AY, Shaltout A (1989) Frequent relapser minimal change nephrosis: an unrecognized X-linked disorder? Eur J Pediatr 149:205–207 Badr El-Din MK (1960) A familial convulsive disorder with an unusual onset during intrauterine life. A case report. J Pediatr 56:655–657 Barakat AY, Khoury LA, Allam CK, Najjar SS (1982) Diffuse mesangial sclerosis and ocular abnormalities of two siblings. Int J Pediatr Nephrol 3:33–35 Bashan N, Lancu TC, Lerner A, Fraser D, Potashnik R, Moses SW (1981) Glycogenosis due to liver and muscle phosphorylase kinase deficiency. Pediatr Res 15:299–303 Bayoumi R, Saar K, Lee Y, Nurnberg A, Reis G, Nur- E-Kamal MA, Al-Gazali LI (2001) Localisation of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia, and distinctive facies to chromosome 15q26. J Med Genet 38:369–373 Ben Hamida M, Hentati F, Ben Hamida C (1990) Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred. Neurology 40:245–250 Ben Hamida M, Belal S, Sirugo G, Ben Hamida C, Panayides K, Ioanannou P, Beckman J, Mandel JL, Hentati F, Koenig M, Middleton L (1993) Friedreich’s ataxia phenotype not linked to chromosome 9 and associated with selective vitamin E deficiency in two Tunisian families. Neurology 43:2179–2183 Borochowitz Z, Barak M, Hershkowitz S (1991) Familial congenital micromelic dysplasia with dislocation of radius and distinct face: a new dysplasia syndrome. Am J Med Genet 39:91–96 Bosley TM, Alrainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP (2008) The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet 146A:1235–1240 Boyadjiev SA, Justice CM, Eyaid W, Eyaid W, McKusick VA, Lachman RS, Chowdry AB, Jabak M, Zwaan J, Wilson AF, Jabs EW (2003) A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosomes 14q13-q21. Hum Genet 113:1–9 Boyadjiev SA, Fromme JC, Ben J, Chong SS, Nauta C, Hur DJ, Zhang G, Hamamoto S, Schekman R, Ravazzola M, Orci L, Eyaid W (2006) Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat Genet 38:1192–1197 Camera G, Ferraiolo G, Leo D, Spaziale A, Pozzolo S (1993) Limb/pelvis-hypoplasia/aplasia syndrome (Al-Awadi/Raas-Rothschild syndrome): report of two Italian sibs and further confirmation of autosomal recessive inheritance. J Med Genet 30:65–69 Choury E, Kfoury J, Delague V, Jalkh N, Bejjani P, Serre JL, Megarbane A (2008) A novel locus for autosomal recessive primary torsion dystonia (DYT17) maps to 20p11.22-q13.12. Neurogenetics 9:287–293 Chu ET, Rosenwasser LJ, Dinarello CA, Rosen FS, Geha RS (1984) Immunodeficiency with defective T-cell response to interleukin 1. Proc Natl Acad Sci USA 81:4945–4949 Dallaire L, Perreault G (1974) Hereditary multiple intestinal atresia. Birth Defects 10(4):259–264 de Longh RU, Rutland J (1989) Orientation of respiratory tract cilia in patients with primary cilia dyskinesia, bronchiectasis and normal subjects. J Clin Pathol 42:613–619 Der Kaloustian VM, Slim MS, Mishalany HG (1974) Familial congenital duodenal atresia. Pediatrics 54:118 Der Kaloustian VM, Jarudi NI, Khoury MJ, Afifi AK, Bahuth NB, Deeb ME, Shammas J, Mikati MA (1985a) Familial spinocerebellar degeneration with corneal dystrophy. Am J Med Genet 20:325–339 Der Kaloustian VM, Ratl H, Malouf J, Hatem J, Slim M, Tomeh A, Khouri J, Katayli F (1985b) Tetralogy of fallot and pubmonary atresia in siblings. Am J Med Genet 21:119–122 Dincsoy MY, Salih MAM, Al-Jurayyan N, Al-Saadi M, Patel PJ (1995) New syndrome: multiple congenital malformations in two sibs reminiscent of hydrolethalus and pseudotrisomy 13 syndromes. Am J Med Genet 56:317–321 Dudin AA, Thalji A (1991) Diaphragmatic hernia and epidermolysis bullosa in two sibs. Am J Med Genet 39:498–499

208

A.S. Teebi

Efrati Y, Mares A (1985) Infantile achalasia associated with deficient tear production. J Clin Gastroenterol 7:413–415 El-Shanti HI, Ferguson PJ (2007) Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–19 El-Shanti H, Ahmad M, Ailouni K (2003) Alopecia universalis congenital, XY gonadal dysgenesis and laryngomalacia: a novel malformation syndrome. Eur J Pediatr 162(1):36–40 Epstein PA, Kidd KK (1981) Dermo-distortive urticaria: an autosomal dominant dermatologic disorder. Am J Med Genet 9:307–315 Epstein PA, Kidd KK, Sparkes RS (1981) Genetic linkage analysis of dermo-distortive urticaria. Am J Med Genet 9:317–321 Fadhil M, Ghabra TA, Deeb M, Der Kaloustian VM (1983) Odontoonychodermal dysplasia: a previously apparently undescribed ectodermal dysplasia. Am J Med Genet 14:335–346 Faqeih E, Al-Akash SI, Sakati N, Teebi AS (2007) Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome. Am J Med Genet 143A:1951–1957 Farag TI, Teebi AS (1989) Apple peel syndrome in sibs. J Med Genet 26:67–68 Farag TI, Teebi AS (1990) Autosomal recessive inheritance of hypertelorism, hypospadias and tetralogy of Fallot? Am J Med Genet 35:516–518 Farag TI, Al-Awadi SA, Hunt MC, Satyanath S, Zahran S, Usha R, Uma R (1987) A family with spondyloepimetaphyseal dwarfism: a “new” dysplasia or Kniest disease with autosomal recessive inheritance? J Med Genet 24:597–601 Farag TI, Al-Awadi SA, El-Badramany MH, Usha R, El Ghanem M (1993a) Second family with “apple peel” syndrome affecting four siblings: autosomal recessive inheritance confirmed. Am J Med Genet 47:119–121 Farag TI, Al-Awadi SA, Marafi MJ, Bastaki L, Al-Othman SA, Mohammed FM, Al-Suliman IS, Krishna-Murthy DS (1993b) The newly recognized limb/pelvis-hypoplasia/aplasia syndrome: report of a Bedouin patient and review. J Med Genet 30:62–64 Farag TI, Farah S, Sabry M, Roushdi N, Kasrawi B, El-Bousiri W (1996) Heredo-familial spastic ataxia syndrome associated with profound mental retardation, retinitis pigmentosa and high arched palate: a new syndrome. Clin Genet (in press) Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, EEL-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). L Med Genet 42(7):551–557 Freundich E, Statter M, Yatziv S (1981) Familial pellagra-like skin rash with neurologic manifestations. Arch Dis Child 56:146–148 Froster UG, Rehder H, Hohn W, Oberheuser F (1993) Craniofacial anomalies, abnormal hair, camptodactyly and caudal appendage (Teebi-Shaltout syndrome): clinical and autopsy findings. Am J Med Genet 47:717–722 Frydman M, Cohen HA (1993) Leuconychia totalis in two sibs. Am J Med Genet 47:540–541 Frydman M, Greiber C, Cohen HA (1985) Uncomplicated familial hypospadias: evidence for autosomal recessive inheritance. Am J Med Genet 21:51–55 Frydman M, Etzioni A, Eidlitz-Markus T, Avidor I, Varsano I, Shechter Y, Orlin JB, GershoniBaruch R (1992) Rambam-Hasharon sydrome of psychomotor retardation, short stature, defective neutrophil motility and Bombay phenotype. Am J Med Genet 44:297–302 Fuhrmann W, Fuhrmann-Reiger A, de Sousa F (1980) Poly-, syn-I and oligodactyly, aplasia and hypoplasia of fibula, hypoplasia of pelvis and bowing of femora in three sibs – a new autosomal recessive syndrome. Eur J Pediatr 133:123–129 Fuhrmann W, Fuhrmann-Reiger A, Jovanovic V, Rehder H (1981) A new autosomal recessive skeletal dysplasia sydrome – prenatal diagnosis and histopathology. In: Papadatos CJ, Bartsocas CS (eds) Skeletal dysplasias. Alan R. Liss, New York, pp 519–524 Galadari I, Mohsen S (1993) Leuconychia totalis associated with keratosis pilaris and hyperhidrosis. Int J Dermatol 32:524–525

7 New Syndromes First Reported Among Arabs

209

German J, Rasch EM, Huang CY, MacLeod J, Imperato-McGinley J (1981) Human infertility due to production of multiple-tailed spermatozoa with excessive amounts of DNA (Abstract). Am J Hum Genet 33:64A Gershoni-Baruch R, Drugan A, Bronshtein M, Zimmer EZ (1990) Roberts sybdrome or X-linked amelia? Am J Med Genet 37:569–572 Giaccai L (1952) Familial and sporadic acro-osteolysis. Acta Radiol 38:17–29 Guilford P, Ayadi H, Blanchard S, Chaib H, Le Paslier D, Weissenbach J, Drira M, Petit C (1994a) A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum Mol Genet 3:989–993 Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, Petit C (1994b) A non-syndromic form of neurosensory, recessive deafness maps to the pericentric region of chromosome 13q. Nat Genet 6:24–28 Habib R, Bois E (1973) He´te´roge´nite´ de syndromes ne´phrotiques a de´but pre´coce de nourrison (syndrome ne´phrotique “infantile”). Helv Paediatr Acta 28:91–107 Habord MG, Harden A, Harding B, Brett EM, Baraitser M (1990) Megalencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 21:164–168 Hamamy HA, Teebi AS, Oudjhane K, Shegem NN, Ajlouni KM (2007) Severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility in two brothers. new syndrome? Am J Med Genet 143A:229–234 Harboyan G, Mamo J, Der Kaloustian VM, Karam FA (1971) Congenital corneal dystrophy, progressive sensorineural deafness in a family. Arch Opthalmol 85:27–32 Haverkamp F, Zerves K, Rosskamp R (1989) Three sibs with achalasia and alacrimia: a separate entity different from triple A syndrome. Am J Med Genet 34:289–291 Heathcote K, Rajab A, Magre J, Syrris P, Besti M, Patton M, Delepine M, Lathrop M, Capeau J, Jefferey S (2002) Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. Diabetes 51:1291–1293 Hentati A, Pericak-Vance MA, Hung W-Y, Belal S, Laing N, Boustany R-M, Hentati F, Ben Hamida M, Siddique T (1994) Linkage of “pure” autosomal recessive familial paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity. Hum Mol Genet 3:1262–1267 Herman RH, Overholt EL, Hagler L (1969) Familial life-long persistent fever of unknown origin responding to dexamethasone and uronic acids. Am J Med 46:142–153 Hershkovitz E, Shalitin S, Levy J, Leiberman E, Weinshtock A, Varsano I, Gorodischer R (1995) The new syndrome of congenital hypoparathyroidism associated with dysmorphism, growth retardation and developmental delay. Israel J Med Sci 31:293–297 Hone J, Accili D, Al-Gazali LI, Lestringant G, Orban T, Taylor S (1994) Homozygosity for a novel mutation (11e 119 ! Met) in the insulin receptor gene in five siblings with familial insulin resistance. J Med Genet 9:715–716 Jaber L, Shohat M, Bu X, Fischel-Ghodsian N, Yang H-Y, Wang S-J, Rotter JI (1992) Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J Med Genet 29:86–90 Jalili IK, Smith NJD (1988) A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet 25:738–740 Kajtar P, Mehes K (1994) Bilateral coats retinopathy associated with aplastic anaemia and mild dyskeratotic signs. Am J Med Genet 49:374–377 Kalam MA, Hafeez W (1992) Congenital hypoparathyroidism, seizures, extreme growth failure with developmental delay and dysmorphic features – another case of this new syndrome. Clin Genet 42:110–113 Kasturi J, Basha HM, Smeda SH, Swehli M (1982) Hereditary sideroblastic anaemia in 4 siblings of a Libyan family – autosomal inheritance. Acta Haematol 68:321–324

210

A.S. Teebi

Khaldi F, Bennaceur B, Hammou A, Hamza M, Gharbi HA (1988) An autosomal recessive disorder with retardation of growth, mental deficiency, ptosis, pectus excavatum and camptodactyly. Pediatr Radiol 18:432–435 Khaldi F, Bennaceur B, Gharbi HA (1989) Nanisme oste´ochondrodysplasique familial associe´ a` une surdite´ et une he´re´do-de´ge´nere´scence tape´to-re´tinienne. Arch Fr Pediatr 46:429–432 Knox-Macaulay HHM, Bashawri L, Davies KE (1993) X-linked recessive thrombocytopenia. J Med Genet 30:968–969 Kohn G, Malinger G, El Shawa R, Scheinfeld A, Tepper R, Ornoy A, Lachman R, Rimoin DL (1995) Bilateral ulna hypoplasia, club feet and mental retardation: a new mesomelic syndrome. Am J Med Genet 56:132–135 Konig R (2006) Teebi hypertelorsim syndrome. Clin Dysmorphol 12:187–189 Kozlowski K, Bacha L, Massen R, Ayati M, Sator S, Brahimi L (1988) A new type of spondylometaphyseal dysplasia – Algerian type: report of five cases. Pediatr Radiol 18:221–226 Kurban AK, Azar HA (1969) Familial continuous skin peeling. Br J Dermatol 81:191–195 Labrune P, Assathiany R, Penso D, Odievre M (1992) Progressive vitiligo, mental retardation, facial dysmorphism and urethral duplication without chromosomal breakage or immunodeficiency. J Med Genet 29:592–594 Landau D, Mishori-Dery A, Hershkovitz R, Narkis G, Elbedour K, Carmi R (2003) A new autosomal recessive congenital contractural syndrome in an Israel Bedouin kindred. Am J Med Genet A 117A(1):37–40 Laplane R, Fontaine J-L, Lagardere B, Sambury F (1972) Nanisme syndesmodysplasique familial: une entite´ morbide nouvelle. Arch Fr Pediatr 29:831–838 Learman Y, Katznelson MB-M, Bonne-Tamir B, Engel J, Hertz M, Goodman RM (1981) Symphalangism with multiple anomalies of the hands and feet: a new genetic trait. Am J Med Genet 10:245–255 Lestringant G, Berge T (1989) Porokeratosis punctata palmaris et plantaris: a new entity? Arch Dermatol 125:816–819 Lison M, Kornbut B, Feinstein A, Hiss Y, Boichis H, Goodman RM (1981) Progressive spastic paraparesis, vitiligo, premature greying and distinct facial appearance: a new syndrome in 3 sibs. Am J Med Genet 9:351–357 Lubani MM, Al-Saleh QA, Teebi AS, Moosa A, Kalawi MH (1991) Cystic fibrosis and helicobacter pylorigastritis, megaloblastic anemia, subnormal mentality and minor anomalies in two siblings: a new syndrome? Eur J Pediatr 15:253–255 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115:730–734 Malouf J, Alam S, Kanj H, Muffarij A, Der Kaloustian VM (1985) Hypergonadotropic hypogonadism with congestive cardiomyopathy: an autosomal recessive disorder? Am J Med Genet 20:483–489 McLaren DS, Zekian B (1971) Failure of enzymatic cleavage of beta-carotene: the cause of vitamin A deficiency in a child. Am J Dis Child 121:278–280. Medlej-Hashim M, Mustapha M, Chouery E, Weil D, Parranaud J, Salem N, Delague V, Loiselet J, Lathrop M, Petit C, Megarbane A (2002) Non-Syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34.3 and prevalence of DFNB1 mutations. Eur J Hum Genet 10:391–394 Megarbane A (2003) Unknown diagnosis in two male cousins with facial abnormalities, optic atrophy, abnormal EEG, and severe psychomotor retardation. Am J Med Genet 116A:381–384 Megarbane A, Cormier-Daire V (2001) Severe mental retardation, short stature, facial anomalies, joint laxity, and dislocations in two sisters: previously undescribed MCA/MR syndrome. Am J Med Genet 102:153–156

7 New Syndromes First Reported Among Arabs

211

Megarbane A, Kharrat K, Kreichati G (1998) Four sibs with dislocated elbows, bowed tibiae, scollosis, deafness, cataract, microcephaly, and mental retardation: a new MCA/MR syndrome. J Med Genet 35(9):755–758 Megarbane A, Stephan E, Kassab R, Ashoush R, Salem N, Bouvagnet P, Loiselet J (1999) Autosomal dominant secundum atrial septal defect with various cardiac and noncardiac defects: a new midline disorder. Am J Med Genet 83:193–200 Megarbane A, Delague V, Ruchoux MM, Rizkallah E, Maurage CA, Violet L, Rouaix-Emery N, Urtizberea A (2001a) New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 101:135–141 Megarbane A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck L (2001b) Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104:221–224 Megarbane A, Waked N, Chouery E, Moglabey YB, Saliba N, Mornet E, Serre JL, Slim R (2001c) Microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers. Am J Med Genet 98:244–249 Megarbane A, Hersh JH, Chouery E, Fabre M (2002) Craniosynostosis, telecanthus, scalp hair abnormalities, and sensorineural deafness in two sibs. Am J Genet 109(4):323–327 Megarbane A, Gannage-Yared MH, Khalife AA, Fabre M (2003a) Primary hypergonadotropic hypogonadism, partial alopecia, and Mullerian hypoplasia: report of a second family with additional findings. Am J Med Genet A 119A(2):214–217 Megarbane A, Rassi S, Chouery E, Delague V, de Nanclares P, Leal G, Tabet M, Castano L, Loiselet J (2003b) A new dominant branchiogenic-deafness syndrome with internal auditory canal hypoplasia and abnormal extremities. Am J Med Genet 120A:276–282 Megarbane A, Daou L, Megarbane H, Cave H, Choury E, Verloes A (2004a) New autosomal recessive syndrome with short stature and facio-auriculo-thoracic malformation. Am J Med Genet 128A:414–417 Megarbane H, Haddad M, Delague V, Renoux J, Boehm N, Megarbane A (2004b) Further delineation of the odonto-onycho-dermal dysplasia syndrome. Am J Med Genet 129A: 193–197 Megarbane A, Melick N, Daou L (2004c) A newly recognized skeletal dysplasia with rhizomelic limbs and retinitis pigmentosa. Am J Med Genet 130A:176–180 Megarbane A, Ghanem I, Waked N, Dagher F (2006) A newly recognized autosomal recessive syndrome with short stature and oculo-skeletal involvement. AmJ Med Genet 140A: 1491–1496 Megarbane A, Samaras L, Chedid R, Chouery E, Chretien D, Cailluad C, Abou-Ghoch J, Jalkh N (2008) Development delay, dysmorphic features, neonatal spontaneous fractures, wrinkled skin, and hepatic failure: a new metabolic syndrome? Am J Med Genet 146A: 3198–3201 Mendelsohn HB, Kraus M, Berant M, Lichtig C (1982) Familial early-onset nephritic syndrome: diffuse mesangial sclerosis: clinico-pathological study of a kindred. Acta Paediatr Scand 71:753–758 Mikaelian DO, Der Kaloustian VM, Shanin NA, Barsoumian VM (1970) Congenital ectodermal dysplasia and hearing loss. Arch Otolaryngol 92:85–89 Mikati MA, Barakat AY, Sulh HB, Der Kaloustian VM (1984) Renal tubular insufficiency, cholestatic jaudice and multiple congenital anomalies – a new multisystem syndrome. Helv Paediatr Acta 39:463–471 Mikati MA, Najjar SS, Sahli IF, Melhem RE, Mansour S, Der Kaloustian VM (1985) Microcephaly, hypergonadotropic hypogonadism, short stature and minor anomalies: a new syndrome. Am J Med Genet 22:599–608 Milner RDF, Khallouf KA, Gibson R, Hajianpour A, Mathew CG (1993) A new autosomal recessive anomaly mimicking Fanconi’s anaemia phenotype. Arch Dis Child 68:101–103 Mishalany HG, Der Kaloustian VM (1971) Familial multiple level intestinal atresia: report of two siblings. J Pediatr 79:124

212

A.S. Teebi

Mishalany HG, Najjar FB (1968) Familial jejunal atresia: three cases in one family. J Pediatr 73:753–755 Mishalany HG, Der Kaloustian VM, Ghandour MH (1970) Familial congenital duodenal atresia (letter). Pediatrics 47:629–632 Mishalany HG, Der Kaloustian VM, Ghandour MH (1971) Familial congenital duodenal atresia. Pediatrics 46:633–634 Mousa ARA-M, Al-Din ASN, Al-Nassar KE, Al-Rifai KMJ, Sunba RM, MSN BK (1986) Autosomally inherited recessive spastic ataxia, macular corneal dystrophy, congenital cataracts, myopia and vertically oval temporally titled discs – report of a Bedouin family: a new syndrome. J Neurol Sci 76:105–121 Mukamel M, Weitz R, Metzker A, Varsano I (1985) Spastic paraparesis, mental retardation and cutaneous pigmentation disorder: a new syndrome. Am J Dis Child 139:1090–1092 Mustapha M, Chouery E, Chardenoux S, Naboulsi M, Paronnaud J, Lemainque A, Megarbane A, Loiselet J, Weil D, Lathrop M, Petit C (2002) DFNB31, a recessive form of sensorineural hearing loss, maps to chromosome 9q32-34. Eur J Hum Genet 10:210–212 Nachlieli T, Gershoni-Baruch R (1992) Dextrocardia, cleft palate, choreoathetosis and mental retardation in an infant born to consanguineous parents. Am J Med Genet 42:458–460 Naguib KK, Al-Awadi SA (1990) Hypoplastic tibiae with post axial polysyndactyly in two sibs: further confirmation of a new syndrome. Am J Med Genet 35:588–589 Najjar SS, Der Kaloustian VM, Nassif SI (1973) Genital anomaly, mental retardation and cardiomyopathy: a new syndrome? J Pediatr 83:286 Najjar SS, Takla RJ, Nassar VH (1974) The syndrome of rudimentary testes: occurrence in 5 siblings. J Pediatr 84:119–122 Najjar SS, Der Kaloustian VM, Ardati KO (1984) Genital anomaly and cardiomyopathy: a new syndrome. Clin Genet 26:371–373 Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF (2009) Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet 84(2):266–273 Pipkin AC, Pipkin SB (1950) A pedigree of generalized lentigo. J Hered 41:79–82 Prezant TR, Shohat M, Jaber L, Pressman S, Fischel-Ghodsian N (1992) Biochemical characterization of a pedigree with mitochondrially inherited deafness. Am J Med Genet 44: 465–472 Prezant TR, Bohlman AJV, MC BuX, Oztas S, Qiu W-Q, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Flischel-Ghodsian N (1993) Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and nonsyndromic deafness. Nat Genet 4:289–294 Raas-Rothschild A, Goodman RM, Meyer S, Katznelson MB-M, Winter ST, Gross E, Tamarkin M, Ben-Ami T, Nebel L, Maschiach S (1988) Pathological features and prenatal diagnosis in the newly recognized limb/pelvis-hypoplasia/aplasia syndrome. J Med Genet 25:687–697 Raas-Rothschild A, Dijkhuizen T, Sikkema-Raddatz B, Werner M, Dagan J, Lerer I (2009) The 8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: report on two patients and review of the literature. Am J Med Genet 52:140–144 Rajab A, Heathcote K, Joshi S, Jeffery S, Patton M (2002) Heterogeneity for congenital generalised lipodystrophy in seventeen patients from Oman. Am J Med Genet 110:219–225 Rajab A, Mochida GH, Hiil A, Ganesh V, Bodell A, Riaz A, Grant PE, Shugart YY, Walsh CA (2003a) A novel form of pontocerebellar hypoplasia maps to chromosomes 7q11-21. Neurology 60(10):1664–1667 Rajab A, Khaburi M, Spranger S, Kunze J, Spranger J (2003b) Congenital generalized lipodystrophy, mental retardation, deafness, short stature, and slender bones: a newly recognize syndrome? Am J Med Genet A 121A:271–276

7 New Syndromes First Reported Among Arabs

213

Rajab A, Kunze J, Mundlos S (2004) Spondyloepiphyseal dysplasia Omani type: a new recessive type of SED with progressive spinalinvolvement. Am J Med Genet A 126A(4):413–419 Rajab A, Sy Y, Abdulgalil A, Kahiri S, Ahmed R, Mochida GH, Bodell A, Barkovich AJ, Walsh CA (2006) An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation. Am J Med Gene A 140(14):1504–10 Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME (2007a) A novel form lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143A: 2761–2767 Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME (2007b) A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143A:2761–2767 Rajab A, Aldinger KA, El-Shirbini HA, Dobyns WB, Ross ME (2009) Recessive development delay, small stature, microcephaly and brain calcifications with locus on chromosome 2. Am J Med Genet 149A:129–137 Ramesh V, Gardner-Medwin D (1992) Familial paroxysmal rhabdomyolysis: management of two cases of the non-exertional type. Dev Med Child Neurol 34:73–79 Reardon W, Hurst J, Farag TI, Hall C, Baraitser M (1990) Two brothers with heart defects and limb shortening: case reports and review. J Med Genet 27:746–751 Reardon W, Wilson J, Cavanagh N, Baraitser M (1993) A new form of familial ataxia, deafness and mental retardation. J Med Genet 30:694–695 Reardon W, Hockey A, Siberstein P, Kendall B, Farag TI, Swash M, Stevenson R, Baraitser M (1994) Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification and CNS disease. Am J Med Genet 52:58–66 Revesz T, Fletcher S, Al Gazali LI, De Buse P (1992) Bilateral retinopathy, aplastic anaemia and central nervous system abnormalities: a new syndrome? J Med Genet 29:673–675 Richardson RJ, Kirk JMW (1990) Short stature, mental retardation and hypoparathyroidism: a new syndrome. Arch Dis Chid 65:1113–1117 Richieri-Costa A (1987) Profound limb deficiency, thoracic anomalies, unusual facies and normal intelligence. The Al-Awadi syndrome – report of a Brazilian patient. Rev Bras Genet 10:611–616 Rosenak D, Ariel I, Arnon J, Dianant YZ, Ben Chetrit A, Nadjari M, Ziberman R, Yaffe H, Cohen T, Ornoy A (1991) Recurrent tetra amelia and pulmonary hypoplasia with multiple malformations in sibs. Am J Med Genet 38:25–28 Rutland J, de Longh RU (1990) Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 323:1681–1684 Rybak MM, Foley TP, Kozlowski K (1991) Spondylo-metaphyseal dysplasia Algerian type: confirmation of a new syndrome. Am J Med Genet 40:304–306 Sabel Aish SF, Dajani B (1980) Benign familial fleck retina. Br J Ophthalmol 64:652–659 Sackey K, Sakati N, Aur RJA, Shebib S, Sabbah RS, Rifai S (1985) Multiple dysmorphic features and pancytopenia: a new syndrome? Clin Genet 27:606–610 Salcedo JR (1984) An autosomal recessive disorder with glomerular basement membrane abnormalities similar to those seen in the nail patella syndrome. Am J Med Genet 19:579–584 Salih MAM, Bender DA, McCreanor GM (1985a) Lethal familial pellagra-like skin lesions associated with neurologic and developmental impairment and the development of cataracts. Pediatrics 76:787–793 Salih MAM, Lake BD, El Haj MA, Atherton DJ (1985b) Lethal epidermolytic epidermolysis bullosa: a new autosomal recessive type of epidermolysis bullosa. Br J Dermatol 113:135–143 Salti IS, Salem Z (1979) Familial hypogonadotropic hypogonadism with alopecia. Can Med Assoc J 121:428–434 Sanjad SA, Sakati NA, Abu Osba YK, Kaddora R, Milner RDG (1991) A new syndrome of congenital hypoparathyroidism seizure, growth failure and dysmorphic features. Arch Dis Child 66:193–196 Senee V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec J-C, Charon C, Nicolino M, Boileau P, Cavener DR, Bougneres P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a

214

A.S. Teebi

rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38:682–687 Shani M, Theodor E, Frand M, Goldman B (1974) A family with protein-losing enteropathy. Gastroenterology 66:433–445 Sheba C, Shani M, Frand M, Theodor E, Rotem Y (1968) Familial protein losing enteropathy. Proc Tel-hashomer Hosp 7:62–66 Shield JPH, Judge MR, Reardon W, Baraister M, Nohria M, Malone M, Harper JI (1992) Lethal congenital erythroderma: a newly recognized genetic disorder. Clin Genet 41:273–277 Sirinavin C, Buist NRM, Mokkhaves P (1982) Digital clubbing, hyperhidrosis, acroosteolysis and osteoporosis: a case resembling pachydermoperiostosis. Clin Genet 22:83–89 Ste´phan E (1954) Bloc auriculo-ventriculaire chez troiz members d’une meme famille. Rev Med Moyen Orient 11:246–248 Ste´phan E (1978) Hereditary bundle branch system defect. Survey of a family with 4 affected generations. Am Heart J 95:89–95 Stratton RF (1991) Teebi hypertelorism syndrome (brachycephalofrontonasal dysplasia) in a US family. Am J Med Genet 39:78–80 Sulh HMB, Steinmann B, Rao VH, Dudin G, Zeid JA, Slim M, Der Kaloustian VM (1984) EhlersDanlos syndrome type IV D: an autosomal recessive disorder. Clin Genet 25:278–287 Sztriha L, Al-Gazali LI, Varady E, Goebel HH, Nork M (1999) Autosomal recessive micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediatrics 30(3):141–145 Sztriha L, Johansen JG, Al-Gazali LI (2005) Extreme microcephaly with agyria-pachygyria, partial agenesis of the corpus callosum, and pontocerebellar dysplasia. J Child Neurol 20 (2):170–172 Taha D, Barbar M, Kanaan H, Williamson Balfe J (2003) Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet 122A:269–273 Teebi AS (1987) New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28:581–591 Teebi AS (1991) Trigonobrachycephaly, bulbous bifid nose, macrostomia, acral anomalies and hypotonia in sibs: new syndrome. Am J Med Genet 38:529–531 Teebi AS (2000) Nablus mask-like facial syndrome. Am J Med Genet 95:407–408 Teebi AS, Al-Awadi SA (1991) Kuwaiti type faciodigitogenital syndrome. J Med Genet 28:805–808 Teebi AS, Al-Saleh QA (1989) Autosomal dominant sneezing disorder provoked by fullness of stomach. J Med Genet 26:539–540 Teebi AS, Druker HA (2000) Brachycephaly, cutis aplasia congenital, blue sclerae, hypertelorism, polydactyly, hypoplastic nipples, failure to thrive, and developmental delay: a distinct autosomal recessive syndrome? Clin Dysmorphol 10:69–70 Teebi AS, Shaltout AA (1989) Craniofacial anomalies, abnormal hair, camptodactyly and caudan appendage. Am J Med Genet 33:58–60 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK (1986a) Hypogonadotropic hypogonadism, mental retardation, obesity and minor skeletal abnormalities: another new autosomal recessive syndrome from the Middle East. Am J Med Genet 24:373–378 Teebi AS, Al-Awadi SA, Opitz JM, Spranger J (1986b) Severe short limb dwarfism resembling Grebe chondrodysplasia. Hum Genet 74:386–390 Teebi AS, Al-Awadi SA, White AG (1987) Autosomal recessive microcephaly with normal intelligence. Am J Med Genet 26:355–359 Teebi AS, Al-Awadi SA, Marafie MJ, Bushnaq RA, Satyanath S (1988a) Osteoporosispseudoglioma syndrome with congenital heart disease: a new association. J Med Genet 25: 32–36 Teebi AS, Naguib KK, Al-Awadi SA, Al-Saleh QA (1988b) New autosomal recessive faciodigitogenital syndrome. J Med Genet 25:400–406

7 New Syndromes First Reported Among Arabs

215

Teebi AS, Al-Saleh QA, Hassoon MM, Farag TI, Al-Awadi SA (1989a) Macrosomia, microphthalmia cleft palate and early infant death: a new autosomal recessive syndrome. Clin Genet 36:174–177 Teebi AS, Sundareshan TS, Hammouri MY, Al-Awadi SA, Al-Saleh QA (1989b) A new autosomal recessive disorder resembling Weaver syndrome. Am J Med Genet 33:479–482 Teebi AS, Dupuis L, Wherrett D, Khoury A, Zucker KJ (2004) Alpocia congenital universalis, microcephaly, cutis marmorata, short stature and XY gonadal dysgenesis: variable expression of El-Shanti syndrome. Eur J Pediatr 163(3):170–172 Temtamy SA (1986) The DR syndrome or Okihiro syndrome? (Letter). Am J Med Genet 25:173–174 Temtamy SA, Shalash BA (1974) Genetic heterogeneity of the syndrome: microphthalmos with congenital cataract. Birth Defects 10(4):292–293 Temtamy SA, Sinbawy AHH (1974) Cataract, hypertrichosis and mental retardation (CAHMR): a new autosomal recessive syndrome. Am J Med Genet 41:432–433 Temtamy SA, El-Meligy M, Badrawy HS, Meguid SA, Safwat HM (1974a) Metaphyseal dysplasia, anetoderma and optic atrophy: an autosomal recessive syndrome. In: Bergsma D (ed) Skeletal dysplasia. Excerpta Medica, Amsterdam, pp 61–71 Temtamy SA, El-Meligy R, Osman NM, Meguid SA, Salem S (1974b) A “new” bone dysplasia with autosomal recessive inheritance. Birth Defects 10(10):165–170 Temtamy SA, Shoukry AS, Ghaly I, El-Meligy R, Boulos SY (1975) The Duane radial dysplasia syndrome: an autosomal dominant disorder. Birth Defects 11(5):344–345 Temtamy SA, Abdel Salam M, Aboul- Ezz EHA, Hussein HA, Helmy SMH, Salash BA (1991) A new autosomal recessive MCA/MR syndrome with craniofacial dysmorphism, absent corpus callosum, iris colobomas and connective tissue dysplasia (Abstract). Am J Hum Genet 49 (Suppl):167 Temtamy SA, Meguid NA, Ismail SI, Ramzy MI (1998) A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249–255 Thiele H, Sakano M, Kitagawa H, Sugahara K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S (2004) Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci USA 101(27):10155–10160 Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, Gabizon D, Liberman UA (1985) Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 312:611–617 Tieder M, Modai D, Shaked U, Samuel R, Arie R, Halabe A, Moar J, Weissgarten J, Aberbukh Z, Cohen N, Edelstein S, Liberman UA (1987) “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets: two phenotypic expressions of a common genetic defect. N Engl J Med 316:125–129 Tischfield MA, Bosley TM, Salih MAM, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan WM, Andrews C, Erickson RP, Engle EC (2005) Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37: 1035–1037 Toriello HV, Delp K (1994) Teebi hypertelorism syndrome: report of a third family. Clin Dysmorphol 3:335–339 Traboulsi EI, Faris BM, Der Kaloustian VM (1986) Persistent hyperplastic primary vitreous and recessive oculo-dento-osseous dysplasia. Am J Med Genet 24:95–100 Trattner A, Hodak E, Sagie Lerman T, David M, Nitzan M, Garty BZ (1991) Familial congenital anterior cervical hypertrichosis associated with peripheral sensory and motor neuropathy – a new syndrome? Am Acad Dermatol 25:767–770 Tsur M, Linder N, Cappis S (1987) Hypospadias in a consanguineous family. Am J Med Genet 27:487–489 Urbach D, Hertz M, Shine M, Goodman RM (1986) A new skeletal dysplasia syndrome with rhizomelia of the humerus and other malformations. Clin Genet 29:83–87

216

A.S. Teebi

Verloes A, Dodinval P, Beco L, Bonnivert J, Lambotte C (1990) Lambotte syndrome, microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies and early lethality – a new sublethal multiple congenital anomaly/mental retardation syndrome in four sibs. Am J Med Genet 37:119–123 Viljoen D, Goldblatt J, Wallis C, Beighton P (1987) Familial rhizomelic dysplasia: phenotypic variation or heterogeneity? Am J Med Genet 26:941–947 Wilf-Miron R, Goodman RM (1987) Facio-thoracic-genital syndrome: a newly recognized birth defect syndrome. J Craniofac Genet Dev Biol 7:19–22 Williams DR, Hadeed A, Najim al-Din AS, Wreikat AL, Lees AJ (2005) Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 20:1264–1271 Woodhouse NJY, Sakati NA (1983) A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness and ECG abnormalities. J Med Genet 20:216–219 Woods CG, Stricker S, Seemann P, Stern R, Cox J, Sherridan E, Roberts E, Springell K, Scott S, Karbani G, Sharif SM, Toomes C, Bond J, Kumar D, Al-Gazali L, Mundlos S (2006) Mutations in WNT7A cause a range of limb malformations, including Fuhrmann and Al-Awadi/RaasRothschild/Schinzel phocomelia syndrome. Am J Hum Genet 79:402–408 Zimmer EZ, Taub E, Sova Y, Divon MY, Pery M, Peretz BA (1985) Tetra-amelia with multiple malformations in six male fetuses in one kindred. Eur J Pediatr 144:412–414 Ziv Y, Frydman M, Lange E, Zelnik N, Rotman G, Julier C, Jaspers NGJ, Dagan Y, Abeliovicz D, Dar H, Borochowitz Z, Lathrop M, Gatti RA, Shiloh Y (1992) Ataxia-telangiectasia: linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome. Hum Genet 88:619–626 Zlotogora J, Nubani N (1989) Is there an autosomal recessive form of the split hand and split foot malformation? J Med Genet 26:138–140 Zlotogora J, Sagi M, Shabany YO, Jarallah RY (1993) Syndrome of tetra amelia with pulmonary hypoplasia. Am J Med Genet 47:570–571

Part IV Genetic Disorders in Arab Countries and Geographic Regions

Chapter 8

Genetic Disorders in Egypt Samia A. Temtamy, Mona S. Aglan, and Nagwa A. Meguid

The Country and Population Egypt is a Mediterranean North African country (Fig. 8.1). This strategic position attracted many invaders throughout its history. Therefore, in addition to its Pharaonic origin, gene flow to its population occurred from the Ethiopian, Greco–Roman, Arab, Turkish, French, and English settlers. The common heritage among the countries bordering the Mediterranean is not restricted to historical or cultural aspects. There are considerable commonalities in the gene pools of the Mediterranean Northern and Southern rim countries. This “genetic sharing” has resulted from the considerable human movements (i.e., migration, invasion, and trade) throughout history in this area. The total population of Egypt according to 2007 estimates was 76 million and the total number of livebirths was approximately 1.8 million per year (El-Nekhely et al. 2008).

Historical Background Ancient Egypt was one of the most advanced and productive civilizations in antiquity, spanning 3,000 years before the “Christian” era. Their hieroglyphic language, system of organization and recording of events give contemporary researchers insights into their daily activities. The lives of ancient Egyptians were shaped by the environment around them, both for good and for bad. The land, the

S.A. Temtamy (*) Professor of Human Genetics, Clinical Genetics Department, Human Genetics and Genome research division, National Research Centre, Cairo, Egypt email: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_8, # Springer-Verlag Berlin Heidelberg 2010

219

220

S.A. Temtamy et al.

Fig. 8.1 Map of Egypt

river and the climate were a great benefit to the people, but in some circumstances, that environment contributed to disease (Kozma 2006). The first medical book of human and comparative anatomy and the first experience in surgery and pharmacy came from Egypt. Evidence of medical organization in ancient Egypt comes from both literature and archeology. The first medical papyrus was discovered in 1862 and was attributed to the “father of medicine” Imhotep. It contained information on 48 surgical cases in addition to the first description of the circulation of blood. The second remarkable papyrus, the Ebers papyrus, dating back to 1555 BC, contained 876 remedies using 500 substances. Many other medical papyri have been discovered. There is also some evidence

8 Genetic Disorders in Egypt

221

suggesting that women also held medical posts and doctors were very much specialized. Egypt has also left us time travelers: its mummies. The arid climate and religious necessity for preservation have given us a remarkable glimpse at the health of its people. Mummies and the diseases they reveal offer insight into the past (Sullivan 1995). Ancient Egypt gives us some of the earliest evidence for both congenital and acquired diseases. It is a major source of archeological information on achondroplasia and other dwarf conditions. A well-known example is the statue of the dwarf Seneb from the Old Kingdom (4th Dynasty) recording all his family members. Other examples include Pereniankh, Khnumhotpe, and Djeder. One poignant specimen is an achondroplastic woman with her undeliverable fetus. There were at least two dwarf gods: Ptah, who was associated with regeneration and rejuvenation; and Bes, who was a protector of sexuality, childbirth, women and children. Sarry El-Din (2002) reviewed the documented skeletal abnormalities in ancient Egypt including a probable case of Apert syndrome in a child from Nubia, examples of Klippel–Feil syndrome dating back to the Ptolemaic period, two cases with transitional vertebrae from the old kingdom and nine cases of achondroplasia in addition to the two previously reported achondroplasia cases from an Egyptian sample related to the Giza Old Kingdom (Hussien et al. 1990). The G!A transition in the FGFR3 gene at cDNA position 1,138 diagnostic of achondroplasia was detected in cloned polymerase chain reaction products obtained from the dry mummy of the Semerchet tomb, Egypt (first dynasty, approximately 4,890–5,050 BP [before present] by Pusch et al. (2004). Multiple basal–cell nevus syndrome (Satinoff and Wells 1969) and alkaptonuria (Stenn et al. 1977) were preserved in mummies and skeletons back in Egyptian history. Two embalmed fetuses were recovered from Tutankhamen’s tomb in 1926. One had spina bifida; clubfoot, cleft palate, and hydrocephalus have also been found. Recently, in Cairo, radiological studies of King Tutankhamun mummy revealed that he was suffering from cleft palate and the right foot had a low arch with equinovarus deformity and Kohler disease (Hawass et al. 2010). Marin et al. (1999) found a band at the level of the HbS mutated fragment in a sample of three pre-dynastic Egyptian mummies, indicating that they were affected by sickle cell anemia. Tainmont (2007) found a dislocated mummy of a child of Ancient Egypt with Osteogenesis imperfecta (OI). The burial sites and artistic sources provide glimpses of the dwarfs and the positions they held in daily life in ancient Egypt. Wisdom writings and moral teachings commanded respect for dwarfs and other individuals with disabilities (Kozma 2006). The origins of the ancient Egyptian state and its formation have received much attention through analysis of mortuary contexts and skeletal material. Genetic diversity was analyzed by Zakrzewski (2007). The author studied craniometric variation within a series of six time-successive Egyptian populations in order to investigate the evidence for migration over the period of the development of social hierarchy and the Egyptian state. The results indicated overall population continuity over the Pre-dynastic and early Dynastic, and high levels of genetic heterogeneity, thereby suggesting that state formation occurred as a mainly indigenous process.

222

S.A. Temtamy et al.

Significant differences were found in morphology between both geographically pooled and cemetery-specific temporal groups, indicating that some migration occurred along the Egyptian Nile Valley over the periods studied.

Current Genetic Facilities in Egypt While Egypt has shown considerable progress in the prevention and combating of infectious diseases, genetic disorders remain a major health problem. The importance of medical genetics in pediatric departments of Egyptian universities was well appreciated in the early 1960s at Cairo and Ain Shams Universities by Dr Ekram Abdel-Salam and Dr Nemat Hashem. In 1966, Dr. Samia Temtamy finished her Ph. D. at Johns Hopkins University, USA, in Human Genetics as the first specialized geneticist in Egypt and established the specialty of human genetics at the National Research Centre (NRC). In 1967, Dr Suzan Roshdy started the medical genetics unit at the Medical Research Institute in Alexandria. This was followed by the initiation of medical genetics units in other universities such as El-Mansoura and Alexandria Universities. Mubarak City of Scientific Research encompasses centers for frontier sciences including genetic engineering and biotechnology. Human genetic courses are now introduced in the curriculum of medical students in most universities. Specialized postgraduate degrees in the field of Medical Human Genetics are offered to graduates from Medical schools in Egypt at Ain-Shams and Alexandria Universities. Training programs given by specialized geneticists from different institutions are offered to physicians from the Ministry of Health and Population.

Consanguineous Marriages and Their Implications In Egypt, consanguineous marriages have been known to take place since the time of the Pharaohs, when inbreeding pedigrees were recorded; Queen Hatshpsut (18th Dynasty) (158–1350 BC) was the daughter of the half-brother–sister marriage of Thothmus and Aahmes. Her mother Aahmes was the product of two successive generations of marriages of full brothers and sisters. The results of consanguineous marriages were evident within the Pharaonic household. Autopsy of Amenophis III mummy demonstrated gynaecomastia and signs of feminization, including hypogonadism, probably as a result of inbreeding. A mummified stillborn discovered in Tutankhamen’s tomb had Sprengel disease, possibly as a result of consanguineous practices of the Royal court (Sullivan 1995). According to official census returns from Roman Egypt (first to third centuries) preserved on papyrus, 23.5% of all documented marriages in the Arsinoites district in the Fayum (n ¼ 102) were between brothers and sisters. In the second century, the rates were 37% in the city of Arsinoe and 18.9% in the surrounding villages. Documented pedigrees suggested a minimum mean level of inbreeding equivalent to a coefficient of inbreeding of 0.0975 in second-century Arsinoe. Undocumented sources of inbreeding and an estimate based on the frequency of close-kin unions

8 Genetic Disorders in Egypt Table 8.1 Frequency of parental consanguinity in the Egyptians

Table 8.2 Birth incidence of malformations in Egyptian newborns: per thousand

223 City Cairo All Egypt All Egypt

Frequency% 32 28.96 36.2 (rural areas) 20.37 (urban areas) Assiut 36.9 Alexandria 22.8 (urban areas) Giza 31.79 All Egypt 38.9 25.4 (urban areas) 55.2 (rural areas) All Egypt 33.1

City/sample Alexandria (live born) Cairo (live born) Mansoura (live & stillborn) Cairo & Mansoura (live born) Cairo (live born) Cairo, Mansoura, Alexandria, Giza (live born) Giza (live & stillborn) Giza (live born)

References Temtamy and Loutfy (1970) Hafez et al. (1983) Abdel Salam et al. (1985) Temtamy et al. (1994c) Mohamed (1995) Temtamy et al. (1998b) Khayat and Saxena (2000)

El-Nekhely et al. (2008)

Prevalence 11.6

References Stevenson et al. (1966)

15.8 23.0

Karim et al. (1970) Hafez et al. (1983)

13.0

Hafez and Hashem (1988)

24.0 24.0

Abdel Salam et al. (1985) Temtamy (1998)

31.7

Temtamy et al. (1998b)

8.2

Abdel-Salam et al. (2007b)

indicated a mean coefficient of inbreeding of F ¼ 0.15–0.20 in Arsinoe and of F ¼ 0.10–0.15 in the villages at the end of the second century. These values were several times as high as any other documented levels of inbreeding (Scheidel 1997). Studies of the frequency of parental consanguinity in the Egyptian population ranged from 20.37 to 42%. Differences were related to geographic locations. Higher rates were observed in rural areas compared to urban areas (Table 8.1). The total parental consanguinity rate was 33.1%, of which 18.2% comprised first cousins, 7.3% second cousins and 7.6% more distant than second cousins (El-Nekhely et al. 2008). Although birth incidence studies of congenital malformations have shown that the overall incidence of malformations as a whole is similar to other populations (Table 8.2), there was a relative excess of autosomal recessive disorders due to the high rate of consanguinity. Among 2,600 cases attending the Human Genetics Clinic at the NRC, monogenic disorders were found in 53.1% with 34.2% consistent with autosomal recessive inheritance (Dardir 2000). The phenomenon of multiple genetic disorders in the same individual or sibship has been observed in Egyptian patients with a consanguinity rate of 77.8% in the studied families (Temtamy et al. 2004c).

224

S.A. Temtamy et al.

The role of consanguinity and advanced maternal age on reproductive losses in Alexandria was studied by Mokhtar and Abdel-Fattah (2001) including 730 couples with a history of reproductive losses and 2,081 normal couples. Consanguinity frequency was 68.8%, among whom 56.2% were first cousins. Prenatal loss and infant deaths were highly encountered among consanguineous marriages (p<0.0001).

Reported Genetic Disorders Among Egyptians Disorders of the Central Nervous System (CNS) CNS anomalies are the most prevalent congenital malformations in Egyptians as confirmed by numerous epidemiological studies (Table 8.3).

Mental Retardation (MR) In a study of MR in children referred to the NRC (Temtamy et al. 1991c), the etiology of mental retardation was chromosomal in 25.9%, of whom Down syndrome was diagnosed in 25%, MCA/MR syndromes in 25.7%, inborn errors of metabolism (IEM) in 18.3%, idiopathic MR in 16.38%, X-linked MR in 0.5%, unclassified diseases in 10.3% and MR due to environmental factors in 3.1%. Chromosomal aberrations in patients with multiple congenital anomalies and mental retardation were studied in detail (Temtamy et al. 1987). Temtamy et al. (1994c) found an overall prevalence of mental subnormality of 3.9% in the Assuit Governorate. In another study including 120 cases of MR and congenital anomalies, 26% were due to chromosomal abnormalities, 28% were syndromes due to single-gene disorders, 13.3% were caused by teratogens and 33.4% were unclassified (Shawky et al. 2000a). Meguid et al. (2007) found the prevalence of fragile X syndrome among Egyptian males to be 0.9:1,000, constituting 6.4% among mentally subnormal males. Temtamy et al. (1996a) pointed to the phenotypic overlap between Kabuki and fragile X syndrome. Afifi and Aglan (2002) studied the anthropometric characteristics of 16 males with fragile X syndrome. Other studies of fragile X Table 8.3 Frequency of CNS anomalies in Egypt

City/District Alexandria Alexandria Mansoura Mansoura & Ain-Shams Alexandria Giza

Frequency 3.79/1,000 3.75/1,000 4/1,000 4.3/1,000

Reference Stevenson et al. (1966) Ismail (1977) Hafez et al. (1983) Hafez and Hashem (1988)

3.5/1,000 9/1,000

Al-Anssary (1995) Temtamy et al. (1998b)

8 Genetic Disorders in Egypt

225

syndrome are available (Temtamy et al. 1988; El-Aleem et al. 1995; Abdel Salam et al. 1996).

Neural Tube Defects (NTD) The incidence of NTD is unusually high among Egyptians (3.7–6.96%). Thirtyseven percent had severe defects and 16% had other associated abnormalities as part of the syndrome (Hafez and Hashem 1988). Abdel-Aleem et al. (2006) reported C677T polymorphism of the 5, 10-Methylenene tetrahydrofolate reductase (MTHFR) gene as a risk factor of neural tube defects among Egyptian families. Gaber et al. (2007) investigated maternal serum vitamin B12 levels and the risk of NTDs in 36 women who were, or had been, pregnant with an NTD-affected fetus. The results showed that low vitamin B12 concentration was associated with an approximately two- to three-fold increased risk for NTDs.

Convulsive Disorders Badr El-Din (1960) was the first to describe familial intrauterine convulsive disorder, later recognized to be due to pyridoxine deficiency. Salem and El-Serafy (2001) studied 200 patients with isolated epilepsy. Seventy-eight percent were genetically determined, of whom direct inheritance from one parent was present in 15%, more than one sib was affected in 18% and a positive family history in 39%. Parental consanguinity was detected in 20.87% of cases. Inheritance pattern in this group included: AR (28%), AD (14%), X-linked recessive (23%) and mitochondrial inheritance in 35%.

CNS Malformations In a study of 29 cases with microcephaly, Temtamy et al. (1998d) found parental consanguinity in 55.1% compared to 33% in the general population. Microcephaly as part of the syndrome was diagnosed in 48.2% of cases while environmental causes were recorded in 17.2%. Microcephaly associated with IEM was present in 6.8 and 3.4% had isolated microcephaly. Shawky et al. (2000c) studied clinical genetic aspects of 44 hydrocephalic infants, and single cases with aneurism of Galen and arachnoid cyst, and found four of eight familial cases with X-linked hydrocephalus, with parental consanguinity in 40% of all cases. Isolated Dandy–Walker malformation associated with brain stem dysgenesis in male sibs was reported by Abdel-Salam et al. (2006). Thirteen children from 12 families who presented with developmental delay and were diagnosed by CT and MRI as having neuronal migration disorders were studied by Zaki et al. (2001). According to neuroimaging findings, lissencephaly

226

S.A. Temtamy et al.

was the commonest (n ¼ 9), followed by unilateral open lip schizencephaly (n ¼ 2), periventricular heterotopia (n ¼ 1) and hemimegalencephaly (n ¼ 1). In another study carried out by Zaki et al. (2002) including 30 Egyptian children with malformations of cerebral cortical development (MCD), lissencephaly represented 57.14% followed by schizencephaly (n ¼ 6), periventricular nodular heterotopia (n ¼ 3), hemimegalencephaly (n ¼ 2), focal cortical dysplasia (n ¼ 2), polymicrogyria (n ¼ 1) and transmantle dysplasia (n ¼ 1). Multiple associated MCDs constituted 13.3% of the patients. Consanguinity was present in 70% and four families had more than one affected member. The authors reported rare disorders as lissencephaly with cerebellar hypoplasia in two male sibs (LCHa), isolated cobblestone complex variant in two sibs, lissencephaly ambiguous genitalia (LAG), microlissencephaly, septo-optic dysplasia, bilateral periventricular nodular heterotopias (BPNH) in a male patient, transmantle dysplasia and unreported rare clinical features in MDS. Zaki et al. (2005) studied 17 cases with holoprosencehaly (HPE) and correlated their clinical and neuroradiological findings with cytogenetic and molecular cytogenetic results using 7q36 probe. Semilobar was the commonest form of HPE (66.6%), alobar in 20%, while both lobar and midline interhemispheric (MIH) variant accounted for 6.7% of patients. Maternal diabetes was found in 20% of patients being the commonest teratogen in HPE. Other studies detected abnormal cytogenetic disorders in 5 patients. A new Joubert syndrome (MIM 213300) and related cerebellar disorders classification system was proposed by Zaki et al. (2008). The authors tested their classification system on 13 Egyptian families with 24 affected cases. AHI1 gene mutations of Joubert syndrome-related disorders (JSRDs) were demonstrated by Valente (2006). Brancati et al. (2008) have shown that mutations in a novel ciliary gene, RPGRIP1L, cause both JSRDs and Meckel–Gruber syndrome. They suggested that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they represent an overall rare cause of JSRD (<2%). The findings in ten patients with Aicardi–Goutie`res syndrome (MIM: 225750) were described by Abdel-Salam et al. (2004a). The authors presented variability in the age of onset, clinical picture and neuroimaging findings even in the same family. Callosal dysgenesis was studied in 55 children by Ismail et al. (2003). Unusual association of simplified gyral pattern and sparse hair with microcephaly–lymphoedema was reported by Mazen and Zaki (2006).

Hereditary Ataxias Guinena et al. (1954) reported on Friedreich ataxia (MIM: 229300). Congenital and familial cerebro–cerebellar diplegia was reported by Barrada et al. (1954). Helal (2000) studied the clinical and genetic aspects of hereditary ataxias in 40 cases. They were classified into: 10 cases (40%) of Friedreich ataxia, 12 cases (30%) of spastic ataxia (MIM: 270550), 12 cases (30%) including 3 cases with autosomal

8 Genetic Disorders in Egypt

227

dominant (AD) hereditary paraplegia (MIM: 270750), and individual cases with AD spinocerebellar ataxia, Holmes ataxia (MIM: 212840), olivopontocerebellar ataxia (OMIM: 258300), AR congenital ataxia, AR episodic ataxia in childhood and Wilson disease (OMIM: 277900). Among the familial cases AR inheritance was found in 90% while AD was found in 10% only. A novel mutation in BAP/SIL1 gene causes Marinesco–Sjo¨gren syndrome (MIM: 248800) in an extended pedigree reported by Karim et al. (2006). AbdelAleem and Zaki (2008) described an Egyptian family having spinocerebellar ataxia type 1 (SCA2) (MIM: 183090) affecting three generations with marked molecular and clinical anticipation observed in the index case. The proband showed that an amplified allele with marked CAG expansion in the form of a smear of the size of 69–75 repeats resulted from maternal transmission.

Genetic Disorders of the Muscles Hashem (1978) classified 260 cases with muscle disorders into the following categories: Neurogenic myopathies (139 cases), AR muscle dystrophy (94 cases), Duchenne muscular dystrophy (66 cases) and metabolic myopathies (11 cases). Among 36 infants with hypotonia El-Harouni et al. (1994) found nine cases with DMD, two with congenital muscle dystrophy, nine with congenital myopathies, three with central hypotonia, six with spinal muscular atrophy, two with limb girdle muscle dystrophy and five were undefined. Mitochondrial abnormalities in muscle and gingival biopsies from patients with different forms of mitochondrial myopathies were studied by El-Harouni et al. (1996b). Dardir (2000) found 57 out of 2,600 general genetic referrals to have muscle disorders. Thirty-six cases had Duchenne muscular dystrophy (63%). One case had myotonic dystrophy, 13 had congenital myopathies (22%), three had Fukayama muscle dystrophy (5%), two had nemaline myopathy and there were single cases with limb girdle muscle dystrophy and ocular myopathy.

Muscular Dystrophies (MD) El-Harouni et al. (1996a) studied the CNS involvement in progressive congenital muscle dystrophy (Fukuyama type) in two families. Hussein et al. (1999) studied 61 cases with Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/ BMD). They detected deletions in 42% of cases with DMD, among which 90% were especially clustered in exons 50 and 51. Large deletions were more frequent than single exon deletions. Farrag et al. (2000) presented molecular studies on 38 deletion negative male patients with MD (15 DMD, 23 BMD). Mutations were identified in 50% of patients (80% DMD, 33% BMD). All identified mutations were novel. A duplication

228

S.A. Temtamy et al.

mutation was the most common. Of all deletion negative cases, 30% showed duplication of exon 2. Effat et al. (2000) found 55% of deletion mutations within the dystrophin gene among the 100 families they studied with DMD/BMD. Sixty percent of the detected deletions involved multiple exons spanning the major or the minor hot spot of the dystrophin gene. The remaining 40% mainly involved exon 45. El-Harouni et al. (2003) examined the genotype/phenotype correlation in 250 DMD/BMD male patients with double deletion (Ddel) mutations in comparison with those having single deletions (Sdel). They found that patients with double deletion mutations within the dystrophin gene had a milder phenotype compared to patients harboring single deletions at either major or minor hot spots of the gene. Elhawary et al. (2004) studying152 unrelated dystrophin patients using multiple primers, detected 78 (51.3%) probands with deletion mutations. The frameshift rule was confirmed positively ranging for 50–67% of the cases depending on the type of disease. There were no double deletions in the Egyptian dystrophin males. In a comparative study of the patterns of dystrophin gene deletion in Egyptian DMD/BMD patients, El Sherif et al. (2007) found a percentage of 61.1% deletion, which was higher than data from previous Egyptian studies, and most of the deletion was localized in the major hot spot region between exons 44 and 52 and 5% of the cases with duplication. Shawky et al. (2006a, c) examined muscle biopsy in cases with DM dystrophies and studied 59 affected males and 35 of their female relatives who were at risk. They concluded that the unbalanced IP-RP-HPLC-STR assay represents an excellent molecular tool for carrier-status identification.

Spinal Muscle Atrophy (SMA, MIM 253300) Shawky et al. (2001b) studied DNA molecular studies of the SMA in 33 patients. Homozygous deletion of exon 7 was detected in 55% of cases, 36% of whom also had a homozygous deletion of exon 8. The adult patients were heterozygous for an abnormal size exon 8. The remaining patients had either compound heterozygote deletion of exons 7 and 8 or were normal for both. There may therefore be 5q-unlinked SMA or SMA due to other mutations. Essawi et al. (2007a) also detected a homozygous absence of SMN1 exons 7 and 8, or exon 7 only, in 80% of patients. Of those patients, 45% were also deleted for NAIP exon 5, thus concluding that the molecular basis of SMA in Egyptian patients has a similar pattern to that reported in other populations.

Skeletal and Limb Malformations The classic book “The Genetics of Hand Malformations” by Temtamy and McKusick (1978) includes published literature and genetic studies of limb malformations in

8 Genetic Disorders in Egypt

229

addition to new reported families from USA and Egypt. Temtamy et al. (1981a) and Temtamy (1982) subsequently studied the genetics in rare limb malformations in Egyptian children, and provided a review of the classification of hand malformations as isolated defects. Temtamy et al. (2000a) studied 40 cases referred because of congenital limb malformations. Isolated limb malformations represented 37.5% with a consanguinity rate of 20%, while those as a part of syndrome represented 62.5% with a consanguinity rate of 40%. Different limb anomalies were represented. In another more recent study carried out by Temtamy et al. (2007a) including 319 cases with limb and/or skeletal anomalies, contracture deformities were the commonest group among the referred cases (27.5%) followed by skeletal dysplasias and bone disorders in 19.0% of cases. Brachydactyly, reduction defects and polydactyly were present in 15.5, 14.0, 13.6%, respectively. Other groups including arachnodactyly, syndactyly, symphalangism, congenital constriction rings, and macrodactyly constituted less than 10% each. Out of the 319 studied cases, 225 cases were the offspring of consanguineous parents, representing 70.5%. In syndromes with both autosomal dominant and recessive patterns of inheritance, the recessive types were more common such as in multiple pterygium syndrome and Robinow syndrome.

Skeletal Dysplasias Mutations of the FGFR3 in patients with achondroplasia (MIM 100800) and hypochondroplasia (MIM 146000) were studied by Abdel-Aleem et al. (2003). Aglan et al. (2009) provided full data on 20 cases with achondroplasia. Molecular analysis of 18 of their cases showed the G380R common mutation in 14 patients (77.8%). Digestion of the same 164bp PCR fragment with MspI edonuclease (indicating G to C transversion) produces two fragments of 107 and 57bp. This MspI restriction site was evident in only one patient (0.5%) of the selected group who had associated agenesis of corpus callosum. Genetic heterogeneity in spondylo-epi-metaphyseal dysplasias (SEMDs) was evident in the study carried out by Temtamy et al. (2007c) including 20 cases with SEMDs. Their study included nine patients from different consanguineous families with Dyggve–Melchior–Clausen disease (DMC) (MIM 223800). One case had Smith–McCort Dysplasia (SMC) (MIM: 607326), two male patients were consistent with SEMD, X-linked with mental deterioration (MIM 300232), four patients had SEMD-joint laxity (MIM 271640), a single case with SEMD-Strudwick type (MIM 184250) and another with SEMD, hypotrichosis (MIM 183849). Elsayed (2005) described another case of DMC disease. The fact that many reported cases came from an Arab origin probably suggests a relatively high frequency of the DYM gene in Arabs. Ellis–van–Creveld (EVC) syndrome in three unrelated consanguineous families (OMIM: 225500) were reported by Mostafa et al. (2005). Pseudodominant inheritance was documented in one of their families. Temtamy et al. (2008) reported LINE1-mediated deletion of EVC, EVC2, C4orf6 and STK32B in three sibs with

230

S.A. Temtamy et al.

EVC syndrome and borderline intelligence. EVC syndrome was confirmed by molecular studies in eight more cases including mutations in either EVC or EVC2 genes (Valencia et al. 2009). Aglan et al. (2004) studied seven patients with the oculo–auriculo–vertebral spectrum (OAVS) (MIM 164210); three of them had hemifacial microsomia (HFM) and four patients were classical of Goldenhar syndrome (GS). Two unrelated Egyptian families; had several members in successive generations with unilateral congenital brachial palsy (Zaki et al. 2004); the high rate of consanguinity and affected sibs was highly suggestive of autosomal recessive inheritance with variable expression. Cases with 3-M syndrome (OMIM: 273750) were described by Temtamy et al. (2006b). Homozygosity of a single nucleotide deletion in exon 55 causing a premature stop codon in exon 56 of COL11A2 was detected in two sibs with oto–spondylo–megaepiphyseal dysplasia (OSMED) (MIM: 215150) (Temtamy et al. 2006d). Temtamy et al. (1989b) described two sibs with OI. OI with joint contractures (Bruck syndrome) (MIM 259450) was reported by Blacksin et al. (1998). More than 50 cases with different types of OI and syndromes with bone fragility were studied by Temtamy and Aglan including Bruck syndrome and osteoporosis-pseudoglioma syndrome (MIM: 259770), some cases with OI were consistent with AR inheritance (unpublished data). Two sisters with Larsen syndrome (MIM 245600) were presented by Knoblauch et al. (1999). The clinically unaffected parents originated from the South of Egypt and were first cousins denoting autosomal recessive inheritance. Other patients with AR Larsen syndrome were studied by Temtamy and Aglan (unpublished data). Four patients with two rare types of Ehlers–Danlos syndrome were reported by Temtamy et al. (2004b). Meguid (1993) described a patient with frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot. Shawky and Elsayed (2000) reported Melnick–Needles syndrome (MIM 309350) with primary amenorrhea. Temtamy and Aglan studied another case with the syndrome (unpublished data). Cranioectodermal dysplasia (MIM: 218330) in two Egyptian cases was reported by Afifi et al. (2003). Fibrodysplasia ossificans progressive (MIM 135100) was reported by Shawky et al. (2003d). Shawky and Sadik (2007) studied a case with frontofacionasal dysplasia associated with facial heamangioma (MIM 229400).

Congenital Contractures Temtamy et al. (2004a) studied forty-six patients with congenital contractures of limbs. They were classified into four main categories, which were further subdivided into 16 entities. Category (I) included congenital contractures that affected primarily the musculoskeletal system; 18 cases were in this category comprising eight entities including four patients with distal arthrogryposis type 1 (MIM 108120), two sibs and their father with Trismus-pseudocamptodactyly Syndrome (MIM 158300), three patients with digitotalar dysmorphism (MIM 126050), two cases with congenital clasped thumb (OMIM 314100), two males with

8 Genetic Disorders in Egypt

231

clasped thumb club foot syndrome (OMIM 601776), isolated camptodactyly (MIM 114200) in two cases, one female with classical arthrogryposis and amyoplasia (MIM 108110) and a male with Dupuytren contracture (MIM 126900) and a family pedigree consistent with autosomal dominant inheritance. Category (II): Twenty-one cases had musculoskeletal involvement in addition to other system malformations or anomalies comprising six entities, of which 11 cases had multiple pterygium syndrome (MIM 178110, 265000, 312150); most were consistent with AR inheritance, four patients with Freeman-Sheldon syndrome (MIM 193700, 277720), two cases with arthrogryposis multiplex congenita, distal, type II with craniofacial abnormalities (MIM 108140), two with congenital contractural arachnodactyly (MIM 121050) and one patient with Stickler syndrome (MIM: 108300). Category (III): Six patients had musculoskeletal involvement plus lethality, CNS anomalies or mental retardation. Four were diagnosed as Pena–Shokeir syndrome, one case with Aase–Smith syndrome (MIM 147800) and another showed dup (1)(p36.136.2). Category (IV): Contracture deformities of limbs due to environmental factors, which were present in two cases only. Autosomal recessive pterygium syndrome with severe muscular atrophy was reported by Meguid et al. (1997b). Meguid et al. (1997c) studied Schwartz-Jampel syndrome (MIM 255800). Camptodactyly, arthropathy, coxa vara and pericarditis syndrome (MIM 208250) was reported by El-Garf et al. (2003).

Reduction Defects Genetic studies on limb reduction defects carried out by Temtamy et al. (2006a) have shown that limb absence or reduction defects are not an uncommon malformation among Egyptian children. Limb reduction defects were isolated in eight cases, while 14 cases had other associated malformations as a part of syndrome including Poland syndrome (MIM: 173800), thrombocytopenia absent radius syndrome (TAR) (MIM: 274000), Fanconi anemia (MIM: 227650), Holt–Oram syndrome (MIM: 142900), Goldenhar Syndrome, GS (MIM: 164210), femur-fibula-ulna complex (MIM: 228200), ulnar-mammary syndrome (MIM 181450) and ectrodactyly, ectodermal dysplasia and clefting syndrome (MIM: EEC1 129900; EEC2 602077; EEC3 604292). A patient with TAR syndrome had a microdeletion on chromosome 1q21.1. Both her phenotypically unaffected mother & brother were carriers for this microdeletion (unpublished data). Three Egyptian patients with Adams–Oliver syndrome (MIM: 100300), offspring of three unrelated consanguineous families with additional rare manifestations of the eye and skin, and previously unreported retrocerebellar cyst and asymmetrical cerebellar hypoplasia, were described by Temtamy et al. (2007b). Meguid et al. (1995) illustrated the clinical variability in EEC syndrome. Meguid and Ashour (2001) reported the rare association of holoprosencephaly and split hand and foot. Ashour and El-Badry (2004) described two patients with isolated ectrodactyly, and six cases with split hand/split foot as a part of two syndromes; five of which were consistent with EEC syndrome and one female

232

S.A. Temtamy et al.

patient with ectrodactyly, ectodermal dysplasia, macular dystrophy syndrome (EEM) (MIM: 225280). Temtamy et al. (2003a) reported two sisters with atypical Baller–Gerold syndrome (MIM 218600). El-Kamah and Temtamy (2003) studied nine patients with Holt–Oram syndrome (MIM 142900). Temtamy et al. (2003c) reported mild facial dysmorphism and quasidominant inheritance in two patients with Cenani–Lenz syndrome (MIM 212780). Four patients with Roberts syndrome (MIM 268300) were reported by Temtamy et al. (2006c). Heterochromatin repulsion of chromosomes was a constant finding in the studied patients demonstrated by DABI stain supporting the possibility that mutations in Roberts syndrome lie in centromere related proteins which may also play a role in body patterning. Femoral facial syndrome (MIM: 134780) was reported in an Egyptian male with bilateral undescended testis by Shawky et al. (2006d). Temtamy and Aglan studied another patient with the syndrome (unpublished data).

Brachydactyly Temtamy and Aglan (2008) presented a pedigree of an Egyptian family with 10 affected members in three generations with brachydactyly type A1 (MIM 112500). The authors also reported a patient with du-Pan syndrome (MIM 228900) and a new case with Temtamy preaxial brachydactyly syndrome (MIM: 605282). This is in addition to a case with Rubinstein–Taybi Syndrome (MIM 180849) and two sibs with autosomal recessive Robinow syndrome (MIM 268310). A genetic study on Robinow syndrome (OMIM: 180700, 268310) was carried out by Sourour (1987). El-Ruby et al. (1998) reported cases with autosomal recessive inheritance. Meguid and Aglan (2002) studied eight cases with Robinow syndrome; seven were consistent with autosomal recessive inheritance. Ali et al. (2007) identified novel mutations in the frizeled-like cysteine-rich domain of ROR2 causing Robinow syndrome.

Other Limb Anomalies and Skeletal Malformations Temtamy and Loutfy (1970) reported polysyndactyly in an Egyptian family. An Egyptian Jewish family in which polysyndactyly was transmitted through four generations with 17 affected individuals was presented by Fried and Mundel (1974). The first evidence of autosomal recessive inheritance of some rare disorders was provided by the occurrence of the same disorder in sibs or cousins as reported in progeria (MIM: 176670) (Gabr et al. 1960) and in Marden–Walker syndrome (MIM: 248700) (Temtamy et al. 1975b). Acrocallosal syndrome (MIM: 200990) with hypogenitalism was reported by Temtamy and Meguid (1989). Abdel-Aleem et al. (2002) studied the molecular

8 Genetic Disorders in Egypt

233

screening of GLI 3 gene in various polydactyly phenotpes in a group of patients. Phenotypic variations versus genetic differences in the oral-facial-digital syndromes (MIM: 252100) were illustrated by Temtamy et al. (2003b). Ibrahim (1997) studied genetic syndromes with abnormal cranial volume and shape. Temtamy et al. (1975d) discussed limb malformations associated with clover leaf skull anomalies. Shawky et al. (2002a) studied 50 patients with craniosynostosis. Thirty patients had primary craniosynostosis divided into 3 subgroups according to skull shape; subgroup I with oxycephaly included 17 patients (13 with primary isolated oxycephaly, one associated with Arnold-Chiari malformation, two with Crouzon syndrome and one with Apert syndrome). Subgroup II included ten cases with primary isolated scaphocephaly and subgroup III “heterogeneous”. Most cases with primary craniosynostosis were sporadic (86.7%). Twenty patients had secondary craniosynostosis (ten cases with CP, four with MPS, three with shunt craniosynostosis, one with osteopetrosis, one with neglected vitamin D-resistant rickets and one case had encephalocele with multiple congenital anomalies). Other publications included studies of individual patients with Carpenter syndrome (MIM: 201000), Pfeiffer syndrome (MIM: 101600), hyperphosphatasia (MIM: 239300), mandibuloacral dysplasia (MIM: 248370), autistic features in Rubinstein–Taybi syndrome (MIM: 180849) and Coffin–Siris syndrome associated with deafness (MIM: 135900) (Temtamy 1966; Temtamy et al. 1974c, 1975c, d, 1990b; Meguid and Temtamy 1988; El-Rifai et al. 1993; Temtamy and Sanad 2001; Afifi and El-Bassyouni 2005). A case report with MURCS association (OMIM: 601076) and additional findings was presented by Shawky et al. (2007b). El-Khateeb (2008) reported an Egyptian patient with the rare association between bullous congenital ichthyosiform erythroderma and hypocalcemic vitamin D-resistant rickets. From the experience of the first two authors at the Limb and Skeletal Malformations Clinic (LSMC), Medical Services Unit (MSU), NRC; we Temtamy and Aglan diagnosed and counseled cases with different isolated types of limb anomalies, SEMD, SMD, SED, craniometaphyseal dysplasia (MIM: 218400), hyperphosphatasia, diastrophic dysplasia (MIM: 222600), congenital contractural arachnodactyly (MIM: 121050) with cases consistent with AR inheritance, in addition to individual cases with rare syndromes including: Al-Awadi/Raas-Rothschild syndrome (MIM 276820) (Fig. 8.2), rickets-alopecia syndrome (MIM: 277440), AR spondylocostal dysostosis (MIM: 277440), Winchester–Torg syndrome, trichorhinophalangeal dysplasia, occulodentodigital syndrome (MIM 164200), focal dermal hypoplasia (MIM 305600), Farber disease presenting with digital contractures (MIM 228000), congenital AR insensitivity to pain (MIM 24300), Langer mesomelic dysplasia (MIM 249700), Fraser syndrome (MIM: 219000), metatrophic dwarfism (MIM 250600), Montreal dwarfism (MIM: 210700), Aarskog syndrome (100050) and syndromes with craniosynostosis including Apert (MIM 101200), Crouzon (MIM 123500), Pfeiffer (MIM: 101600) and Carpenter syndrome (MIM 201000) (Fig. 8.3) (unpublished data).

234

S.A. Temtamy et al.

Fig. 8.2 Al-Awadi/Rass-Rothschild syndrome (Temtamy & Aglan, LSMC, NRC)

Fig. 8.3 Carpenter syndrome (Temtamy & Aglan, LSMC, NRC)

Hematological Disorders Mahmoud et al. (1987) compared blood group results in Dakahleia Govornorate, Egypt, with the data reported in neighboring countries, and found a high frequency of B, NS, cDe and K genes, a moderately high frequency of P and the presence of Fy gene in Egypt. The authors suggested that the Egyptian population appeared as a mixture of African, Asiatic and Arabian characteristics.

8 Genetic Disorders in Egypt

235

Beta-thalassemia Beta-thalassemia is the commonest cause of chronic haemolytic anemia in Egypt. The estimated carrier rate is 9–10% (El-Beshlawy et al. 1993). Over 1,000 are expected to be affected annually. A preventive program of the disease should be multifaceted with its technical component based on carrier screening and prenatal diagnosis through mutation detection. Habib and Bo¨o¨k (1982, 1983) studied the effect of consanguinity and incidence of thalassemia in Egypt. Novelletto et al. (1990) found that eight mutations accounted for 77% of betathalassemia chromosomes in patients from the Nile delta region. The commonest were IVS-1 nt 110, IVS-1 nt 6 and IVS-1 nt 1. Each mutation was associated with a specific haplotype, with the exception of IVS-1 nt 110, found on three different chromosomal backgrounds. Their data showed that testing for the eight detectable mutations made feasible prenatal diagnosis in 65% of at risk couples and exclusion testing in an additional 25% of cases. Rapid detection of a 13.4-kb deletion causing delta beta thalassemia in an Egyptian family by polymerase chain reaction was reported by Craig et al. (1993). Thirty-four beta-thalassemia and three Hb S/beta-thalassemia patients originating from different regions of Egypt were studied, by Hussein et al. (1993). The causative mutation was found in 69 of 71 (97%) beta-thalassemia genes. Four mutations accounted for 78% of beta-thalassemia genes in this population; IVS-1, nt 110 (41%), IVS-1 nt 6 (13%), IVS-1, nt 1 (13%), and IVS-2, nt 848 (11%). El-Hazmi et al. (1995) presented preliminary data on the prevalence of 14 mutations in the Arab populations and showed wide variation in the molecular basis of beta-thalassemia in different Arab ethnic groups. Their study included 253 beta-thalassemia patients drawn from eight Arab countries (Jordan, Egypt, Syria, Lebanon, Yemen, and Saudi Arabia) living in Saudi Arabia. The most frequently encountered mutations were IVS-I-110 and IVS-II-1, which were identified in the population of each Arab country. The IVS-I-1 and IVS-II-745 mutations were encountered in Jordanians, Egyptians, and Syrians. It was found that some known severe mutations such as IVS-I, nt1 and codon 39 showed moderate clinical presentation whereas other mild mutations as IVS-I, nt6 cases were severely affected (Hussein et al. 1997; Rady et al. 1997; Temtamy et al. 1997). The previous studies pushed the authors towards further studying of modifying factors such as the effect of co-inheritance of some alpha-globin gene abnormalities such as 3.7 Alpha-globin gene deletion and Gamma-globin gene polymorphism on beta-thalassemia phenotype. Co-inheritance of alpha deletion and Gamma-globin gene polymorphism has ameliorated the phenotype in 5.7% of the studied cases and disease severity could not be explained in 20.9% (Hussein et al. 2003). The molecular defects and their impact on thalassemia intermedia cases were studied by El-Kamah et al. (2003). They detected mild homozygous genotype in 38.8% of the mild cases, 45% of the moderate cases and 21% of the severe cases, concluding that severity could not be explained only by Beta-globin gene mutation.

236

S.A. Temtamy et al.

Shawky et al. (2003c) identified the prevalent b-thalassemia mutant alleles of fetal DNA in maternal circulation using denaturing high performance liquid chromatography (DHPLC). The most prevalent genotypes were b+IVS1nt110/ b0IVS1nt1, b+IVS1nt110/ b0CD39 and b0IVS1nt1/b+IVS1nt6 with 14.28% each. In Alexandria, the commonest mutation was IVS-I-110 (62%), followed by IVS1-6 (7%) and IVS-I-1 (4%). Other mutations such as IVS-II-1 and Cd-39 were not found in any of the studied patients (Omar et al. 2005). El-Gawhary et al. (2007) studied 95 thalassemic patients from Fayoum in Upper Egypt, Cairo, Alexandria, and Tanta in Lower Egypt and the Nile Delta, and found the most common allele encountered in their study was IVS-I-6 (T!C) (36.3%); the second most common mutation was IVS-I-110 (G!A) (25.8%). They also reported three homozygous cases for the promoter region, 87 (C!G), allele with a frequency of 3.2%. DNA sequencing of uncharacterized cases (14 cases, 15 alleles) revealed six cases (six alleles) of codon 27 (G!T), and three cases (three alleles) of the IVS-II-848 (C!A) mutation. Codon 37 (G!A) in the homozygous state was found in one patient with parental consanguinity. The frameshift codon 5 (CT)mutation was detected in two of their uncharacterized cases. The codon 15 (TGG!TGA) mutations were detected in one patient (one allele, 0.5%). The authors concluded that screening for beta-thalassemic mutations for the seven most frequent alleles in Egypt succeeded in determining the beta-globin genotype in 84.2% of patients (91.6% of the expected alleles). Hussein et al. (2007) found 12 different mutations in 51 unrelated chromosomes in patients from Suez Canal region. The three most frequent mutations were IVS-I-110 (G!A), IVS-I-1 (G!A) and IVS-I-6 (T!C). They also identified the first homozygous case of a rare mutation, codon 24 (G; +CAC), displaying a thalassemia major phenotype. El-Beshlawy (2005) reported the Egyptian experience with the use of different oral iron chelators compounds on thalassemia patients, most of them although effective in animals have shown unacceptable toxicity with the exception of Deferiprone (DFP) and ICL670. Abdelrazik (2007) concluded that beta-thalassemic major patients with transfusional iron overload can be safely and effectively treated with an alternate therapy of DFO/DFP with a progressive fall in the mean serum ferritin and significant improvement of myocardial performance. El-Beshlawy et al. (2008a) found that the toxicity of DFP was mild to moderate and acceptable; most commonly, transient arthropathy and nausea/vomiting were observed. They recommended a combination therapy of both DFP and deferoxamine (DFO) in reducing transfusional iron overload compared to either drug alone in thalassemia patients. El-Beshlawy et al. (2008b) reported the correction of aberrant pre-mRNA splicing by antisense oligonucleotides (ASON) in beta-thalassemia patients with IVSI-110 mutation, suggesting the applicability of ASON for the treatment of thalassemia. Abdelrazik and Ghanem (2007) found that failure of puberty is common in thalassemic patients and necessitates newer protocols of treatment, correct blood transfusion and chelation therapy.

8 Genetic Disorders in Egypt

237

Alpha-thalassemia Novelletto et al. (1989) estimated the frequency of deletional alpha-thalassemia in the Egyptian population at 0.08 by DNA analysis of a newborn random sample. No alpha 0 determinants were found. The most frequent alpha+ determinant was the -alpha 3.7 type I in association with the medium allele at inter-zeta HVR. The -alpha 4.2 and alpha anti 3.7 arrangements were found at very low frequencies.

Fanconi Anemia (MIM: 227650) Fanconi anemia is heterogeneous and at least eight complementation groups have been delineated. Pronk et al. (1995) reported localization of the Fanconi anemia complementation group A gene to chromosome 16q24.3. Temtamy et al. (2007d) studied 48 patients clinically suspected to have Fanconi anemia (FA), 20 parents of confirmed FA cases and ten normal individuals as control group. The main aims were to test the methods of induction of chromosomal breakage (by diepoxybutane, DEB, and mitomycin C, MMC) in cases, carriers and controls. Thirty-one cases were found to have FA. Parental consanguinity rate was 97% in affected cases. Using DEB all affected cases showed chromosomal breakage with a range of (1.2–12.1) and a mean of 4.3. Normal controls did not show any breakage. Similar results were found using MMC. Ninety percent of parents revealed chromosomal breakage by DEB but not by MMC. The study confirmed that DEB was more sensitive in revealing FA carriers when compared to MMC. Clinically, pancytopenia was found in 91% of cases with FA, short stature in 52%, skin pigmentation in 52%, microcephaly in 48% and upper limb anomaly (preaxial reduction defect and thumb polydactyly) in 57% of cases.

Sickle cell disease (OMIM: 603903) The first report of sickle cell anemia was given by Abbasy (1951). Other reports of sickle cell anemia and double heterozygotes B thalassemia sickle cell anemia were described by Hashem (1978). The author found that among 166 families with chronic hemolytic anemias, 31 patients had sickle cell anemia or its variants: HbSS (10), HbCC (2) and other hemoglobinopathies (19). El-Hazmi et al. (1999) studied the haplotypes of the beta-globin gene as prognostic factors in sickle cell disease. In a study of 25 patients with sickle cell disorders, Shawky et al. (2003b) found 15 patients (60%) homozygous for A–T translocation while 10 patients were heterozygous. Benin haplotype was found to be the most common (52%) followed by atypical haplotype (36%). There was no correlation between clinical severity and haplotypes. El-Beshlawy et al. (2006a) studied the role of L-carnitine on the diastolic dysfunction and pulmonary

238

S.A. Temtamy et al.

hypertension in randomly selected 37 sickle cell disease (SCD) children for a period of 6 months.

Glucose-6-Phosphate Dehydrogenase Deficiency (G-6PD) Deficiency (MIM: 305900) Hashem and Nour (1969) recorded an incidence of G6PD deficiency of 6% among Egyptian male controls in their sample and that of 11% in heterozygous females. They proved the existence of a series of alleles with varying efficiency in mediating G6PD synthesis. McCaffrey and Awny (1970) screened 650 males from different governorates of Egypt and found an incidence of deficiency of 4.9%. Screening of 1,315 males from two Egyptian oases for G6PD found an incidence of 5.9%. There was a correlation between high frequency of G6PD deficiency and high frequency of slow acetylation rate (Hussein et al. 1992). Usanga and Ameen (2000) investigated a total of 3,501 male subjects from six Middle Eastern countries living in Kuwait for quantitative and phenotypic distribution of red cell glucose-6-phosphate dehydrogenase (G6PD). The ethnic origins of those investigated were Kuwait, Egypt, Iran, Syria, Lebanon, and Jordan. The distribution of G6PD deficiency among the different ethnic groups varied widely, ranging from 1.00% for Egyptians to 11.55% for Iranians.

Coagulation Defects Abdelrazik et al. (2007a) found that hemophilias were the most prevalent congenital coagulation disorders among children. Congenital disorders constituted 71.4% of their studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B were more frequent than severe cases in both types. Children with hemophilia may have reduced bone mineral density (BMD) compared with age- and gender-matched controls. This reduction in BMD was independent of differences in age and body size. Children with more established hemophilic arthropathy exhibited the lowest BMD and BMD Z-score (Abdelrazik et al. 2007b). El-Bostany et al. (2008) studied 43 consecutive children with various bleeding manifestations. Children were recruited from three pediatric centers; two in Cairo and one in Saudi Arabia. The study revealed that 27.9% of studied children were found matching for criteria of Von Willebrand Disease (VWD), 25.5% had hemophilia A, 7% hemophilia B, 16.3% had platelet dysfunction and 23.3% had bleeding manifestations with undiagnosed cause. Hussein et al. (2008) studied the use of DNA markers for carrier detection and prenatal diagnosis in 46 families with at least one child affected with hemophilia A. The incidence of BCL1 (+) allele was 74%, 72% and 60% in patients, mothers and control group. Thus, 48% of the studied families were informative for this marker

8 Genetic Disorders in Egypt

239

alone. Nine different alleles of VNTR (St14) were observed in mothers and six alleles in affected cases and six in the female control group. The authors concluded that the combined use of both BCL1 and St14 markers raised the informative rate to 63.6%.

Other Haematologic and Immunologic Disorders In a study of 22 Egyptian patients with Diamond–Blackfan anemia (OMIM: 105650), El-Beshlawy et al. (2002) concluded that Cyclo Sporine A (CSA) therapy should be tried in steroid-resistant Diamond–Blackfan anemia patients before blood transfusion or corticosteroid therapy complications are instituted. Among 70 Egyptian individuals with hereditary hemochromatosis (OMIM: 235200), the allele frequencies were: H63D in 21.4% (+/2.1%) of cases and none had the common C282Y mutation (Settin et al. 2006).

Familial Mediterranean Fever (FMF, MIM249100) In a study carried out by Al-Alami et al. (2003) aiming at identifying the frequency of MEFV mutations and carrier frequency in a mixed Arabic population including Egypt (231), Syria (225), Iraq (176) and the Kingdom of Saudi Arabia (107). Out of the 58 alleles of the 29 probands, only 31 mutations were identified and M694V and V726A were the most common pointing to their higher penetrance. The mutation E148Q was the most common among the healthy adult cohort, but was not present in affected individuals concluding that E148Q has reduced penetrance and thus, a proportion of the individuals genetically affected with FMF remain asymptomatic. The collective mutant allele frequency “q” was 0.101. The expected carrier rate was 18.1% (one in 5.5) while the observed carrier rate was 18.4% (one in 5.4) with an overall carrier rate is one in five. Zekri et al. (2004) studied the prevalence of the most common MEFV gene (FMF gene) mutations, M694V and V726A in Familial Meditteranean Fever (FMF) in 20 Egyptian patients. The M694V mutation was detected in 20 patients (100%) and V726A mutation in 17 patients (85%). Similar results were reported by Settin et al. (2007b). Out of their 66 studied patients with FMF, positive mutations were detected among 42 cases (63.6%), of them 14 (21.2%) were compound heterozygotes, seven (10.6%) were homozygotes while 21 (31.8%) were simple heterozygotes. Allele M694V was the most frequent one (18.8%) followed by V726A (17.4%) and M680I (12.1%). Al-Daraji et al. (2008) studied the gastric changes following colchicine therapy in patients with FMF. In contrast with previous reports, they did not find any definitive change in the large intestine.

240

S.A. Temtamy et al.

Inborn Errors of Metabolism It has been estimated that one in every 32 Egyptian carries a gene for IEM (Hashem 1978). Shawky et al. (2001c) emphasized the importance of selective screening programs for detection of probands and their highly risk relatives for prevention and therapy. The authors studied 280 cases suspected of having IEM out of 450 cases with MR. Fifty one cases (11.32%) had confirmed inborn errors of aminoacid metabolism. Forty cases had PKU (78%), four cases with generalized aminoaciduria (7.84%), two cases with non ketotic hyperglycinemia, two cases with hyperprolinemia, two cases with histidenemia (3.92%) and one case with homocystinuria (1.96%). In a study of 197 patients with isolated MR, Temtamy et al. (1990a) found 83 patients with IEM, 77.1% had disorders of aminoacid metabolism and 22.7% had MPS. Among 282 cases referred to the Human Genetics Department, NRC, El-Bassyouni et al. (1999b) found 24.8% with signs or symptoms suggestive of IEM. Ninety-one percent were proved to have IEM including: mucopolysaccharidosis (MPS) (16.3%), phenylketonuria (PKU) (13.7%), galactosemia (13%), homocystinuria (11.3%), and Gaucher disease (9.8%). Ismail et al. (1996a) studied certain treatable IEM (PKU, galactosemia and congenital hypothyroidism) in Alexandria governorate including two groups of newborn infants. Group A included a random sample of 3,000 infants attending different Health offices in Alexandria for BCG vaccination. Group B included all the infants born to high-risk families attending the clinic of Human Genetics Department, Medical Research Institute (nine infants; seven with family history of PKU and two with family history of congenital hypothyroidism). In group A, one baby with transient hyperphenylalaninemia (HPA) (0.33%) and one presumptive case of galactosemia (0.33%) were found. In Group B, four infants were detected among the infants of PKU families. Elsobky and Elsayed (2004) performed extended metabolic screening (EMS) of 231 cases (44 neonates and 187 children) with symptoms suggestive of IEM. Abnormal results were found in 22.73% of neonates and in 26.66% of those with previous neonatal death. First cousin marriage was present in 80% of neonates with abnormal EMS. Abnormal screen included organic acidemias (13.63%), aminoacidopathies (4.55%) and fatty acid oxidation defects (4.55%). Abnormal results were detected in 8.56% of children including aminoacidopathies (5.88%), organic acidemias (1.07%), cystic fibrosis (CF), congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (1.61%). PKU was present in 6.48% of children with MR, 10% of cases presenting with convulsions had MSUD and another 10% had CAH.

Phenylketonuria (PKU) (MIM: 261600) A prevalence of 1.5% of aminoacidopathies was reported by Shawky et al. (2007a), among which PKU was found to be the commonest (1.11%) while the remaining

8 Genetic Disorders in Egypt

241

diagnosed cases (urea cycle defects, hyperglycinemia, maple syrup urine disease, alkaptonuria, trimethylaminuria) represented 0.07% each. In a population study of 15,000 newborns aged 1 week–1 month, PKU was detected by neonatal screening in 1:7,500 (Temtamy 1998). A previous study by Hashem (1978) found a prevalence of 1: 22,276. Among 480 mentally retarded patients referred to the Human Genetics Clinic, Alexandria University; Hashishe (1992) found 12 cases with PKU, ten cases had the classic type and two cases with atypical PKU. The high average inbreeding coefficient indicated the important role played by consanguinity. Shawky et al. (2000b) studied 240 index cases with hyperphenylalaninemia both from Lower and Upper Egypt. Classic PKU was found in 92.08% of cases. No cases with dihydropteridine reductase deficiency were found among 13 patients with PKU not responding to dietary management (Fateen et al. 2000). Mutation analysis at the phenylalanine hydroxylase (PAH) locus was undertaken in 56 Egyptian hyperphenylalaninemic patients by Hashem et al. (1996). Selected screening for 11 known mutations and denaturing Gradient gel electrophoresis (DGGE) analysis of the entire coding sequence and exon/intron boundaries led to the identification of a new mutation (I224T), four previously described mutations, and several polymorphisms. A high degree of molecular heterogeneneity at the PAH locus was established by examining RFLP haplotypes and PAH mutations in the families of 13 Egyptians with phenylketenouria (PKU). Effat et al. (1999) identified nine different mutations among the 26 alleles of 13 different Egyptian patients; [IVS 10nt11g (8/26), [IVS 2nt5g-c] (4/26), [R261Q] (3/26), [R176X] (2/26), [Y206D] (2/26), [S231P] (2/26), [Y198fs], [593-614del22bp], (2/26), [G46fs], [136/137delG]; (1/26), and [E178G] (1/26). Six of these mutations [IVS 2nt5g-c], [R176X], [Y198fs], [R261Q], [S231P] and [IVS 10nt11g] were common to other Mediterranean populations. Two novel mutations to the Egyptian population were also observed ([Y206D] and [G46fs]). Their preliminary findings confirm IVS 10nt11g as a major mutation among Mediterranean mutations. Shawky et al. (2006b) studied 51 unrelated probands with PKU. They identified a novel missense CpG site R243P mutation in addition to three new known mutations L48S, delEX3 and Y277D not yet found in the Egyptian population. The most common mutation was represented by IVS10nt546. Effat et al. (2008) by screening for six Mediterranean mutations identified a heterogeneous pattern among 90 unrelated Egyptian PKU patients with a high frequency of IVS10-11 G>A (17%). The high heterozygosity of the mutant PAH locus in Egypt suggests that multiple founder effects would explain the presence of hyperphenylalaninemia in Egypt. Rapid carrier screening using short tandem repeats in the PAH gene was carried out by Shawky et al. (2002b). Variations in the number of STR in the 16 families studied, gave rise to polymorphisms that proved to be suitable markers for PKU carrier detection and prenatal diagnosis. The most frequent allelic fragment size in PKU patients was 246 bp (35.7%), which together with a fragment of 254 bp accounted for 60.7% of the mutant chromosome.

242

S.A. Temtamy et al.

Alpha-One Antitrypsin Deficiency (MIM: 107400) Hereditary Tyrosinemia (MIM276700) Abdel-Ghaffar et al. (1998) studied 160 children with chronic liver disease. Tyrosinemia was found in 7.2% of cases, and abnormal AAT phenotype was found in 3.8% (PiM in 2.2%, PiMS in 1.1%, PiZZ in 0.5%.

Biotinidase Deficiency (MIM: 253260) In a survey of 1,036 newborns, Abdullah et al. (1994) found biotinidase deficiency in 0.3%. Hindawy et al. (1999) studied 21 cases with convulsions; biotinidase deficiency was diagnosed in 7% of cases.

Galactosemia (MIM: 230400) A newborn screening survey on 15,000 newborns, galactosemia was found in 1/2,350 (Temtamy 1998) and in 13% of 701 patients screened for symptoms of IEM (El-Bassyouni et al. 1999b). In a study of 2,238 neonates including of 1,794 normal babies, 70 prematures and 374 high-risk neonates, Fateen et al. (2004) found one case of galactosemia among the normal neonates and 26 cases among the high-risk group. Nineteen patients suffered from uridyltransferase deficiency, the parents of 16 (88.8%) of this classic form were consanguineous. The other eight affected neonates were epimerase deficiency patients. Five (62.5%) of them were born to consanguineous parents. Badawy et al. (2003) reported the clinical and nutritional status of seven patients with galactosemia.

Lysosomal Storage Disorders Twenty out of 355 children in a study of cytogenetic and biochemical findings of the mentally handicapped in Alexandria were due to lysosomal storage disorders (El-Shafei 1999). In a study by Temtamy et al. (2000c), ten cases with suspected lysosomal storage disorders were diagnosed as four cases with sialuria, three cases with neuronal lipofuscinosis, two cases with MPS and one case with Tay–Sachs disease. In a study of 30 patients with developmental delay or loss of previously acquired milestones, Shawky et al. (2006e) diagnosed one case with Gaucher disease, one case with Aryl sulphatase A pseudodefficiency, one case with Pelizaeus Merzbach disease and two cases with infantile metachromatic dystrophy. Of 1,240 outpatients referred to the Human Genetics Clinic between 1997 and 1998, 248 (20%) had inborn errors of metabolism, 36 (14%) of which were diagnosed as MPS. Parental consanguinity was present in 82% of these patients. Deficiency of

8 Genetic Disorders in Egypt

243

alpha-L-iduronidase (IDUA) enzyme in leukocytes and increased urinary mucopolysaccharides excretion were detected in 17 patients (El-Bassyouni et al. 1999a). Hashem (1978) reported 77 families with MPS, 23 cases had Hurler syndrome, 16 had Morquio disease, 12 had Hunter disease, ten cases with Hurler/Scheie, nine had San philippo, four cases with Marateau–Lamy and three cases had Scheie. Report of the first family of glycogen storage disease among Egyptians was given by el-Gholmy et al. (1965). Aboul-Ezz et al. (1988b) studied the gingival ultrastructural changes in a patient with glycogen storage disease. Endo et al. (2005) provided the first report of molecular characterization in three consanguineous Egyptian patients with glycogen storage disease type IIIa (OMIM: 232400). The authors identified three different individual AGL mutations; of these, two were novel deletions [4-bp deletion (750–753delAGAC) and 1-bp deletion (2673delT)] and one the nonsense mutation (W1327X) was previously reported. Haplotype analysis of mutant AGL alleles showed that each mutation was located on a different haplotype. Their results indicated the allelic heterogeneity of the AGL mutation in Egypt. Khalifa et al. (2000) reported a 9-year-old male with a-mannosidosis. Temtamy et al. (1994b) were the first in Egypt to report Gaucher disease (OMIM: 230800) confirmed by enzymatic assays in children. Phenotype–genotype expression of Gaucher disease in Egyptian infants and children was studied by Khalifa et al. (1999). Shawky and Elsayed (2004) reported the unusual finding of concentric ventricular hypertrophy and multiple stones in the right kidney in a patient with Gaucher disease. A study of 22 Egyptian children with Gaucher disease revealed that two-thirds of the patients were from consanguineous pedigrees and 14/22 patients were homozygous or compound heterozygous for L444P and D409H mutations (El-Beshlawy et al. 2006b). Symptomatic and radiological skeletal disease was common. The study showed that Enzyme Replacement Therapy (ERT) was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain. Hashem (1978) reported 36 cases of neurolipidosis, Leigh disease in 13 cases, GM1 gangliosidosis in 11 cases, GM2 gangliosidosis in six cases, mucolipidosis in six cases and a single case with Refsum disease. Metachromatic leukodystrophy (ML) was diagnosed in seven cases. In a study of 59 children with seizures and psychomotor retardation carried out by Shatla et al. (1999), one patient had Tay-Sachs disease (MIM: 272800) and two patients had Sandhoff disease (MIM: 268800). Out of 112 patients presenting with progressive motor and mental retardation, GM2 gangliosidosis was suspected in 60 cases (53.3%). Deficiency of Hexosaminidase A or A and B enzymes was detected in 31 patients (27.1%) diagnosed as GM2 gangliosidosis. According to the age of onset and type of hexosaminidase deficiency, patients were classified into: Type I “Tay–Sachs disease” 18/31 (58%) cases; Type II “Sandhoff disease” 3/31 (10%) cases; Type III “Juvenile GM2 gangliosidosis” including 10/31 (32%) cases. Parental consanguinity was reported in 22/31 (73.3%) cases, and familial cases with affected sibs were detected among 23% of the studied patients (El-Harouni et al. 2002).

244

S.A. Temtamy et al.

ML (MIM: 250100) was diagnosed by enzyme assay in 35.9% of 701 patients with symptoms suggestive of IEM (El-Bassyouni et al. 1999b). In a study of 110 children with progressive deterioration of motor and mental abilities, ML was diagnosed in 18 cases by biochemical, brain imaging and neurophysiological studies including enzyme assay. Parental consanguinity was reported in 14 out of the 18 studied cases (Meguid et al. 2003a). Abdel-Salam and Zaki (2004) described four children with atypical form of Hallervorden–Spatz syndrome (HVS) (MIM: 234200). Calcification of the globus pallidus was an association in all cases. Their report was the second in the literature with this association. Novel truncating mutation in MECP2 gene in a sporadic case with typical Rett syndrome was reported by Abdel-Aleem et al. (2007).

Other Inborn Errors of Metabolism Temtamy et al. (1993) studied patients with MR, progressive neurologic disorders and ultrastructural changes of gingival biopsy suggestive of storage disorders. Twenty-six cases had peroxisomal disorders, 12 cases had adrenoleukodystrophy, seven cases had neonatal adrenoleukodystrophy, and seven cases with peroxisomal disorders of unknown etiology. The authors diagnosed eight cases with sialic acid disorders (six with SALLA disease and two with sialic acid storage). El-Bassyouni et al. (2003) estimated a very long chain of fatty acid in children with peroxisomal disorders. The role of DHA in ameliorating the symptoms in peroxisome biogenesis disorders was studied by Abdel Mawgoud et al. (2007). In a study of 50 high-risk infants and children using GC/MS, 14 cases with organic acid disorders were diagnosed (El-Gammal et al. 2001). Thirty-three children suffering from non-ketotic hypoglycemic attacks were studied by Fateen et al. (1999) using GC/MS, 81.8% were diagnosed as MCADD [OMIM 231680] with a significant elevation of free and total fatty acids. Abdel Ghaffar et al. (2001) reported two sibs with mitochondrial hepatopathy, Leigh syndrome and myopathy. El-Bassyouni et al. (2004) studied the clinical and biochemical aspects in mitochondrial disorders among Egyptian children.

Endocrine Disorders and Abnormal Sexual Differentiation Congenital Hypothyroidism Hypothyroidism was found in 1/5,495 (Hashem 1978) and 1/2,500 newborns (Temtamy 1998). Hashem (1978) found that 75% of all hypothyroidism was due to a primary defect in the thyroid gland or in the enzymatic synthesis of the thyroid hormone, while 25% were secondary to pituitary or hypothalamic disorders.

8 Genetic Disorders in Egypt

245

A national neonatal screening program for hypothyroidism was started in Egypt by the Ministry of Health and Population in 2000. In an Egyptian girl with isolated central hypothyroidism (OMIM: 275100), Bonomi et al. (2001) found a novel nonsense mutation [Q49X] characterized in the patient. The mutant TSHB lacks 60% of the C-terminal amino acid sequence, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods, but the mutant heterodimer is completely devoid of bioactivity.

Disorders of Sexual Differentiation (DSD) One of the main objectives of the study of disorders of sexual differentiation in infancy and childhood is to provide an early decision on the sex of rearing. Temtamy et al. (1998b) reported an incidence of 1:3,000 for DSD. In a study of 208 patients with ambiguous genitalia, Mazen et al. (2008) concluded that 46,XY DSD was more common than 46,XX DSD constituting 65.9% of total cases. Consanguinity was high with 61% in the affected families; however, only 21 cases had a positive family history. There was preference of male sex of rearing (regardless of karyotype), despite a severe degree of ambiguity. Reported Egyptian cases with familial male hermaphroditism were provided by Hashem (1972) and Temtamy et al. (1974d). Four male pseudo-hermaphrodite sisters were reported by Etriby et al. (1966). El-Awady et al. (1987) described familial Leydig cell hypoplasia (OMIM:152790) as a cause of male pseudohermaphroditism in two 46, XY phenotypically female sibs, offspring of a first cousin marriage. Shawky et al. (2001a) tested the presence or absence of SRY gene in 21 patients with intersex using FISH technique and LSR SRY/CEP X dual color probes. G-banding revealed normal male karyotype in ten patients (48%), normal female karyotype in nine patients (43%) and abnormal karyotype in two patients (45, X,+mar) (9%). Mazen et al. (1996) studied 56 patients with DSD and found that hydroxylase deficiency (29%) and androgen end organ unresponsiveness (25%) were the most prevalent etiologies. Thirty cases had male pseudohermaphroditism, 25 cases had female pseudohermaphroditism, eight cases had gonadal dysgenesis and two had syndromic ambiguous genitalia. Out of 133 patients, Mokhtar et al. (2002) found disorders of gonadal differentiation in 69 cases (51.9%). True hermaphrodite was present in 6 patients (4.5%), FPH in 32 patients (24%), 26 patients with MPH (19.5%), seven had partial AI, seven had 5 alpha reductase deficiency and one case had agonadism. Overall; 42 had chromosomal abnormalities (31.6%) and 58 had monogenic disorders (36.9%). The frequency of consanguinity was high (51.9%) with a higher average inbreeding coefficient (0.030.06) than that reported for the Egyptian population in general (0.01). Gad (2002) studied the CYP21 mutations in two patients with CAH (OMIM: 201910). PCR analysis of the patients’ DNA using primers for four common

246

S.A. Temtamy et al.

CYP21 mutations showed that both were homozygous for the I172N mutation. Their mothers were both hetyerozygous for the mutation. In a study of 11 patients with salt-wasting type of CAH due to steroid 21-hydroxylase deficiency by Essawi et al. (2007b), allele specicific PCR was used for the detection of the most common mutations in the CYP21 gene. In the examined 22 alleles, the percentage of undetectable mutations was 50% confirming the heterogeneity of the disorder in Egyptians. Gad et al. (1997) assessed the role of 5-a-reductase deficiency [OMIM: 607306] in the development of micropenis among 29 Egyptian patients with abnormal sexual development. The study showed that isolated micropenis is a heterogeneous disorder and 5 alpha RD, despite its relatively increased prevalence in Egypt, has a minimal role in the etiology. G34R disease underlying mutation is apparently prevalent in Egypt. Essawi et al. (1997) examined androgen resistance (AR) and 5 alpha-reductase 2 (5 alpha R2) gene mutations among a sample of such cases as a first step towards instituting a screening program. Five families with a typical hormonal profile of 5 alpha RD were screened for major deletions of exons 3–5 of the 5 alpha R2 gene. Thereafter, screening for point mutations followed by nucleotide sequencing was carried out. Seven patients with androgen insensitivity syndrome (AIS) were subjected to molecular analysis of AR exons B-H. No major deletions were found in either gene. One family had abnormal electrophoretic mobility on SSCP of exon 5 of the 5 alpha R2 gene; resulting from a point mutation (C to T substitution) at codon 246. Another family, showing retarded mobility on DGGE, had a point mutation (G to A substitution) at codon 889 of the AR gene. In conclusion, the study revealed two mutations previously reported in other geographically distinct populations, inferring the possibility of mutational hot spots in the genes. Molecular analysis of 5 alpha-reductase type 2 gene in eight unrelated children was carried out by Mazen et al. (2003a). Three different homozygous mutations were identified. One patient carried Y235F substitution and two had N160D substitution. All five of the other patients had the G34R mutation. The parents were heterozygous for the mutations, although the mother of one patient was homozygous for the G34R mutation. The authors concluded that the high consanguinity rate in Egypt suggests a common ancestor with a founder gene effect in cases of G34R mutation. Detection of the G34R mutation in the 5 alpha reductase 2 gene by allele specific PCR and its linkage to the 89L allele among Egyptian cases was also reported by Gad et al. (2007). Novel mutations of 5-alpha-reductase type 2 were identified in Egyptian patients with ambiguous genitalia. Hafez et al. (2003) found a homozygous alanine to glutamic acid substitution at position 62 (A62E) in three patients from a large Egyptian kindred. The parents and two XX sisters were heterozygous while a third XX sibling was normal. Mazen et al. (2003b) identified a homozygous A–>G mutation in exon 3 that replaced the asparagine residue at position 160 by an aspartic acid in two unrelated patients. The parents of both patients were all heterozygotes for the N160D substitution.

8 Genetic Disorders in Egypt

247

De Bellis et al. (1992, 1994) demonstrated the clinical, functional, and molecular heterogeneity in the syndrome of partial androgen insensitivity by analyzing the AR gene in three 46, XY Egyptian individuals with partial AIS. Mutation of the androgen receptor (R840S) was found by Mazen et al. (2004) in a patient with partial AIS. A new mutation of the androgen receptor, P817A, causing partial AIS was reported by Lumbroso et al. (2004). A de novo point mutation was found in exon 6 of the AR gene, resulting in an F804L substitution in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis (Gad et al. 2003). Essawi et al. (2009) studied 21 children with 46, XY DSD presenting with androgen end organ unresponsiveness to find out the proportion of cases due to X-linked androgen insensitivity syndrome (AIS:MIM 300068). Five exons out of the 147 (3.4%) showed mutations concluding that the X-linked AR mutation is an uncommon underlying etiology among Egyptian pediatric 46,XY DSD cases. Pals-Rylaarsdam et al. (2005) reported a novel mutantion of the luteinizing hormone receptor (LHR) in a case of familial Leydig cell hypoplasia and pseudohermaphrotidism. The proband was homozygous for two missense mutations, T1121C and C1175T, causing substitutions I374T and T392I. The molecular effects of the mutations were investigated by heterologous expression of the WT LHR, the double mutant LHR, or receptors with either the I374T or the T392I mutation, and measuring hormone binding and cAMP signaling. All mutant LHRs exhibited severe defects, including loss of ligand binding and cAMP production. Immunoblots showed little difference in protein levels between the WT and mutant receptors. Abd El Aziz (2002) studied 55 sex-reversed cases with various phenotypes. Nineteen patients were XX males (34.5%) and 36 were XY sex-reversed females. Meguid et al. (2003b) described a patient with transposition of external genitalia and associated malformations. El-Awady et al. (2004) found Yq(11) microdeletions in four out of 33 (12%) males with idiopathic infertility.

Insulin Dependant Diabetes Mellitus Guirguis et al. (1985) studied patients with insulin-dependent diabetes mellitus (IDDM) and 30 healthy control subjects. Their results showed that patients with IDDM showed a significant increase in frequency of HLA-A2, HLA-B8 and HLAB15. On the other hand, HLA-A3, HLA-B5 and HLA-B7 have been found significantly decreased in patients with IDDM, thus suggesting that these alleles may confer a protective effect from acquiring the disease. When HLA specificities have been studied in relation to the age of onset of the disease, HLA-A29 have been found in higher frequency in the age group after 15 years, while HLA-B15 in that before 15 years. Gaber et al. (1994) studied the human leukocyte antigen class II polymorphisms and genetic susceptibility of IDDM in 50 children. They concluded that IDDM susceptibility and resistance in the Egyptian population is strongly associated with

248

S.A. Temtamy et al.

the expressed DQ alpha- and beta-heterodimers in a dose-effective manner, as already defined in many different ethnic groups. In a study of 40 patients with IDDM, Kamel et al. (2007) found the strongest association with HLA-DQB1 locus. Homozygous DQB1 non Asp was associated with susceptibility to the disease, while the homozygous DQB1 Asp genotype conferred protection.

Genodermatosis El-Hefnawi et al. (1965) discussed the inheritance of Xeroderma Pigmentosa (XP) and its relationship to the ABO blood group system in Egyptian cases. Hashem et al. (1980) described the first survey of DNA repair characteristics among sixteen XP Egyptian patients. The patients were equally distributed between complementation groups A and C. German et al. (1984) questioned its higher incidence in Japan and Egypt than in Europe and America. The author discussed the possibility of the presence of some unidentified selective advantage for the carrier of an XP gene as the probable explanation for these regional increases. Temtamy et al. (1989c) provided a clinical and genetic study of 12 cases with Sjogren–Larsson syndrome (MIM: 270200). Rogers et al. (1995) described the syndrome in two other Egyptian families. Aboul-Ezz et al. (1988a) reported the oral ultrastructure in cases with Sjogren–Larsson syndrome. The biochemical changes in the syndrome were studied by El-Bassyouni et al. (2005). Mutations in transglutaminase 1 gene in the autosomal recessive congenital ichthyosis (ARCI) (OMIM: 242300) were found by Russell et al. (1995). Shawky et al. (2004) studied 43 patients from 16 families with severe lamellar ichthyosis (LI) and ten congenital ichthyosiformis erythroderma (CIE) families. Among the 52 alleles tested, five alleles (9.6%) were identified as having intron-5/exon-6 splice acceptor mutation in two families. The [R142H] mutation was detected in four CIE Egyptian families and one LI phenotype (frequency of 28.8%; 15/52). Abdel Hamed et al. (2007) detected steroid sulfatase gene deletion (STS) in three out of nine cases with X-linked ichthyosis. El-Kabbany et al. (2004) reported Egyptian patients with Dorfman–Chanarin syndrome (MIM: 275630). In a study of 25 Egyptian patients with atopic dermatitis (AD), Metwally et al. (2004) concluded that the high level of IL-18 mRNA expression in AD, and its correlation with serum level of IgE and with severity of the disease indicates that IL-13 is involved in the pathogenesis of the disease and is an important in vivo IgE inducer. Salem et al. (2002) studied 60 cases with psoriasis. Their results revealed that sporadic occurrence was present in 64% of cases, AR inheritance in 20% and AD in 12%. They suggested the possible linkage of psoriasis with two diseases (multiple polyposis of the colon and breast cancer). Polymorphic sites in genes of the TNF-a at position 308, IL-10 at position 1,082 and IL-6 at position 174 as well as 86-base pair variable number tandem

8 Genetic Disorders in Egypt

249

repeat within intron 2 of the IL-1Ra gene were determined as promoter polymorphisms on susceptibility and prognosis of leprosy in studied Egyptian sample of 47 leprotic patients from the Nile Delta region (Hassan et al. 2005). Other reported conditions involving skin in Egyptian patients include, infantile eczema (Hashem et al. 1963; Hashem 1965), cutaneous porphyria (El-Mofty 1964), congenital alopecia areata (MIM: 104000) in a father and his son (El-Nasr and El-Hefnawi 1963a) and dyskeratosis congenita with pigmentation (OMIM: 224230), dystrophia unguium and leukoplakia oris (MIM: 305000) (El-Nasr and El-Hefnawi 1963b). Temtamy and Aglan studied some cases with epidermolysis bullosa. Mutation of Col7A1 gene was detected in a case of epidermolysis bullosa dystrophica (MIM: 226500) in an Egyptian family (unpublished data). Acrodermatitis enteropathica (MIM: 201100) was diagnosed in seven consanguineous Egyptian families by Wang et al. (2001). Homozygosity mapping, places the acrodermatitis enteropathica gene on chromosomal region 8q24.3 Ghaffer et al. (1999) studied neutrophil function in 15 cases with Papillon– Lefe`vre syndrome (MIM: 245000) from four families. Their results confirmed a significantly decreased neutrophil function in probands with Papillon–Lefe`vre syndrome with respect to neutrophil phagocytotic and lytic activity but not with respect to opsonization. Toomes et al. (1999) concluded that loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis in the syndrome. Sinbawy et al. (1988) described familial ocular albinism with heterozygous expression. Neu Laxova syndrome (MIM: 256520) was reported by Meguid and Temtamy (1991). GAPO syndrome (MIM: 230740) with ultrastructural changes in the gingiva was reported by Meguid et al. (1997a), Lawrence–Seip syndrome (MIM: 269700) by Mahmoud (1997). Shawky et al. (2002d) reported a case with jeuvenile hyaline fibromatosis (MIM: 228600). Ramzy and El-Gammal (2004) described another case. El-Kamah et al. (2005) studied the clinical variability in patients with hypomelanosis of Ito (HI) (MIM: 300337). Shawky and Elsayed (2005) described a child with HI and rapidly progressive neuroblastoma. Elejalde syndrome (MIM: 256710) was reported by Afifi et al. (2007). Fahmy et al. (2007) reported multiple bilateral renal tumors in patients with Birt–Hogg–Dube syndrome (OMIM: 135150).

Genetic Eye Disorders This category is apparently common in Egypt, partly due to high consanguineous marriages, and is assumed to cause at least half of all cases of childhood blindness (Gomaa 2007).

250

S.A. Temtamy et al.

Congenital Cataract Moustafa et al. (1981) studied 30 cases of congenital cataract, 23 were sporadic and seven were familial. Parental consanguinity was present in 56.5%. Temtamy and Shalash (1974) suggested AR inheritance for congenital cataract and microphthalmia.

Primary Congenital Glaucoma (PCG) (MIM: 231300) El-Defrawy et al. (1991) studied 42 cases, 20 cases were sporadic and 14 cases were familial. Parental consanguinity was 100% in familial cases and 46.4% in sporadic cases. El-Ashry et al. (2007) identified two novel mutations in a clinical and molecular genetic study of PCG, performed on 11 Egyptian and Saudi Arabian patients. Three CYP1B1 mutations were identified in five PCG patients (45.4%) of which two were novel (homozygous E173K and heterozygous N498D) and the third (G61E) had previously been reported. In addition, ten single nucleotide polymorphisms were identified in CYP1B1 and MYOC genes of which two were novel. Patients with no mutations in the screened genes may have mutations in genes yet to be identified.

Retinitis Pigmentosa Moustafa et al. (1989) studied 50 cases with isolated retinitis pigmentosa; 20 cases were familial and 23 sporadic. Pattern of inheritance was AR in 81.5%, AD in 7.5% and XLR in 11%. A clinical and biochemical study of Egyptian patients with primary retinitis pigmentosa was carried out by El-bastawisy et al. (2005).

Retinoblastoma In a study of 15 cases with retinoblastoma, Shawky et al. (2000d, 2002c) found that mutations were detected among the different exons of retinoblastoma genes with no “hot spots” or predilection to specific exons. Specific point mutations in seven exons of the RB1 gene were identified in 11 out of 15 patients. Mutation of exon 14 was detected in three patients while mutations of exons 17 and 26 were detected each in two patients. Mutations in exons 2, 11, 12, 13 were detected in one patient each. Genotype-phenotype correlations were identified.

Other Disorders Affecting the Eye Temtamy et al. (1996b) reported a family with oculotrichodysplasia (MIM: 257960) in four affected sisters, offspring of consanguineous marriage. A sporadic case with Lowe syndrome (MIM: 309000), and Norrie disease (MIM: 310600) in

8 Genetic Disorders in Egypt

251

an Egyptian family, were studied by Temtamy and molecular prenatal diagnosis after identification of the gene defects in affected family members was provided (unpublished data). Temtamy et al. (2000b) described three cases with Lenz microphthalmia syndrome (OMIM: 309800) associated with rare anomalies. Orodental manifestations of Lenz microphthalmia syndrome were reported by El-Badry and Temtamy (2003). AbdelSalam et al. (2004b) studied cases with anophthalmia and microphthalmia. Shawky et al. (2005) reported a girl with Martsolf syndrome (MIM: 212720). Galal et al. (2005) studied 36 patients presenting with congenital blepharoptosis. Patients were classified into four groups: (1) simple congenital ptosis (28%), (2) blepharophimosis-ptosis-epicanthus inversus syndrome (MIM: 110100) (25%), (3) congenital fibrosis of extraocular muscles (CFEOM) (14%), (4) ptosis associated with syndromes (33%). El-Gammal and Eyada (2006) studied associated eye anomalies in 20 cases with genetic disorders including two sibs with atypical lipoid proteinosis (OMIM: 247100), Temtamy syndrome with ocular coloboma (MIM: 218340), Fanconi anemia, Coffin–Siris syndrome, cystinosis (MIM: 219800), homocystinuria (MIM: 236200), pseudohypoparathyroidism (MIM: 203330), neonatal adrenoleukodystrophy (MIM: 202370), rhizomelic chondrodysplasia punctata (MIM: 215100) and Albright hereditary osteodystrophy (MIM: 103580). Their study included three cases with isolated familial eye anomalies (microphthalmia with colobomatous cyst, microphthalmia-cataract and familial persistent primary vitreous).

Congenital Deafness Ismail et al. (1996b) studied 35 patients with sensorineural hearing loss and high rate of parental consanguinity (75%). They were classified according to their diagnosis into: four cases with dominant inheritance, 21 cases with congenital deafness and autosomal recessive inheritance, one case with childhood deafness also showed autosomal recessive inheritance and one case with X-linked inheritance. Six cases were isolated; their mode of inheritance was indefinite. Two cases of ototoxicity in childhood also suggesting genetic causes were included. Snoeckx et al. (2005) analyzed the GJB2 gene in 159 Egyptians from 111 families with non-syndromic mild to profound hearing impairment (MIM: 220290) and an additional family with Vohwinkel syndrome (MIM: 124500). Sequencing analysis of one randomly chosen individual per family revealed that the c.35delG mutation was present in 24 out of 222 chromosomes (10.8%), making it the most frequent mutation in the GJB2 gene in Egypt. Five other mutations were already described previously [p.Thr8Met, p.Val37Ile, p.Val153Ile, c.333_334delAA, c.1-3172G>A (commonly designated as IVS1+1G>A)]. The study also revealed three other novel gene variants resulting in amino acid substitutions (p.Phe142del, p.Asp117His, p.Ala148Pro). In contrast with most populations, the del (GJB6-D13S1830) mutation upstream of the GJB2 gene was not present in the studied Egyptian patients.

252

S.A. Temtamy et al.

A dominant mutation at a highly conserved residue, p.Gly130Val, was found in the family with Vohwinkel syndrome. The oxidative stress and the role of vitamin E and C on non-syndromic sensorineural hearing loss were studied by El-Bassyouni et al. (2008a, 2008b).

Miscellaneous Disorders Abdel Salam et al. (1986) reported a prevalence rate for CF (OMIM: 219700) of 1/2,632 by screening 18,253 newborns with BM-mec test in meconium samples. Ibrahim et al. (1993) studied 200 children with chronic chest disorders and found elevated sweat chloride in one case. Among 80 children with symptoms and signs of chronic lung disease and/or pancreatic insufficiency screened for the presence of F508 mutation, 20 patients were proved to carry such mutation, of them only one was homozygous and the rest were heterozygous for that mutation (Shawky et al. 2003a). Naguib et al. (2007) screened for CF in Egyptian children with suggestive clinical features to identify causative genetic mutations. Of 61 patients, 12 (20%) had positive sweat chloride screening. Ten of the 12 patients underwent quantitative sweat testing and were positive. Eight CFTR sequence changes were identified in seven affected probands and two were confirmed in one sibling by direct DNA sequencing. The study results suggest that CF is more common in Egypt than previously anticipated. Lissens et al. (2000) analyzed 20 Egyptian males with congenital bilateral absence of the vas deferens (CBAVD) for the presence of 12 common Caucasian CFTR mutations and the intron 8 5T splice variant, IVS-5T, known to be a major cause of CBAVD in Caucasian patients. In 16 of the males without associated renal abnormalities only one deltaF508 carrier was identified, but an exceptionally high frequency of the IVS-5T variant was found (14 of 32 alleles or 43.7%), confirming that this variant is involved in many cases of CBAVD, even in populations where CF is rare. CFTR mutations or the IVS-5T variant were found neither in the remaining four patients with associated renal abnormalities nor in the spouses of the 20 CBAVD patients. However, one patient was homozygous for a leucine to proline substitution at amino acid position 541 (L541P) of the CFTR. It is as yet not clear whether this change is involved in CBAVD in this male. Wahab et al. (2004) reported Pseudo– Bartter’s syndrome in an Egyptian infant with CF mutation N1303K. Ko¨hle et al. (2003) reported the frequent co-occurrence of the TATA box mutation associated with Gilbert syndrome (OMIM: 143500) (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Ibrahim et al. (2005) showed that asthmatic children had a significant high prevalence of the GSTM1-null genotype. Among GSTM1-null children inutero smoke exposure was associated with increased prevalence of asthma. Elhawary and Kamal (2006) studied the lymphotoxin-a gene (LTA) polymorphism in 30

8 Genetic Disorders in Egypt

253

asthmatic children. They found that asthma was significantly more common in subjects with allele A of the LTA*NcoI polymorphism (55%) rather than allele G (45%). In addition the severe persistent asthmatic cases were associated with the LTA*NcoI-AA genotype at a frequency of 80%, while the genotype LTA*NcoIGG was associated with the mildest form of the disease. In a study of 60 asthmatic subjects, Hamza et al. (2006) found that asthma was significantly more common in subjects with TNFA-1031C>T genotypes which is in strong association with the severity of asthma. Heshmat and El-Hadidi (2006) found that serum sCD30 levels correlate with the severity of AD and bronchial asthma. Temtamy studied a male infant affected with Omenn syndrome (MIM: 603554) confirmed by clinical, hematological and immunologic data. He was the offspring of first cousins (unpublished data). Adenosine deaminase deficiency was reported by El-Bassyouni and El-Sayed (2000). Ezzat et al. (2005) confirmed the association of DRB1 *04 and *14 alleles with juvenile rheumatoid arthritis susceptibility and DRB1 *08 with protection in 60 patients with polyarticular onset JRA. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (MIM: 240300) presenting with severe keratopathy in an Egyptian patient with a homozygous R139X mutation in the gene encoding the AIRE protein was reported by Tawfik et al. (2005). In a study of 50 children with chronic rheumatic heart disease (RHD) from the Nile Delta region of Egypt, Settin et al. (2007a) found that predisposition to RHD was influenced by genetic factors including cytokine gene polymorphisms, with possible susceptibility to severe disease with multi-valvular affection among cases with composite polymorphism (TNF-alpha (-308 )A/A and IL-10(-1082) A/A) and (TNF-alpha(308 )A/A and IL-10(1,082) G/G). Sixteen Egyptian children with non familial steroid-resistant nephrotic syndrome (SRNS) (MIM: 600995) were screened by PCR-single-strand conformation polymorphism analysis of NPHS2 gene followed by direct sequencing. NPHS2 mutations were evident in four patients (25%) who were bearing four novel mutations including two frame shift mutations (R238fs and P45fs) and two missense mutations (I136L and F216Y) (Bakr et al. 2008). Among the familial cases in a genetic study of 100 Egyptian children with cleft lip and palate, Temtamy and loutfy (1970) reported several syndromes including: van der Woode syndrome (OMIM: 119300), popliteal pterygium syndrome (MIM: 119500), orofaciodigital syndrome, otopalatodigital syndrome (MIM: 304120), Larsen syndrome, and Roberts syndrome. Mossalam et al. (1974) reported familial Waardenburg syndrome (OMIM: 193500). A case with Waardenburg–Klein syndrome (MIM: 148820) was described by Temtamy et al. (1981b). Anthropometry in Egyptian children with Seckel syndrome (MIM: 210600) was reported by Hosny et al. (1997). Hatem et al. (2003) studied two sibs with Seckel syndrome and associated CNS anomalies. Ismail and Helmy (2000) studied Silver–Russel syndrome (MIM: 180860). Zaki et al. (1989) reported the results of anthropometry and dermatoglyphics in Noonan syndrome (OMIM: 163950). Aglan (2002) provided control data of 16

254

S.A. Temtamy et al.

facial indices calculated in 100 normal Egyptian children using photoanthropometry and compared them to the age to be used to delineate abnormal facial features in dysmorphic cases. Aglan et al. (2003) recorded the similarities and differences in the phenotypic features and clinical findings between 14 cases with Noonan syndrome (NS) and six cases with cardiofaciocutaneous syndrome (MIM: 115150) in 20 Egyptian patients. Temtamy and Shoukry (1975) reported the first Egyptian case with Brachmann de Lange syndrome (MIM: 122470). Temtamy et al. (1994a) described 12 other Egyptian cases with emphasis on the orodental, ear and eye abnormalities and their relation to the severity of expression of the disorder. De Lange syndrome with hemimelia was reported by El-Ruby and Temtamy (1997). In a study of 50 patients with auricular abnormalities, four cases had renal anomalies and all four were diagnosed as MCA syndromes (de-Lange syndrome, Goldenhar and Crouzon syndrome) (Rashad and El-Fiky 2007). Temtamy et al. (1991b) illustrated the variability in Hallerman–Strieff syndrome (OMIM: 264090). Cerebrooculofacioskeletal (COFS) syndrome (OMIM: 214150) with familial 1;16 translocation was reported by Temtamy et al. (1996c). SanjadSakati syndrome (OMIM: 241410) was reported by El-Sawy et al. (2004). Temtamy and Shalash (1975) reported sibs with Bardet–Biedel syndrome (BB) (OMIM: 209900). Miniawi et al. (1981) provided a genetic study of 11 cases with BB syndrome. Temtamy et al. (1989a) added new observations to the syndrome. Farag et al. (1999) reported Prader–Willi syndrome (PW) (OMIM: 176270) with microdeletion in chromosome 15(15q11-q). Farag et al. (1999) also reported two patients with FISH-positive Williams syndrome (OMIM: 194050). In a genetic study of obesity in 50 children, Mazen et al. (2002) found 48% with exogeneous obesity, 30% with PW syndrome, 18% with BB syndrome, 2% with Fra X syndrome and 2% with Down syndrome. Positive parental consanguinity was seen in 58% of cases. Elsayed et al. (2005) studied three patients with BeckwithWiedemann syndrome (MIM130650) with hypomethylation of the KCNQ1OT gene and no abnormal methylation of the H19 gene. Elsobky et al. (2005) reported two cases of Cohen syndrome (MIM216550) from two separate families. Abdel-Salam et al. (2007a) described seven patients (five males and two females) with microcephaly, mild microphthalmia, microcornea, congenital cataracts and hypogenitalism (only in males), consistent with the diagnosis of Micro syndrome (OMIM: 600118). Mutation analysis for two of their patients showed homozygous nonsense mutation of RAB3GAP1 in one while the other showed no evidence of linkage to either RAB3GAP1 or RAB2GAP2.

Novel Syndromes The association of anetoderma, optic atrophy and metaphyseal dysplasia (MIM: 250450) was reported by Temtamy et al. (1974a).

8 Genetic Disorders in Egypt

255

Fig. 8.4 Temtany preaxial brachydactyly syndrome (Temtamy et al. 1998)

A new bone dysplasia with intrauterine growth retardation, facial dysmorphism and recurrent bone fractures and autosomal recessive inheritance was described by Temtamy et al. (1974b). Temtamy et al. (1975a) reported the Duane/radial dysplasia syndrome (MIM 607323). Temtamy and Sinbawy (1991) described two sibs, offspring of normal first cousins with congenital cataract, hypertrichosis, mental retardation, and normal chromosomes (CAHMR) (MIM 211770). Temtamy et al. (1991a) delineated a new type of megalocornea/mental retardation (MMR) syndrome (MMR2) (MIM 249310). A new autosomal recessive MCA/MR syndrome with craniofacial dysmorphism absent corpus callosum, ocular colobomas and connective tissue dysplasia was first delineated by Temtamy et al. (1996d) (Temtamy syndrome MIM 218340). It was noted in two sisters and a brother whose parents were normal first cousins. Temtamy et al. (1998c) reported a child with a new syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, bilateral symmetrical digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits I–III (MIM 605282) (Fig. 8.4). Phocomelia and ipsilateral asymmetric crying face was described by Temtamy et al. (1998a).

256

S.A. Temtamy et al.

Ashour et al. (2003) described a patient, the offspring of first cousins with characteristic skin lesions, suggestive of lipoid proteinosis, and confirmed by skin biopsy. The patient had bilateral congenital cataract, myopic fundus, flat facies, pinched nose and fair hair. A paternal cousin and two second cousins were similarly affected.

References Online Mendelian Inheritance in Man, OMIM (TM): McKusick–Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD). World Wide Web URI: http:// www//ncbi-nlm.nih.gov./OMIM/ Abbasy AS (1951) Sickle cell anemia; first case reported from Egypt. Blood 6:555–558 Abd El, Aziz AM (2002) Phenotypic Variability in Sex-reversed Patients; XX Males and XY Females. Egypt J Med Hum Genet 3:99–110 Abdel Ghaffar TY, El Shakankiry H, Maher K, Gaber A, El-Monaiery M, Galal N, Mohamed H (2001) Mitochondrial hepatopathy associated with mitochondrial encephalomyopathy in two sibs: a case report. Egypt J Med Hum Genet 2:127–136 Abdel Hamed MF, Hussein HA, Helmy NA (2007) Detection of steroid sulfatase gene deletion (STS) in Egyptian males with X-linked ichthyosis. Egypt J Med Hum Genet 8:209–217 Abdel Mawgoud SA, El-Bassyouni HT, Afifi HH, Khalipha AG (2007) The role of DHA in amelioration of symptoms of Peroxisome biogenesis Disorders. Res J Med Med Sci 2:5–13 Abdel Salam E, Abdel-Magid IA, Barakat W (1985) Rate of consanguinity in Egyptian population. J Int Coll Pediatr 3:11 Abdel Salam E, Abdel-Maguid IE, Barakat W, Fathy M (1986) National screening of cystic fibrosis in Egypt. In: Proceedings of the International Conference on cystic fibrosis, Cairo, Egypt Abdel Salam E, Temtamy SA, Abdel El Salam M, Meguid NA, Abdel Meguid IE, Gerzawy A (1996) Study of the fragile X-syndrome in Institutes of mentally retarded in Egypt. Egypt J Pediatr 13:155–169 Abdel-Aleem A, Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 255:413–419 Abdel-Aleem A, Kalf-Suske M, Temtamy SA, Abdel Meguid N, Hassan S, Grzesckik KH (2002) Molecular genetic screening of GLI 3 gene in various polydactyly phenotpes in a group of Egyptian patients. Arab J Lab Med 28:131–146 Abdel-Aleem A, Effat L, Salah N, El-Gammal M, Anwar G, Mazen I (2003) The common FGFR3 gene mutation is detected in Egyptian patients with achondroplasia phenotype. Med J Cairo Univ 71:183–187 Abdel-Aleem AK, Abdel Salam GMH, Kayed HF, Zaki MS (2006) C677T polymorphism of the 5, 10-Methylenene tetrahydrofolate reductase (MTHFR) gene as a risk factor of neural tube defects among Egyptian families. Egypt J Med Hum Genet 7:139–154 Abdel-Aleem A, Zaki MS, Abdel Salam GMH, Shehab MI (2007) Novel truncating mutation in MECP2 gene in a sporadic case with typical Rett syndrome. JAC 18:61–66 Abdel-Ghaffar TY, Fateen E, Zaki I, Abou El-Einein A, Rakha O, El-Monaiery MS, Hassanein BM, Kamel MA (1998) Role of alpha one antitrypsin deficiency and hereditary tyrosinemia type I in liver diseases in Egyptian children. Sci J Al-Azhar Med Fac (Girls) 19:1110–1123 Abdelrazik N (2007) Pattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children’s Hospital experience. Hematology 12:577–585 Abdelrazik N, Ghanem H (2007) Failure of puberty in Egyptian beta thalassemic patients: experience in northeast region - Dakahlia province. Hematology 12:449–456

8 Genetic Disorders in Egypt

257

Abdelrazik N, Rashad H, Selim T, Tharwat L (2007a) Coagulation disorders and inhibitors of coagulation in children from Mansoura, Egypt. Hematology 12:309–314 Abdelrazik N, Reda M, El-Ziny M, Rabea H (2007b) Evaluation of bone mineral density in children with hemophilia: Mansoura University children hospital (MUCH) experience, Mansoura, Egypt. Hematology 12:431–437 Abdel-Salam GM, Zaki MS (2004) Hallervorden–Spatz syndrome. Variable imaging findings. Neurosciences 9:447–450 Abdel-Salam GM, Zaki MS, Lebon P, Meguid NA (2004a) Aicardi-Goutie`res syndrome: clinical and neuroradiological findings of 10 new cases. Acta Paediatr 93:929–936 Abdel-Salam GMH, Ashour AM, El-Essawy R, Kayed HF, El-Badry TH, El-Shazly N (2004b) Anophthalmi/Microphthalmia: clinical, ophthalmological and imaging findings. Med J Cairo Univ 72:427–441 Abdel-Salam GM, Shehab M, Zaki MS (2006) Isolated Dandy–Walker malformation associated with brain stem dysgenesis in male sibs. Brain Dev 28:529–533 Abdel-Salam GM, Hassan NA, Kayed HF, Aligianis IA (2007a) Phenotypic variability in Micro syndrome: report of new cases. Genet Couns 18:423–435 Abdel-Salam GMH, Afifi HH, Zaki MS, Aglan MS, Hegazy I, Torky A, Abdulla KH, Tantawy S, Issa MY, Micheal M, Kamal RM, El-Nekhely I, Temtamy SA (2007b) Congenital anomalies in Giza, Egypt: a cross-sectional study. In: The 5th Meeting of the African Society of Human Genetics in conjunction with the 1st Annual meeting of the Division of Human Genetics and Genome Research Division and The National Society of Human Genetics, NRC, Cairo, Egypt Abdullah NM, Temtamy SA, Fateen EM, Esmat AY, Abdel Salam RM (1994) Screening for biotinidase deficiency in Egyptian neonates and patients with neurological disorders. Arab J Lab Med 21:175–193 Aboul-Ezz EHA, Hilal E, El-Din GAS, Temtamy SA, Ismail SA, Nassar AM (1988a) Oral ultrastructure of xeroderma pigmentosa and Sjogren Larsson syndrome. Afr J Dermatol 1:15–26 Aboul-Ezz EHA, Hilal E, El-Din GAS, Temtamy SA, Nassar AH, Ismail SR (1988b) Oral and ultrastructural studies of the gingiva of a patient with glycogen storage disease. Bull NRC Egypt 13:273–284 Afifi HH, Aglan MS (2002) Anthropometric and Photoanthropometric analysis of males with Fragile X syndrome. JAC 13:447–464 Afifi HH, El-Bassyouni HT (2005) Mandibuloacral dysplasia: a report of two Egyptian cases. Genet Couns 16:353–362 Afifi HH, Mostafa MI, Zaki MS (2003) Cranioectodermal dysplasia: two new Egyptian cases with expansion of the phenotype. JAC 14:145–158 Afifi HH, Zaki MS, El-Kamah GY, El-Darouti M (2007) Elejalde syndrome: clinical and histopathological findings in an Egyptian male. Genet Couns 18:179–188 Aglan MS (2002) Facial photoanthropometry: quantification of dysmorphic features. Gaz Egypt Paed 50:383–397 Aglan MS, Afifi HH, El-Kotoury A, Ashour AM (2003) Noonan and Cardiofaciocutaneous syndromes: clinical evaluation of overlapping manifestations. JAC 14:499–513 Aglan MS, Shehab M, El-Badry TH (2004) Genetic studies of the oculo-auriculo-vertebral spectrum. JAC 15:67–90 Aglan MS, Abdel-Aleem AK, EL-Katoury AIS, Hafez MH, Saleem SN, Otaify GA, Temtamy SA (2009) Clinical, anthropometric, radiological and molecular characteristics of Egyptian achondroplasia patients. Egypt J Med Hum Genet 10:13–25 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24:1055–1059 Al-Anssary MK (1995) A genetic study of congenital malformations in a sample of newborns in Shatby University Maternity Hospital, Alexandria. University of Alexandria, Egypt

258

S.A. Temtamy et al.

Al-Daraji WI, Al-Mahmoud RM, Ilyas M (2008) Gastric changes following colchicine therapy in patients with FMF. Dig Dis Sci 53:2079–2082 Ali BR, Jeffery S, Patel N, Tinworth LE, Meguid N, Patton MA, Afzal AR (2007) Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum. Hum Genet 122:389–395 Ashour AM, El-Badry TH (2004) Comparison between isolated ectrodactyly and split hand/split foot as a part of syndromes: clinical and orodental studies. Egypt J Med Hum Genet 5:79–96 Ashour AM, Temtamy SA, El-Darouti M (2003) A probable new syndrome of lipoid proteinosis, congenital cataract and characteristic facies. Egypt J Med Hum Genet 4:27–33 Badawy IH, El-Bassyouni HT, Ashour AM, Khalifa AG, Fateen EM (2003) Galactosemia: clinical and nutritional study. Egypt Med J NRC 3:135–148 Badr El-Din MK (1960) A familial convulsive disorder with an unusual onset during intrauterine life, a case report. J Pediatr 56:655–657 Bakr A, Yehia S, El-Ghannam D, Hammad A, Ragab M, Sarhan A, Al-Husseni F, Al-Morsy Z (2008) NPHS2 mutations. Indian J Pediatr 75:135–138 Barrada Y, Guinena S, Abd-El-Naby TY (1954) Congenital and familial cerebro-cerebellar diplegia. Gaz Egypt Pediatr Assoc 11:315 Blacksin MF, Pletcher BA, David M (1998) Osteogenesis imperfecta with joint contractures: Bruck syndrome. Pediatr Radiol 28:117–119 Bonomi M, Proverbio MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L (2001) Hyperplastic pituitary gland, high serum glycoprotein hormone alpha-subunit, and variable circulating thyrotropin (TSH) levels as hallmark of central hypothyroidism due to mutations of the TSH beta gene. J Clin Endocrinol Metab 86:1600–1604 Brancati F, Travaglini L, Zablocka D, Boltshauser E, Accorsi P, Montagna G, Silhavy JL, Barrano G, Bertini E, Emma F, Rigoli L, International JSRD Study Group, Dallapiccola B, Gleeson JG, Valente EM, Collaborators (113) (2008) RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 74:164–170 Craig JE, Barnetson R, Weatherall DJ, Thein SL (1993) Rapid detection of a 13.4-kb deletion causing delta beta thalassemia in an Egyptian family by polymerase chain reaction. Blood 81:861–863 Dardir AAM (2000) Clinical, genetic and environmental studies in birth defects. Ph.D. Thesis in Childhood Studies, Ain-Shams University, Cairo, Egypt De Bellis A, Quigley CA, Cariello NF, El-Awady MK, Sar M, Lane MV, Wilson EM, French FS (1992) Single base mutations in the human androgen receptor gene causing complete androgen insensitivity: rapid detection by a modified denaturing gradient gel electrophoresis technique. Mol Endocrinol 6:1909–1920 De Bellis A, Quigley CA, Marschke KB, El-Awady MK, Lane MV, Smith EP, Sar M, Wilson EM, French FS (1994) Characterization of mutant androgen receptors causing partial androgen insensitivity syndrome. J Clin Endocrinol Metab 78:513–522 Effat L, Kuzmin A, Goltsov N, Kasem N, Abdel Meguid N, Kotb S, Temtamy SA, Rushdy S, Woo SLC, Eisensmith RC, El-Awady M (1999) Haplotype and mutations at the PAH Locus in Egyptian families with PKU. Eur J Hum Genet 7:259–262 Effat LK, El-Harouni AA, Amr KS, El-Minisi TI, Abdel Meguid N, El-Awady M (2000) Screening of dystrophin gene deletions in Egyptian patients with DMD/BMD muscular dystrophies. Dis Markers 16:125–129 Effat LK, Essawi ML, Abd El Hamid MS, Hawari N, Gad YZ (2008) Screening for six Mediterranean mutations in 90 Egyptian patients with phenylketonuria. Bratisl Lek Listy 109:17–19 El Sherif RM, Fahmy NA, Nonaka I, Etribi MA (2007) Patterns of dystrophin gene deletion in Egyptian Duchenne/Becker muscular dystrophy patients. Acta Myol 26:145–150 El-Aleem AA, Bohm I, Temtamy SA, El-Awady M, Awadalla M, Schmidtke J, Stuhrmann M (1995) Direct Molecular analysis of the fragile X-Syndrome in a sample of Egyptian and German patients using non-radioactive PCR and Southern blot followed by chemiluminescent detection. Hum Genet 96:577–584

8 Genetic Disorders in Egypt

259

El-Ashry MF, Abd El-Aziz MM, Bhattacharya SS (2007) A clinical and molecular genetic study of Egyptian and Saudi Arabian patients with primary congenital glaucoma (PCG). J Glaucoma 16:104–111 El-Awady MK, Temtamy SA, Salam MA, Gad YZ (1987) Familial leydig cell hypoplasia as a cause of male pseudohermaphroditism. Hum Hered 37:36–40 El-Awady MK, El Shater SF, Ragaa E, Atef K, Shaheen IM, Megiud NA (2004) Molecular study on Y chromosome microdeletions in Egyptian males with idiopathic infertility. Asian J Androl 6:53–57 El-Badry T, Temtamy SA (2003) Orodental manifestations of Lenz microphthalmia syndrome. Egypt J Med Hum Genet 4:45–54 El-Bassyouni HT, El-Sayed K (2000) Adenosine Deaminase Deficiency. Sci J Al-Azhar Med Fac (Girls) 21:243–248 El-Bassyouni HT, Afifi HH, El-Awady MK, Meguid NA (1999a) Mucopolysaccharidosis type I: clinical and biochemical study. East Mediterr Health J 5:259–366 El-Bassyouni HT, Fateen EM, Meguid N, Salwa MY (1999b) A three year experience of screening Egyptian patients for inborn errors of metabolism. Egypt J Paed 16:17–24 El-Bassyouni HT, Abdel Mawgoud SA, Khalipha AG (2003) Peroxisomal disorders in Egyptian children: Estimation of very long chain fatty acids by GC/MS. Med J Cairo Univ 71:391–401 El-Bassyouni HT, Abdallah AA, Wafaa Ghoneim W, Hassan I (2004) Clinical and Biochemical Aspects of Mitochondrial Disorders in Egyptian Patients. Inter J Child Neuropsychiatry 1:41–50 El-Bassyouni HT, Ali OSM, Abdel Maksoud S (2005) Clinical and biochemical changes in Egyptian patients with Sjogren Larsson syndrome. Egypt J Med Hum Genet 6:135–144 El-Bassyouni HT, Ashour AM, Afifi M, Ezat A (2008a) Oxidative stress in nonsyndromic sensorineural hearing loss. J Arab Soc Med Res 3:77–81 El-Bassyouni HT, Ezzat A, Ashour AM, Afifi M (2008b) The therapeutic role of vitamin E and C on non syndromic sensorineural hearing loss. J Arab Soc Med Res 3:69–75 El-bastawisy HI, El-Bassyouni HT, Ezzat A, Bassyouni R, Afifi HH, Nowier SR (2005) Primary retinitis pigmentosa: a genetic and biochemical study in Egyptian patients. JAC 6:367–379 El-Beshlawy A (2005) The Egyptian experience with oral iron chelators. Hematology 10(Suppl 1): 174–175 El-Beshlawy A, Kaddah N, Omran N, Moustafa A, Al-Awady A, Abd-El-Azim K (1993) Detection of Thalassemia carrier among Egyptians. Proc EMS Ann Sci Cong 1:329–347 El-Beshlawy A, Ibrahim IY, Rizk S, Eid K (2002) Study of 22 Egyptian patients with DiamondBlackfan anemia, corticosteroids, and cyclosporin therapy results. Pediatrics 110:e44 El-Beshlawy A, Abd El Raouf E, Mostafa F, Talaat M, Isma’eel H, Aoun E, Hoffbrand AV, Taher A (2006a) Diastolic dysfunction and pulmonary hypertension in sickle cell anemia: is there a role for L-carnitine treatment? Acta Haematol 115:91–96 El-Beshlawy A, Ragab L, Youssry I, Yakout K, El-Kiki H, Eid K, Mansour IM, Abd El-Hamid S, Yang M, Mistry PK (2006b) Enzyme replacement therapy and bony changes in Egyptian paediatric Gaucher disease patients. J Inherit Metab Dis 29:92–98 El-Beshlawy A, Manz C, Naja M, Eltagui M, Tarabishi C, Youssry I, Sobh H, Hamdy M, Sharaf I, Mostafa A, Shaker O, Hoffbrand AV, Taher A (2008a) Iron chelation in thalassemia: combined or monotherapy? The Egyptian experience. Ann Hematol 87:545–550 El-Beshlawy A, Mostafa A, Youssry I, Gabr H, Mansour IM, El-Tablawy M, Aziz M, Hussein IR (2008b) Correction of aberrant pre-mRNA splicing by antisense oligonucleotides in betaThalassemia Egyptian patients with IVSI-110 mutation. J Pediatr Hematol Oncol 30:281–284 El-Bostany E, Omer IN, Al Jouni S, El-Ghoroury E. 2008. The spectrum of inherited bleeding disorders in pediatrics. In: The 13th Congress of the European Hematology Association, 12–15 June El-Defrawy H, Temtamy SA, Sabry S, Meguid NA, El Beltagi T (1991) Genetic study of primary developmental glaucoma. Bull Ophthalmol Soc Egypt 84:99–106

260

S.A. Temtamy et al.

El-Gammal MA, Eyada OK (2006) Eye anomalies in genetic diseases: study of 20 cases. Egypt J Med Hum Genet 7:23–45 El-Gammal M, Temtamy SA, Shawky R, Awadallah M, Rashed M, Aboul Ezz E, Youssef S, Hindawy A (2001) Amino acid and organic acid disorders in 50 high risk Egyptian children. Egypt J Med Hum Genet 2:15–31 El-Garf A, Mahmoud G, Gheith R, Abd El-Aaty G, Abd El-Aaty H (2003) Camptodactyly, arthropathy, coxa vara, and pericarditis syndrome among Egyptians. J Rheumatol 30:1081–1086 El-Gawhary S, El-Shafie S, Niazi M, Aziz M, El-Beshlawy A (2007) Study of beta-Thalassemia mutations using the polymerase chain reaction-amplification refractory mutation system and direct DNA sequencing techniques in a group of Egyptian Thalassemia patients. Hemoglobin 31:63–69 El-Gholmy A, Hashem N, Khalifa AS, Osman N, Abdel Hamid G (1965) Report of the first family of glycogen storage disease among Egyptians. J Egypt Med Assoc 48:130–41 El-Harouni AA, Abul-Ezz EHA, Fadaly GA, Abdel-Salam M, Hindawy A, Nassar AM, Ismail SR (1994) Neuromuscular disorders in Egyptian children: a clinical, genetic and ultrastructure study. New Egypt J Med 10:532–537 El-Harouni AA, Aboul-Ezz EHA, Meguid NA, Temtamy SA (1996a) Central nervous system involvement in progressive congenital muscular dystrophy (Fukuyama Type?) in two Egyptian Families. Egypt J Pediatr 13:83–92 El-Harouni AA, Aboul-Ezz EHA, Temtamy SA (1996b) Mitochondrial abnormalities in muscle and gingival biopsies from patients with different forms of mitochondrial myopatheis. Egypt I Pediatr 13:1–10 El-Harouni AA, Zaki MS, Fateen EM, Meguid NA (2002) GM2 Gangliosidosis: clinical, genetic and biochemical studies among Egyptian patients. Egypt J Neurol Psych Neurosurg 39:87–97 El-Harouni AA, Amr KS, Effat L, Eassawi ML, Ismail S, Gad YZ, El-Awady MK (2003) The milder phenotype of the dystrophin gene double deletions. Acta Neurol Scand 107:400 Elhawary NA, Kamal TM (2006) A Lymphotoxin-a Gene polymorphism and asthma in Egyptian children. Egypt J Med Hum Genet 7:7–14 Elhawary NA, Shawky RM, Hashem N (2004) Frameshift deletion mechanisms in Egyptian Duchenne and Becker muscular dystrophy families. Mol Cells 18:141–149 El-Hazmi MA, Warsy AS, al-Swailem AR (1995) The frequency of 14 beta-thalassemia mutations in the Arab populations. Hemoglobin 19:353–360 El-Hazmi MA, Warsy AS, Bashir N, Beshlawi A, Hussein JR, Temtamy S, Qubaili F (1999) Haplotypes of beta-globin gene as prognostic factors in sickle cell disease. East Mediterr Health J 5:1154–1158 El-Hefnawi H, Smith SM, Penrose LS (1965) Xeroderma pigmentosum. Its inheritance and relationship to the the ABO blood-group system. Ann Hum Genet 28:273–290 El-Kabbany Z, Elsayed SM, Rashad M, Tareef R, Galal N (2004) Dorfman–Chanarin syndrome in Egypt. Am J Med Genet A 129A:214 El-Kamah Gh, Temtamy SA (2003) Variability of cardiac and limb involvement in the Holt–Oram Syndrome. Kasr El Aini Med J 9:223–230 El-Kamah Gh, El-Beshlawy A, Sobh HA, Hussein IR (2003) Phenotypic scoring in thalassemia intermedia and the impact of underlying molecular defects. Med J Cairo Univ 4:323–327 El-Kamah Gh, El-Bassyouni HT, El-Darouty M (2005) Hypomelanosis of Ito: expanding the spectrum of the disease Clinico-pathological variability. Egypt Med J NRC 6:247–266 el-Khateeb EA (2008) Bullous congenital ichthyosiform erythroderma associated with hypocalcemic vitamin D-resistant rickets. Pediatr Dermatol 25:279–282 El-Mofty AM (1964) Cutaneous porphyria in Egyptians. Br J Dermatol 76:268–277 El-Nasr HS, El-Hefnawi H (1963a) Dyskeratosis congenita with pigmentation, dystrophia unguium and leukoplakia oris. J Egypt Med Assoc 46:1109–1122 El-Nasr HS, El-Hefnawi H (1963b) Congenital alopecia areata in a father inherited in his son. J Egypt Med Assoc 46:1353–1356

8 Genetic Disorders in Egypt

261

El-Nekhely I, Namaste S, Shriver EK (2008) Analysis of country situationsurvey: National plan of action. In: The 2nd Conference of the Middle East and North Africa Newborn Screening Initiative, Cairo, Egypt, 12–14 April EL-Rifai WM, Aboul-Ezz EHA, El-Sinbawy AH, El-Sawi A, El-Khayat HA, Temtamy SA (1993) Is deafness a feature of the Coffin–Siris syndrome? J Med Res I 14:263–276 El-Ruby M, Temtamy SA (1997) The De-Lange syndrome with bilateral hemimelia and normal karyotype. Report of a case. Review of limb malformations and genetics of this syndrome. Egypt J Pediatr 14:659–667 El-Ruby MO, Ramzy IM, Meguid NA (1998) Robinow syndrome with unusual manifestations. Egypt J Pediatr 15:13–22 El-Sawy MA, El-Kholy MS, El-Sedfy HH, Sleem MN (2004) Sanjad–Sakati syndrome, case report. Egypt J Med Hum Genet 5:61–66 Elsayed SM (2005) Dyggve–Melchior–Clausen Syndrome: case report. Egypt J Med Hum Genet 6:67–72 Elsayed SM, Rossignol S, Le Bouc Y (2005) Methylation Status of Tthe KCNQ1OT and H19 Genes in Beckwith–Wiedemann Syndrome. Egypt J Med Hum Genet 6:55–61 El-Shafei SS (1999) Cytogenetic and biochemical studies of the mentally handicapped in Alexandria. Bull High Inst Public Health 29:509–518 Elsobky E, Elsayed SM (2004) Extended metabolic screen in sick neonates and children. Egypt J Med Hum Genet 5:1–7 Elsobky E, Elsayed SM, Bahyeldeen L (2005) Cohen syndrome. Egypt J Med Hum Genet 6:207–212 Endo Y, Fateen E, Aoyama Y, Horinishi A, Ebara T, Murase T, Shin YS, Okubo M (2005) Molecular characterization of Egyptian patients with glycogen storage disease type IIIa. J Hum Genet 50:538–542 Essawi M, Nasr H, Mazen I, Gaafar K, Amr K, Hafez M, Gad YZ (2008) Low incidence of androgen receptor mutation among Egyptian children with androgen resistance. Egypt J Med Hum Gen 9:111–119 Essawi M, Gad YZ, El-Rouby O, Temtamy SA, Sabour YA, El-Awady M (1997) Molecular analysis of androgen resistance syndromes in Egyptian patients. Dis Markers 13:99–105 Essawi ML, Effat LK, Shanab GM, Al-Ettribi GM, El-Haronui AA, Karim AM (2007a) Molecular analysis of SMN1 and NAIP genes in Egyptian patients with spinal muscular atrophy. Bratisl Lek Listy 108:133–137 Essawi ML, Sharaf SAE, Effat LK, Hafez MH, Amr KS (2007b) Molecular characterization of 21-hydroxylase deficiency congenital adrenal hyperplasia in Egyptian children: A pilot study. Med J Cairo Univ suppl 75(Suppl 11):55–59 Etriby A, Girgis SM, Ibrahim A, el-Danasoury M, Kahil S (1966) Four male pseudo-hermaphroditic sisters. Dtsch Zahnarztl Z 21:608–614 Ezzat MH, Awwad KS, Shaheen KY, Abdel-Wahab SM, Osman TI (2005) The influence of HLA-DRB1 alleles on polyarticular onset juvenile rheumatoid arthritis susceptibility, severity, and prognosis. Egypt J Med Hum Genet 6:145–171 Fahmy W, Safwat AS, Bissada NK, Curry N, Guirguis N, Clarke HS, Fraig M, Finkbeiner A (2007) Multiple/bilateral renal tumors in patients with Birt–Hogg–Dube´ syndrome. Int Urol Nephrol 39:995–999 Farag HM, Kotb SM, Sweify GA, Fawzy RK, Ismail SR (1999) A diagnostic clinical genetic study of craniofacial dysmorphism. East Mediterr Health J 5:470–477 Farrag AF, Faraghaly WMA, Hoffman EP, Hamed SA (2000) DNA sequence analysis for structure/function and mutation studies in Duchenne/Becker muscular dystrophy patients Abstract). In: Conference of Egypyian Society of Neurology, Psychiatry and Neurosurgery, Assiut, Egypt, 4–6 October Fateen E, Ata H, Oraby A, Gouda A, Temtamy SA, Taodrous G, Dacremont G (1999) The diagnosis of medium chain acyl coenzye A dehydrogenase deficiency (MCADD). Egypt Arab J Lab Med 25:391–406

262

S.A. Temtamy et al.

Fateen E, Schulpis K, El- Sawi M, Tantawy A, Temtamy SA (2000) Determination of dihydopteridine reductase activity in PKU patients with persistent hyperphenylalanemia. Bull Egypt Soc Physiol Sci 20:82–103 Fateen E, El-Shafei S, El-Karaksy H, Mahmoud M, Roshdy S, El-Temtamy S, Shin Y (2004) Diagnosis and management of galactosemia: an Egyptian experience. Bratisl Lek Listy 105:303–309 Fried K, Mundel G (1974) Polysyndactyly and Marfan’s syndrome. J Med Genet 11:141–144 Gaber SA, Mazzola G, Berrino M, Canale L, Cornaglia M, Ghali I, Sergio Curtoni E, Amoroso A (1994) Human leukocyte antigen class II polymorphisms and genetic susceptibility of IDDM in Egyptian children. Diabetes Care 17:1341–1344 Gaber KR, Farag MK, Soliman SE, El-Bassyouni HT, El-Kamah G (2007) Maternal vitamin B12 and the risk of fetal neural tube defects in Egyptian patients. Clin Lab 53:69–75 Gabr M, Hashem N, Hashem M, Fahmi A, Safouh M (1960) Progeria, a pathologic study. J Pediatr 57:70–77 Gad YZ (2002) The I172N mutation in the CYP21 gene as an etiology for salt wasting congenital adrenal hyperplasia. New Egypt J Med 27:243 Gad YZ, Nasr H, Mazen I, Salah N, El-Ridi R (1997) 5a-reductase deficiency in patients with micropenis. J Inherit Metab Dis 20:95 Gad YZ, Mazen l, Lumbroso S, Temtamy SA, Sultan C (2003) A novel point mutation of the androgen receptor (F804L) in an Egyptian newborn with complete androgen insensitivity associated with congenital glaucoma and hypertrophic pyloric stenosis. Clin Genet 63:59 Gad YZ, Khairt R, Mazen I, Osman HG (2007) Detection of the G34R mutation in the 5 alpha reductase 2 gene by allele specific PCR and its linkage to the 89L allele among Egyptian cases. Sex Dev 1:293–296 Galal AH, El-Din AA, Soliman FA (2005) Genetic study of blepharoptosis among Egyptians. Bratisl Lek Listy 106:307–312 German J, Hashem N, El-Hefnawi M, Cleaver JE (1984) Xeroderma pigmentosum in Egypt. III. ABO blood grouping in 22 affected families. Ann Hum Genet 48:61–64 Ghaffer KA, Zahran FM, Fahmy HM, Brown RS (1999) Papillon-Lefe`vre syndrome: neutrophil function in 15 cases fron 4 families in Egypt. Oral Surg Oral Med Oral Pathol Oral Radiol Endoc 88:320–325 Gomaa A (2007) Genetic eye diseases and genetic counselling services in Egypt. Community Eye Health 20:11 Guinena Y, Naby SA, Taher Y (1954) Two cases of compression myelopathy secondary to multiple myelomatosis. J Egypt Med Assoc 37:939–946 Guirguis FK, Sawy ME, Khalil S, Mikhail MM, Zaky A, Helmy MA, Helmy-Khalil S (1985) HLA-A, -B and -C specificities in insulin dependent diabetes mellitus in the Egyptian population. Ann Biol Clin (Paris) 43:233–237 Habib Z, Bo¨o¨k JA (1982) Thalassaemia in the Egyptian population. Hereditas 96:149–58 Habib Z, Bo¨o¨k JA (1983) Consanguinity and incidence of thalassaemia in Egypt. Hereditas 99:215–217 Hafez M, Hashem N (1988) Perinatal screening of neural tube defects among Egyptians. Brain Dysfunct 1:90–102 Hafez M, El-Tahan H, Awadalla M, El-Khayat H, Abdel-Gafar A, Ghoneim M (1983) Consanguineous matings in the Egyptian population. J Med Genet 20:58–60 Hafez M, Mazen I, Ghali I, Sultan C, Lumbroso S (2003) A new mutation of 5-alpha-reductase type 2 (A62E) in a large Egyptian kindred. Horm Res 59:281–284 Hamza RT, Haider M, Teama S, Elhawary NA (2006) Association between polymorphisms within tumor necrosis factor genes and the development of bronchial asthma among Egyptian children. Egypt J Med Hum Genet 7:203–213 Hashem N (1965) The possible role of autosensitization in eczema, as demonstrated by a new experimental technique. J Pediatr 66:248–250 Hashem N (1972) Familial male pseudohermaphroditism. Hum Hered 22:225–238

8 Genetic Disorders in Egypt

263

Hashem N (1978) Preventive aspects of genetic morbidity. Volumes I,II,III. In: Proceedings of First International Conference, Cairo, Egypt, 30 March to 4 April Hashem N, Nour A (1969) Studies on glucose-6-phosphate dehydrogenase deficient Egyptian families. J Med Genet 6:150–156 Hashem N, Hirschhorn K, Sedlis E, Holt LE (1963) Infantile eczema. Evidence of autoimmunity to human skin. Lancet 2:269–270 Hashem N, Bootsma D, Keijzer W, Greene A, Coriell L, Thomas G, Cleaver JE (1980) Clinical characteristics, DNA repair, and complementation groups in xeroderma pigmentosum patients from Egypt. Cancer Res 40:13–18 Hashem N, Bosco P, Chiavetta V, Calı` F, Ceratto N, Romano V (1996) Preliminary studies on the molecular basis of hyperphenylalaninemia in Egypt. Hum Genet 98:3–6 Hashishe MM (1992) Genetic study of phenylketonuria. J Egypt Public Health Assoc 67:443–463 Hassan AM, Nassar S, Elbaz R, Hassan AA, Settin A (2005) TNF-a(-308), IL-10(-1082), IL-6(-174) and IL-1Ra(VNTR) Gene polymorphism in leprosy cases from the Nile delta region of Egypt. Egypt J Med Hum Genet 6:1–20 Hatem NL, Tayel S, Emara H (2003) Seckel syndrome: report of two cases. Egypt J Med Hum Genet 4:13–19 Hawass Z, Gad YZ, Ismail S et al. (2010) Ancestry and pathology in King Tutankhamun’s family. JAMA 303:638–647 Helal SI (2000) Genetic study of hereditary ataxias. M.D.Thesis in Neurology, Cairo University, Egypt Heshmat NM, El-Hadidi ES (2006) Soluble CD30 serum levels in atopic dermatitis and bronchial asthma and its relationship with disease severity in pediatric age. Pediatr Allergy Immunol 17:297–303 Hindawy A, Fateen EM, Hagras AM, Bazaraa HM (1999) Biotinidase deficiency in infants with convulsions. Arab J lab Med 25:381–390 Hosny LA, Ramzy MI, Aglan MS, Zaki ME, Meguid NA, Hussien FH (1997) Anthropometry in Egyptian children with Seckel syndrome. Egypt J Pediatr 14:137–148 Hussein L, Yamamah G, Saleh A (1992) Glucose-6-phosphate dehydrogenase deficiency and sulfadimidin acetylation phenotypes in Egyptian oases. Biochem Genet 30:113–121 Hussein IR, Temtamy SA, El-Beshlawy A, Fearon C, Shalaby Z, Vassilopoulos G, Kazazian gr HH (1993) Molecular characterization of B-Thalassemia in Egypt. Hum Mutat 2:48–52 Hussein IR, Temtamy SA, El-Beshlawy A, El-Awady M, El-Kammaly G, Baffico M, Romeo G (1997) Screening for B-thalassemia mutations in Egypt by reverse dot blot hybridization. Egypt J Genet Cytol 26:261–271 Hussein IR, Temtamy SA, El-Harouni A, El-Awady M, Selim LA, Eissawy M (1999) Molecular and genetic studies in DMD and BMD in Egyptian patients. Egypt J Paediatr 16:245–264 Hussein IR, El-Kamah Gh, El-Beshlawy A, Foda B (2003) The effect of -3.7 Alpha-globin gene deletion and Gamma-globin gene polymorphism on clinical variability of beta thalassemia in Egyptian patients. Med J Cairo Univ 4(Suppl II):299–304 Hussein G, Fawzy M, Serafi TE, Ismail EF, Metwally DE, Saber MA, Giansily M, Schved JF, Pissard S, Martinez PA (2007) Rapid detection of beta-Thalassemia alleles in Egypt using naturally or amplified created restriction sites and direct sequencing: a step in disease control. Hemoglobin 31:49–62 Hussein IR, El-Beshlawy A, Salem A, Mosaad R, Zaghloul N, Ragab L, Fayek H, Gaber K, El-Ekiabi M (2008) The use of DNA markers for carrier detection and prenatal diagnosis of haemophilia A in Egyptian families. Haemophilia 14:1082–1087 Hussien FH, Abdalla ZM, Sarry El-Din AM (1990) Achondroplastic old kingdom dwarf from Giza. In: The VIIIth European Meeting of the Paleopathology Association, Cambridge, 19–22 September Ibrahim NA (1997) Genetic syndromes associated with disorders of cranial volume and shape. MSc thesis, Department of Pediatrics, Faculty of Medicine, Cairo University

264

S.A. Temtamy et al.

Ibrahim MA, Temtamy SA, Fateen E, El-Barbary M, Tantawy A (1993) Sweat chloride in children with chronic chest disorders. Bull Egypt Soc Physiol Sci 13:374–389 Ibrahim MAAF, Shaheen MA, Elhawary NA, Abdel-Fattah RA (2005) Glutathione S-Transferase M1 genotype (GSTM1) plus prenatal exposure to smoke as risk factors for pediatric asthma. Egypt J Med Hum Genet 6:183–190 Ismail SR (1977) CNS Malformations: Incidence related to country and season of birth. J Egypt Soc Obstet Gynecol 3:81 Ismail SI, Helmy NA (2000) Silver–Russel syndrome: Clinical and cytogenetic studies in 25 patients. JAC 11:675–684 Ismail SR, Abdel-Rahim N, Hashishe MM, Abdallah EM (1996a) Newborn screening for certain treatable inborn errors of metabolism in Alexandria. J Egypt Public Health Assoc 71:495–520 Ismail SR, Hashine MM, Mourad MI, Abdel Kader M (1996b) Inheritance of non-syndromal genetic deafness. J Egypt Public Health Assoc 71:403–438 Ismail S, Zaki MS, El-Harouni AA (2003) Callosal dysgenesis: clinical and genetic studies in 55 Egyptian patients. Egypt J Neurol Psych Neurosurg 40:1–10 Kamel AM, Mossallam GI, Adel D, Gamil H, Ismail N, Moneer M (2007) HLA-DQA and DQB alleles and predisposition to insulin dependent diabetes mellitus. Egypt J Med Hum Genet 8:69–86 Karim M et al (1970) Congenital foetal malformations in UAR. Ain Shams Med J 21:527–533 Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, Parsian A (2006) A novel mutation in BAP/SIL1 gene causes Marinesco-Sjo¨gren syndrome in an extended pedigree. Clin Genet 70:420–423 Khalifa AS, Fateen E, Tantawy AAG, Monir E, Cooper A (1999) Phenotype-genotype expression of Gaucher disease in Egyptian infants and children. Egypt J Pediatr 16:631–653 Khalifa AS, Ali HH, El-Garf WT (2000) Alpha-mannosidosis: a case report and review of literature. Egypt J Med Hum Genet 1:207–213 Khayat RG, Saxena PC (2000) Consanguinity and its effect on infant and childhood mortality in Egypt. http://www.divx.com. Knoblauch H, Urban M, Tinschert S (1999) Autosomal recessive versus autosomal dominant inheritance in Larsen syndrome: report of two affected sisters. Genet Couns 10:315–320 Ko¨hle C, Mo¨hrle B, M€ unzel PA, Schwab M, Wernet D, Badary OA, Bock KW (2003) Frequent co-occurrence of the TATA box mutation associated with Gilbert’s syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians. Biochem Pharmacol 65:1521–1527 Kozma C (2006) Dwarfs in ancient Egypt. Am J Med Genet A 140:303–311 Lissens W, Mahmoud KZ, El-Gindi E, Abdel-Sattar A, Seneca S, Van Steirteghem A, Liebaers I (2000) Molecular analysis of the cystic fibrosis gene reveals a high frequency of the intron 8 splice variant 5T in Egyptian males with congenital bilateral absence of the vas deferens. Mol Hum Reprod 6:669–670 Lumbroso S, Wagschal A, Bourguet W, Georget V, Mazen I, Servant N, Audran F, Sultan C, Auzou G (2004) A new mutation of the androgen receptor, P817A, causing partial androgen insensitivity syndrome: in vitro and structural analysis. J Mol Endocrinol 32:679–687 Mahmoud SF (1997) Lawrence-Seip syndrome: report of a case from Egypt. Cutis 60:91–3 Mahmoud LA, Ibrahim AA, Ghonem HR, Jouvenceaux A (1987) Human blood groups in Dakahlya, Egypt. Ann Hum Biol 14:487–493 Marin A, Cerutti N, Massa ER (1999) Use of the amplification refractory mutation system (ARMS) in the study of HbS in predynastic Egyptian remains. Boll Soc Ital Biol Sper 75:27–30 Mazen I, Zaki MS (2006) Unusual association of simplified gyral pattern and sparse hair in an Egyptian patient with microcephaly-lymphoedema. Clin Dysmorphol 15:245–247 Mazen I, Gad YZ, El-Awady MK (1996) Intersex disorders among Egyptian patients. JAC 7:607 Mazen I, Hosny LA, Aziz SS, Hammad SA, Shihab MIK, El-Salam MA, Awadalla M, Mohamed AM (2002) Genetic study of obesity in children. Egypt J Med Hum Genet 3:27–41

8 Genetic Disorders in Egypt

265

Mazen I, Gad YZ, Hafez M, Sultan C, Lumbroso S (2003a) Molecular analysis of 5a-reductase type 2 gene in eight unrelated Egyptian children with suspected 5a-reductase deficiency: prevalence of the G34R mutation. Clin Endocrinol 58:627 Mazen I, Hafez M, Mamdouh M, Sultan C, Lumbroso S (2003b) A novel mutation of the 5alphareductase type 2 gene in two unrelated Egyptian children with ambiguous genitalia. J Pediatr Endocrinol Metab 16:219–224 Mazen I, Lumbroso S, Abdel Ghaffar S, Salah N, Sultan C (2004) Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions. J Endocrinol Invest 27:57–60 Mazen I, Hiort O, Bassiouny R, El Gammal M (2008) Differential diagnosis of disorders of sex development in Egypt. Horm Res 70:118–123 McCaffrey RP, Awny AW (1970) Glucose- 6-phosphate dehydrogenase deficiency in Egypt: with a note on the methemoglobin reduction test. Blood 36:793–796 Meguid NA (1993) Frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot. Clin Genet 44:95–977 Meguid NA, Aglan MS (2002) Clinical and anthropometric study in Egyptian children with Robinow Syndrome. Gaz Egypt Paed 50:399–413 Meguid NA, Ashour AM (2001) Holoprosencephaly and split hand/foot: an additional case with this rare association. Clin Dysmorphol 10:277–279 Meguid NA, Temtamy SA (1988) The Carpenter syndrome first report in an Egyptian girl presenting the kleeblattschaedel anomaly and review of literature. Egypt J Pediatr 5:250–541 Meguid NA, Temtamy SA (1991) The Neu–Laxova syndrome in two Egyptian families. Brief clinical report. Am J Med Genet 41:30–31 Meguid NA, Temtamy SA, Afifi HH, Aboul-Ezz EHA (1995) Clinical variability and chromosomal aberrations in EEC syndrome. Egypt J Pediatr 12:315–324 Meguid NA, Afifi HA, Ramzy MI, Hindawy AT, Temtamy SA (1997a) GAPO Syndrome: first Egyptian case with ultrastructural changes in the gingiva. Clin Genet 52:110–115 Meguid NA, El-Harouni A, Afifi HH, Temtamy SA (1997b) An autosomal recessive pterygium syndrome with severe muscular atrophy: Escobar type. JAC 8:81–87 Meguid NA, El-Harouni A, Temtamy SA (1997c) Genetic, therapeutic and immunologic studies of Schwartz-Jampel syndrome in Egypt. JAC 8:355–361 Meguid NA, Dardir AA, Aglan MS, Fateen EM, Rashad MM (2003a) Metachromatic Leukodystrophy: Biochemical and neurophysiologic studies. Egypt J Neurol Psych Neurosurg 40:139–146 Meguid NA, Temtamy SA, Mazen I (2003b) Transposition of external genitalia and associated malformations. Clin Dysmorphol 12:59–62 Meguid N, Abdel-Raouf ER, Dardir A, Mostafa K (2007) Prevalence of fragile X syndrome among school age Egyptian males. World J Pediatr 3(4):271–275 Metwally SS, Mosaad YM, Abdel-Samee ER, El-Gayyar MA, Abdel-Aziz AM, El-Chennawi FA (2004) IL-13 gene expression in patients with atopic dermatitis: relation to IgE level and to disease severity. Egypt J Immunol 11:171–177 Miniawi LK, Salam MA, Temtamy SA, Kamel WA, Hussein FH, Ghali I (1981) The Laurence– Moon–Bardet–Biedl (LMBB) syndrome, clinical and genetic studies of 11 cases. J Egypt Med Assoc 64:35–49 Mohamed MS (1995) An epidemiological study on consanguineous marriage among urban population in Alexandria. J Egypt Public Health Assoc 70:293–305 Mokhtar MM, Abdel-Fattah MM (2001) Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 17:559–565 Mokhtar MM, Nazmy NA, Mahrous HS (2002) Genetic study of abnormal sexual differentiation in Alexandria, Egypt. Egypt J Med Hum Genet 3:63–76 Mossalam L, El-Khodary AF, Temtamy SA (1974) Waardenburg’s Syndrome in Egypt. Ain Shams Med J 25:43

266

S.A. Temtamy et al.

Mostafa MI, Temtamy SA, El-Gammal MA, Mazen I (2005) Unusual pattern of inheritance and orodental changes in the Ellis–Van Creveld syndrome. Genet Couns 16:75–83 Moustafa MS, Temtamy SA, El-Gammal MY, Abdel-Sayed S, El-Salam MA, El-Baroudy R (1981) Genetic studies of congenital cataract. MetabPediatr Ophthalmol 314:233–244 Moustafa MS, Temtamy SA, El-Gammal M, Abdel-Sayed S, Meguid NA (1989) Genetic studies on retinitis pigmentosa. Bull Ophthalmol Soc Egypt 28:285–293 Naguib ML, Schrijver I, Gardner P, Pique LM, Doss SS, Abu Zekry MA, Aziz M, Nasr SZ (2007) Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis. J Cyst Fibros 6:111–116 Novelletto A, Hafez M, Di Rienzo A, Felicetti L, Deidda G, El-Morsi Z, al-Tonbary Y, El-Ziny M, Abd-El-Gelil N, Terrenato L (1989) Frequency and molecular types of deletional alphathalassemia in Egypt. Hum Genet 81:211–213 Novelletto A, Hafez M, Deidda G, Di Rienzo A, Felicetti L, El-Tahan H, El-Morsi Z, El-Ziny M, Al-Tonbary Y, Sittien A et al (1990) Molecular characterization of beta-thalassemia mutations in Egypt. Hum Genet 85:272–274 Omar A, Abdel Karim E, Gendy WE, Marzouk I, Wagdy M (2005) Molecular basis of betathalassemia in Alexandria. Egypt J Immunol 12:15–24 Pals-Rylaarsdam R, Liu G, Brickman W, Duranteau L, Monroe J, El-Awady MK, Gad YZ, Shenker A (2005) A novel double mutation in the luteinizing hormone receptor in a kindred with familial Leydig cell hypoplasia and male pseudohermaphroditism. Endocr Res 31:307–323 Pronk JC, Gibrson RA, Savoia A, Wyker M, Morgan NV, Melchionda S, Ford D, Temtamy SA, Ortega JJ, Jansen S, Havenga C, Cohn RJ, de Ravel TJ, Roberts I, Westerveld A, Eastron DF, Joenje H, Mathew CG, Arwert F (1995) Localization of the Fanconi anaemia complementation group A gene to chromosome. Nat Genet 11:338–340 Pusch CM, Broghammer M, Nicholson GJ, Nerlich AG, Zink A, Kennerknecht I, Bachmann L, Blin N (2004) PCR-induced sequence alterations hamper the typing of prehistoric bone samples for diagnostic achondroplasia mutations. Mol Biol Evol 21:2005–2011 Rady MS, Baffico M, Khalifa AS, Heshmat NM, Sciaratta El-Moselhy S, GV HIR, Temtamy SA, Romeo G (1997) Identification of Mediterranean B-Thalassemia mutations by reverse dot blot in Italians and Egyptians. Hemoglobin 21:59–69 Ramzy MI, El-Gammal MA (2004) Juvenile hyaline fibromatosis (Murray-puretic–Drescher syndrome) oral, systemic and histopathological findings in an Egyptian girl. Egypt J Med Hum Genet 5:69–78 Rashad M, El-Fiky SM (2007) Prevalence of renal anomalies in children with auricular malformations among attendance of genetics clinic in Ain Shams University. Egypt J Med Hum Genet 8:191–197 Rogers GR, Rizzo WB, Zlotogorski A, Hashem N, Lee M, Compton JG, Bale SJ (1995) Genetic homogeneity in Sjo¨gren–Larsson syndrome: linkage to chromosome 17p in families of different non-Swedish ethnic origins. Am J Hum Genet 57:1123–1129 Russell LJ, DiGiovanna JJ, Rogers GR, Steinert PM, Hashem N, Compton JG, Bale SJ (1995) Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet 9:279–283 Salem MSZ, El-Serafy OA (2001) Genetic study of isolated epilepsy among Egyptians. Egypt J Med Hum Genet 2:115–126 Salem MSZ, Rashid HM, Arnaoat HH, Assaf MI (2002) Genetically-determined predisposing factors in psoriasis. Egypt J Med Hum Genet 3:113–125 Sarry El-Din AM (2002) Congenital skeletal anomalies in paleopopulations. Review article. Human Genetics Department, National Research Centre, Cairo Satinoff MI, Wells C (1969) Multiple basal cell naevus syndrome in ancient Egypt. Med Hist 13:294–297 Scheidel W (1997) Brother-sister marriage in Roman Egypt. J Biosoc Sci 29:361–371 Settin A, El-Bendary M, Abo-Al-Kassem R, El Baz R (2006) Molecular analysis of A1AT (S and Z) and HFE (C282Y and H63D) gene mutations in Egyptian cases with HCV liver cirrhosis. J Gastrointestin Liver Dis 15:131–135

8 Genetic Disorders in Egypt

267

Settin A, Abdel-Hady H, El-Baz R, Saber I (2007a) Gene polymorphisms of TNF-alpha (-08), IL-10(-1082), IL-6(-174), and IL-1Ra(VNTR) related to susceptibility and severity of rheumatic heart disease. Pediatr Cardiol 28:363–371 Settin A, El-Baz R, Abd Rasool M, El-Khalegy H, El-Sayed O, El-Bendary M, Al-Nagar AS (2007b) Clinical and molecular diagnosis of Familial Mediterranean Fever in Egyptian children. J Gastrointestin Liver Dis 16:141–145 Shatla H, El-Shakankiry HM, Fateen E, Ahmed NS, Mustafa HA (1999) Prevalence of GM2 gangliosidosis among cases with early onset seizures and psychomotor retardation. Bull Egypt Soc Physiol Sci 19:249–273 Shawky RM, Elsayed SM (2000) Melnick-needles osteodystrophy with amenorrhea: the first Egyptian patient. Egypt J Med Hum Genet 1:163–171 Shawky RM, Elsayed SM (2004) Gaucher disease with pulmonary, cardiac and renal involvement: Improvement on fractionation of Cerezyme dose. Egypt J Med Hum Genet 5:55–59 Shawky RM, Elsayed SM (2005) Hypomelanosis of Ito associated with neuroblastoma. Egypt J Med Hum Genet 6:73–79 Shawky RM, Sadik DI (2007) Frontofacionasal dysplasia: another observation. Egypt J Med Hum Genet 8:225–227 Shawky RM, El-Sawy MA, Nowier SR (2000a) Study of Egyptian patients with multiple congenital anomalies and mental retardation. Egypt J Med Hum Genet 1:215–234 Shawky RM, El-Sedfy HH, Abd El-Hamid H (2000b) Phenotypic expression of hyperphenylalaninemia syndromes among Egyptians. Egypt J Med Hum Genet 1:1235–248 Shawky RM, Mokhtar GM, Abdel Hay A, Agaiby E (2000c) Some genetics aspects of congenital hydrocephalus. Egypt J Med Hum Genet 1:197–205 Shawky RM, Salem MSZ, Rifaat MM, Ali MA, Zico OAO, Abd Al-Azeem AA (2000d) Molecular mutations of retinoblastoma gene among Egyptian children. Egypt J Med Hum Genet 1:83–90 Shawky RM, Abd-El-Aleem KM, El-Sobki ES, El-Safoury HM, Khalifa OA (2001a) Detection of SRY gene in Egyptian children with ambiguous genitalia using FISH technique. Egypt J Med Hum Genet 2:1–14 Shawky RM, El-Aleem KA, Rifaat MM, Moustafa A (2001b) Molecular diagnosis of spinal muscular atrophy in Egyptians. East Mediterr Health J 7:229–237 Shawky RM, Riad MS, Osman HM, Bahaa NM (2001c) Screening for some inborn errors of amino acid metabolism which impair mental function. Egypt J Med Hum Genet 2:71–91 Shawky RM, Abdel Fattah SM, Abdelaziz EA, El-Sayed NS (2002a) Genetic study of Egyptian children with craniosynostosis. Egypt J Med Hum Genet 3(25–44):2002 Shawky RM, El-Aleem KA, Rifaat MM, el-Naggar RL, Marzouk GM (2002b) Rapid carrier screening using short tandem repeats in the phenylalanine hydroxylase gene. East Mediterr Health J 8:49–54 Shawky RM, Salem MSZ, Rifaat MM, Alazeem AA (2002c) Retinoblastoma gene mutations among Egyptian patients. Egypt J Med Hum Genet 3:101–111 Shawky RM, Zaky EA, EI-Sayed SM, Aly MR, El-Zawahry KA, Sedhom K (2002d) Juvenile hyaline fibromatosis. a case report. Egypt J Med Hum Genet 3:85–93 Shawky RM, Abd El Khalek KA, Abd-El Fattah SM, Moselhi SE, Rifaat MM, Kamal TM, Aly MR, EI-Garf WT (2003a) Biochemical and molecular study of Cystic Fibrosis among high risk group patients with chronic lung disease. Egypt J Med Hum Genet 4:97–111 Shawky RM, Khalifa AS, Elkholy MS, Refaat MM, Kamal TM, Elkholy SA, Hughes A, McGibbon D (2003b) Genotype phenotype correlation and hormone profile in sickle cell anaemia. Egypt J Med Hum Genet 4:63–75 Shawky RM, Khalifa AS, Mokhtar GM, Rifaat MM, Kamal TM, Elhawary NA, Elnewhy R (2003c) Prenatal diagnosis of b-thalassemia via automated DHPLC analysis of fetal cells in maternal circulation. Egypt J Med Hum Genet 4:1–12 Shawky RM, Zaky EA, Bahy-Eldeen L, Elsayed SM (2003d) Fibrodysplasia ossificans progressiva: a case report. Egypt J Med Hum Genet 4:43–47 Shawky RM, Sayed NS, Elhawary NA (2004) Mutations in transglutaminase 1 gene in autosomal recessive congenital ichthyosis in Egyptian families. Dis Markers 20:3252–332

268

S.A. Temtamy et al.

Shawky RM, Elsedfy HH, Mouharam W (2005) Martsolf syndrome. Egypt J Med Hum Genet 6:213–216 Shawky RM, Eldin LB, Helal SA, Eltonbary KY (2006a) Study of muscle biopsy in children with muscular dystrophy. Egypt J Med Hum Genet 7:215–225 Shawky RM, Elhawary NA, Elsedafy HH, Elsayed SM, Abdel-Hamid H (2006b) Updated listing of mutation map at the human phenylalanine locus among Egyptian population. Egypt J Med Hum Genet 7:15–22 Shawky RM, Elhawary NA, Salem MSZ, Elgebaly HH, El-Sayed NS (2006c) Gene analysis and carrier detection of Duchenne muscle dystrophy in Egyptian families. Egypt J Med Hum Genet 7:227–240 Shawky RM, Elsobky E, Elsayed SM, Mohram W (2006d) Femoral Hypoplasia–Unusual Facies Syndrome: femoral facial Syndrome (FFS): a recessive severe skeletal form. Egypt J Med Hum Genet 7:251–254 Shawky RM, Fateen EM, Zaghloul MS, Salem AA (2006e) Prevalence of some lipidosis among Egyptian children with neurodegenerative disorders. Egypt J Med Hum Genet 7:47–73 Shawky RM, El-Sedfy HH, Mahmoud AO, Rashad M, Bahaa Eldin EM (2007a) Study of amino acid disorders among a high risk group of Egyptian infants and children. Egypt J Med Hum Genet 8:173–189 Shawky RM, Talaat IM, El-Hakin IZ, Elsayed SM (2007b) MURCS association: a case report. Egypt J Med Hum Genet 8:219–224 Sinbawy AH, Temtamy SA, Meguid NA (1988) Familial ocular albinism with heterozygous expression. Bull Ophthalmol Soc Egypt 81:341–345 Snoeckx RL, Hassan DM, Kamal NM, Van Den Bogaert K, Van Camp G (2005) Mutation analysis of the GJB2 (connexin 26) gene in Egypt. Hum Mutat 26:60–61 Sourour EM (1987) A clinical genetic study of Robinow syndrome. M.Sc. Thesis in Human Genetics, Medical Research Institute, Alexandria University Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977) Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science 197:566–568 Stevenson AC, Johnston HA, Stewart MIP, Golding DR (1966) Congenital malformations. A report of a series of consecutive births in 24 countries. WHO, Geneve, Switzerland Sullivan R (1995) A brief journey into medical care and disease in Ancient Egypt. J R Soc Med 88:141–145 Tainmont J (2007) History of osteogenesis imperfecta or brittle bone disease: a few stops on a road 3000 years long. B-ENT 3:157–173 Tawfik S, Azim MA, Peterson P, Donaldson MD (2005) Autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy presenting with severe keratopathy in an Egyptian patient with a homozygous R139X mutation. Horm Res 64:96–99 Temtamy SA (1966) Genetic factors in hand malformations. Ph.D Thesis in Human Genetics, The Johns Hopkins University, USA Temtamy SA (1982) Classification of hand malformations as isolated defects: an overview. J Genet Hum 30:281–290 Temtamy SA (1998) Prevention of genetic diseases and malformations in newborns. Minist Health Popul Sci J 2:22–27 Temtamy SA, Aglan MS (2008) Brachydactyly. Review article. Orphanet J Rare Dis 3:15 Temtamy SA, Loutfy A (1970) Some genetic and surgical aspects of cleft lip-cleft palate problem in Egypt. Cleft Palate J 7:578 Temtamy SA, McKusick VA (1978) The genetics of hand malformations. Alan R Liss, NewYork, for the National Foundation-March of Dimes, BD:OAS XIV 3, reprinted in 1987 and in 2001 Temtamy SA, Meguid NA (1989) Hypogenitalism in the acrocallosal syndrome. Am J Med Genet 32:301–305 Temtamy SA, Sanad MH (2001) Variable autistic features in Rubinstein–Taybi syndrome. New Egypt Med J 24:60–66

8 Genetic Disorders in Egypt

269

Temtamy SA, Shalash B (1974) Genetic heterogeneity of congenital cataract, microphthalmia and nystagmus. Birth Defects Orig Art Ser Urinary System and Others X:292 Temtamy SA, Shalash B (1975) Laurence–Moon–Bardet–Biedel: syndrome in sibs. Birth Defect: Orig Art Ser Malformation Syndromes XI:202 Temtamy SA, Shoukry SA (1975) Cornelia de Lange syndrome in and Egyptian Child. Birth Defects Orig Art Ser Malformation Syndr XI:362 Temtamy SA, Sinbawy AH (1991) Cataract, hirsuitism and mental retardation (CAHMR). A new autosomal recessive syndrome. Am J Med Genet 41:432–434 Temtamy SA, El-Meligy MR, Badrawy HS, Abdel Meguid MS, Safwat HM (1974a) Metaphyseal dysplasia, anetoderma and optic atrophy, an autosomal recessive syndrome. Birth Defects Orig Art Ser Skeletal Dysplasias X(12):61 Temtamy SA, El-Meligy MR, Osman N, Abdel Meguid MS, Salem S (1974b) A new bone dysplasia with autosomal recessive inheritance. Med Genet Today, Birth Defects Orig Art Ser X(10):165 Temtamy SA, El-Meligy MR, Salem S, Osman N (1974c) Hyperphosphatasia in an Egyptian child. Skeletal Dysplasias Birth Defects Orig Art Ser X(12):292 Temtamy SA, Loutfy AA, Hetta F, Raafat M, Attiya OM, Boulos SY (1974d) Familial male hermaphroditism. Urinary system and others. Birth Defects Orig Art Ser X:243 Temtamy SA, Shoukry AS, Ghaly L, El-Meligy B, Boulos SY (1975a) The Duane/radial dysplasia syndrome: an autosomal dominant disorder. New chromosomal and malformation syndromes. Birth Defects Orig Art Ser XI:344 Temtamy SA, Shoukry AS, Raafat M, Mihareb S (1975b) Marden–Walker syndrome. Evidence for autosomal recessive inheritance. Birth Defects Orig Art Ser Malformation Syndromes XI:104 Temtamy SA, Shoukry SA, El-Meligy MR (1975c) Pfeiffer Syndrome. Birth Defects Orig Art Ser Limb Malformation X:229 Temtamy SA, Shoukry SA, Fayad I, El-Meligy MR (1975d) Limb malformations in the colver-leaf skull anomaly. Birth Defects Orig Art Ser Malformation Syndr XI:247 Temtamy SA, Abdel-Hamid G, Salam MA, El-Badrawy F, Hussein FH, El-Miniawy LK, German J, Abul-Dahab Y (1981a) Genetic studies in rare limb malformations in Egyptian children. Med J Cairo Univ 49:71–86 Temtamy SA, Hussein FH, El Miniawi LK (1981b) The Waardenburg Syndrome in Egypt Revisited. In: Huber A, Klein D (eds) Neurogenetics and Neuroophtalmology, vol 5, Developments in neurology. Elsevier, Amsterdam, pp 407–422 Temtamy SA, Abdelsalam M, Meguid NA, Ismail SR (1987) Chromosomal aberrations in patients with multiple congenital anomalies and mental retardation. JMRI 8(Suppl):211–232 Temtamy SA, El-Salam MA, Meguid NA, Gerzawy AS, Hendawi A (1988) Fragile X-linked mental retardation in Egyptian males. Egypt J Pediatr 5:251–267 Temtamy SA, El-Salam MA, Aboul-Ezz EHA, Meguid NA, Zaki ME (1989a) New observations on the Laurence–Moon and Bardet–Biedl Syndromes. New Egypt J Med 3:715–720 Temtamy SA, Ismail SR, Nassar AM, Aboul-Ezz EHA (1989b) Orodental ultrasturcture studies of pulp and gingiva in two sibs with osteogenesis imperfecta. J Med Res Inst, Alexandria University 10:281–290 Temtamy SA, Youssef N, El-Sawi M (1989c) Sjogren-Larsson Syndrome in Egypt. Clinical and Genetic Study of 12 Cases. Egypt J Pediatr 6:125–138 Temtamy SA, El-Awady MK, Barakat MMA, Kheir El-Din AA, Fahim AT, Abdel-Hamid S (1990a) Screening for some inborn errors of metabolism causing mental retardation in Egyptians. New Egypt J Med 4:621–627 Temtamy SA, Salam MA, Zaki MA, Meguid NA, Aboul-Ezz E (1990b) Rubinstein–Taybi syndrome in Egyptians. J Med Res Inst 11:55–72 Temtamy SA, Abdel-Hamid J, Hussein F, Abdel-Salam N, Meguid NA, Aboul-Ezz EHA, Zaki ME (1991a) Megalocornea mental retardation syndrome (MMR): Delineation of a new entity (MMR-2) (Abstract). Am J Hum Genet Suppl 49:125, Proc. of 8th International Cong. of Hum. Genet.Washinghon DC, USA

270

S.A. Temtamy et al.

Temtamy SA, Meguid NA, Aboul-Ezz EHA (1991b) Genetic heterogeneity and phenotypic variability in Hallermann–Strief syndrome. Egypt J Pediatr 8:323–332 Temtamy SA, Salam AM, Hussein FH, Meguid NA, El-Gindy E (1991c) Clinical, biochemical and cytogenetic studies of mental retardation in Egyptian children. J Pub Health Assoc IXVI (Suppl):189–199 Temtamy SA, El-Sawy MA, Abul-Ezz EHA, El-Din MK, Fateen EM, Meguid NA, Samy G, Dacremont SC, Leroy JG, El-Bassyouni HT (1993) Screening for peroxisomal and sialic acid disorders in progressive neurologic disorders among Egyptian children. Appl Endocrinol Egypt 11:17–44 Temtamy SA, Aboul Ezz EHA, Sinbawy AH, Mouris AL, Meguid NA, El Sawi M (1994a) Orodental, ear and eye anomalies in Egyptian Brachman de Lange syndrome cases. J Egypt Health Assoc IXIX(3, 4):164–184 Temtamy SA, Fateen EM, Wahba S (1994b) A fluorometric leucocyte B- glucosidase assay for Gaucher’s disease in Egyptian children. Bull Egypt Soc Physiolsci 14:376–388 Temtamy SA, Kandil MR, Demerdash AM, Hassan WA, Meguid NA, Afifi HH (1994c) An epidemiological/genetic study of mental subnormality in Assiut governorate. Egypt Clin Genet 46:347–351 Temtamy SA, Aboul-Ezz EHA, Afifi HH, Kamel AK, Abdel Aleem A (1996a) Phenotypic overlap between Kabuki make up syndrome and Prader–Willi like phenotype of the fragile X-syndrome. Cairo Dent J 12:69–75 Temtamy SA, Aboul-Ezz EHA, Meguid NA (1996b) A Second family with oculotrichodysplasia syndrome (OTD) confirming the syndrome and its autosomal recessive inheritance. Egypt J Pediatr 13:105–118 Temtamy SA, Meguid NA, Mahmoud A, Hosny H, Shawky AM, Saad M (1996c) COFS Syndrome with familial 1, 16 tanslocation. Clin Genet 50:240–243 Temtamy SA, Salam MA, Aboul-Ezz EHA, Hussein HA, Helmy SAH, Shalash BA (1996d) New autosomal recessive multiple congenital abnormalities/mental retardation syndrome with craniofacial dysmorphism absent corpus callosum, iris colobomas and connective tissue dysplasia. Clin Dysomorphol 5:23–240 Temtamy SA et al (1997) New DNA techniques for identification of mutations in the beta globin gene in Egyptian Beta Thalassemia patients. Terminal Evaluation Report ICGEB collaborative research program. ICGEB ref. #: CRP/EGY 93-01. Principle investigator, Prof. Dr. Samia A Temtamy Temtamy SA, Mazen I, Hindawy A (1998a) The association of ipsilateral phocomelia and asymmetric crying facies. A mere association or a new syndrome? JAC 9:443–451 Temtamy SA, Meguid N, Mazen I, Ismail SR, Kassem NS, Bassiouni R (1998b) A genetic epidemiological study of malformations at birth in Egypt. East Mediterr Health J 4:252–259 Temtamy SA, Meguid NA, Ismail SA, Ramzy MI (1998c) A new multiple congenital anomaly, mental retardation syndrome with preaxial brachydactyly, hyperphalangism, deafness and orodental anomalies. Clin Dysmorphol 7:249–255 Temtamy SA, Meguid NA, Ismail SI, El Henawy MS, Kamel AK, Zaki MS (1998d) Genetic studies and computed cranial tomography in microcephaly. Egypt J Pediatr 15:1–12 Temtamy SA, Al-Diwany KM, Mohamed AM, Meguid NA, Badran N, El-Sayed L, Abu Hashem SH (2000a) Genetic counselling in children with limb malformations. Egypt J Med Hum Genet 1:55–72 Temtamy SA, Ismail SI, Meguid NA (2000b) Lenz microphthalmia syndrome: three additional cases with rare associated anomalies. Genet Couns 11:147–152 Temtamy SA, Nemat AM, Ramzy MI, Fateen E, Meguid NA, Abul-Ezz EHA (2000c) Ultrastructure of gingival biopsy in lysosomal storage disorders. Cairo Dent J 16:287–295 Temtamy SA, Aglan MS, Nemat A, Eid M (2003a) Expanding the phenotypic spectrum of the Baller–Gerold Syndrome. Genet Couns 14:299–312 Temtamy SA, El-Ruby MO, Nemat AH (2003b) Phenotypic variations versus genetic differences in the oral-facial-digital syndromes. Egypt J Med Hum Genet 4:79–96

8 Genetic Disorders in Egypt

271

Temtamy SA, Ismail SI, Nemat A (2003c) Mild facial dyspmorphism and qausidominant in heritance in Cenani–Lenz Syndrome. Clin Dysmorphol 12:77–85 Temtamy SA, Aglan MS, Ashour A, El Badry T, Helmy N, Hussien HA (2004a) Genetic studies of congenital contractures of limbs. Egypt J Med Hum Genet 5:1–58 Temtamy SA, El Kamah Gh, Ismail S, Mazen I, Darouti M (2004b) Report of four Egytian cases representing two new rare types of Ehlers–Danlos Syndrome. JAC 15:91–111 Temtamy SA, Ismail S, El-Kamah Gh, El-Bassyouni HT, Kotouri AIS, Ramzy M, Zaki ME (2004c) The phenomenon of multiple genetic disorders in the same individual or sibship Relevance to consanguinity. Med J Cairo Univ 27(Suppl II):157–173 Temtamy SA, Abdel-Hady SH, Salem FA, El-Ruby MO, Aglan MS, Tomarek RH, Al-Awady H (2006a) Genetic studies of limb reduction defects. Egypt J Med Hum Genet 7:155–192 Temtamy SA, Aglan MS, Ashour AM, Ramzy MI, Hosny LA, Mostafa MI (2006b) 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol 15:55–64 Temtamy SA, Ismail S, Helmy NI (2006c) Roberts syndrome: a study of 4 new Egyptian patients with comparison of clinical and cytogenetic studies. Genet Couns 17(1–13):2006 Temtamy SA, Minnikk MM, Abdel-Salam GMH, Hassan NA, Ala-Kokko L, Afifi HH (2006d) Oto-Spondylo-Megaepiphyseal Dysplasia (OSMED): Clinical and radiological findings in Egyptian sibs homozygous for premature stop codon mutation in the COL11A2 gene. Am J Med Genet 140:1189–1195 Temtamy SA, Aglan MS, Aboul-Ezz EHA, Ashour AM, El-badry TH (2007a) A study of 319 Egyptian cases with limb and skeletal Malformations. In: The 5th Meeting of the African Society of Human Genetics in conjunction with the 1st Annual meeting of the Division of Human Genetics and Genome Research Division and The National Society of Human Genetics, NRC, Cairo, Egypt Temtamy SA, Aglan MS, Ashour AM, Zaki MS (2007b) Adams–Oliver Syndrome: further evidence of an autosomal recessive variant. Clin Dysmorphol 16:141–149 Temtamy SA, Aglan MS, El-Gammal MA, Hosny LA, Ashour AM, El-Badry TH, Awad SA, Fateen E (2007c) Genetic heterogeneity in spondylo-epi-metaphyseal dysplasias: a clinical and radiological study. Egypt J Med Hum Genet 8:147–172 Temtamy SA, Ismail SR, El-Beshlawy AM, Mohamed AM, Kotb SM, Eid MM (2007d) Fanconi anemia: cytogenetic and clinical studies on a group of Fanconi anemia patients in Egypt. Haema 10:61–67 Temtamy SA, Aglan MS, Valencia M, Cocchi G, Pacheco M, Ashour AM, Amr KS, Helmy SMH, El-Gammal MA, Lapunzina P, Goodship JA, Ruiz-Perez VL (2008) Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis-van Creveld syndrome with borderline intelligence. Hum Mutat 29:931–938 Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS (1999) Lossof-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23:378–380 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50:158–161 Valencia M, Lapunzina P, Lim D, Zannolli R, Bartholdi D, Wollnick B, Al-Ajlouni O, Eid S, Cox H, Buoni S, Hayek J, Martinez-Frias ML, Antonio P-A, Temtamy S, Aglan MS, Goodship JA, Ruiz-Perez VL (2009) Widening the mutation spectrum of EVC & EVC2¼ectopic expression of Weyers variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling. Hum Mutat 30:1667–1675 Valente EM, Brancati F, Silhavy JL, Castori M, Marsh SE, Barrano G, Bertini E, Boltshauser E, Zaki MS, Abdel-Aleem A, Abdel-Salam GM, Bellacchio E, Battini R, Cruse RP, Dobyns WB, Krishnamoorthy KS, Lagier-Tourenne C, Magee A, Pascual-Castroviejo I, Salpietro CD, Sarco D, Dallapiccola B, Gleeson JG; International JSRD Study Group (2006) AHI1

272

S.A. Temtamy et al.

gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol 59:527–534 Wahab AA, Janahi IA, Marafia MM (2004) Pseudo–Bartter’s syndrome in an Egyptian infant with cystic fibrosis mutation N1303K. J Trop Pediatr 50:242–4 Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, Al-Aboosi MM, Al-Shanti H, Gitschier J (2001) Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 68:1055–1060 Zaki ME, Temtamy SA, Hussein FH, El-Ruby MO (1989) Anthropometric and dermatoglyphic studies on Noonan syndrome. Proc Egypt Acad Sci 39:227–235 Zaki MS, El-Sabbagh MH, Saleem NA (2001) Neuronal migration disorders: clinical, neuroimaging and neurophysiologic studies. Gaz Egypt Ped Assoc 49:235–245 Zaki MS, Saleem SN, Helmy NA (2002) Clinico-radiological features of malformations of cerebral cortical development (MCD) in childhood and their genetic background. Med J Cairo Univ 70(Suppl):1–18 Zaki MS, El-Sabbagh MH, Aglan MS (2004) Familial congenital brachial palsy: a report of two affected Egyptian families. Genet Couns 15:27–36 Zaki MS, Kayed HF, Saleem SN, Abdel Salam GMH (2005) Holoprosencephaly spectrum in Egyptian patients: clinico-radiological and genetic aspects. Egypt Med J NRC 4:20–34 Zaki MS, Abdel-Aleem A, Abdel-Salam G, Marsh SE, Silhavy JL, Barkovich AJ, Ross ME, Saleem SN, Dobyns WB, Gleeson JG (2008) The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families. Neurology 70:556–565 Zakrzewski SR (2007) Population continuity or population change: formation of the ancient Egyptian state. Am J Phys Anthropol 132:501–509 Zekri AR, el-Bassuoni MA, Hammad OM, Sakr MA, Ibrahim AA (2004) Application of refractory fragment amplification system for detection of Egyptian variant of Familial Mediterranean Fever. Egypt J Immunol 11:103–110

Chapter 9

Genetic Disorders in Ancient Egypt Chahira Kozma

Ancient Egypt The ancient Egyptian civilization originated in North Eastern Africa along the banks of the Nile River around 3000 BCE. It ended in 30 BCE, when the Roman Empire conquered Egypt and made it a province. The ancient Egyptians left a superb legacy of mathematics, language, architecture, agriculture techniques, and monumental buildings. This legacy is preserved through an elaborate system of Hieroglyphic writing, artistic documentation on tombs and temple walls, and numerous masterpieces that have lasted until the present time. The hot and dry climate of Egypt as well as the process of artificial mummification left many skeletal and biological remains intact, including evidence of genetic conditions and in particular skeletal disorders (Kozma 2008). In general, the sources of evidence come from biological and artistic resources. Although written evidence, in the form of medical papyri, are abundant from ancient Egypt, they usually relate to remedies, incantations, and magic spells for the treatment of medical, surgical, and gynecological conditions. The medical papyri do not mention or describe congenital disorders.

Biological Evidence Due to the hot and dry climate of Egypt, a substantial number of biological remains are well preserved in the form of naturally mummified corps and complete or partial skeletons. In their ardent desire for immortality, the ancient Egyptians mastered the technique of artificial mummification and left thousands desiccated mummies, C. Kozma Department of Pediatrics, Georgetown University Hospital, 3800 Reservoir Rd N.W., Washington DC, USA e-mail: [email protected]; [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_9, # Springer-Verlag Berlin Heidelberg 2010

273

274

C. Kozma

which are available for modern-day studies. A substantial number of those biological remains that span thousands of years have been intensely researched by archeologists and scientists, making Egyptian paleopathology one of the best studied among ancient civilizations.

Dwarfs The pharaohs and nobles of ancient Egypt were enchanted to have in their households pygmies and dwarfs (Dasen 1993). The high value placed on dwarfs in ancient Egypt is highlighted by the praise given to Harkuf, a general who served King Pepi II (2278–2184 BCE), when he returned from an African expedition with precious treasures and a pygmy or a dwarf who could perform exotic dances. Pepi II wrote Harkhuf a letter expressing his delight at the prospect of seeing this man dance. The king urged Harkuf to take great care of this man and to post good guards to keep him from falling off the boat on the way to the royal residence. Harkuf was so delighted with the letter that he had it engraved on the cliffs outside of his tomb, where it can still be seen. An abbreviation of the letter of the child king, who was then about 8 years of age, is as follows: Come northward to the Residence immediately. Leave (everything) and bring this pygmy with thee, which thou hast brought living from the land of Akthiu (possibly Somalia), for the dances of the God, to rejoice and gladden the heart of thee. When he (the pygmy) goes down with thee to the vessel, appoint trustee people, who shall be about him on each side of the vessel; take care lest he fall into the water. If thou arrives of the Residence, this pygmy being with thee alive. My Majesty will do for thee a greater thing in accordance with the heart’s desire of My Majesty to see this pygmy.

The biological evidence of dwarfs is abundant from ancient Egypt and includes several complete and partial skeletons, which are located in Egyptian and British museums. Some of the skeletons have been adequately studied and published and some are known from excavators’ observations. The majority of skeletons represent achondroplasia (Hamada and Rida 1972). A skeleton of a female worker that dates back to the Old Kingdom was found in the necropolis of Giza, a major funerary complex where the pyramids are located. She had achondroplasia and was found with a fetus in situ. It is believed that she died during delivery.

The Badarian Skeleton The earliest biological evidence of dwarfs in ancient Egypt dates back to 4500 BCE, the Badarian Period. The partial skeleton was thoroughly studied when it was located in the Museum of the Royal College of Surgeons in England. Its current location is unknown. The skull and mandible are normal; however, the clavicles are slim. The small bones of the hands, the ribs, and the scapulae are normal. The head of the humerus is malformed. The radii and ulnae are small and symmetrical with

9 Genetic Disorders in Ancient Egypt

275

the radial tuberosity, and ligamentous prominences of the radii are pronounced. The head is malformed and lacks the usual even contour (Fig. 9.1). These abnormalities are not characteristic of achondroplasia and they represent another short-limbed dwarfism, possibly epiphyseal dysplasia (Jones 1932).

The Dwarf from the Tomb Complex of King Wadj The skeleton was located in a tomb in Saqqara, a vast funerary complex to the south of Cairo. It dates back to 3100–2800 BCE. It is located at Cairo University, Egypt. When unearthed, the tomb was unplundered and contained four different types of jars. The long bones are very short and the fibulae bowed (Fig. 9.2). To most Egyptologists, the changes are attributed to short-limb dwarfism, most likely achondroplasia (Emery 1954; Weeks 1970).

The Dwarfs from the Tomb of King Semerkhet These skeletons date back to 3050–2890 BCE and are located in the Natural History Museum in London (BMNH AF.11.4/427). The specimens consist of a skull, humerus, femur, three tibiae, and two fibulae. The shortened skull base contributes to the appearance of a depression in the middle third of the face. The nasal bones and the frontal processes of the maxilla are broad and the short face is accentuated by the prognathism of the alveolar portion of the maxilla. The long bones are very short and have relatively normal diameter of the shafts and epiphyses. The tibiae have slight medial bowing of the distal half. The humerus is short with the abnormal joint pathology associated with achondroplasia (Fig. 9.3). The secondary teeth and the fused epiphyses and apophyses indicate young adulthood (Putschar and Ortner 1985). The maximum length of the femur is 250 mm, of the humerus is 165 mm, of the fibula is 213 mm, and of the tibia is 215 mm.

The Dwarf Pereniankh The dwarf Pereniankh was an elite dwarf who lived between 2350 and 2175 BCE. His funerary statue, which is on display at the Egyptian Museum of Cairo, was found along with his skeleton in Giza not far from the great pyramids (Hawass 2004). The statue shows him seated on a chair and wearing a short kilt. His face is round and his neck is short and thick. His extremities, especially his legs, are short. Examination of his skeleton revealed the characteristic traits of achondroplasia including short and squat upper and lower limbs. It was estimated that he was about 40 years old when he died. The facial part of his skull is missing. The measurements of the long limbs of the skeleton and those of the statue matched, and it was

276 Fig. 9.1 The Badarian skeleton. (a) Skull, (b) Mandibles, (c) Clavicles, (d) Radii, (e) Ulnae, (f) Humeri, (g) Vertebrae

C. Kozma

9 Genetic Disorders in Ancient Egypt

277

Fig. 9.2 Left: A skeleton of a male achondroplastic dwarf from the Old Kingdom. Right: A skeleton of an average size person from the same burial complex for comparison. Courtesy of the Egypt Exploration Society, London

concluded that there was a realistic attempt to model Pereniankh’ skeletal disorder. His legs are slightly different in size, possibly because of elephantiasis. Both sides of his chair are inscribed with his name and titles, “the dancing dwarf in the Great Palace, the one who pleased his majesty everyday, Per-ni-ankh-w.”

Mucopolysaccaridoses The Natural History Museum in London has a pair of deformed humeri from early dynastic Egypt (BMNH AF.11.3/75). Both humeri are abnormally short. The diaphysis is normal in diameter, with a well-developed deltoid tuberosity. The humeral head exhibits severe malformation of the articular surface with pitting of the subchondral plate, particularly on the right. The left humerus is about 2 cm shorter than the right (Fig. 9.4). The external morphology of the humeral heads suggests an almost complete failure in the development of the epiphysis (Brothwell 1965). Ortner and Putschar argued against achondroplasia and suggested mucopolysaccharidoses because of the almost complete failure in the development of the epiphysis. The fusion of the distal humeral epiphyses and apophyses indicates a minimum age of about 14 or the possibility of young adulthood.

278 Fig. 9.3 Anterior view of skull and long bones of dwarfs. Specimen BMNH AF.11.41427. Courtesy of the Natural History Museum, London

C. Kozma

9 Genetic Disorders in Ancient Egypt

279

Fig. 9.4 Humeri with possible mucopolysaccaridoses. Specimen BMNH AF.11.3/75. Courtesy of the Natural History Museum in London

Osteogenesis Imperfecta A rare example of osteogenesis imperfecta comes from ancient Egypt and dates back to 1000 BCE. The skeleton was in a coffin and is currently in the British Museum (Registry No. 41603). It consists of skull bones, clavicles, ribs, long bones of the upper and lower extremities, and a few small bones of the hands (Fig. 9.5). In general, the bones are of a pale brown color, friable, and extremely light. The skull is described to have the Tam O’Shanter effect (a tight-fitting Scottish cap). The weight of the brain cannot be supported and settled into a beret-like effect. The skull has an enlarged vault with multiple wormian bones, elongated eye orbit, and multiple ossification centers. Most of the teeth were scattered among the bones. They are brittle, discolored, and have poorly developed roots. Furthermore, the teeth have a disorder of the tubular structure of the dentine, which is compatible with dentinogenesis imperfecta. The bones of the lower extremities are showing significant antero-lateral bowing and distortion due to multiple fractures. Radiographic examination of the bones showed the cortex to be composed of thin wavy lines, and the spongiosa being reduced to scattered amorphous wisps (Gray 1970).

The Stillborn Children of King Tutankhamen King Tutankhamen ruled Egypt from 1333 to 1324 BCE. It is believed that he was the son of Amenhotep IV (better known as Akhenaten) and Kia, a minor queen. King Tutankhamen married his half-sister, the daughter of Akhenaten and his famous wife, Queen Nefertiti. When his tomb was discovered in 1922–1923, two

280

C. Kozma

Fig. 9.5 A skeleton of a child with Ostegenesis imperfecta. Registry # 41603. Courtesy of the British Museum of London

miniature coffins containing two embalmed children, both stillborn, were found. The first fetus, a female, was estimated to be about 5 months of gestation. It measures less than 30 cm and is well preserved. The second fetus, also a female, is estimated to be between 7 and 9 months in gestational age. It is less well preserved than the other and measures 38.5 cm. When the body was examined and X-rayed in 1978, it was found to have scoliosis, spina bifida, and Sprengel

9 Genetic Disorders in Ancient Egypt

281

deformity (Harrison et al. 1979 ). Currently, both fetuses are being examined by CT scan for further clarification of any congenital anomalies. Because Egyptologists have long debated whether these mummies were the stillborn children of King Tut and Ankhesenamun, DNA analyses are being carried out by the Egyptian scientific community for further identification of their lineage (Lorenzi 2008).

The Pharaoh Siptah: Clubfoot Deformity vs. Polio or Cerebral Palsy? The mummy of the pharaoh Siptah (1194–1188 BCE) is on display in the Royal Mummy Room in the Egyptian Museum of Cairo. It shows a clear deformity of the left leg and foot due to poliomyelitis, clubfoot deformity, or cerebral palsy (Smith 2000). The left leg is significantly shortened, with the foot in vertical position (Fig. 9.6). The diagnosis of poliomyelitis continues to be debated after the mummy was reexamined (Aufderheide and Rodriquez-Martin 1998). It was observed that the left foot compensated for the shorter leg by dislocation of the tarsal and metatarsal bones, tendon, and muscles.

Facial and Skull Malformations Two examples of agenesis of the premaxilla are recorded from ancient Egypt. The first example is a skull that was located from a cemetery located to the south of the city of Assiut. It dates back to 700 BCE and belongs to a female who was past middle age. Examination of the skull reveals a marked reduction in the size of the hard palate due to absence of the premaxillary part as well as the horizontal plates of the palatine bones. Otherwise the skull is normal. The provenance of the second skull is unknown. It is from an adult female (Fig. 9.7). The premaxilla and the incisor teeth are absent. The mandibles show prognathism most likely related to the subnormal development of the maxilla (Derry 1938). The Nubian pathology collection in the Natural History British Museum has a complete cranium of an adult female with cleft palate (BMNH 210 72/291). The dental alveoli appear intact; however, most of the teeth were lost postmortem. The palatal defect is bilateral and involves the central and posterior portions of the palate (Filer 1995). An example of hydrocephalus comes from the Roman Period in Egypt. The skeleton is of a man who is at least 30 years of age. The facial bones are normal, but the circumference of the head measured 66 cm, the normal being around 55 cm. Examination of the skeleton revealed an evidence of a left-sided weakness and over development of the right arm perhaps from using a crutch in the form of a long staff (Derry 1913).

282

C. Kozma

Fig. 9.6 The mummy of pharaoh Siptah showing a deformity of the left leg and foot. The Egyptian Museum of Cairo

Vertebrae and Other Spine Anomalies A study done on 272 skeletons dating back to the Old Kingdom, during the time of the early pyramid builders, found that nine cases (3.33%) were affected with spina bifida occulta in the sacral region and six cases (2.22%) had transitional vertebrae at the lumbosacral joint, namely sacralisation and lumbarisation. Spina bifida occulta

9 Genetic Disorders in Ancient Egypt

283

Fig. 9.7 Agenesis of premaxilla. Notice the absent incisor teeth, hypoplastic maxilla, and prognathism

is the most common developmental defect of the vertebral column in historical skeletal series. This condition has to be differentiated from the more serious problem of spina bifida cystica, which is the neural tube defect (Sarry El-Din and Abd El-Shafy El Banna 2006). Several researchers have reported ankylosing spondylitis among several ancient Egyptian mummies as well as at least three pharaohs: Amenhotep II, Ramses II, and his son, Merenptah. The mummies were investigated with radiographic examinations. The mummy of Amenhotep II (1390–1352 BCE) showed calcification of the paraspinous ligaments and obliteration of the sacroiliac joint. Ramses II (1279–1212 BCE) lived and ruled Egypt until the advanced age of 87 years. His mummy was examined in Cairo as well in Paris. The ligaments along the spine were ossified and the sacroiliac joint was effaced. Many Egyptologists are of the opinion that Ramsess II seems relatively stiff when portrayed in various images. Radiographic imaging of Merenptah (1213–1203 BCE), who succeeded his father Ramsess II as a relatively old man, shows indications of severe hypertrophic arthritis, which is most likely due to ankylosing spondylitis (Feldtkeller et al. 2003).

Sickle Cell Anemia The existence of hemoglobinopathies, thalassemia, and sickle cell anemia, has long been suspected in ancient Egypt among mummies with severe anemia. A molecular investigation was done on six Egyptian Predynastic mummies (3200 BCE) located in Turin Museum, Italy. They had evidence of severe hemolytic anemia. DNA was extracted from dental samples, a modified PCR was applied, and the amplified

284

C. Kozma

DNA was studied by electrophoresis. In three individuals, there was a band at the level of the HbS mutated fragment, indicating the presence of sickle cell anemia. These molecular results represent additional confirmation of the presence of sickle cell anemia in ancient Egypt. Previous histological studies revealed sickle cells in a mummy from the same collection (Marin et al. 1999).

Arteriosclerosis Although arteriosclerosis is considered to be a new disease, at least 10–20% of mummies from ancient Egypt show evidence of arteriosclerosis. Radiological examination by various pathologists showed calcifications of the aorta, femoral, and carotid arteries. A sample of the aorta of Merenptah revealed extreme calcareous degeneration, with the formation of large bone-like plaques (Magee 1998). Mummification was an expensive process and was affordable by the rich and middle and upper classes, who enjoyed animal fats, abundant food, and perhaps were subjected to some stress. The mummy of Ramsess II showed arteriosclerosis. He exhibited tortuous calcareous temporal arteries. Calcification was found in his carotid arteries and deposits of calcium were identified by radiological examination between his first and second metatarsal bones (Francois and Lichtenberg 1994).

Alkaptonuria (Ochronosis) Several mummies from ancient Egypt have been diagnosed with possible alkaptonuria or ochronosis. Radiological examination of the spine of those mummies revealed dense shadows in the region of the lumbar disks with narrow, translucent zones adjacent to the dense zones and mineralization of the intervertebral disks. In one mummy, dating from 1500 BC, analysis showed extensive calcification of the intervertebral disks and articular narrowing in both hip and knee joints. Biopsy cores from the right hip showed parallel black zones in the region of the articular surfaces, leading to a clinical diagnosis of ochronosis. The black pigment was extracted, analyzed, and compared with an air-oxidized homogentisic acid polymer. The two substances were apparently identical. Chemical analysis of the dark substance supports the diagnosis of ochronosis, an autosomal recessive disorder (Stenn et al. 1977).

Artistic Evidence of Genetic Disorders Through representations and inscriptions on tomb and temple walls, thousands of funerary objects, and documents on papyri, the ancient Egyptians left an immense legacy about their culture, religion, Gods, governmental affairs, and personal and

9 Genetic Disorders in Ancient Egypt

285

daily life. As a result, we are well informed about the daily life of the ancient Egyptians and in particular achondroplastic dwarfs (Kozma 2006).

Dwarfs The artistic evidence of dwarfs is quite abundant and covers the full spectrum of Egyptian civilization (Dawson 1938). In fact, as early as Predynastic Times, many statuettes of dwarfs were found in burial places, suggesting that they were prized enough to accompany the deceased to the afterlife (Fig. 9.8). Among the treasures of King Tutankhamen, there is a female dwarf that has the typical characteristics of achondroplasia (Fig. 9.9). Achondroplastic dwarfs had magical significance. They were associated with the sun God and numerous figurines and amulets were formed in their shape. The function of the dwarfs was to protect the living and the dead from dangers facing them including diseases, venomous animals, snakes, and crocodiles. There were at least two dwarf Gods, Ptah and Bes. God Ptah was associated with regeneration and rejuvenation. God Bes was a protector of sexuality, childbirth, women, and children. Several high-ranking dwarfs achieved important status and had expensive tombs close to the pyramids. Many ordinary dwarfs were employed as personal attendants, animal tenders, jewelers, fishermen, and entertainers.

Fig. 9.8 Two Predynastic statuettes (Catalogues: 71.532, 71.534). They are naked with shaven heads, pointed ears, and their hands resting on their hips. The upper arms are short, fat, and twisted. The lower extremities are very short and malformed. The female pubic area is triangular and marked by holes. The sex of the male figurine is identified by a small protrusion. Courtesy of the Walters Art Museum, Baltimore, Maryland

286

C. Kozma

Fig. 9.9 Female dwarf from the tomb of Tutankhamen. The Egyptian Museum of Cairo, Egypt

In several New Kingdom papyri, dwarfs are described as rising up to the sky and going down to the underworld. In the Magical and Medical Papyri of the New Kingdom, the dwarf God is invoked to stand by the speaker: “O that dwarf of the sky, O that dwarf of the sky. O dwarf great of face, with high back and short thighs. O great pillars, extending from the sky to the underworld. O Lord of the great corps which rests in Heliopolis. O great living lord.” In incantation three against the snakes in the same papyrus, the name of the dwarf is invoked for protection from the snakes: “O, dwarf! My magical powers are against my enemies. To render the influence of the poison of the snakes harmless. May they be free from intrusion for ever” (Leitz 1999).

Dwarf Gods The dwarf Gods Ptah and Bes were the best known and were involved in magical practices to protect the living and the dead.

God Ptah God Ptah was the greatest of the Gods of Egypt. He was considered the first of all the Gods and the master architect of the universe. Ptah was a creator God who

9 Genetic Disorders in Ancient Egypt

287

brought all things to being by thinking of them with his mind and saying their names with his tongue. He was also the patron God of craftsmen, artisan designers, builders, architects, masons, and metal workers (Aterman 1999). As a craftsman, Ptah was said to have carved the divine bodies of the royalty. Ptah was especially revered by the artisan’s community of Deir-el-Medina, near Western Thebes. In his human form, he is depicted as a man with a beard, wrapped up like a mummy, with his hands emerging from the wrappings in front and holding the symbols for life, stability, and power. Ptah is occasionally depicted in the form of an achondroplastic dwarf (Melzer 1986). In this form, he is usually naked, with short limbs, a relatively long trunk, and a large head with prominent forehead. Sometimes he is shown grasping and biting snakes to highlight his protective role against harmful creatures threatening ancient Egyptians. In his dwarf form, he is very distinct from God Bes and in general does not carry weapons.

The God Bes God Bes was a very popular God. He was thought to help ensure fertility, keep women safe in childbirth, and look after children. Also, he was the dwarf God of music and warfare and the patron of many functions. Although his cult dates back to the Old Kingdom (about 2613–2160 BCE), he was most prominent in the New Kingdom (1550–1070 BCE), and his cult lasted until the Greco Roman Period, where he was a favored deity. His temple, which dates back to the Ptolemaic period, was excavated in the Baharia oasis in the middle of Egypt and was in use until the fourth century AD (Hawass 2000) Bes was very prominent in the religious concerns of the ordinary people of ancient Egypt. He was frequently incorporated in household items to protect people from dangers facing them, and to bring prosperity and protection to the home. His figures were placed inside houses, painted on walls, and incorporated into furniture such as beds and chairs, cosmetic containers, and medicine bottles. Bes is depicted as an achondroplastic dwarf with a grotesque mask and lion mane. Often, he is depicted brandishing a sword to keep evil away and holding or standing on serpents and crocodiles. He is represented with a large skull and a prominent forehead. He has proximal shortening of the upper and lower extremities. Often, he is shown in a hybrid nature combining animal and feline features, and wearing a monkey skin on his back. He was also featured in the Mammisi or birth houses, which were located near major temples. Although the role of Bes has evolved significantly through the Dynasties, his most important function was the protection of women during childbirth. In several papyri from 1539 to 1069 BCE, the magical power of dwarfs, perhaps of the God Bes, is appealed to protect women in childbirth and delivery of the placenta. In a magical papyrus at Leiden, there is a spell to facilitate birth, called “the spell of the dwarf ”: O good dwarf, come, because of the one who sent you . . . come down placenta, come down placenta, come down!

288

C. Kozma

The prayer was to be recited four times over a clay figure of the dwarf God that had been placed on the head of the woman in labor. In the spell of the vulva, the woman in labor pain screams: “To the man for a dwarf-statute of clay” (Borghouts 1971).

Elite Dwarfs There was a significant value placed on dwarfs in ancient Egypt. Several elite dwarfs, especially from the old kingdom (2686–2190 BCE), achieved important status. Their magnificent burial sites were located in the royal cemeteries, Giza and Saqqara. Their names, titles, and captions on their statues indicate their important roles in society and their close association with the king. Some of them were Seneb, Khnumhotep, and Djeho. Another elite dwarf is Pereniankh, who was described in the earlier section regarding biological evidence. The dwarf Seneb served during the fourth dynasty of pharaohs Khufu and Djeder (2575–2467 BCE). His statue is on display in the Egyptian Museum of Cairo. It represents an excellent portrait of ancient Egyptian art. Seneb, most likely an achondroplastic dwarf, is seated in the position of a scribe. His wife and children are of average size. The statue depicts a family group with a great sense of harmony and balance. Seneb has short hair, large eyes, and a pronounced nose and mouth. His upper and lower extremities show the proximal shortening characteristic of achondroplasia. His mild facial features can be suggestive of hypochondroplasia. However, ancient Egyptian artists often depicted achondroplastic dwarfs with normal faces possibly because of conventional reasons. Since his skeleton was never found, an accurate diagnosis cannot be made. As this example illustrates, physical handicap was not an impossible barrier to success in the ancient Egyptian society. The paintings on the walls of his tomb reveal the main stages of his carrier. Twenty titles are inscribed on his tomb such as: beloved of the lord, overseer of weaving of the palace, overseer of dwarfs (suggesting that there were other dwarfs in the palace), and overseer of the crew of the ship (Dasen 1988). The dwarf Khnumhotpe held the title of the “Keeper of the Royal Wardrobe.” He dates back to the Old Kingdom. His titles, which were found on his statue, suggest that he belonged to the household of a high official. His figurine, which measures 18 in and is made out of painted limestone, is on display in the Egyptian Museum of Cairo. He has a large cranial vault and elongated skull. Although his facial features are pronounced, they are essentially normal. He shows rhizomelic shortening of the upper extremities. His lower extremities are very short. His back is arched, his abdomen is protruded, and he has a stocky torso. The dwarf Djeho, an achondroplastic dwarf, lived during the 30th Dynasty. He has a very impressive representation in the Egyptian Museum of Cairo. His life-size naked figure, which measures 120 cm, is carved in a profile on the lid of his granite sarcophagus (Baines 1992). The figure shows an accurate depiction of the features

9 Genetic Disorders in Ancient Egypt

289

Fig. 9.10 The dwarf Djeho carved in profile. The Egyptian Museum of Cairo, Egypt

of achondroplasia. The dwarf Djeho has a prominent forehead, depressed nasal bridge, and an enlarged anterior–posterior diameter of his skull. His hands are short and reach to the hips. Both his both upper and lower extremities reveal proximal shortening. Other characteristics include mild kyphosis, protruded abdomen, and normal male genitalia (Fig. 9.10).

Ordinary Dwarfs Dwarfs were often depicted in Old Kingdom funerary art in the vast necropolises of Saqqara and Giza performing a variety of jobs. The repetition of certain pictures in tombs makes it possible to draw conclusion about their societal role at that period (Sampsell 2001). Dwarfs specialized in certain occupations including jewelry. A superb scene from the tomb of Mereruka at Saqqara, a vizier to king Teti and his son-in-law, depicts dwarfs making splendid pieces of jewelry among averagesize workers. On many reliefs, dwarfs look after household pets, especially dogs and monkeys. This role appears to be restricted to male dwarfs who often tamed monkeys. In their roles as personal attendants, dwarfs are often shown in a privileged relationship with their master. Several Egyptian queens from the Old Kingdom had female dwarfs as attendants. Dwarfs worked also as fishermen, keeper of the wardrobe, nurses to young children, and supervisors of clothing and linen.

290

C. Kozma

Pharaoh Akhenaten Akhenaten reigned in the mid-1300s BCE in ancient Egypt. He was married to Nefertiti, his principal wife who bore him six daughters. He also had other wives including Kia, who was probably the mother of King Tutankhamen. Akhenaten is famous for his religious reforms, where the polytheism of ancient Egypt was abandoned, and the new religion focused on monotheism and centered around Aten, the God of the solar disk. During his reign, both art and religion were subjected to dramatic and significant changes. Artistic representation of Akhenaten gives him a bizarre appearance with an elongated head, large breasts, slender limbs, protruding belly, and wide hips (Ghalioungui and Dawakhly 1965). He looked more feminine than masculine giving rise to multiple theories; none of them appears to be valid (Fig. 9.11). One speculation is that he suffered from sexual differentiation disorders. The fact that he had several children argued against this possibility. The other suggested diagnosis is Marfan syndrome due to his disproportionate limbs and elongated face. The argument against this diagnosis is that Akhenaten’s head shape was portrayed normal before he changed his name and adopted the new monotheistic religion. Furthermore, an altered shape of head in antiquity indicated a high

Fig. 9.11 Pharaoh Akhenaten. The Egyptian Museum of Cairo, Egypt

9 Genetic Disorders in Ancient Egypt

291

social status. The evidence of the cranial deformation is limited to artistic representations and not observed on skulls from that period. The artistic representation of Akhenaten and his family influenced the portrayal of people from that period and soon disappeared after his death. The accurate diagnosis of Akhenaten remains difficult since his mummy and the mummies of his close relatives have not been located and many of his monuments were destroyed and demolished soon after his death.

The Doorkeeper Roma The doorkeeper Roma lived in the 18–20th Dynasty (Ghalioungui and El Dawakhly, 1965–1080 BCE). A funerary stela shows him with a leg abnormality, which required him to use a cane. Despite his disability, he achieved a high status, acquired wealth, and was married with at least one child. His leg is wasted and shortened and accompanied by an equinus deformity of the foot (Fig. 9.12). The exact medical diagnosis and the cause of this deformity continue to be debated. Some favor that Roma’s deformity is the result of a congenital clubfoot deformity. The other view is that of a case of poliomyelitis contracted in childhood before the completion of skeletal growth causing extreme shortening of the leg with severe wasting (Nunn 1996).

The Queen of Punt The Queen of Punt, who is depicted in an unusual form due to severe lordosis and heavy deposits of fats, continues to represent a diagnostic dilemma, giving rise to numerous speculations. The land of Punt is thought to be near present-day Somalia and Eritrea. Queen Hatshepsut, who ruled Egypt between 1479 and 1457 BCE,

Fig. 9.12 The Doorkeeper Roma with his wife and child (1550–1080 BCE). Specimen ÆIN 134. Courtesy of New Carlsberg Glyptotek, Copenhagen

292

C. Kozma

Fig. 9.13 The sketch depicts the prince followed by the Queen of Punt, their two sons, and their daughter. Their hands are held in adoration and prayer gestures. While the prince and the two sons are normal, the queen and her daughter appear to be affected with a similar disorder

dispatched an expedition to the land of Punt to obtain precious commodities. The details of the expedition, including portraits of the prince and Queen of Punt and their children, are recorded on the walls of Deir El Bahri temple, in Upper Egypt in great details. The face of the queen is rough and rugged. She is obese with multiple skin folds and symmetrical deposits of fat on the trunk, limbs, and thighs. Her spine is bent forward because of significant lordosis. Her upper extremities and hands are normal except for the excess skin folds. Her legs are very short (Fig. 9.13). The queen’s daughter has a similarly but less-pronounced appearance, which may suggest a familial pattern (Mariette 1877). The illustration of the queen of Punt continues to arouse the curiosity of physicians and Egyptologists alike. Several differential diagnoses have been proposed to explain the queen pathology including Launois Bensaude lipomatosis, Dercum disease (significant fat accumulation), neurofibromatosis type I, lipodystrophy, achondroplasia, familial obesity, Proteus syndrome, elephantiasis, and X linked dominant hypophosphatemic rickets. Steatopygia has been suggested. It refers to significant fat accumulation in and around the buttocks and is usually seen as a normal variant in some tribes in South West Africa. Recently Farag and Iskandar coined a new pathology “Queen of Punt Syndrome” (Farag et al. 1999).

The Pygmies Dancers The three pygmy dancers, part of an ivory toy, are located in the Egyptian Museum of Cairo. A fourth dancing figure that belongs to the same set is in the Metropolitan Museum of Art in New York. The figures date back to the Middle Kingdom

9 Genetic Disorders in Ancient Egypt

293

(1990–1780 BCE). The statuettes are connected to a string and danced when the string was pulled. They represent a realistic depiction of pygmies who were imported to ancient Egypt from Central Africa for their dancing ability. They have round faces, broad noses, and thick lips as well as bulging buttocks and bowed legs, which is typical of pygmies of Southern Africa. Contrary to achondroplastic dwarfs, their bodies are stout and proportionately short (Martino 2005).

Conclusion The artistic and biological evidence provides a rich legacy and documentation of the positions of individuals with skeletal dysplasia and other genetic disorders in daily life in ancient Egypt, and their acceptance in society. Several Egyptologists and researchers have concluded that the image of individuals with dwarfs and those with disabilities in ancient Egypt is essentially positive (Sullivan 2001). In the tombs of some high officials, individuals with disabilities are depicted alongside the deceased. In the tomb of Baqt I, who was an elite man, there is a dwarf, a man with hunchback, and a man with clubfeet, who accompanied the tomb owner in the afterlife (Fig. 9.14). It is believed that these men had a prestigious status due to their proximity to the tomb owner, wearing pointed kilts, and being of a larger scale than the servants (Newberry 1893). Another indication of the positive attitude toward individuals with disabilities in ancient Egypt is revealed in moral teachings. The Papyrus Insinger that dates back to the Late Period portrays the wise person as being moral and pious: The blind one whom the God bless, his way is open The Lame one whose heart is on the way of the God, his way is smooth.

Fig. 9.14 The sketch depicts a dwarf, a man with a hunchback, and a man with clubfeet who accompany a noble man in the after life

294

C. Kozma

Ancient Egyptians had a strict code of ethics. The instructions of Amenemope, who lived during the reign of Amenhotpe III, taught and commanded respect for dwarfs and other individuals with handicapping conditions: Do not jeer at a blind man nor tease a dwarf Neither interfere with the condition of a cripple; Do not taunt a man who is in the hand of God, Nor scowl at him if he errs.

Additional instructions of Amenemope give positive images of attitudes toward human limits. It also teaches that care for the old, sick, and malformed is a moral duty, because “Man is clay and straw, the God is his builder. The Wise Man should respect people affected by reversal of fortune” (Simpson 1973).

References Aterman K (1999) From Horus the child to Hephaestus who limps: a romp through history. Am J Med Genet 83:53–63 Aufderheide AC, Rodriquez-Martin C (1998) The Cambridge encyclopedia of human paleopathology. Cambridge University Press, Cambridge, p 76 Baines J (1992) Merit by proxy: the biographies of the dwarf Djeho and his patron Tjaiharpta. JEA 78:241–257 Borghouts JF (1971) The magical tests of papyrus Leiden. Brill, Leiden, p 29 Brothwell DR (1965) Digging up bones. London, Trustees of the British Museum Natural History, p 164 Dasen V (1988) Dwarfism in Egypt and classical antiquity: iconography and medical history. Med Hist 32:253–276 Dasen V (1993) Dwarfs in ancient Egypt and Greece. Clarendon Press, Oxford, pp 17–159 Dawson WR (1938) Pygmies and dwarfs in ancient Egypt. J Egypt Archaeol 24:85–189 Derry DE (1913) A case of Hydrocephalus in an Egyptian of the Roman period. J Anat Physiol 47:436–458 Derry DE (1938) Two skulls with absence of the premaxilla. J Anat 72:295–298 Emery WB (1954) Great tombs of the First Dynasty; excavations at Saqqara. Oxford University Press, Oxford, p 36 Farag TI, Sabry MA, Iskandar A (1999) Queen of punt syndrome. Am J Hum Genet Supplement: Abstract A803 Feldtkeller E, Lemmel EM, Russell AS (2003) Ankylosing spondylitis in the pharaohs of ancient Egypt. Rheumatol Int 23:1–5 Filer J (1995) Egyptian bookshelf disease. Sources of evidence. The British Museum Press, London, p 36 Francois D, Lichtenberg R (1994) Mummies: a voyage through eternity. Harry N. Abrams, New York, p 83 Ghalioungui P, El Dawakhly Z (1965) Health and healing in ancient Egypt. Al-Maaref, Cairo, pp 19–20 Gray PHK (1970) A case of osteogenesis imperfecta with associated dentinogenesis imperfecta dating from antiquity. Clin Radiol 21:106–108 Hamada G, Rida A (1972) Orthopaedics and orthopaedic diseases in ancient and modern Egypt. Clin Orthop Relat Res 89:253–268 Harrison RG, Connolly RC, Ahmed S et al (1979) A mummified foetus from the tomb of Tutankhamun. Antiquity 53:19–21

9 Genetic Disorders in Ancient Egypt

295

Hawass Z (2000) Valley of the golden mummies. The temple of Bes. Harry N. Abrams, New York, p 169 Hawass Z (2004) The dancing dwarf. The Ambassadors Online Magazine. The forum for culture and civilization. Volume 7-Issue 2. http://ambassadors.net./selected.study.htm. Accessed 27 Feb 2009 Jones EWAH (1932) Studies in achondroplasia. J Anat 66:569–573 Kozma C (2006) Dwarfs in ancient Egypt. Am J Med Genet 140A:303–311 Kozma C (2008) Historial review: skeletal dysplasia in ancient Egypt. Am J Med Genet A 146A:3104–3112 Leitz C (1999) Magical and medical papyri of the New Kingdom. British Museum Press, London, pp 11–45 Lorenzi R (2008) Fetus mummies were likely King Tut’s. Discovery Channel. dsc.discovery.com/ news/2008/08/15/king-tut-fetus.html. Accessed 27 Feb 2009 Magee R (1998) Arterial disease in antiquity. Med J Aust 169:663–666 Mariette A (1877) Deir-el-Bahari, documents topographiques, historiques et ethnographiques recueillis dans ce temple pendant les fouilles exe´cute´es par Auguste Mariette-bey. Leipzig J C Hinrichs. Plate 5 Marin A, Cerutti N, Massa ER (1999) Use of the amplification refractory mutation system (ARMS) in the study of HbS in Predynastic Egyptian remains. Boll Soc Ital Biol Sper 75:27–30 Martino E (2005) Three dancing dwarves. J Endocrinol Invest 28:100 Melzer R (1986) Ptah, the dwarf God of ancient Egypt. Adler Mus Bull 12:1–3 Newberry PE (1893) Beni Hasan II. ASE 2, London, p XXXII Nunn JF (1996) Ancient Egyptian medicine. The pattern of disease. University of Oklahoma Press, Oklahoma, pp 64–95 Putschar WGJ, Ortner DJ (1985) Identification of pathological conditions in human Skeletal remains. Skeletal dysplasias. Smithsonian Institution Press, Washinton DC, pp 331–332 Sampsell BM (2001) Ancient Egyptian dwarfs. KMT 12:60–73 Sarry El-Din AM, Abd El-Shafy El Banna R (2006) Congenital anomalies of the vertebral column: a case study on ancient and modern Egypt. Int J Osteoarchaeol 6:200–207 Simpson WK (1973) In: Simpson WK, Simpson WK (eds) The Literature of Ancient Egypt. The instructions of Amenemope. Yale University Press, New Haven CT, pp 241–265, With translations by RO Faulkner, EF Wente, WK Simpson Smith GE (2000) The royal mummies (Catalogue Ge´ne´ral du Muse´e du Caire, 1912). (Duckworth Egyptology). Bath, Bath Press, p Plate LXII Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977) Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science 197:566–568 Sullivan R (2001) Deformity-A modern Western prejudice with ancient origins. Proc R Coll Physicians Edinb 31:262–266 Weeks KR (1970) The Anatomical knowledge of the Ancient Egyptians and the representation of the figure in Egyptian Art. PhD Thesis, Yale University

Chapter 10

Genetic Diseases in Iraq Hanan Ali Hamamy

Geography and History Iraq occupies the northeastern corner of the Arab world; Iran lies to the East and Turkey lies to the North (Fig. 10.1). Its total land surface is 438,000 km2. The northern part is mountainous; the central region is occupied by the Tigris–Euphrates Plain; the south is characterized by marshes; and deserts predominate in the west. Despite its hot, parched, and windswept land, Mesopotamia became one of the earliest civilizations. Early in the fifth millennium, BC, farmers abandoned their villages in northern Mesopotamia and migrated southward to the Tigris–Euphrates Plain. These earliest inhabitants of southern Mesopotamia were known as the Ubaidians; they were later infiltrated by the Semitic nomads from the Syrian Desert and the Arabian Peninsula. The Sumerians did not arrive on the scene until about 3,500 B.C. (Kramer 1967), although their possible origin in southern Iraq cannot be excluded (Roux 1980). The cross-fertilization of the groups of people living in southern Mesopotamia brought about an ethnic and cultural fusion that was to initiate the Sumerian civilization. After lasting for about 1,500 years, the Sumerian capital Ur was destroyed and shortly thereafter the Akkadian civilization arose founded by the Amorites, who were Semites of the Arabian deserts. Later on, the Babylonian civilization in central Iraq and the Assyrian civilization in Northern Iraq emerged. These civilizations produced some of the earliest writings and some of the first sciences, mathematics, laws and philosophies of the world; hence the common epithet for Iraq: the “Cradle of Civilization.”

Hanan A. Hamamy Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland (formely Al-Mustansiriyah Medical College, Baghdad, Iraq) e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_10, # Springer-Verlag Berlin Heidelberg 2010

297

298

Hanan A. Hamamy

Fig. 10.1 Iraq Map http://www.lib.utexas.edu/maps/iraq.html

The Population The population structure reveals ethno-linguistic diversity. The ancient population of Iraq has long been assimilated and absorbed by the successive waves of migration and settlement. The Iraqi genetic makeup of today reflects the admixture of these various groups. The last population census was carried out in 1997 with the exclusion of the autonomous Kurdish provinces in the North giving a figure of 20 millions. The 1999 estimate was 22.5 million (World Health Report 2000), whereas the total population for Iraq in 2005–2008 is estimated at around 28–29 millions (WHO, EMRO country profiles; World Bank Iraq data sheet). The population is composed of about 75–80% Arabs and 15–20% Kurds, the latter inhabiting the mountainous regions of the north and northeast. Although considerable intermingling has taken place, a major proportion still retains a separate character and continues to speak its own Kurdish language. Turks and Turkomen also inhabit the northern regions. Other ethnic groups are quite small and include the Yazidis living west and north of Mosul. The predominant religion is Islam (Shi’a and Sunni). The Christian communities of about 3% are chiefly descendants of the ancient population that was not converted to Islam when it took root in Iraq in the seventh century AD. They are subdivided among various Christian sects including Chaldeans, members of the Orthodox Church, and

10

Genetic Diseases in Iraq

299

Assyrians. The Assyrians, of Arab Semitic origin, are the original people of the Assyrian civilization in northern Mesopotamia who in about AD 175 were converted to Christianity. From a demographic perspective the population of Iraq as of many other Arab countries is characterized by marriage at a young age, advanced maternal and paternal ages with customary consanguineous marriage and large family sizes (Hamamy and Alwan 1994; Al-Gazali et al. 2006; Hamamy and Bittles 2008).

Basic Health Indicators and Genetic Services in Iraq Abundant natural and human resources enabled Iraq to attain the status of a middleincome country in the 1970s. The country developed good infrastructure and a wellperforming education and healthcare system, widely regarded as the best in the Middle East. Income per capita rose to over US$3,600 in the early 1980s. Since that time, successive wars and economic sanctions have stifled growth and development and debilitated basic infrastructure and social services. Despite the country’s rich resource endowment, Iraq’s human development indicators are now among the lowest in the region, and the income per capita has continued to drop with an estimated GDP per capita of $480–630 in 2003 (The World Bank). Some rise was estimated in 2004 to $1,180 GDP per capita (WHO, EMRO country profiles), and to $3,500 in 2007 (CIA World Factbook). Results of the 1999 UNICEF Iraq Child and Maternal Mortality survey among 23,105 eligible respondents in the south/center of Iraq showed that infant mortality rate (IMR) has increased from 47 deaths per 1,000 live births for the period 1984–1989, to 108 deaths per 1,000 live births for the period 1994–1999 (Ali and Shah 2000). Another report on IMR for 1978 and 1998 of 16 Arab countries in the Eastern Mediterranean region extracting its data from World Health Organization and United Nations Children’s Fund sources showed that IMR in all countries showed a sharp decline from 1978 to 1998 except in Iraq, where the IMR rose from 84 in 1978 to 95/1000 livebirths in 1998 [Shawky 2001]. The IMR in 2003 was estimated at 107.9 deaths per 1,000 livebirths (WHO, EMRO country profiles), 37 deaths per 1,000 livebirths in 2006 [UNICEF], and 45.4 deaths per 1,000 live births in 2008 [CIA World Factbook], and the estimated life expectancy at birth in 2005 was 58 years (WHO, EMRO country profiles). The average perinatal mortality rate for Iraq was estimated at 28 per 1,000 live births during the period 1980–1990 (the period before sanctions) and 108 per 1,000 live births during the period 1990–1999 following the 1991 Gulf war and the economic sanctions. The important causes of neonatal deaths are low birth weight, perinatal infections and birth asphyxia (Nasheit 2003). A cross-sectional study carried out in the Obstetric Department, Al-Kadhimiya Teaching Hospital in Baghdad involving 300 full-term newborns from January 1, 2002, through December 31, 2004, showed that ten anthropometric measurements

300

Hanan A. Hamamy

in Iraqi newborns were less than their published figures in other populations (Al-Mefraji et al. 2006). The decline in the health-care system following the successive wars and sanctions in Iraq touched all medical services including genetic services. The rapid progress in genetic services and research experienced by the world in the past 20 years did not involve Iraq, a wealthy country that has markedly regressed in this field. Community genetic services are currently scarce and patchy in Iraq with no national programs for the prevention of genetic diseases. The severe lack of medical genetic specialists in the country reflects on the scarcity of genetic clinic services. In Baghdad, one of the genetics unit founded in 1981 was linked to the Al-Yarmouk Teaching Hospital (Hamamy 1984) while another was linked to Baghdad University Medical College (Al-Taha 1996). Both units are not functioning properly following the wars and sanctions. A recent Genetic subspecialty Clinic at Al-Nahrain College of Medicine in Baghdad is offering basic genetic services. Hematology specialists and thalassemia centers in Baghdad, Mosul, Basrah, Dohuk and other governorates are offering their services to patients with hereditary blood disorders.

Consanguineous Marriages Social, religious, cultural, political and economic factors play roles in favoring consanguineous marriages among the new generations just as strongly as they did among the older generations, particularly in rural areas. In a study of consanguinity among the urban population of Baghdad (Hamamy et al. 1986), the coefficient of inbreeding (F) was estimated at 0.0225, and first cousin marriage rate at 29.2% (Table 10.1). Iraqi society, however, has a long tradition of consanguinity, and the cumulative estimate of (F) may exceed the estimated value which is calculated for a single generation (Bittles et al. 1993). The highest rates of marriages to close relatives are consistently reported in the more traditional rural areas and among the poorest and least educated in society (Bittles et al. 1993). It is thus expected that the consanguinity rate among the rural population in Iraq would exceed the rate reported from the urban population of Baghdad. Figures on nationwide consanguinity rates in Iraq are lacking. The 1999 UNICEF Iraq Child and Maternal Mortality survey among 23,105 respondents in Table 10.1 Consanguinity rates among 4491 families in Baghdad Hamamy et al. (1986)

Degree of consanguinity First cousin First cousin once removed Second cousin Further than second cousin Total

Consanguineous n % 1,311 29.2 453 10.1 321 514

7.1 11.4

2,599

57.9

Non-consanguineous n %

1,892

42.1

10

Genetic Diseases in Iraq

301

the south/center of Iraq showed a total consanguinity rate of 60% and 47% among 14,035 respondents in the Kurdish autonomous region (Sulaimaniya, Duhok and Arbil) (Ali and Shah 2000). A questionnaire was administered to 989 mothers attending the maternal and child health clinics to assess the role of consanguinity in reproductive health. Among consanguineous marriages as compared to non-consanguineous marriages, a higher rate of pregnancies per family, a lower rate of abortions, and a higher rate of infant deaths were reported (Table 10.2). The increased postnatal mortality among the offspring of consanguineous parents may be related to the action of deleterious recessive genes and multi-gene complexes inherited from a common ancestor. The higher parity rate among consanguineous couples counterbalances the higher infant mortality; as a result, there is equality in the number of living children among consanguineous and nonconsanguineous couples. Several studies have reported greater numbers of children born to consanguineous than to non-consanguineous couples where a positive association between consanguinity and fertility was confirmed (Bittles et al. 1991). A number of social factors may be strongly implicated, including younger parental age at marriage and in particular younger maternal age. It has also been suggested that the larger number of births in consanguineous mating is in part a planned reproductive compensation response by the parents in the face of increased early postnatal mortality. The incidence of major congenital malformations is significantly higher among children of consanguineous parents than among those of non-consanguineous parents; confirmed in the study conducted in Baghdad (Hamamy and Al-Hakkak 1989). The distribution of 166 cases of stratified congenital anomalies according to the consanguinity rates of their parents indicate that rates of different types of congenital anomalies increased with the degree of consanguinity, being highest in the first cousin mating (Table 10.3). This may be partly explained by the presence of a number of undiagnosed autosomal recessive conditions. Traditional cousin marriages may be discouraged for reasons other than their general risks for reproductive health and other than the relatively higher risks of childhood mortality and morbidity. On individual bases, when a severe autosomal recessive condition segregates in a family, genetic counseling becomes of utmost importance in prevention of the disorder by minimizing further intermarriages in the family. Iraqi families are inclined to large sibship size: total fertility rate in 2004 was estimated as six (WHO EMRO country profiles). Early genetic counseling after Table 10.2 Reproductive parameters among consanguineous and nonconsanguineous mating Hamamy et al. (1986)

Variables Number of families Average number of pregnancies/family Abortion rate Stillbirth rate Infant death rate

Consanguineous Non-consanguineous 572 417 4.5 3.8 8.9% 2.4% 3.5%

11.1% 2.4% 2.4%

302

Hanan A. Hamamy

Table 10.3 Distribution of 166 cases of stratified congenital anomalies according to consanguinity rates of their parents Hamamy and Al-Hakkak (1989) Anomalies First cousin Second cousin Not related Total n % n % n % n % 38 50 20 26.3 18 23.7 76 45.8 MCA+/MRa Hypotonia/motor retardation 35 70 12 24 3 6 50 30.1 Single congenital malformation 8 36.4 6 27.3 8 36.4 22 13.3 All anomalies 9 50 5 27.8 4 22.2 18 10.8 90 54.2 43 25.9 33 19.9 166 100 a MCA MR: multiple congenital anomalies with or without mental retardation

the birth of one affected child could prevent the birth of further affected children and reduce the prevalence of inherited disease by 50% (WHO 1985). Furthermore, diagnostic facilities for prenatal diagnosis of genetic disorders are not available, thus limiting the use of this prevention tool. Based on personal experience, efforts to minimize further intermarriages in families with segregating autosomal recessive disorders face many difficulties due to the existence of deeply rooted social beliefs. Repeated long counseling sessions involving various family members are usually required. The term “hereditary disorder” may arouse a multitude of feelings of hostility and denial, often leading to disregard of the risk information given to the family. Families fear that their daughters would be stigmatized and would not get married. Preliminary experience has revealed that response to genetic counseling could differ dramatically depending on the cultural and educational level of the parents; this factor may be more important than the severity of the disease in the family. An educated working mother would be alarmed by the birth of a single affected baby and would undertake any available procedure to prevent the birth of another. However, a poorly educated or illiterate woman might continue to conceive despite having several affected children, partly because of the pressure from the husband’s family (Hamamy 1984).

Population Genetics Investigation of the ABO gene frequencies among the Iraqi population revealed differences among various ethnic groups and geographic areas. These differences may be partly endogenous and partly caused by outer influences of neighboring populations (Table 10.4). Although the number of individuals studied is small, gene frequency distribution indicates that blood group (B) is more common than (A) in southern Iraq, while blood group (A) is more frequent than (B) in Mosul in Northern Iraq as well as among the Kurds, Turkomen and Assyrians. Rh (D) positivity was exhibited in 92 and 94.4% of the population of Mosul and Arbil respectively in North Iraq (Saleem and Mahmoud 1988; Rofoo et al. 1995), and 96.7% of the population of Basrah, in south Iraq (Al-Kasab et al. 1987).

10

Genetic Diseases in Iraq

Table 10.4 Distribution of ABO blood groups in Iraq Region or sector (reference) Number of individuals surveyed O Baghdad (Mourant et al. 1976) 1,403 36.3 Mosul (Mourant et al. 1976) 333 41.4 Mosul (Saleem and Mahmoud 1988) 3,177 34.7 Mosul Total 3,510 35.7 Basrah (Abdullah 1976) 6,400 36.8 Basrah (Al-Kasab et al. 1987) 610 46.4 Basrah (Abdullah 1981) 92 39.1 Basrah, Total 7,102 37.6 Ramadi (Al-Agidi et al. 1977) 63 46.1 Arbil (Rofoo et al. 1995) 23247 37.7% Kurds (Mourant et al. 1976) 1,529 35.3 Kurds (Al-Khafaji and Al-Rubeai 1976) Duhok 314 38.5 Sulaimaniya 3,916 36 Kirkuk 340 37.1 Baghdad 616 35.9 Arbil 1,059 39 Kurds, Total 7,774 36.4 Turkmen (Mourant et al. 1976) 128 36.7 Assyrians (Ikin et al. 1965) 99 39.4

303

% blood groups A B 31.1 25.6 30.6 18.9 28.8 23.9 29.3 22.8 27.8 29.1 24.1 26 21.7 32.6 27.4 28.9 23.8 25.4 32.4% 23.5% 30.2 19.6 34.7 34.3 35.9 37 33.2 33.7 38.3 27.3

21.3 23 22.1 20.8 22.9 22 17.2 25.3

AB 7 9 12.6 12.2 6.3 3.4 6.5 6 4.8 6.4% 14.9 5.4 6.7 5 6.3 4.9 7.9 7.8 8

Investigators from Mosul medical College (Ahmad and Taha 1983) studying N-acetylation frequency among 57 volunteers revealed that 58, 7 and 35% were slow, intermediate and rapid acetylators respectively. In Baghdad, among 67 volunteers, frequency of slow and rapid acetylators was 71.6 and 28.4% respectively (Najim et al. 2005). In North America and Europe, 50% of the population is reported to be slow inactivators, in contrast to the Japanese, who are predominately rapid inactivators (Emery and Mueller 1992). The results of a study of Phenylthiocarbamide [P.T.C.] taste sensitivity and threshold among 110 Iraqi Medical students of Arab ethnic origin indicated that the incidence of tasters was 78.2% (Shah and Sattar 1981). Among a sample of 21,462 Iraqi subjects, 2.9% were reported to have color blindness (Jamil et al. 1994).

Genetic Disorders in Iraq Data on the epidemiology and magnitude of genetic diseases in Iraq are scarce and patchy. The available information is predominantly derived from analysis of referred cases to genetics or other related units rather than from direct population surveys. Mendelian genetic disorders reported from Iraq are listed in Table 10.5.

304

Hanan A. Hamamy

Table 10.5 Mendelian disorders reported from Iraq Disease MIM No Autosomal Dominant Aarskog’s syndrome 100050 Achondroplasia 100800 Apert’s syndrome 101200 Saethre-Chotzen 101400 Albright hereditary osteodystrophy 103580 Stickler’s syndrome 108300 Gorlin-Goltz 109400 Cornelia De Lange 122470

Crouzon syndrome Nuclear cataract congenital MODY Coffin-Siris syndrome Frontal nasal dysplasia Holt Oram Opitz syndrome Kallmann’s syndrome Klippel-Trenaunay-Weber Treacher Collins Moebius syndrome Fascioscapulohumeral muscular dystrophy Limb girdle muscular dystrophy Neurofibromatosis Noonan syndrome Osteogenesis Imperfecta

123500 123580 125850 135900 136760 142900 145410 147950 149000 154500 157900 158900 159000 162200 163950 166200

Gardner’s syndrome Peutz-jegher syndrome Porphyria: acute intermittent Progeria Retinitis pigmentosa

175100 175200 176000 176670 180100

Ectrodactyly Tuberous sclerosis Waardenburg’s syndrome

183600 191100 193500

Freeman-Sheldon syndrome Autosomal Recessive hypotrichosis with monilethrix hairs and congenital scalp erosions Brachydactyly, Type C Carpenter syndrome Congenital adrenal hyperplasia alkaptonuria Retinal aplasia Bardet Biedl syndrome Seckel syndrome Familial carnitine deficiency Chondrodysplasia punctata

193700

References Al-Hakeem and Hamamy (1992) Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Yazachi (1986) Personal observation, unpublished; Al-Hakeem and Hamamy (1992), Al-Rawi et al. (1986) Personal observation, unpublished Personal observation, unpublished Alwan and Shamdeen (1989) Al-Mosawi (2006) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Hamamy and Al-Taha (1989a) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Azzawi et al. (1987) Al-Azzawi et al. (1987) Al-Sharbati et al. (1993) Hamamy and Al-Taha (1989b) Personal observation, unpublished; Al-Khaidhaire (1994) Safar and Sawa (1992) Al-Shawk et al. (1983) Al-Windawi and Al Naama (1984) Sarsam and Izzat (1986) Personal observation, unpublished; Al-Kanani (1990) Personal observation, unpublished Al-Rawi et al. (1986) Personal observation, unpublished; Al-Hakeem and Hamamy (1992), Al-Huwaizi (1987) Amin-Zaki et al. (1972) Al-Hakeem and Hamamy (1992) Schaffer et al. (2006)

113100 201000 201910 203500 204000 209900 210600 212140 215100

Baraitser and Burn (1983) Personal observation, unpublished Personal observation, unpublished Al-Mefraji (2008) Personal observation, unpublished Beales et al. (2001) Børglum et al. (2001) Shahar et al. (1988) Personal observation, unpublished (continued)

10

Genetic Diseases in Iraq

Table 10.5 (continued) Disease Cockayne syndrome Cohen syndrome Cystic fibrosis cystinosis Wolfram syndrome Epidermolysis bullosa Fanconi’s anemia

305

MIM No 216400 216550 219700 219800 222300 226600 227650

Galactosemia Gangliosidosis Glycogen storage disease Paget Disease, Juvenile Hypophosphatasia Icthyosiform erythroderma Icthyosis Kartagener’s syndrome Kartagener’s syndrome Laurence-Moon’s syndrome Meckel Gruber Familial Mediterranean fever Megalencephaly with Dysmyelination Microcephaly Microphthalmia Orofaciodigital syndrome II Hurler syndrome Sanfilippo’s syndrome Morquio’s syndrome Werdnig-Hoffman Duchenne-like, autosomal recessive (SARCMD) nephronophthisis Nephrotic syndrome: congenital Congenital nephrosis Niemann-Pick Disease, Type C1 primary hyperoxaluria Laron dwarfism

230400 230500 232200 239000 241500 242100 242300 244400 244400 245800 249000 249100 249240 251200 251600 252100 252800 252900 253000 253300 253700 256100 256300 256300 257220 259900 262500

Polycystic kidney; infantile Multiple pterygium syndrome Retinitis pigmentosa

263200 265000 268000

Smith-Lemli-Opitz Pendred syndrome Trichorhinophalyngeal Usher syndrome Xeroderma pigmentosum

270400 274600 275500 276900 278700

Xeroderma pigmentosa

278720

De-Sanctis-Cacchioni’s syndrome

278800

References Personal observation, unpublished Al-Hakeem and Hamamy (1992) Al-Hassani (1977) Al-Mosawi (2002) Nagi (1979) Personal observation, unpublished Personal observation, unpublished; Al-Hakeem and Hamamy (1992) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Cundy et al. (2002) Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Al-Hassani (1977) Al-Hassani (1977) Personal observation, unpublished Personal observation, unpublished Bakir and Murtadha (1975) Harbord et al. (1990) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Al-Rawi et al. (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished Teebi (1994) Al-Mosawi (2002) Al-Nadawi and Atra (1984) Nagi and Nouri (1974) Fensom et al. (1990) Al-Mosawi (2002) Personal observation, unpublished; Sarsam and Izzat (1986) Personal observation, unpublished Personal observation, unpublished Personal observation, unpublished; Al-Kanani (1990) Personal observation, unpublished Al-Huwaizi (1990) Al-Hakeem and Hamamy (1992) Personal observation, unpublished Al-Jadiry et al. (1987), Al-Saleem et al. (1984) Al-Khatib and Abdul Hadi (1995), Al-Hadithi and Al Saleem (1991) Al-Jadiry et al. (1987) (continued)

306 Table 10.5 (continued) Disease Retinal detachment, cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly Megarbane Syndrome

Hanan A. Hamamy

MIM No 605822

References Schmidt et al. (2001)

606527 (AR or XR)

Megarbane et al. (2001)

X-linked Androgen insensitivity Hypohidrotic ectodermal dysplasia FG syndrome G6PD deficiency

300068 305100 305450 305900

Leber’s optic atrophy oculocerebrorenal syndrome Rennpening’s syndrome Fragile X syndrome Juberg-Marsidi Becker muscular dystrophy Duchenne muscular dystrophy

308900 309000 309500 309550 309580 310200 310200

Hamamy and Al-Taha (1989b) Personal observation, unpublished Al-Hakeem and Hamamy (1992) Al-Naama et al. (1984), Amin-Zaki et al. (1972), Hamamy and saeed (1981) Al-Kanani (1990) Al-Mosawi (2002) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Al-Hakeem and Hamamy (1992) Personal observation, unpublished Personal observation, unpublished; Al-Azzawi et al. (1987) Yaseen (1995) Personal observation, unpublished

Congenital nystagmus 310700 Orofaciodigital syndrome I 311200 MIM based on McKusick OMIM, 11 December 2008

Congenital Malformations Studies on the birth prevalence of congenital and genetic disorders that are lethal or cause lifelong impairment if untreated indicated that, of the six World Health Organization (WHO) regions, the highest rate of 65 affected per 1,000 live births was reported in the Eastern Mediterranean region that includes the majority of Arab countries (Alwan and Modell 2003). These figures were supported by a recent March of Dimes report which estimated birth defects to be 69.9 per 1,000 live births in most Arab countries and 75.2 per 1,000 live births in Iraq, as opposed to 52.1 per 1,000 live births in Europe, North America, and Australia (Christianson and Howson 2006). The 1993 World Development Report (World Bank 1993) indicated that congenital malformations constitute 6.5% of the total disease burden for children less than 5 years of age in developing countries as well as 4% of 5 deaths for ages between 0 and 4 years. There are few published reports on the frequency of congenital malformations among newborns in Iraq.

10

Genetic Diseases in Iraq

307

In a study among 6,988 newly born infants in Ramadi obstetric and pediatric hospitals during the year 1990, the prevalence of gross congenital anomalies was reported to be 0.79% (Al-Ani and El Sebai 1994). During a prospective study of 5,974 consecutive birth from October 1993 to March 1994 at Basrah maternity and child hospital, the prevalence of major congenital malformations was given as 7.7 per total births (6.9 per 1,000 livebirths and 147per 1,000 stillbirths. Main defects included skeletal malformations [2.5 per 1,000], central nervous system abnormalities [1.84 per 1,000], known syndromes [1.25 per 1,000], urogenital system abnormalities [1 per 1,000], and skin abnormalities [0.33 per 1,000]. There were significant differences in congenital malformation rates in newborns of consanguineous versus non consanguineous parents. On the other hand there was no significant association with maternal age (Habeeb and Al-Sadoon 1995). Another study from Basrah on 392 livebirths in 2003–2004 showed that 1.78% had congenital defects (Shiyaa et al. 2006). Among 7,135 births in Baghdad Hospital, major congenital malformations were detected in 10.091 per 1,000 live births. Central nervous system and multiple malformations represented the commonest type. The rate of consanguineous marriages among parents of malformed babies was significantly higher than the rate among parents in the control group [64, 48% respectively], and the coefficient of inbreeding among parents of malformed babies and controls were 0.027 and 0.024 respectively. Consanguineous marriage was high among all types of congenital malformations except that of extremities (Mahdi 1992). In a prospective study on 24,250 schoolchildren in Baghdad–Alresafa, the frequency of cleft lip and/or cleft palate was 1.24 per 1,000 (Al Zubaidee and Hammash 1997). The scant data obtained through analyzing various etiological factors indicate an increased frequency of autosomal recessive disorders. Among 377 children with congenital anomalies referred to the genetic counseling clinic in Yarmouk Teaching Hospital in Baghdad between 1981 and 1986 (Hamamy 1989), etiological factors included 16.7% chromosomal aberrations, 40% single gene disorders, 2.9% multifactorial disorders and 2.9% environmental causes. The etiology remained undetermined in 37.5% of all cases. Among cases with single gene etiology, a high proportion of 66% was attributed to autosomal recessive conditions. In other words, 26.3% of all affected children suffered from autosomal recessive diseases. The consanguinity rate among parents of all children was remarkably high, at 77%, with 53% of first cousin marriages. Even when families with proven autosomal recessive conditions were excluded, the consanguinity rate among the rest of the parents was 68.2%. This figure is higher than the consanguinity rate of the general population, pointing to the possible contribution of autosomal recessive genes among cases with undetermined etiology. A similarly high rate of consanguinity (70%) was observed earlier among parents of a smaller group of congenitally malformed patients (Hamamy 1984). A compilation of all cases with congenital anomalies seen in the Al-Yarmouk Genetics Clinic from 1981 to 1990 showed a similar pattern (Table 10.6).

308

Hanan A. Hamamy Table 10.6 Etiological factors in 494 children with congenital anomalies referred to Al-Yarmouk Genetic Unit

Etiology Chromosome abnormality Mendelian disorders Multifactorial Environmental

% of total 18.4 40.9 4.7 36

Surgical intervention on 36 cases with neonatal intestinal obstruction during the period 1986–1996 showed that the main causes were imperforate anus (27.8%), duodenal atresia (13.9%) and colonic atresia and meconium ileus (11.1% each) (Nasir et al. 2000). Several rare congenital anomalies have been reported in Iraq, such as the case of accessory nose associated with unilateral complete congenital choanal atresia seen in Najaf, Iraq, (Al-Helo et al. 2008), posterior choanal atresia (Shehab et al. 1998), bilateral agenesis of parotid salivary glands in Sulaymania (Al-Talabani et al. 2008), and congenital prepubic sinus (Al-Wattar 2003). Eight hundred primary school children, 520 males and 280 females ranging in age from 7 to 12 years, studied for the presence of mitral valve prolapse (MVP) showed an incidence of 3.1%, with no significant sex difference. This study points out that MVP is more common in children in Mosul city than other parts of the world (Shaikhow and Al Jawadi 1989).

Mental Retardation A study of 185 mentally retarded children referred to the Children’s Department of Medical City in Baghdad between 1978 and 1983 (Al-Rawi et al. 1986) showed a parental consanguinity rate of 76%, with 46% being first cousins. This high proportion suggests the possible etiological role of autosomal recessive genes in mental retardation. A family history of mental retardation was reported in 27% of the cases. Down syndrome was detected in 8% of the cases, where 73.3% and 86.6% were born to mothers and fathers over 35 years, respectively. Other cases included microcephaly (4.9%), kernicterus (4.9%), phenylketonuria (3.8%), hypothyroidism (3.3%), tuberous sclerosis (1.6%), mucopolysaccharidosis (1.1%), Cornelia de Lange syndrome (0.5%), and familial spastic paraplegia (0.5%). Precise diagnosis in about 40% of all cases was undetermined. Another study (Al-Hakeem and Hamamy 1992) was undertaken in six special educational and rehabilitation institutions for the mentally handicapped in Baghdad. Down syndrome comprised 25.7% of the studied population. The male/female ratio of 3.8:1 detected in this study may point to the role played by X-linked recessive conditions as well as other factors leading to increased male preponderance in special institutions, such as the social trend of keeping the mentally retarded females at home rather than enrolling them in a special school.

10

Genetic Diseases in Iraq

309

Clinical evaluation of 138 boys with undiagnosed mental retardation together with cytogenetic analysis of 60 of them verified the etiology in 31.9% of all cases (Al-Hakeem and Hamamy 1992). Autosomal and X-linked recessive genes caused 10.8 and 14.6% of all cases, respectively. Diagnosed cases included a child with XYY karyotype and another with the fragile X syndrome. Among 21 patients with undiagnosed severe mental retardation (MR) recruited from Al-Rajaa institution for MR in Najaf province, 14 patients revealed obvious chromosomal abnormalities (67%). Of the established chromosomal abnormalities, 13 patients were found to have autosomal abnormalities (61%), while one patient had sex chromosomal abnormality. Structural autosomal abnormalities (ring chromosomes and translocation) represented the majority of cases. A single case of mosaic Down’s syndrome was seen (Yasseen and Al-Musawi 2001). New cases of mental retardation seen in a private pediatric clinic in Baghdad 1988–1997 amounted to 447 cases (2.6% of all new consultations). Male to female ratio was 1.4. The group of MR related to perinatal difficulties amounted to 50.1% of cases. Hypoxic injury was responsible for more than one fourth of all cases (Al-Thamery 1999). Biochemical tests confirmed the diagnosis of aminoacidopathy in 48% of 768 Iraqi children clinically suspected with inborn errors of metabolism. Cystinuria, galactosemia and phenylketonuria were the major groups of aminoacidopathy distributed in these children, followed by Hartnup disease, Fanconi syndrome, maple syrup urine disease, occulocerebrorenal disease, homocystinuria. tyrosinosis, mucopolysacharoidosis and histidinaemia, respectively (Abboud 1993).

Down Syndrome The birth incidence of Down syndrome in Iraq has not been cytogenetically investigated. The contribution of Down syndrome to the etiology of mental retardation ranged between 8 and 26% in different studies (Al-Rawi et al. 1986; Al-Hakeem and Hamamy 1992). The effect of consanguinity on the occurrence of Down syndrome was investigated in Baghdad (Hamamy et al. 1990). Eightythree infants and children with cytogenetically confirmed Down syndrome were distributed according to parental consanguinity (Table 10.7). The results showed that the rate of consanguinity was lower among parents of trisomic children than the Table 10.7 Distribution of 83 down syndrome cases according to parental consanguinity Hamamy et al. (1990) Consanguinity Trisomy Mosaicism Both No % No % No % Not related 53 77.9 8 53.3 61 73.5 First cousins 11 16.2 4 26.7 15 18.1 Second cousins 4 5.9 3 20 7 8.4 total 68 81.9 15 18.1 83 100

310

Hanan A. Hamamy

general population figures. The difference, however, was not apparent in cases of Down syndrome with mosaic chromosome pattern. Karyotype analysis of 150 cases of Down’s syndrome in Baghdad showed that 90.7, 5.3 and 4% were trisomic, mosaic and translocation Down’s syndrome respectively (Farman and Shakir 1976). An interesting finding was the demonstration of an increased rate of sister chromatid exchanges in lymphocytes of Down syndrome patients and their parents (Shubber et al. 1991). This genomic instability and deranged DNA repair mechanisms were accentuated by exposure to mutagenic agents. This may suggest a role for genomic instability in non-disjunction events. However, it may suggest that both non-disjunction and the genomic instability may have resulted from exposure to mutagenic or clastogenic environmental factors.

Infertility Problems Among the undiagnosed azoospermic men studied for genetic etiology, 39% had first cousin parents as compared to 30% among the general population of the same area. Klinefelter syndrome was diagnosed in 22.9% of 131 azoospermic men, while 3.1% of cases revealed a polymorphic large Y chromosome and 2.3% showed Kallmann syndrome (Hamamy and Al-Taha 1989a). In another study on 64 infertile males with azoospermia or oligospermia in Kufa, Iraq (Yasseen et al. 2001), Klinefelter syndrome was diagnosed in seven patients (11%), while an autosomal translocation was seen in one patient. The contribution of chromosome anomalies among 200 women with primary amenorrhea was studied (Hamamy and Al-Taha 1989b). The results revealed that chromosomal abnormalities were implicated in 8.5% of cases who have Turner syndrome. Testicular feminization syndrome was diagnosed in 6.9% while 8% of cases have presumably autosomal recessive disorders manifesting as primary amenorrhea with or without other stigmata such as deafness or alopecia. Absence of Mullarian derivatives was found in another 7% of cases with 46, XX karyotype suggestive of Rokitansky-Kuster-Hauser syndrome. One case of Noonan syndrome (0.5%) was seen. Unpublished data showed that 41% of parents of females with primary amenorrhea of unknown etiology were first cousins. The contribution of chromosome aberrations in spontaneous abortions was studied in 100 couples with repeated fetal death (Hamamy and Al-Taha 1996). The study revealed that one partner in eight couples (8%) had a chromosomal anomaly. In 4% of males, the polymorphic long Y chromosome was found. Although the number studied is small, an interesting finding was that a consanguinity rate of 67% was observed among couples who experienced infant deaths or congenitally malformed offspring in addition to fetal loss, as compared to a consanguinity rate of 42% among couples with early spontaneous abortion only. A negative correlation between early spontaneous abortion frequency and rate of

10

Genetic Diseases in Iraq

311

first cousin marriages has been observed among a sample of the population in Baghdad (Hamamy et al. 1986). An interesting finding in couples with unfavorable reproduction in Baghdad is the demonstration of an increased frequency of sister chromatid exchanges in their somatic cells (Hamamy et al. 1992). This indicates persisting DNA lesions resulting from various conditions which may include exposure to environmental mutagens and clastogens or a possible presence of inherent genetic instability. Association behavior of acrocentric chromosome in 57 infertile males assessed at Kufa University, Iraq, showed statistically significant difference in infertile male classes compared to control groups. This significant increase in the satellite association is proposed to have another indirect causal factor, which influenced spermatogenesis (Yasseen and Aunuiz 2002).

Blood Disorders Hemoglobinopathies and glucose-6 phosphate dehydrogenase (G6PD) deficiency are common in Iraq, a situation similar to most neighboring countries (Hamamy and Alwan 1994; Al-Gazali et al. 2006, Hamamy and Bittles 2008). Available data on the frequency of hemoglobinopathies in various regions in Iraq is presented in Table 10.8. Beta thalassemia major is an important health problem throughout Iraq, including the Dohuk region, where there are more than 250 registered patients, in a population of about one million. The problem is further accentuated by the high rate of consanguineous marriages estimated at 25.3% in the region. Among parents of 104 unselected beta-thalassemia major/intermedia patients, registered at the

Table 10.8 Distribution of hemoglobinopathies in Iraq Region (reference) Studied population

Basrah (Al Kasab et al. 1987) Basrah (Al Kasab et al. 1987) Basra (Hassan et al. 2003) Baghdad (Yahya et al. 1996) Dohuk (Al-Allawi, Al-Dousky, accepted) Sulaimaniya (Jalal et al. 2008)

bthalassemia carrier rate

bthalassemia major

athalassemia carrier rate

610 women 15–44 years 10–12 years

Sickle cell carrier rate 16%

Sickle Bdcarrier cell anemia rate 1.7% 2.6%

1,064 couples 14–60 years 502 pregnant women 1,182 premarital screening

4.6%

1,472 premarital screening

4.14%

4.4%

6.5% 1%

3.7%

3.3%

0.2% 1.2%

0.1%

0.27%

0.14%

312

Hanan A. Hamamy

Dohuk Thalassemia Care Center, consanguinity rate was 64.4% (Al-Allawi et al. 2006). Molecular studies of hemoglobinopathies in Iraq are scarce. In one study from Dohuk on 104 b-thalassemia patients, 12 different mutations were identified. The eight most frequent mutations constituting 81.7% of all defects included in order of frequency: IVSII-1 (18.3%), codon 44 (12.5%), codon 5 (10.6%), IVSI-1 (8.7%), IVSI-6 (8.7%), codon 39 (8.7%), codons 8/9 (7.7%), and IVSI-5 (6.7%). Less frequent mutations involved codons 8, 22, 30 and IVS-1-110. The molecular defects remained uncharacterized in 12 cases (1–1.5%). Hb A2 levels in the 102 cases with beta-thal minor ranged between 3.4 and 8.0% (mean of 5.45 0.98) (Al-Allawi et al. 2006). The Dohuk region lies at the extreme north of Iraq, midway between Iran, Turkey and Syria. This region includes four main towns surrounded by hundreds of small towns and villages, in a rough mountainous terrain. Its population is estimated at around one million, mainly Kurdish Muslims, with a small Kurdish Yezidi minority. The detection of 12 different mutations responsible for betathalassemia in this region reflects the interaction of the population throughout history during various occupations and migrations. To some extent, the pattern of these mutations is unique since the 12.5% frequency of codon 44 is much higher than has been reported in any of the surrounding countries or elsewhere, and is only surpassed by its frequency in Jewish Kurds originating from this same area (Al-Allawi et al. 2006). A new beta-chain silent variant in a family with multiple hemoglobin disorders was detected and named Hb Iraq-Halabja beta10 (A7) Ala!Val (GCC!GTC): (Deutsch et al. 1999). From Mosul in northern Iraq (Kheder and Bashir 1990), data on 37 obligatory beta-thalassemia carriers has indicated that three quarters had an elevated HB F level above 1%, with a range of 1.7–3.3%. It was found that the most common a-thalassemia genotypes in 51 individuals with unexplained hypochromia and/or microcytosis from the Dohuk region in northern Iraq were –a3.7/a a, followed by – –MED-I/a a, then – a 3.7/– a 3.7, respectively, detected in 84.3% of the above individuals. Other genotypes identified sporadically were – a 4.2/a a, apoly A1 a/a a (AATAAA>AATAAG), a Adana a/a a [Hb Adana, codon 59 (Gly a Asp) or HBA1:c.179G>A] and a Evanston a/a a [Hb Evanston, codon 14 (Trp a Arg) or HBA1:c.43 T>C]. Three cases (5.88%) remained uncharacterized even after sequencing. All nine Hb H cases carried the – a 3.7/– –MED-I genotype (Al-Allawi et al. accepted 2009). In Mosul, among 700 thalassemics, 105 transfusion dependent children, 2.5–18 years of age attended Ibn-Al-Atheer teaching hospital in Mosul City, Iraq, during 2005 (Al-Samarrai et al. 2008). In Sulaimaniya, a Kurdish city in Northern Iraq, Hb C trait, homozygous hereditary persistence of fetal hemoglobin, and Hb H disease were detected in 0.14, 0.07, and 0.07% respectively among 1,472 subjects attending the premarital checkup. Consanguinity rate in the studied population was 24.3%. Among the 1.5

10

Genetic Diseases in Iraq

313

million population of this city, there were 600 registered cases of beta-thalassemia major/intermedia (Jalal et al. 2008). Sickle cell anemia affected the weight and height of 75 males aged 18 years with sickle cell anemia (SCA); 77.3% showed weights below the 5th centiles and 46.6% had heights below the 5th centile (Mansour 2003). Reports indicate that the clinical severity of SCA in Southern Iraq is intermediate betweeen the African and Saudi types (Al-Shawi 1988; Al-Kasab 1980). A rare medical case was also reported for the first time in Iraq in a woman of 35 years of age born with cyanosis not accompanied with dyspnea, the cause of cyanosis was found to be a rare hemoglobin called methaemoglobin M (Bashir and Al Taee 1988). The frequency of glucose-6-phosphate-dehydrogenase (G6PD) deficiency in Iraq ranges between 8.4 and 13% (Table 10.9), with some variability in distribution among ethnic groups (Table 10.10) In the study on 305 males and 394 females using Beutler’s fluorescent spot test for screening (Hamamy and Saeed 1981), the extent of deficiency varied with age , being highest among children and lowest in those over 50 years. About 35% of female heterozygotes could be detected using this test. The level of G6PD enzyme activity was higher among neonates than among adults (Al-Naama et al. 1994).

Table 10.9 G6PD deficiency in Iraq Region (Ref) Males Baghdad (Amin Zaki et al. 1,043 1972) Baghdad (Hamamy and 305 Saeed 1981) Basrah (Al-Naama et al. 1994), level of enzyme activity was measured

Number Females Both 409 1452

% of G6PD deficiency Males Females Both 8.6 8.5 8.6

394

12.4

8.8

7.9

9.7

9.2 6.1 15.3

11.8

699 456 neonates

186 adults Baghdad (Hilmi et al. 2002) 758 Basra (Hassan et al. 2003) 1,064 couples

Table 10.10 G6PD deficiency in some ethnic groups in Iraq Ethnic group Number of samples examined Males Femalesa a b Arab 489 703 191 85 Kurd 211a 34b 45 Turkuman 142a 18b 53 Chaldean 131a 35 Assyrian 70a a Amin-Zaki et al. (1972) b Hilmi et al. (2002)

10.4

12.5

Frequency of G6PD deficiency Males Femalesa a b 9.4% 6% 8.4% 7.6%a 8.8%b 7.3% 6.3%a 5.6%b 6.6% 8.4%a 9.4% 11.4%a 8.5%

314

Hanan A. Hamamy

In a study from Basrah, human erythrocyte G6PD activity was estimated using a quantitative spectrophotometric technique (Al-Naama et al. 1984). The reference value for G6PD was found to be 6.9 2.6IU/g Hb (mean SD) using hemolysates of 166 male and female healthy individuals. Similarly, the activity of 6-phosphogluconate dehydrogenase was found to be 5.9 0.99 IU/gm Hb. Complete G6PD deficiency (zero activity) and partial deficiency (below 4.3 IU/g Hb) were detected in 9.05 and 3.95% of 177 tested individuals respectively. An overall incidence of G6PD deficiency was thus found to be 13% among both sexes in the Basrah population. An interesting positive association of G6PD deficiency with diabetes mellitus was observed in 318 diabetics in Baghdad (Saeed et al. 1985). The distribution of G6PD deficiency varied with age, sex and duration of diabetes. The underlying nature of this positive association remains unknown. The authors favor the idea that G6PD deficiency is the result of, rather than a predisposing cause in diabetes mellitus. Among 758 randomly selected healthy Iraqi males aged 18–60 years, the predominant non-deficient G6PD phenotype was G6PD B (92.6%), G6PD Aþ was found in a polymorphic frequency (1.3%). In 46 deficient cases, 31 were fully characterized, including 17 cases with features consistent with G6PD Mediterranean variant, while 12 had other biochemical features and were labeled as nonMediterranean variant. The remaining two deficient cases were characterized as G6PD A– variant (Hilmi et al. 2002). The prevalence rate of factor V Leiden as detected by DNA analysis was 3% among 100 Iraqi blood donors. Although this is much lower than the prevalence rates of 14.2, 13.6, and 12.25% reported in Lebanon, Syria, and Jordan, respectively and to a lesser extent than the rates in Turkey (7.4%) and Iran (5.5%), the Iraq rate is comparable to the prevalence of 2.5% reported in Saudi Arabia. This may be related to a common origin and closer links between the population of Iraq (including Baghdad) and that of the Arabian Peninsula throughout history (Al-Allawi et al. 2004). Among one hundred and fifty consecutive healthy blood donors from the regional blood bank in Dohuk-Iraq, Factor V Leiden and Prothrombin G20210A carrier states were found in 1.2% and 3% of the individuals respectively. The MTHFR C677T homozygous and heterozygous states were confirmed in 8% and 44% respectively. The study demonstrated that while the prevalence of Prothrombin and MTHFR mutations were rather consistent with the pattern seen in surrounding countries in the Mediterranean region, Factor V Leiden prevalence was the least ever reported from any other population in the region. The latter finding suggests that the contribution of Factor V Leiden to thrombotic states in Northern Iraq may not be as significant as it is in other countries in the region (Al-Allawi et al. personal communication).

Familial Mediterranean Fever (FMF) This genetic disorder affecting mainly people of Mediterranean origin has been reported in Iraq (Bakir and Murtadha 1975). The study on 41 cases included 26 Arabs, 10 Armenian, three Kurds and two Assyrians. In about half the cases, the

10

Genetic Diseases in Iraq

315

disease began in the first decade, and in 75% of cases, before the end of the second decade. As in other studies on Arabs (Barakat et al. 1986), the incidence of amyloidosis in this series was quite low. Another study on 80 cases of FMF in Iraq showed that amyloidosis occurred in only two cases (Bakir et al. 1979). Recently, molecular studies among a cohort of 176 healthy adult Iraqis showed that the FMF mutation E148Q was detected in 29 per 352 chromosomes. The V726A mutation was detected in 9 per 352 chromosomes. Mutations M694V, M694I and M680I were not detected. This gives a mutant allele frequency “q” of 0.108, and a calculated carrier rate of 11.4% (Al-Alami et al. 2003). A unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians was observed supporting the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another (Balow et al. 1997). A high frequency of carriers of FMF of 29–39% was found among Iraqi Jews (Stoffman et al. 2000).

Common Multifactorial Diseases Remarkable changes have taken place in the epidemiological pattern of disease in Iraq during the last four decades. Declining incidence of infectious and nutritional disorders has been associated with an apparent increase in morbidity and mortality from common multifactorial diseases such as hypertension, coronary heart disease, diabetes mellitus, and cancer. As in other Arab countries (Alwan and King 1992; Alwan 1993), diabetes and hypertension have emerged as major health problems. A study performed in a small village, population 15 years and over in southern Iraq, using glucose tolerance test, revealed an overall prevalence of diabetes of 4.8% (Al-Kasab et al. 1979). The figure is probably an underestimate since it does not provide information on impaired glucose tolerance, and also it may not reflect the situation in the urban population. A more recent study providing data on diabetes mellitus and impaired fasting glucose (IFG) in Basrah, Iraq for the period of April–May 2007 among 3,176 participants gave a combined prevalence of 7.43% for diabetes and 2.02% for IFG (Mansour et al. 2008). A study involving 1,175 diabetic patients in Baghdad revealed that type 1 diabetes was present in 16.5% of cases, and type 2 diabetes occurred in over 82.5% of cases. Maturity onset diabetes of youth (MODY), an autosomal dominant condition, was reported in less than 1% of cases (Alwan and Shamdeen 1989). The health system in Iraq underwent progressive decline since the embargo or the economic sanctions that followed the second gulf war in 1991. The war in 2003 exacerbated this decline by causing further damage to the infrastructure, with lack of security leading to impaired drug distribution. Electricity problems contributed to the difficulties in drug storage. Currently, the Iraqi health system is unable to

316

Hanan A. Hamamy

cope with the healthcare needs of its population. Of a population of 27 million Iraqis, the prevalence of type 2 Diabetes is reaching epidemic proportions, affecting an estimated two million people–7.43% of the overall Iraqi population. During the period January to December 2007, 2,688 patients with diabetes of 1–30 years duration and A1C 7% were seen at the diabetes out-patient clinic in Al-Faiha general hospital in Basrah. These patients responded to the question of “Why do you think that it is difficult to control your diabetes?” Main causes given in their response were no drug supply from primary health care center (PHC), drug shortage, high expense of drugs and migration (Mansour 2008). A survey study was conducted on 158 subjects aged over 25 years living in two villages near Mosul. The overall prevalence of diabetes was 10.1% (Mulla Abed and Waad Allah 1992). The prevalence of hypertension among an examined population sample over the age of 15 years was 12.3 and 9.5% for the urban and rural populations respectively (Alwan et al. 1982). Increase in age and obesity was accompanied by a progressive rise in the prevalence of hypertension. Detection rate was found to be quite low, since over 80% of cases were undiagnosed prior to the survey. The point prevalence of hypertension [HT] among 1,098 male workers was found to be 11.8% (Hussien and Jamil 1993). A cross-sectional study recruiting 1,427 school aged students (6–12 years) from eight primary schools in Baghdad during the period November 2001 to May 2002 showed that the overall prevalence of hypertension was 1.7% with no significant gender distribution (Subhi 2006).

Childhood Blindness From 1970 onward, genetically determined diseases accounted for 81% of childhood blindness (Al-Kanani 1990). The most commonly encountered conditions were congenital cataract (28.3%), retinitis pigmentosa (27.4%), congenital glaucoma (12.3%), and Leber’s optic atrophy (8.5%). The consanguinity rate of parents of the affected was, however, not significantly different from that of the general population.

Deafness In Baghdad, eight schools accepted deaf-mute children aged 6–16 years; in the academic year 1987–1988, 797 children from 702 families were enrolled. Family studies of the deaf-mute children indicated that deaf-mutism was acquired in 16.2% and congenital in 83.8%. Among the congenital group 39.3% are multiplex families with affected sibs and normal parents, strongly pointing to an autosomal recessive etiology. Moreover, among the singles families, rate of first cousin marriages was

10

Genetic Diseases in Iraq

317

49.5% as compared to 30.1% among the group with acquired deaf-mutism, implying the action of autosomal recessive genes (Harith 1990; personal). A comprehensive survey of 7,500 children in Mosul was carried out from December 1997 through to December 2000. The overall prevalence of hearing impairment was 10%. The proportions of those with sensorineural hearing loss and those with severe to profound bilateral sensory-neural hearing loss were 1.6% and 0.15% respectively. This prevalence rate of severe to profound sensory-neural hearing loss is considered high when compared to the rate in developed countries (Al-Allaf et al. 2003).

Short Stature Among 120 patients aged 6–18 years with short stature (Sarsam and Izzat 1986), familial isolated growth hormone deficiency was diagnosed in 40%. One family had four children with Laron dwarfism. Idiopathic panhypopituitarism was the etiological factor among 4.2% while 2.5% manifested a craniopharyngioma. The diagnosis of celiac disease confirmed by jejunal biopsy accounted for 16.7% of cases of short stature. An important etiological factor among girls was Turner syndrome, accounting for 15.8% of short stature cases among the girls. Hypothyroidism was documented in 6.7% of cases. Monogenic disorders seen in this study included achondroplasia, hypophosphatasia, and progeria.

Conclusions Iraq is considered a country in turmoil due to the devastating impact of three major wars and a long period of imposed economic sanctions in the past three decades. The decline in health services and basic health indicators has markedly hampered the development of genetic services and genetic research in the country, at a time when the rest of the Arab world and the World in general are making huge advances in this field. The data given in this chapter is derived from the few publications on genetic diseases that have been mostly retrieved from local journals [WHO, IMEMR]. This data reflects the minimum of the burden of genetic and congenital disorders in the country. Despite the scarcity of epidemiologic studies on the frequency of hereditary disorders in Iraq, the analysis of available data indicates that some disorders occur in high frequencies, causing considerable suffering, severe disabilities, and early death. Hemoglobin disorders and enzymopathies, autosomal recessive disorders in general, Down’s syndrome, and congenital malformations are generally considered examples of common problems. The magnitude of multifactorial disorders such as hypertension, diabetes mellitus and coronary artery disease is growing significantly.

318

Hanan A. Hamamy

More data on the types and frequencies of genetic disorders in Iraq is required. Emphasis should be directed toward research on the major causes of congenital malformations and the contribution of teratogenic factors. The impact of consanguinity on the rate of birth defects needs thorough investigations. The provision of genetic services in Iraq is currently inadequate given the prevalence and burden of genetic diseases. Improving this situation calls for major efforts including the implementation of projects that involve increasing the genetic literacy of the general public and the health care sector, designing comprehensive courses and campaigns to familiarize primary health care workers with counseling needs and skills and with referral guidelines for high-risk families, updating medical, nursing, and paramedical curricula to incorporate information on community genetics, and training clinical and laboratory genetic specialists to meet the short- and long-term goals of genetic disease prevention and management. National newborn screening programs for metabolic errors and hypothyroidism are needed, as well as national premarital screening programs for hemoglobinopathies. Community genetic programs could be structured according to local needs and in accordance with social, cultural and religious beliefs. Acknowledgment I am deeply grateful to Professor Nasir Al-Allawi, Professor of Hematology, Scientific supervisor of Hemoglobinopathy preventive program, College of Medicine, University of Dohuk, Iraq, for providing me with valuable data and references on hereditary blood disorders in Iraq.

References Abboud M (1993) Aminoacidopathies among Iraqi children suspected with inborn errors of metabolism. J Fac Med Baghdad 35(2):57–60 Abdullah NF (1976) Human blood groups in Basrah. Man (NS) 11:239–242 Abdullah NF (1981) Distribution of blood groups among the Iraqi Arabs. J Fac Med Baghdad 23(4):453–472 Ahmad RA, Taha IA (1983) Acetylation in Iraqi population. Iraqi Med J 31:53–57 Al-Agidi SK, Papiha SS, Roberts DF (1977) Immunoglobulin levels in Iraq. Clin Exp Immunol 29(2):247–255 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Allaf A, Ali A, Muneer M (2003) Deafness in chilren and the need for cochlear implants. J Bahrain Med Soc 15(4):219–222 Al-Allawi N, Al-Dousky A. Frequency of Hemoglobinopathies and Service Indicators for their Preventive Program in the Dohuk Governerate-Iraq. Accepted for publication in East Mediterr Health J Al-Allawi N, Badi A, Imanian H, Nikzat N, Jubrael J, Najmabadi H (2009) Molecular characterization of α-thalassemia in the Dohuk region of Iraq. Haemoglobin 33(1):37–44 Al-Allawi N, Jubrael J, Baban N, Gedeon G. Thrombophilic Mutations in Blood Donors in DohukIraq. Personal communication Al-Allawi N, Jubrael J, Hilmi F (2004) Factor V Leiden in Blood Donors in Baghdad (Iraq). Clin Chem 50(3):677–678

10

Genetic Diseases in Iraq

319

Al-Allawi NA, Jubrael JM, Hughson M (2006) Molecular characterization of beta-thalassemia in the Dohuk region of Iraq. Hemoglobin 30(4):479–486 Al-Azzawi HT, Al-Salihi AR, Saleem IH, Fadhli AA, Zaidan ZA (1987) alpha Naphthyl acetate esterase activity in monocytes and lymphocytes of normal and muscular dystrophic individuals. Iraqi Med J 35(1):19–24 Al-Ani S, El Sebai HF (1994) Gross congenital malformations in neonates in Ramadi city during the year 1990: types, incidence, and possible teratogens J. Fac Med Baghdad 36(4):609–614 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. BMJ 333 (7573):831–834 Al-Hadithi F, Al Saleem T (1991) Ocular manifestations of xeroderma pigmentosa in Iraq. Saudi J Ophthalmol 5(1):6–8 Al-Hakeem S, Hamamy H (1992) Genetic studies on institutionalized mentally retarded males with special reference to the FragileX syndrome. Extracted from MSc Thesis, Al-Mustansiriya Medical College, Baghdad Al-Hassani M (1977) Cystic fibrosis in Iraqi children. J Trop Paed 23:36–137 Al-Helo S, Taghi AS, Mahboba S (2008) Unusual case of accessory nose associated with unilateral complete congenital choanal atresia. Saudi Med J 29(9):1342–1343 Al-Huwaizi F (1987) Waardenburg’s syndrome in an Iraqi family. J Fac Med Baghdad 29 (1):81–85 Al-Huwaizi F (1990) Pendred’s syndrome in eleven Iraqi patients. Pendred’s syndrome in eleven Iraqi patients. J Community Med 3(2):123–126 Al-Jadiry A, Rustam H, Al-Saleem T, Ismail MA (1987) Xeroderma pigmentosum. Saudi med J 8:468–475 Ali MM, Shah IH (2000) Sanctions and childhood mortality in Iraq. Lancet 355(9218):1851–1857 Al-Kasab F (1980) Sickle cell disease in southern Iraq. Med J Basrah Univ 3(2):25–38 Al-Kasab F, Al-Kafajei A, Kutty P, Al-Windawi S, Antony R, Zuabie A, Al-Septi S (1987) Hematological profile of women in the reproductive age in southern Iraq. Iraqi Med J 35(1):33–38 Al-Kasab FM, Alkafajei AM, Medbigh SH (1979) The prevalence of diabetes mellitus in a rural community in Iraq. Int J Epidemiol 8(1):69–71 Al-Khafaji SD, Al-Rubeai MA (1976) The frequencies of the ABO and Rh(D) blood groups in the Kurdish population of Iraq. Ann Hum Biol 3(2):189–191 Al-Khaidhaire S (1994) A new concept in diagnosis of osteogenesis imperfecta. J Fac Med Baghdad 36(2):225–229 Al-Khatib A, Abdul Hadi T (1995) Squamous cell carcinoma of the skin of face in patients with xeroderma pigmentosum. J Fac Med Baghdad 37(3):397–400 Al-Kanani S (1990) Childhood blindness in Iraq J Fac Med Baghdad 32(1):103–108 Al-Mefraji SH (2008) May-Jun. Alkaptonuria in a 5-year-old boy in Iraq. East Mediterr Health J 14(3):745–746 Al-Mefraji SH, Al-Tawil NG, Karim LA (2006) Anthropometric measurements of a group of newborns in a teaching hospital in Baghdad. Saudi Med J 27(6):870–873 Al-Mosawi AJ (2006) Genetic drift. Letter from Baghdad: Coffin–Siris syndrome in a girl with absent kidney. Am J Med Genet 140(16):1789–1790 Al-Mosawi AJ (2002) The etiology of chronic renal failure in 54 Iraqi children. Pediatr Nephrol 17(6):463–464 Al-Naama MM, al-Naama LM, al-Sadoon TA (1994) Glucose-6-phosphate dehydrogenase, hexokinase and pyruvate kinase activities in erythrocytes of neonates and adults in Basrah. Ann Trop Paediatr 14(3):195–200 Al-Naama L, Al-Gailany K, Al-Kaysi G (1984) Human erythrocytes glucose 6-phosphate dehydrogenase and 6-phosphogluconate in Basrah area. J Fac Med Baghdad 26(1):101–109 Al-Nadawi M, Atra A (1984) Congenital nephrotic syndrome. J Fac Med Baghdad 26(3):97–102 Al-Rawi F, Al Naddawi M, Al Musawi Z (1986) Mental retardation in Iraqi children. J Fac Med Baghdad 28(4):29–36

320

Hanan A. Hamamy

Al-Samarrai AH, Adaay MH, Al-Tikriti KA, Al-Anzy MM (2008) Evaluation of some essential element levels in thalassemia major patients in Mosul district, Iraq. Saudi Med J 29(1):94–97 Al-Shawi TS (1988) A study of Sickle Cell Disease in young adult males in Iraq. MSc thesis. College of Medicine, University of Baghdad, Iraq Al-Shawk S, Mathur S, Al Nasiri N (1983) Peutz-Jeghers syndrome presenting with hypoproteinemia: a case report and review of the literature. Iraqi Med J 31:121–128 Al-Saleem T, Abulkiel A, Sabri Z, Alash N. (1984) Skin cancer in Iraq. J Fac Med Baghdad 28:29–36 Al-Sharbati MM, Al-Chalabi TS, Rummani SF (1993) School screening for scoliosis in Baghdad. Saudi Med J 14:298–302 Al-Taha S (1996) A survey of a genetic clinic patients for chromosomal, genetic syndromes and congenital malformations as detected by clinical and chromosomal studies1989–90vs 1992–93. J Fac Med Baghdad 38(2):137–140 Al-Talabani N, Gataa IS, Latteef SA (2008) Bilateral agenesis of parotid salivary glands, an extremely rare condition: report of a case and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105(3):e73–e75 Al-Thamery D (1999) Frequency of mental retardation in a private paediatric clinic in Baghdad. Ann Coll Med Mosul 25(1–2):35–40 Alwan A, King H (1992) Diabetes in the eastern Mediterranean region. World Health Stat Q 45 (4):355–359 Alwan AA, Al-Tahafi NA, Saleh AM (1982) Studies on the prevalence of hypertension in Iraqi rural and urban communities. Iraqi Med J 29–30:61–70 Alwan A, Shamdeen L (1989) Clinical Presentation of Iraqi diabetes in Iraq. Proceedings of the second Scientific Research exhibition, Ministry of higher education and Scientific Research, Baghdad Alwan AA (1993) Cardiovascular diseases in the eastern Mediterranean region. World Health Stat Q 46(2):97–100 Alwan A, Modell B (2003) Recommendations for introducing genetics services in developing countries. Nat Rev Genet 4:61–68 Al-Wattar KM (2003) Congenital prepubic sinus: an epispadiac variant of urethral duplication: case report and review of literature. J Pediatr Surg 38(4):E18 Al-Windawi S, Al Naama L (1984) Acute intermittent porphyria: 2 cases from Southern Iraq. J Fac Med Baghdad 26(4):85–91 Al-Yazachi MB (1986) Gorlin syndrome, Naevoid basal cell carcinoma. J Fac Med baghdad 28:69–76 Amin-Zaki L, el-Din ST, Kubba K (1972) Glucose-6-phosphate dehydrogenase deficiency among ethnic groups in Iraq. Bull World Health Organ 47(1):1–5 Al-Zubaidee A, Hammash M (1997) Cleft lip and palate in children of Baghdad’s Al-Resafa schools. J Fac Med Baghdad 39(1):53–60 Bakir F, Murtadha M (1975) Periodic peritonitis. Report of 41 cases without amyloidosis. Trans R Soc Trop Med Hyg 69(1):111–117 Bakir F, Murtadha M, Issa N (1979) Amyloidosis and Periodic Peritonitis (Familial Mediterranean Fever). West J Med 131(3):193–195 Balow JE Jr, Shelton DA, Orsborn A, Mangelsdorf M, Aksentijevich I, Blake T, Sood R, Gardner D, Liu R, Pras E, Levy EN, Centola M, Deng Z, Zaks N, Wood G, Chen X, Richards N, Shohat M, Livneh A, Pras M, Doggett NA, Collins FS, Liu PP, Rotter JI, Kastner DL et al (1997) Highresolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups. Genomics 44(3):280–291 Baraitser M, Burn J (1983) Recessively inherited brachydactyly type C. J Med Genet 20:128–129 Barakat MH, Karnik AM, Majeed HW, el-Sobki NI, Fenech FF (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs—a study of 175 patients and review of the literature. Q J Med 60(233):837–847

10

Genetic Diseases in Iraq

321

Bashir F, Al Taee M (1988) Congenital methemoglobinemia due to haemoglobinopathy-M. Jordan Med J 21(1):61–68 Beales PL, Katsanis N, Lewis RA, Ansley SJ, Elcioglu N, Raza J, Woods MO, Green JS, Parfrey PS, Davidson WS, Lupski JR (2001) Genetic and mutational analyses of a large multiethnic Bardet-Biedl cohort reveal a minor involvement of BBS6 and delineate the critical intervals of other loci. Am J Hum Genet 68:606–616 Bittles AH, Mason WM, Greene J, Rao NA (1991) Reproductive behavior and health in consanguineous marriages. Science 252(5007):789–794 Bittles AH, Grant JC, Shami SA (1993) Consanguinity as a determinant of reproductive behaviour and mortality in Pakistan. Int J Epidemiol 22(3):463–467 Børglum AD, Balslev T, Haagerup A, Birkebaek N, Binderup H, Kruse TA, Hertz JM (2001) A new locus for Seckel syndrome on chromosome 18p11.31–q11.2. Eur J Hum Genet 9 (10):753–757 Christianson A, Howson C, Modell B (2006) Global Report on Birth Defects. The Hidden Toll of Dying and Disabled Children. White Plains, N.Y, March of Dimes Birth Defects Foundation CIA World Factbook https://www.cia.gov/library/publications/the-world-factbook/geos/iz.html Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Mulley J, Love DR, Seidel J, Fawkner M, Banovic T, Callon KE, Grey AB, Reid IR, Middleton-Hardie CA, Cornish J (2002) A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11:2119–2127 Deutsch S, Darbellay R, Offord R, Frutiger A, Kister J, Wajcman H, Beris P (1999) Hb IraqHalabja beta10 (A7) Ala–>Val (GCC–>GTC): a new beta-chain silent variant in a family with multiple Hb disorders. Am J Hematol 61(3):187–193 Emery A, Mueller R (1992) Elements of medical genetics. Churchill Livingstone, Edinburgh Farman N, Shakir A (1976) Karyotypic analysis of 150 cases of Down’s syndrome in Iraq. J Ment Def Res 20:83–87 Fensom AH, El Kalla S, Bizzari R, Fahmy NA, Semrin A, Benson PF, Shubbar AI (1990) Clinical Presentation and Diagnosis of Niemann- Pick Disease Type C. Emirates Med J 8:215–219 Habeeb S, Al-Sadoon I (1995) The incidence of congenital malformation and associated risk factors in Basrah city. J Fac Med Baghdad 37(4):520–526 Hamamy H, Al-Bayati N, Al-Kubaisy W (1986) Consanguineous marriages in Iraqi urban population and the effect on pregnancy outcome and infant mortality. Iraqi Med J 34:76–80 Hamamy H, Alwan A (1994) Hereditary disorders in the Eastern Mediterranean Region. Bull World Health Organ 72(1):145–154 Hamamy H, Bittles A (2008) Genetic Clinics in Arab Communities: Meeting Individual, Family and Community Needs. Public Health Genomics 12(1):10.1159/000153428 Hamamy H, Shubber EK, al-Allak BM (1992) Sister chromatid exchange frequencies in a group of individuals with unfavorable reproductive health. Eur J Obstet Gynecol Reprod Biol 43(1):45–49 Hamamy H, Al-Taha S (1989a) Cytogenetic Investigations in a Referred Population of Azoospermic Males. J Fac Med Baghdad 31(3):311–315 Hamamy H, Al-Taha S (1989b) Cytogenetic Investigations in 201 Females with Primary Amenorrhea. J Fac Med Baghdad 31(3):317–322 Hamamy H (1984) Chromosome Studies and Genetic Counseling in Iraq: One Year’s Experience. Saudi Med 5:46–52 Hamamy H (1989) Genetic factors and congenital malformations. Proceedings of the Fifth Conference of the Scientific Research Council, Baghdad 5(2):1–8 Hamamy HA, al-Hakkak ZS, al-Taha S (1990) Consanguinity and the genetic control of Down syndrome. Clin Genet 37(1):24–29 Hamamy HA, al-Hakkak ZS (1989) Consanguinity and reproductive health in Iraq. Hum Hered 39 (5):271–275 Hamamy HA, Saeed TK (1981) Glucose-6-phosphate dehydrogenase deficiency in Iraq. Hum Genet 58(4):434–435

322

Hanan A. Hamamy

Harbord MG, Harden A, Harding B, Brett EM, Baraitser M (1990) Megalencephaly with dysmyelination, spasticity, ataxia, seizures and distinctive neurophysiological findings in two siblings. Neuropediatrics 21:164–168 Harith A (1990) The aetiological contribute to severe sensorineural hearing impairment in children. J Community Med 3(2):111–121 Hassan MK, Taha JY, Al-Naama LM, Widad NM, Jasim SN (2003) Frequency of haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Basra. East Mediterr Health J 9(1–2):45–54 Hilmi FA, Al-Allawi NA, Rassam M, Al-Shamma G, Al-Hashimi A (2002) Red cell glucose6-phosphate dehydrogenase phenotypes in Iraq. East Mediterr Health J 8(1):42–48 Hussien H, Jamil H (1993) The prevalence rate of hypertension among a group of industrial population-Iraq. J Community Med 6(1):51–55 Ikin EW, Mourant AE, Lehman H (1965) The blood groups and hemoglobin of the Assyrians of Iraq. Man 65:110–111 Jalal S, Al-Allawi N, Faraj A, Ahmed N (2008) Prevalence of hemoglobinopathies in SulaimaniIraq. Dohuk Med J 2(1):17–79 Jamil L, Yaldo M, Jamil H (1994) A study of the prevalence rate of obvious eye diseases in Baghdad city-Iraq. J Fac Med Baghdad 36(4):671–676 Kheder HH, Bashir FZ (1990) Beta thalassemia trait in Mosul. Saudi Med J 11(6):460–462 Kramer SN (1967) Editors of time-life books. Time-Life Books, New York, Cradle of Civilizations Mahdi A (1992) Consanguinity and its effect on major congenital malformations. Iraqi Med J 40–42:170–176 Mansour AA (2008) Patients’ opinion on the barriers to diabetes control in areas of conflicts: The Iraqi example. Confl Health 2:7 Mansour AA, Wanoose HL, Hani I, Abed-Alzahrea A, Wanoose HL (2008) Diabetes screening in Basrah, Iraq: a population-based cross-sectional study. Diabetes Res Clin Pract 79(1): 147–150 Mansour AA (2003) Influence of sickle hemoglobinopathy on growth and development of young adult males in Southern Iraq. Saudi Med J 24(5):544–546 Megarbane A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck L (2001) Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104(3):221–224 Mourant AE, Kopec AC, Domaniewska-Sobczak K (1976) The distribution of the human blood groups and other polymorphism. Oxford University Press, London Abed M, Waad Allah S (1992) The prevalence of diabetes mellitus in a rural community in Northern Iraq. Med J Basrah Univ 10(1–2):63–69 Nagi NA (1979) Diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A clinical and genetic study. Postgrad Med J 55(644):377–380 Najim RA, Al-waizt M, Al-Razzuqi RA (2005) Acetylator phenotype in Iraqi patients with allergic contact dermatitis. Ann Saudi Med 25(6):473–476 Nasheit NA (2003) Perinatal and neonatal mortality and morbidity in Iraq. J Matern Fetal Neonatal Med 13(1):64–67 Nasir GA, Rahma S, Kadim AH (2000) Neonatal intestinal obstruction. East Mediterr Health J 6(1):187–193 Rofoo F, Hashim H, Al Jaff H (1995) Disribution of ABO and RH blood group systems among Arbil population. Zanco J Med Sci 2(1):21–25 Roux G (1980) Ancient Iraq. Penguin Books, London Saeed TK, Hamamy HA, Alwan AA (1985) Association of glucose-6-phosphate dehydrogenase deficiency with diabetes mellitus. Diabet Med 2(2):110–112 Safar S, Sawa T (1992) Gardner’s syndrome: the place of colectomy in the management: a study of two families. J Fac Med Baghdad 34(4):453–460

10

Genetic Diseases in Iraq

323

Saleem M, Mahmoud N (1988) Distribution of A B O and Rh D blood group systems among Mosul population. Ann Coll Med Mosul 14(1):61–65 Sarsam H, Izzat M (1986) Short stature in Iraq. J Fac Med Baghdad 28(4):37–47 Schaffer JV, Bazzi H, Vitebsky A, Witkiewicz A, Kovich OI, Kamino H, Shapiro LS, Amin SP, Orlow SJ, Christiano AM (2006) Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. J Invest Dermatol 126(6):1286–1291 Schmidt H, Rudolph G, Hergersberg M, Schneider K, Moradi S, Meitinger T (2001) Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred–a possible new syndrome. Clin Genet 59(2):99–105 Shah G, Sattar N (1981) The incidence of phenyl thiocarbamide [PTC] taste threshold and sensitivity in Iraqi Arabs. Med J Basrah Univ 4(2):121–131 Shahar E, Brand N, Shapira Y, Barash V, Gutman A (1988) Familial carnitine deficiency: further evidence for autosomal recessive transmission with variable expression. J Neurol Neurosurg Psychiatry 51(2):298–300 Shaikhow S, Al Jawadi A (1989) Incidence of mitral valve prolapse in children. J Fac Med Baghdad 31(2):181–184 Shawky S (2001) Infant mortality in Arab countries: sociodemographic, perinatal and economic factors. East Mediterr Health J 7(6):956–965 Shehab N, Al Hubaitty A, Al Hiyalli Y (1998) Choanal atresia. Ann Coll Med Mosul 24(1–2):50–53 Shiyaa N, Balasim R, Habib O (2006) Pregnancy outcome and fate of neonates: a hospital-based study. J Bahrain Med Soc 18(1):19–22 Shubber EK, Hamami HA, Allak BM, Khaleel AH (1991) Sister-chromatid exchanges in lymphocytes from infants with Down’s syndrome. Mutat Res 248(1):61–72 Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, Danon Y, Halpern GJ, Lifshitz Y, Shohat M (2000) Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 8(4):307–310 Subhi MD (2006) Blood pressure profiles and hypertension in Iraqi primary school children. Saudi Med J 27(4):482–486 Teebi A (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 UNICEF. http://www.unicef.org/infobycountry/iraq_statistics.html WHO Index Medicus for the Eastern Mediterranean Region. http://www.who.int/library/databases/emro/en/index.html WHO Advisory Group Report [1985]: Community approaches to the control of hereditary diseases HDP/WG/85-10 WHO, EMRO country profiles. http://www.emro.who.int/emrinfo/index.asp?Ctry=irq World bank http://web.worldbank.org/WBSITE/EXTERNAL/COUNTRIES/MENAEXT/IRAQEXTN/0, menuPK:313111pagePK:141159piPK:141110theSitePK:313105,00.html World Bank. World Development Report (1993) Investing in health. Oxford University Press, New York World Bank Iraq data sheet http://www.iraqslogger.com/downloads/DATASHEETIraqDec2006. pdf World Health Report, 2000 http://www.who.int/whr/2000/en/annex02_en.pdf Yahya H, Khalel K, Al-Allawi N, Helmi F (1996) Thalassaemia genes in Baghdad, Iraq. East Mediterr Health J 2:31–35 Yaseen N (1995) Inheritance pattern of nystagmus in Iraqi families. Med J Tikrit Univ 1(1):25–35 Yasseen A, Aunuiz A, Al-Mosawi M (2001) Chromosome studies in male patients suffering from infertility. Saudi Med J 22(3):223–226 Yasseen A, Aunuiz A (2002) High frequency of satellite association in metaphases of infertile male patients. Saudi Med J 23(4):427–431 Yasseen AA, Al-Musawi TA (2001) Cytogenetics study in severely mentally retarded patients. Saudi Med J 22(5):444–449

Chapter 11

Genetic Disorders in Jordan Majed Dasouki and Hatem El-Shanti

The Country and Population Like many of its modern neighboring Arab countries, Jordan was part of the Ottoman Empire until the end of World War I. Under the mandate of the British government in 1923, Jordan became a political entity known as “Transjordan.” However, Jordan gained its independence and was declared a Kingdom in 1946. In 1948, Jordan witnessed a mass migration of at least 700,000 Palestinians as a result of the creation of the state of Israel. The union of Transjordan and the West Bank (of Palestine) in 1950 produced the current name of the Hashemite Kingdom of Jordan. As a result of the 1967 war, the West Bank fell under Israel’s occupation and another wave of Palestinian refugees moved to Jordan adding to its population. Geographically, Jordan is almost entirely landlocked, with the port of Aqaba in the far south being its only outlet to the red sea. Palestine and Israel separate Jordan from the Mediterranean sea, Saudi Arabia lies to the south and east, Iraq to the northeast, and Syria to the north (Fig. 11.1). Three climate zones characterize Jordan, running from the west to the east of the country. These zones include the Jordan Valley which is largely below sea level and considered semitropical; the highlands east of the Jordan Valley which can be considered to have a Mediterranean climate; and the low-lying desert to the east of the highlands. Jordan is about the size of the state of Indiana, USA. Over 80% of Jordan’s land is characterized by semi-desert conditions with some scattered wetlands including the Azraq Basin. Administratively, Jordan is divided into 12 governorates, which are grouped into three regions – the North region (Irbid, Jarash, Ajloun, and Mafraq), the Central region (Amman, Zarqa, Balqa, and Madaba), and

H. El-Shanti (*) Director, Shafallah Medical Genetics Center, Doha, Qatar Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA e‐mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_11, # Springer-Verlag Berlin Heidelberg 2010

325

326

M. Dasouki and H. El-Shanti

IRAQ

SYRIA

Irbid West Bank Amman GAZA

ISRAEL

JORDAN SAUDI ARABIA

Al Aqabah

Fig. 11.1 Geographic map of Jordan showing neighboring countries

the South region (Karak, Tafielah, Ma’an, and Aqaba) (Fig. 11.1). The major cities are Amman (the capital), Zarqa, and Irbid. Jordan is a small country with limited natural resources and a 13% unemployment rate in 2008. The bulk of Jordan’s labor force is engaged in providing services, 20% in industry and only 2.7% in agriculture. Jordan’s major exports include clothing, fertilizers, potash, phosphates, vegetables, and pharmaceuticals. The Hashemite Kingdom of Jordan experienced a significant growth in its population, which increased from half a million in 1952 to 5.85 millions in 2008, with about two millions inhabiting the capital “Amman.” In addition to the influx of Palestinians in 1948 and 1967, Jordan had few other major population influxes following the Lebanese civil war and most recently the Iraqi invasion of Kuwait in 1990 and the United State’s invasion of Iraq in 2003. Overall, these population shifts resulted in about tenfold increase in the population, over a 50-year period and resulted in a partial or total admixture of the incoming individuals with the basal population. In 2008, the average number of persons per family was 5.4 and infant

11

Genetic Disorders in Jordan

327

mortality rate (per 1,000 live births) was 19. Life expectancy for males was 71.6 years compared with 74.4 years for females (www.moh.gov.jo). Jordanian citizens make up 93% of the population and 95–98% of Jordan’s people are Arabs. The remaining non-Arabs of the population are mainly Circassians, Chechens, Armenians, Kurds and Gypsies. The majority of Jordanians are Muslims while 6% are Christians. Jordan has an overall literacy rate of 91.1%. Health services in Jordan are provided though the Ministry of Health hospitals, Armed forces Health Centers and the private sector.

Genetic Services Genetic services in Jordan began on a small scale with the establishment of a cytogenetics laboratory at the University of Jordan in the late 1980s. It continues to provide basic chromosomal analysis, in addition to a few molecular-based cytogenetic tests. The first clinical genetics clinic also began at the University of Jordan in 1992 and was staffed by one medical geneticist. It lasted for a short period of time. In 1994, another cytogenetics laboratory and medical genetics clinic were then started at Jordan University of Science and Technology and lasted for 10 years. The cytogenetics laboratory is still functional. Since the mid 1990s, a few additional laboratories at the Ministry of Health hospitals and commercial laboratories began offering limited cytogenetic, biochemical and molecular genetics services. Also, clinical genetics services were incorporated into the National Center for Diabetes, Endocrinology and Genetics, since its inception in1997 until the current time. Currently, there are no board-certified practicing medical geneticists in Jordan. However, Jordan’s manpower includes a few Ph.D. level molecular geneticists and cytogeneticists who trained in the US, as well as locally trained staff. Prenatal genetic diagnosis is practiced on a very small scale in Jordan. In the private health sector, there are a few in vitro fertilization (IVF) centers which offer limited pre-implantation genetic diagnosis.

Consanguinity Similar to many Arabic countries, the traditional practice of consanguineous marriages is very common in Jordan with rates as high as 60% (Al-Salem and Rawashdeh 1993; Khoury and Massad 1992; Nabulsi 1995) and first cousin marriages being the most common. While the rates of consanguineous marriages had changed over the last few decades, they continue to be high (Hamamy et al. 2005). Several studies suggested that consanguinity among Jordanians contributed to the increased incidence of various common and rare autosomal recessive disorders (identity by descent; IBD), birth defects, infant mortality, reproductive wastage, adverse pregnancy outcomes in general, and childhood mental retardation (Aqrabawi 2008;

328

M. Dasouki and H. El-Shanti

Cook and Hanslip 1966; Hamamy et al. 2007a, 2007b; Janson and Dawani 1994; Janson et al. 1990; Khoury and Massad 2000; Obeidat et al. 2008) but not to the frequency of pre-eclampsia or its severity (Badria et al. 2001; Badria and Amarin 2003). The “2007” Jordan: Population and Family Health Survey (http://pdf.usaid. gov/pdf_docs/PNADN523.pdf) showed that 40% of married women aged 15–49 reported consanguinity, with 5% being double first cousin marriages and patrilineal consanguineous marriages being more common than matrilineal ones. Demographic characteristics that favor consanguinity include: rural (49%) vs. urban (38%), North and South regions vs. Central region (43 and 45%, respectively, vs. 37%) and Badia areas compared to non-Badia areas (47 vs. 39%), less educated (47%) than higher educated (31%). Also, women in Amman, Zarqa, Madaba, and Aqaba are more likely to enter into non-consanguineous marriages than women in other governorates. Age at marriage and the woman’s socioeconomic status are inversely related to consanguinity while duration of marriage was not a significant factor. The high consanguinity rate in Jordan and throughout the Arab world in general had a significant impact on medical practice, research, and health policy. Facilitated by the high incidence of consanguinity and large family sizes, several new genetic syndromes and new features of previously recognized syndromes had been described in the medical literature. The advent and application of novel molecular genetics technologies coupled with international collaborative research efforts led to the discovery of the genetic basis for several novel genetic disorders. There are no specific studies that address the magnitude of economic and psychosocial burden genetic disorders have on individuals or the population as a whole. Although the 2008 report from the Jordan Ministry of Health (www.moh.gov.jo) indicates that only 0.17% of all health visits were related to genetic disorders (congenital malformations and chromosomal disorders). We believe that the burden on the public health system is more significant than suggested by this report. To overcome the health burden imposed by consanguinity, preventive strategies should focus on several factors including increasing public awareness and adequate education of health professionals on genetic diseases, carrier testing when applicable and premarital and preconception testing and counseling for common disorders. Preimplantation genetic diagnosis, and prenatal diagnosis and termination of pregnancy (within the allowed limits of religion) should also be made available and be integral parts of this strategy (Teebi and El-Shanti 2006). In a national effort to prevent or control certain common genetic disorders such as thalassemia, premarital examinations had been mandated by law since 2004. Due to limited resources including the unavailability of trained genetic health professionals this law had a limited impact if any on the incidence or severity of genetic disorders in Jordanian communities. Only 18% of ever-married women and/or their husbands underwent premarital medical examinations according to the 2007 Jordan: Population and Family Health Survey. Despite these significant limitations, it appears that premarital examination is more frequent among women of older ages at first marriage, women with higher education, those residing in urban areas, in the Central region and in the non-Badia areas than among other women.

11

Genetic Disorders in Jordan

329

Chromosomal Disorders In 785 chromosomal analyses done in Northern Jordan, the investigators found 105 children (13.3% ) with trisomy 21 (four with de novo Robertsonian translocations), 16 with sex chromosome aneupolidies (2%) including six with Klinefleter syndrome and ten with Turner syndrome. Structural chromosomal abnormalities were identified in 22 patients (2.8%). The overall yield of chromosomal abnormalities in their experience was 18.2% (El-Shanti and Al-Alami 2002). Advanced maternal age carries with it some known maternal and fetal health risks including hypertension, diabetes mellitus, antepartum hemorrhage, large babies, trisomy 21 and twin pregnancy (Amarin and Akasheh 2001). In this study, and both the advanced maternal age and young age groups, combined incidence of chromosomal aneuploidies was 2.2% while 4.2% of the babies had congenital malformations.

Neurological Disorders Based on the World Bank and WHO disability prevalence estimate of 10% in any given population, Jordan’s National Demographic Committee (NDC) estimated that the incidence of disability in Jordan’s population is slightly over 10%. Among those disabled, 75% of all projected disabilities are mild, 20% are moderate and 5% are severe. In Jordan, the application of those percentages for expected numbers of children with mild, moderate and severe disability to the population of 0–18-year-olds (2,375,222) results in projections of 178,141 children with mild disabilities, 47,504 with moderate disabilities and 11,876 with severe disabilities (http://www.ncfa.org.jo/admin/publications/NCFA%20Report%20English.doc). Physical and cognitive disability of various degrees occur in many neurogenetic disorders. Recognition of these disorders usually helps with the management and prognosis of these disorders. Studies of neurogenetic disorders among Jordanians are limited and are largely descriptive. However, there is an increasing number of such studies that shed light on the pathogenesis of some of these disorders. High perinatal morbidity or meningitis in infancy leading to a combination of severe mental retardation and cerebral palsy and a high degree of consanguinity favored genetic causes of mental retardation in a group of 203 severely mentally retarded children born during 1975–1985 (Janson et al. 1990). In a group of 29 children with neuromigrational disorders evaluated at a tertiary medical center, lissencephaly was found to be the most common disorder (58.6%) and was frequently associated with consanguinity (88.2%) and positive family history (76.4%) (Al-Qudah 1998). These findings strongly suggest a monogenic basis for lissencephaly. Other central nervous system anomalies included: pachygyria (13.8%), neuronal heterotopias (10.3%), schizencephaly (13.8%) and

330

M. Dasouki and H. El-Shanti

hemi- megalencephaly (3.4%). Neuromigrational disorders and associated abnormalities were frequently seen (48.2%). Primary Microcephaly (MCPH) is a genetically heterogeneous congenital disorder characterized by a small head circumference at least four SD below the age and sex average, normal brain structure and otherwise normal physical growth and normal karyotype. Some degree of non-progressive mental retardation, as well as seizures, may occur in affected children. A genome-wide scan was performed on five families from the Netherlands and Jordan, with 14 microcephalic individuals (Wallerman et al. 2003). Mapping and haplotype analysis suggests that the gene causing microcephaly, MCPH5, is located on chromosome 1. Hyperekplexia is a rare non-epileptic disorder characterized by excessive startle response to acoustic, visual, or other stimuli. Patients with hyperekplexia are often misdiagnosed as having epilepsy. The disorder was described in nine Jordanian families (Masri and Hamamy 2007). All families were referred with the diagnosis of uncontrolled seizures with onset of the disease in the neonatal period and with variable and atypical presenting features. The inheritance profile in 4 families was compatible with autosomal recessive and in one family with autosomal dominant inheritance. In the remaining four families, the disorder appeared to be sporadic. Childhood epilepsy is a relatively common disorder and etiologically heterogeneous. A case-control study from Irbid, Jordan, demonstrated that positive family history for epilepsy, head trauma, febrile convulsions and abnormal perinatal history correlated with epilepsy while consanguinity did not show a similar correlation (Daoud et al. 2003). Predictors for seizure recurrence included partial seizure and positive family history while sex, age, duration of seizure and consanguinity were not strong predictors (Daoud et al. 2004). In 55 infants with epilepsy, various etiologies (hypoxic-ischemic encephalopathy, cortical malformations, neurocutaneous syndromes, metabolic disorders and craniosynostosis) were identified in about 50% of babies (Masri et al. 2008a). Again, parental consanguinity, family history of global developmental delay, family history of epilepsy and a positive perinatal history were strong predictors of infantile epilepsy. An unusual autosomal recessive Pallido-pyramidal syndrome is characterized by clinical signs and symptoms of subacute, juvenile onset, severe levodoparesponsive Parkinsonism, cortico-spinal tract disease, dementia and supranuclear upgaze paresis was termed Kufor–Rakeb syndrome (Najim al-Din et al. 1994). Significant atrophy of the globus pallidus and the pyramids as well as generalized brain atrophy in later stages were demonstrated on brain MRI. Using linkage analysis, it was first mapped to chromosome 1p36 (Hampshire et al. 2001) and then assigned as PARK9 locus (Lees and Singleton 2007; Williams et al. 2005). Loss of function mutation (exon 16, 22bp dup) in the predominantly neuronal P-type ATPase gene, ATP13A2, was then identified as the cause of this Parkinsonism syndrome (Ramirez et al. 2006). In 11 consanguineous families with 17 individuals with recessively inherited young-onset parkinsonism evaluated for mutations in the parkin and PINK1 genes, homozygous exon 4 parkin gene deletion & 2 novel PINK1 gene mutations (P416R and S419P) were identified (Myhre et al. 2008).

11

Genetic Disorders in Jordan

331

Autosomal recessive ataxias are a heterogeneous group of rare disorders characterized by early onset ataxia associated with neurologic, ophthalmologic or systemic signs. A 13-year-old girl with Ataxia Telangiectasia developed craniopharyngioma and non-Hodgkin’s lymphoma (Masri et al. 2006). The ataxias associated with myoclonus, epilepsy and progressive neurological degeneration are usually included with the progressive myoclonus epilepsies, one of which is UnverrichtLundborg disease. Using a genome-wide screen for linkage, a distinct locus for autosomal recessive ataxia to chromosome 12 q12 was mapped in an inbred Jordanian family with four affected siblings (El-Shanti et al. 2006a). The clinical phenotype was characterized by ataxia noted at the onset of walking with dysarthria and bulbar features, but no cerebellar hypoplasia on MRI. All four patients developed a fine tremor that progressed to a coarse action tremor, as well as atonic seizures. Seizures and tremors improved upon treatment with Valproic acid while the ataxia did not improve. In affected members of three reported families a homozygous mutation in the PRICKLE1 (R104Q) was identified which is consistent with a founder effect (Bassuk et al. 2008; Berkovic et al. 2005; El-Shanti et al. 2006a). A 10 generation inbred family with 50 affected individuals distributed over five consecutive generations with spastic paraplegia was reported (El-Shanti et al. 1999b). The mode of inheritance is either autosomal recessive or autosomal dominant with incomplete penetrance or variable expression of the age at onset. The age at onset seems to decrease with successive generations, either due to a true anticipatory phenomenon or to increased awareness. The distribution and frequency of common pediatric myopathies in Jordan was reported (Al-Qudah and Tarawneh 1998). Seventy-three percent of the myopathies were due to muscular dystrophy, half of which were accounted for by congenital muscular dystrophy (CMD). High rates of consanguinity and positive family history of muscular dystrophy were reported in those families suggesting autosomal recessive basis. Other muscular dystrophies such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy (MD), limb-girdle muscular dystrophy (LGMD), and facio-scapulo-humeral dystrophy (FSHD) were also identified in decreasing order. Several new neurogenetic syndromes were also reported in some Jordanian families (Christodoulou et al. 2000; Hamamy et al. 2007c; Hiyasat et al. 2002; Middleton et al. 1999). A previously unrecognized autosomal or X-linked recessive syndrome in two brothers who had facial dysmorphism, sloping shoulders, enamel hypoplasia, severe myopia, deafness and borderline intelligence was described (Hamamy et al. 2007c). Autosomal recessive, “Jerash type” distal hereditary motor neuropathies characterized by progressive weakness and atrophy of the lower limbs plus pyramidal features and early childhood onset in seven consanguineous families was described (Middleton et al. 1999). The responsible gene was mapped by linkage analysis to chromosome 9p21.1-p12 (Christodoulou et al. 2000). “D-CHRAMPS syndrome”: Cerebellar hypoplasia, Hypergonadotrophic hypogonadism, Retinitis pigmentosa, Alopecia, Microcephaly, Psychomotor retardation, and Short stature syndrome is a novel disorder which was reported but its gene locus had not been mapped yet (Hiyasat et al. 2002).

332

M. Dasouki and H. El-Shanti

Eye Diseases Studies of color blindness showed a prevalence of 8.72% in males and 0.33% in females with calculated color blindness gene allele frequencies of 0.087 in males, 0.003 in females and 0.016 in the total population (Al-Aqtum and Al-Qawasmeh 2001). The pattern of childhood blindness reflects a high frequency of genetic causes, especially autosomal recessive inheritance coupled with high consanguinity rates (Al-Salem and Rawashdeh 1992). In Northern Jordan it was found that 43% of blindness was caused by genetic disorders including tapetoretinal degenerations, glaucomas and congenital cataracts (Al-Salem et al. 1996). A large, highly inbred family from the Jordan valley consisting of about 2,000 living subjects in whom affected members had Leber congenital amaurosis (LCA) was described (Al-Salem 1997). A 31-member subset of this family was investigated and a homozygous (Q2646X) mutation in RETGC was identified (El-Shanti et al. 1999a). Isolated dominantly inherited ectopia lentis due to mutations in the fibrillin one gene had been reported previously. Two large consanguineous families with autosomal recessive isolated ectopia lentis were first reported (Al-Salem 1990). By homozygosity mapping, the gene was first mapped to chromosome 1p13.2–q21.1 then a homozygous truncating mutation (p.Y595X) was found in the ADAMTSL4 gene which disrupts the integrity of the lenticular zonular fibers (Ahram et al. 2009). Wolfram syndrome (DIDMOAD-Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is an autosomal recessive neurodegenerative disorder with locus heterogeneity. Sixteen patients from four different Jordanian families were studied; none of them had diabetes insipidus and several patients had profound upper gastrointestinal ulceration and bleeding (Ajlouni et al. 2002; Al-Sheyyab et al. 2001; Al-Till et al. 2002; Hadidy et al. 2004; Jarrah et al. 1999). Linkage to WFS1 (4p16.1) was excluded in three families which then showed linkage to 4q22–24 (WFS2) (El-Shanti et al. 2000). A pathogenic (E37Q) mutation in the ERIS (endoplasmic reticulum intermembrane small protein) gene was demonstrated in these families, which creates a new splice site and produces a smaller protein (Amr et al. 2007). Unlike Wolframin (WFS1), ERIS was not found to be mutated in isolated deafness.

Inborn Errors of Metabolism A small number of inborn errors of metabolism in Jordanians had been formally reported in the medical literature. The true spectrum and frequency of various metabolic disorders in Jordanians remains unknown. While basic screening for common biochemical genetic disorders is generally available, arriving at a specific diagnosis for many metabolic disorders is not possible without sending biological samples outside Jordan which is expensive and often times logistically difficult. Therefore, development of local and regional expertise in various groups of

11

Genetic Disorders in Jordan

333

metabolic disorders is necessary to provide timely and relatively inexpensive services. Recently, a limited national newborn screening program targeting congenital hypothyroidism and phenylketonuria began. According to the 2008 Jordan’s Ministry of Health report, there are 148 Jordanian patients with PKU who attend its clinics. These patients had 636 visits during 2008 which resulted in an average of 4.3 visits per year per patient. The prevalence of PKU in Jordan is therefore estimated at 0.26/10,000 individuals. Congenital adrenal hyperplasia was studied and it was found that 85% had classical presentation with salt wasting type in two thirds of these patients (Al-Maghribi 2007). In a family with several affected siblings, Aspartoacylase (Canavan disease) was reported and an exon 1 (p.G27R) mutation was identified (Masri and Hamamy 2006). The Centre for Arab Genomic Studies Work Group (2006) conducted a retrospective study for metabolic disorders described at Al-Wasl Hospital in Dubai between 1997 and 2006 (http://www.cags. org.ae/) and identified a few metabolic disorders among Jordanians living in the UAE, including one child with glycogen storage disease and two with maple syrup urine disease (MSUD). Pyruvate Kinase deficiency was reported in two unrelated patients with chronic hemolytic anemia which improved after splenectomy (Karadsheh 1993). A case of Wolman disease was diagnosed based on the radiological evidence of bilateral adrenal calcifications and foam cells in the bone marrow (Mahdi et al. 1991). Decreased “acid esterase” activity in skin fibroblasts confirmed the diagnosis. The concurrence of Papillon–Lefevre syndrome (PLS) and type 1 oculocutaneous albinism (OCA1) was reported in two Jordanian brothers. Both were found with compound heterozygous mutations in the cathepsin C (CTSC; c.3181G>A) and tyrosinase genes [c.817G>C/p.W272C] (Hattab and Amin 2005; Hewitt et al. 2004). These two genes are closely linked within 1Mb region on chromosome 11q14.2–14.3. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be common among Jordanians. In a group of 333 males, Usanga and Amin found 3.6% to be deficient (Usanga and Ameen 2000). The frequencies of GDPD A- and G6PD B- variants were 0.006 and 0.031 respectively. Some Jordanian patients with various metabolic disorders underwent therapeutic bone marrow transplantation (Abdel-Rahman et al. 2008). Polymorphisms in transferrin C, haptoglobin and mitochondrial DNA (mtDNA) had also been studied (Gonzalez et al. 2008; Janaydeh et al. 2004; Saha 1985). Lysosomal storage disorders (LSD) represent a large group of metabolic disorders characterized by deficiency of one of the several lysosomal acid hydrolases which leads to substrate accumulation in various organs including the brain and reticulo-endothelial system. The lipidoses (Gaucher and Fabry disease) are the most common types of LSD. Gaucher disease was reported in ten Jordanian patients (http://www.lsdregistry.net/gaucherregistry/). Two brothers with infantile Pompe disease were also recognized (personal observation). Trimethylaminuria (TMAU) is an autosomal recessive metabolic disorder characterized by an odor resembling that of rotten or decaying fish which occurs due to excess excretion of trimethylamine in body fluids (urine, breath, sweat, and reproductive fluids). Affected individuals have either an increased percent of total trimethylamine (free trimethylamine [TMA] plus the non-odorous metabolite

334

M. Dasouki and H. El-Shanti

TMA N-oxide) excreted in the urine as unmetabolized free TMA or the concentration of unmetabolized TMA in the urine. Defects in the FMO3 (flavin monooxygenase 3) gene cause TMAU. TMAU was found in 1.7% (2/116) Jordanian, 3.8% Ecuadorian and 11.0% (11/100) New Guinean individuals excreting 80% or less of their total trimethylamine as the N-oxide (Mitchell et al. 1997). Drug metabolism was assessed in Jordanians as well. CYP2D6 (Debrisoquine4-hydroxylase) is responsible for Dextromethorphan O-demethylation to dextrophan. Using thin layer chromatography, Irshaid et al. (1993) found that 2.9% of Jordanian volunteers were poor metabolizers of Dextromethorphan resulting in a 0.17 allele frequency. CYP2C19 is a clinically important enzyme that metabolizes a wide variety of drugs, including the anticonvulsant mephenytoin, anti-peptic ulcer drugs such as omeprazole, certain antidepressants, and the antimalarial drug proguanil. Mutation in the CYP2C19 gene causes poor metabolism of these drugs. In a group of 194 unrelated, healthy volunteers, 4.6% were found to be poor metabolizers giving an allele frequency of 0.215 which is similar to what had been observed in European populations (Hadidi et al. 1995).

Cardiovascular Disorders Congenital heart disease (isolated or syndromic) is a relatively common birth defect. In a group of 60 babies with cleft lip and/or cleft palate, 47% had congenital heart disease. Congenital heart disease was more frequent (60%) in the group of babies with combined cleft lip and cleft palate (Aqrabawi 2008). No chromosomal studies were done in any of these patients.

Pulmonary Disorders A raised protein level in the meconium of an infant with cystic fibrosis (CF) was described by Buchanan and Rapoport (1952) in an infant with meconium ileus (Buchanan and Rapoport 1952). Nazer prospectively screened 7,682 Jordanian neonates using this technique (Nazer 1992). Three of the four babies who had abnormally elevated meconium albumin levels had abnormal sweat chloride test. Therefore, the incidence of CF in Jordanians is about 1:2,560 live births. The clinical profile of CF appears to be different and more severe than it is in western countries. In Northern Jordan, a high frequency of pancreatic insufficiency (75%), history of meconium ileus (6.6%) and high mortality during infancy (23%) were found (Rawashdeh and Manal 2000). Twenty-four different CFTR gene mutations were identified in this population of 202 individuals with CF. The DF508 mutation accounted for only 7.4% of all CFTR mutations (Rawashdeh and Manal 2000). Similar findings were reported, in 72 children, where 20 different CFTR gene mutations were identified including five novel ones (296 þ 9A-T, T338M,

11

Genetic Disorders in Jordan

335

T760M, 3679delA, and G1244D) (Kakish 2001). Kakish also suggested an association between CF and infantile hypertrophic pyloric stenosis, which he observed in two children (Kakish 2002). Ciliary dyskinesia associated with hydrocephalus and mental retardation in a large three generation consanguineous Jordanian family with four affected brothers and possibly their maternal uncle was described (Al-Shroof et al. 2001). Chromosome analysis was normal while electron microscopy of the nasal cilia from three affected siblings showed features of primary ciliary dyskinesia. Computed tomographic scans of the brains of all four affected siblings showed hydrocephalus. Family history was consistent with autosomal recessive inheritance if the maternal uncle’s history was excluded and it was suggested that this phenotype is caused by a novel gene (Al-Shroof et al. 2001). Pulmonary alveolar microlithiasis (PAM) is a rare slowly progressive autosomal recessive lung disease characterized by the deposition of calcium phosphate microliths throughout the lungs. It is caused by mutations in SLC34A2 (Corut et al. 2006). PAM was recently described in an 8-month-old male infant presenting with worsening respiratory distress and cyanosis (Dahabreh and Najada 2009). Chest X-ray and CT scan showed diffuse reticulo-nodular densities and open lung biopsy showed diffused alveolar calcium deposits.

Gatrointestinal Disorders Many variants of alpha-1-antitrypsin (PI) had been described, and worldwide gene frequencies for allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V were tabulated (Roychoudhury and Nei 1988). The frequencies of the three common subtypes of PI M were studied in Jordan (Saleh et al. 1986). In comparison with other populations, PI*M3 was found to be low (0.038) and PI*M2 rather high (0.155). A highly significant difference in Lactose malabsorption (hypolactasia) was demonstrated between Jordanian Bedouins (24%), and Jordanians from the urban/ agricultural zone of western Jordan and Palestine (75%) using Lactose tolerance tests with breath hydrogen determination (Hijazi et al. 1983). These findings suggested that milk dependence in nomadic desert populations resulted in selective pressures in favor of the lactase persistence gene and hypolactasia gene frequencies were increased in people migrating from the desert border in Jordan to the Mediterranean shore. A single allele, carrying the T13910 variant 14 kb upstream of lactase LCT gene, fully correlates with Lactase Persistence (LP) in many global populations (Enattah et al. 2008). Sequencing of analysis of 56 random Jordanian DNA samples known to be of mixed origin revealed three LP mutations (C/T13910, T/G13915, T/C13913) The allele frequencies for each of these mutations was 0.054, 0.054, and 0.009 respectively. The total LP gene mutation allele frequency was 0.117. Dermatitis, diarrhea, alopecia, and growth failure are the cardinal clinical features of acrodermatitis enteropathica (AE), a rare autosomal recessive disorder caused by insufficient uptake of zinc by the intestine. AE can be fatal unless the diet

336

M. Dasouki and H. El-Shanti

is supplemented with zinc. The AE gene was mapped to chromosome 8q24.3 using a genome-wide screen done on 17 individuals from a consanguineous Jordanian family (Wang et al., 2001). The intestinal zinc transporter (SLC39A4) was found to be the gene responsible for AE (Kury et al. 2002; Wang et al. 2002). This gene is expressed in the apical membrane of mouse intestinal enterocytes. The Jordanian family was found to have a homozygous “G630R” mutation. Juvenile polyposis syndrome is an autosomal dominant disorder that predisposes gene carriers to various types of tumors. The risk of malignant transformation in the hamartomatous gastrointestinal polyps seen in JPS patients is approximately 20%. BMPR1 and SMAD4 are the only genes known thus far to cause JPS (Handra-Luca et al. 2005). Two Jordanian siblings having JPS while their father had non-polyposis colon cancer at the age of 35 have been described (Al-Jaberi and El-Shanti 2002).

Genitourinary Disorders The estimated prevalence of chronic renal failure in children in Jordan is 51 per million population and the incidence as 10.7 new cases per million child population per year (Hamed 2002). The most common causes of chronic renal failure were urological abnormalities and malformations (42%) followed by hereditary renal disorders (42%). He also reported on renal cysts and associated malformations in pediatric autopsy material (Hamed et al. 1998). In Jordanian adults who underwent renal biopsies, focal segmental glomerulosclerosis was the most common histological diagnosis (Wahbeh et al. 2008). Congenital nephrotic syndrome (Finnish type) is a serious renal disease in Jordanian children with 100% mortality by 5 years of age (Hamed 2003; Hamed and Shomaf 2001). Thirty such children were diagnosed based on their clinical findings and light microscopic examinations of their renal biopsies. Chronic renal insufficiency developed in 17, and five of them needed chronic peritoneal dialysis. Galloway-Mowat syndrome is an autosomal recessive disorder characterized by an early onset of the nephrotic syndrome and central nervous system anomalies. Mutations in podocyte proteins, such as nephrin, alpha-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. The genetic defect in Galloway-Mowat syndrome is as yet unknown. Two Jordanian children were diagnosed as having Galloway–Mowat syndrome (Srivastava et al. 2001).

Autoimmune, Autoinflammatory and Rheumatologic Disorders The distribution of the different HLA phenotypes and genotypes was determined through a comprehensive study (Sanchez-Velasco et al. 2001). Twenty alleles for the locus HLA-A and 46 for the HLA-B locus were detected, which indicates the existence of high polymorphism in this area. The results suggest that both

11

Genetic Disorders in Jordan

337

HLA class I and class II polymorphism of the Jordanian population demonstrates considerable heterogeneity, which reflects ancient and recent admixture with neighboring populations, and important human migratory trends throughout the history. The association of the different HLA phenotypes and genotypes with multiple sclerosis (MS) has been the subject of one study (Brautbar et al. 1982). It showed that there is a lack of association of A3 and B7 and MS in the Jordanian population. Chediak–Higashi Syndrome (CHS) is a rare autosomal recessive disorder of the immune system, characterized by chronic infections, neutropenia, partial oculocutaneous albinism, and bleeding diatheses with partial neuropathy. Eight patients with CHS from three unrelated families were reported from Jordan, with a review of the clinical literature (Al-Sheyyab et al. 2000). A similar but unrelated group of disorders, designated as Griscelli syndromes, has been reported from Jordan (Masri et al. 2008b). Familial Mediterranean Fever (FMF) is characterized by recurrent self-limiting episodes of fever and painful polyserositis affecting mainly the peritoneum, pleura and synovium. FMF is an autosomal recessive disorder, with considerable prevalence in specific ethnic groups, namely, non-Ashkenazi Jews, Armenians, Turks, and Arabs (El-Shanti et al. 2006b). There is a plethora of reports regarding the clinical, genetic and mutational spectrum in the Jordanian population (Al-Alami et al. 2003; Al-Wahadneh and Dahabreh 2006; El-Shanti et al. 2006b; El-Shanti 2001, 2003; Majeed et al. 2000a; Majeed et al. 2005; Majeed et al. 2002; Majeed et al. 1999; Medlej-Hashim et al. 2000, 2005; Milhavet et al. 2008; Rawashdeh and Majeed 1996; Touitou et al. 2007). It is important to identify if there is a distinctive pattern of the relationship between MEFV and the FMF phenotype. Achieving this goal will lead to the establishment of adequate population screening protocols for early and presymptomatic identification of patients and the provision of prophylactic colchicine therapy. Chronic recurrent multifocal osteomyelitis (CRMO) is a relatively rare childhood disease that presents with pain in the bone with or without associated fever (El-Shanti and Ferguson 2007; Ferguson and El-Shanti 2007). A syndromic form of CRMO was first described by Dr. Hassan Abdel Majeed and his colleagues in 1989 (Majeed et al. 1989) and was subsequently named after him as the Majeed syndrome. Affected individuals present with periodic fevers, early-onset CRMO (age range 3 weeks to 19 months), microcytic congenital dyserythropoietic anemia, and often transiently occurring inflammatory dermatosis (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). Like sporadic CRMO, there is a predilection for the metaphyses of the long bones, and the radiographs demonstrate extensive lytic lesions with areas of sclerosis (Majeed et al. 2001). The congenital dyserythropoietic anemia presents during the first year of life and the resultant anemia varies in severity from mild to transfusion-dependent (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The dermatosis is most often Sweet syndrome. Majeed syndrome is an autosomal recessive disorder caused by mutations in LPIN2 (Ferguson et al. 2005). The gene responsible for Majeed syndrome was localized to the short arm of chromosome 18 using homozygosity mapping, because the first two described families were inbred. To date, three different homozygous mutations

338

M. Dasouki and H. El-Shanti

in LPIN2 have been found in each of the reported families with Majeed syndrome, all of whom are Arabic (Al-Mosawi et al. 2007; Ferguson et al. 2005) (available at http://fmf.igh.cnrs.fr/infevers). Behcet disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation, and skin lesions. The etiology of the disease is currently unknown but evidence suggests that there is a strong genetic component mediating the chronicity of the disorder. There is a strong BD society in Jordan that provides support, services and information to patients and families (Tamimi and Madanat 2003). Several studies have involved Jordanian BD patients to examine associations between specific clinical aspects of the disease and DNA polymorphisms (Takemoto et al. 2008; Verity et al. 1999a, b), as well as association studies in search of etiologic genetic factors (Ahmad et al. 2005; Baranathan et al. 2007; Verity et al. 2000; Wallace et al. 1999, 2007; Yang et al. 2004). In addition, there are several descriptive reports on the BD patient population (Madanat et al. 1993, 2003; Madanat and Madanat 2008).

Endocrinological Disorders Diabetes Mellitus is quite prevalent in Jordan and that is attributed to changes in dietary habits and life style (Ajlouni et al. 2008). Surveys of the prevalence of the different types of DM, its associations and complications has been professionally carried out in Jordan (Abdallah et al. 2007; Abdel-Aal et al. 2008; Abu Ali et al. 2008; Ajlouni et al. 1998a, 1999; Al-Till et al. 2005; Awadallah and Hamad 2000; Jbour et al. 2003b; Khatib et al. 2006; Radaideh et al. 2004). A genotypic and phenotypic variant of a syndromic form of DM, Wolfram syndrome (DIDMOAD; Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) has been described from Jordan and its clinical picture has been clearly outlined (Ajlouni et al. 2002; Al-Sheyyab et al. 2001; Al-Till et al. 2002; Hadidy et al. 2004; Jarrah et al. 1999). The variant was mapped to the long arm of chromosome 4 (El-Shanti et al. 2000) and the gene encoding for the responsible protein, ERIS, was identified 8 years later (Amr et al. 2007). The effect of metformin on the androgenic profile of diabetic and normal men was prospectively studied (Shegem et al. 2002, 2004). Similar to all neighboring countries, as well as the developed world, obesity is forcefully emerging as a public health problem in Jordan (Ajlouni et al. 1998b). According to a recent study, age-standardized prevalence of obesity in Northern Jordan was 28.1% for men and 53.1% for women. Irrespective of age or measure used, women always had a considerably higher prevalence of obesity than men. There has been a significant increase in the prevalence of obesity over a period of ten years for both men and women aged 60 years and above only. This study demonstrated alarming rates of obesity and of its associated comorbidities among Jordanians (Khader et al. 2008). Other studies, done in Jordan, indirectly showed that obesity is remarkably increasing (Hasan et al. 2001; Jaddou et al. 2003; Khader et al. 2007; Majali et al. 2003).

11

Genetic Disorders in Jordan

339

Kallman syndrome is a genetically heterogeneous disorder associated with hypogonadism and anosmia. The clinical picture of 32 patients from 12 families was delineated and the presenting features were outlined (Abujbara et al. 2004). A standard clinical smell testing protocol was devised from the National Center for Diabetes, Endocrinology and Genetics to allow for accurate and culturally appropriate evaluation of anosmia (Ahmad et al. 2007). Congenital adrenal hyperplasia has been studied in Jordan and atypical forms were reported (Ajlouni et al. 1996; Arnaout 1992). The classic type, due to the 21hydroxylase deficiency has been reported on recently, especially in relation to the development of sexual organs (Al-Maghribi 2007). In a recent study aimed to display the spectrum of initial presentation and etiology among children with precocious puberty and to assess any association between the clinical features and the underlying cause of the condition, congenital adrenal hyperplasia was diagnosed in four boys and four girls, and hypothyroidism in three girls (Taher et al. 2004). Rare causes of hypogonadism were reported (Hiyasat et al. 2002; Jbour et al. 2003a), as well as a rare family with true hermaphroditism (Jarrah et al. 2000).

Genodermatosis Although autosomal recessive disorders of skin are often diagnosed such as epidermolysis bullosa, ectodermal dysplasia and ichthyosis, these are not usually reported in the literature. A case of lamellar ichthyosis was reported secondary to the development of acute lymphocytic leukemia (Al-Sheyyab et al. 1996). Alopecia with partial, total or universal has been reported in Jordanians in association of other abnormalities. Two Christian Jordanian sisters and their brothers were reported with primary hypogonadism, partial alopecia and defective Mullerian development (only in the sisters) (Al-Awadi et al. 1985). Five children from two unrelated families were reported with alopecia universalis, laryngomalacia, short stature and gonadal dysgenesis (El-Shanti 2004; El-Shanti et al. 2003). One more patient was reported upon from Toronto with the same syndromic features (Teebi et al. 2004). AE is caused by insufficient uptake of zinc by the intestine. The AE gene was mapped to chromosome 8q24.3 using a consanguineous Jordanian family (Wang et al. 2001). The Jordanian family was found to have a homozygous “G630R” mutation, once the gene was identified (Wang et al. 2002).

Skeletal and Dental Disorders Nine Jordanian families having 20 individuals affected with amelogenesis imperfecta (AI) and 41 unaffected were studied by light and scanning electron microscopy along with amino acid analysis of the enamels (Nusier et al. 2004). The authors

340

M. Dasouki and H. El-Shanti

proposed to classify the disorder as “autosomal recessive generalized thin hypoplastic AI,” giving importance to the mode of inheritance, as well as the clinical form (Nusier et al. 2004). The cathepsin C gene (CTSC) encodes a cysteine lysosomal protease belonging to the papain family, called dipeptidyl peptidase I. The enzymatic function of this protease is the removal of amino terminal dipetides of the protein substrate. In the immune cells, the protease plays a role in removing the activation dipeptide from many of the leukocyte and mast cell granule-associated proteinases, which is considered an essential step for the PMN mediated killing of pathogens. Mutations in the CTSC gene have been implicated in PLS, Haim-Munk syndrome, and prepubertal periodontitis where early onset periodontitis is a common manifestation. Several families with these disorders were reported and mutations within CTSC were found (Hart et al. 2000; Hattab and Amin 2005; Hattab et al. 1995; Nusier et al. 2002). Two siblings with Ellis-Van Creveld were presented to include their oral findings, summarized as multiple broad labial frenula with abnormal attachments, congenital missing incisors and anomalous teeth (Hattab et al. 1998). The same group presented the oral findings in a case resembling Grebe chondrodysplasia (Hattab et al. 1996). Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive skeletal dysplasia with radiographic changes in the spine similar to Spondyloepiphyseal dysplasia tarda with clinical, though not radiographic, resemblance to rheumatoid arthritis (El-Shanti et al. 1997). It is a prevalent condition among the Arabs and has been reported from Jordan. The gene responsible for this disorder was mapped to the long arm of chromosome 6 (El-Shanti et al. 1998), and later identified as WISP3 (Hurvitz et al. 1999). Several other reports of different other skeletal disorders originated from Jordan, such as mulitple enchondromatosis (Mahafza 2004), Raine syndrome (Mahafza et al. 2001) and Holt–Oram syndrome (Boehme and Shotar 1989).

Hematological and Oncologic Disorders The hemoglobinopathies constitute a large heterogeneous group of hemoglobin disorders, including b-thalassemia, a-thalassemia and sickle cell anemia. The prevalence of these disorders is significantly high in the Jordanian population (Bashir et al. 1992a, b), which mandated premarital testing for b-thalassemia. There are several manuscripts that describe different clinical aspects and care of children with b-thalassemia (Abu Alhaija et al. 2002; Al-Rimawi et al. 2005, 2006; Al Qaddoumi 2006; Barkawi et al. 1991; Hattab et al. 2001). The spectrum of mutations in the b-globin gene was the subject of several studies (Adekile et al. 1994; Al Qaddoumi 2006; el-Hazmi et al. 1995; Sadiq et al. 2001; Sadiq and Huisman 1994). On the other hand, there are several studies of the clinical and molecular aspects of a-thalassemia (Adekile et al. 1994; Al Qaddoum 2006). Sickle cell anemia is not

11

Genetic Disorders in Jordan

341

systematically studied, despite its considerable prevalence (Al-Rimawi et al. 2006; Al-Salem 1991; Al-Salem and Ismail 1990; Barkawi et al. 1991; Bashir et al. 1992a, b; Talafih et al. 1996). Rare forms of anemias have been subjects of several reports, such as the congenital dyserythropoietic anemia of Majeed syndrome (Majeed et al. 2001), selective vitamin B12 malabsorption anemia (Al-Alami et al. 2002, 2005) and Fanconi anemia (Al-Sheyyab et al. 1998). Glucose-6-dehydrogenase (G-6-PD) deficiency is quite prevalent in the Jordanian population but due to its mild symptoms it has not gained significant systematic studying of its clinical and molecular aspects except in recent years (Karadsheh et al. 2005a, b; Kurdi-Haidar et al. 1990; Talafih et al. 1996; Usanga and Ameen 2000). Several studies looked at variants and at mutations and their distribution in the population (Karadsheh et al. 2005a, b). Molecular screening for G6PD mutations in two Jordanian populations revealed six different mutations and higher incidences of G6PD deficiency and G6PD A- (376A!G þ 202G!A) mutation in Jordan Valley than in the Amman area (Karadsheh et al. 2005b). One manuscript deals with treatment issues relative to the acute hemolytic anemia (Al-Rimawi et al. 1999). Bleeding disorders, whether rare or common, are reported from Jordan with some depth in studying their etiology (Al-Sheyyab et al. 2001; Awidi 1992; Qublan et al. 2006; Rosenberg et al. 2005). The frequency of factor V Leiden has been studied, somewhat extensively, probably due to its role in technology assisted pregnancy (Awidi et al. 1999; Eid and Rihani 2004; Eid and Shubeilat 2005; Nusier et al. 2007; Qublan et al. 2006, 2008; Verity et al. 1999a). It appears that about 20% of the population are heterozygous and 5% are homozygous for the Leiden allele (Eid and Shubeilat 2005). The ABO blood group allele frequency was studied in the Jordanian population as part of larger studies (Hosseini-Maaf et al. 2003, 2005). There are a mediocre number of reports regarding cancer genetics despite the high impact of cancer on the Jordanian society. There is one study exploring the frequency of P53 gene polymorphism in healthy Jordanians and comparison to the frequency of the polymorphisms in cancer patients (Mahasneh and Abdel-Hafiz 2004). A study that investigated the presence of germ-line mutations in BRCA1 among 135 breast cancer patients revealed six germ-line mutations (Atoum and Al-Kayed 2004); however, it followed two studies of risk factors relating to breast cancer (Atoum and Al-Hourani 2004a, b). The investigation of hormone receptor positivity among Jordanian patients with breast cancer showed that the prevalence of hormone receptor positivity in breast cancer of Jordanian women is lower than that of the western populations (Almasri and Al Hamad 2005; Sughayer et al. 2006). A major study that investigated methylation patterns in colorectal carcinoma from three Middle Eastern countries including Jordan showed that it has differing gene methylation patterns and mutation frequencies that indicate dissimilar molecular pathogenesis, probably reflecting different environmental exposures (Chan et al. 2005). Studies on the molecular aspects of lymphomas in Jordan included a study on Bcl-2 rearrangements (Almasri et al. 2005), the presence of ‘The transforming mutation’ E17K/AKT1in B-cell lymphomas (Mahmoud et al. 2008), and the Frequency of t(14;18) in follicular carcinoma (Ismail et al. 2009).

342

M. Dasouki and H. El-Shanti

Conclusion Jordan is a developing country with limited natural resources. Jordan has one of the highest rates of consanguinity among the Arab countries which is clearly associated with a significant number of recognizable and novel genetic disorders. Over the last few decades, health care services improved significantly in Jordan while the health needs of its people continue to grow, as well. Care for patients with chronic diseases including genetic disorders is becoming increasingly important. The available genetic services appear to be limited, fragmented and do not meet the need of the people of Jordan. While significant gains in knowledge about the spectrum of genetic disorders among Jordanians had been achieved, the magnitude and breadth of the health, financial and socioeconomic effects had not been adequately studied or appreciated. Making early identification, education, prenatal genetic diagnosis readily available along with allocation of adequate technical, financial and manpower resources should help control the huge impact genetic disorders have on Jordan’s population.

References Abdallah S, Ahmad AT, Batieha A, Ajlouni K (2007) Diabetes mellitus: the leading cause of haemodialysis in Jordan. East Mediterr Health J 13(4):803–9 Abdel-Aal NM, Ahmad AT, Froelicher ES, Batieha AM, Hamza MM, Ajlouni KM (2008) Prevalence of dyslipidemia in patients with type 2 diabetes in Jordan. Saudi Med J 29 (10):1423–8 Abdel-Rahman F, Hussein A, Rihani R, Hlalah O, El Taani H, Sharma S, Nserat T, Sarhan M (2008) Bone marrow and stem cell transplantation at King Hussein cancer center. Bone Marrow Transplant 42(Suppl 1):S89–S91 Abu Alhaija ES, Hattab FN, al-Omari MA (2002) Cephalometric measurements and facial deformities in subjects with beta-thalassaemia major. Eur J Orthod 24(1):9–19 Abu Ali RM, Al Hajeri RM, Khader YS, Shegem NS, Ajlouni KM (2008) Sexual dysfunction in Jordanian diabetic women. Diabetes Care 31(8):1580–1 Abujbara MA, Hamamy HA, Jarrah NS, Shegem NS, Ajlouni KM (2004) Clinical and inheritance profiles of Kallmann syndrome in Jordan. Reprod Health 1(1):5 Adekile AD, Gu LH, Baysal E, Haider MZ, al-Fuzae L, Aboobacker KC, al-Rashied A, Huisman TH (1994) Molecular characterization of alpha-thalassemia determinants, beta-thalassemia alleles, and beta S haplotypes among Kuwaiti Arabs. Acta Haematol 92(4):176–81 Ahmad T, Zhang L, Gogus F, Verity D, Wallace G, Madanat W, Fayyad F, James T, Neville M, Kanawati C et al (2005) CARD15 polymorphisms in Behcet’s disease. Scand J Rheumatol 34(3):233–7 Ahmad AT, Jbara MA, Hiyasat D, Bateiha A, Ajlouni KM (2007) The standard clinical smell testing protocol of the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan: JOR test. Am J Otolaryngol 28(6):388–91 Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84(2):274–8 Ajlouni KM, Arnaout MA, Qoussous Y (1996) Congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency with skeletal abnormalities. J Endocrinol Invest 19(5):316–9

11

Genetic Disorders in Jordan

343

Ajlouni K, Jaddou H, Batieha A (1998a) Diabetes and impaired glucose tolerance in Jordan: prevalence and associated risk factors. J Intern Med 244(4):317–23 Ajlouni K, Jaddou H, Batieha A (1998b) Obesity in Jordan. Int J Obes Relat Metab Disord 22(7): 624–8 Ajlouni K, Qusous Y, Khawaldeh AK, Jaddou H, Batiehah A, Ammari F, Zaheri M, Mashal A (1999) Incidence of insulin-dependent diabetes mellitus in Jordanian children aged 0-14 y during 1992–1996. Acta Paediatr Suppl 88(427):11–3 Ajlouni K, Jarrah N, El-Khateeb M, El-Zaheri M, El Shanti H, Lidral A (2002) Wolfram syndrome: identification of a phenotypic and genotypic variant from Jordan. Am J Med Genet 115(1):61–5 Ajlouni K, Khader YS, Batieha A, Ajlouni H, El-Khateeb M (2008) An increase in prevalence of diabetes mellitus in Jordan over 10 years. J Diabetes Complications 22(5):317–24 Al Qaddoumi AA (2006) Co-inheritance of alpha and beta-thalassemia in a Jordanian family. Clin Lab Sci 19(3):165–8 Al-Alami JR, Tayeh MK, Al-Sheyyab MY, El-Shanti HI (2002) Linkage analysis of a large inbred family with congenital megaloblastic anemia. Saudi Med J 23(10):1251–6 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–9 Al-Alami JR, Tanner SM, Tayeh MK, de la Chapelle A, El-Shanti H (2005) Homozygous AMN mutation in hereditary selective intestinal malabsorption of vitamin B12 in Jordan. Saudi Med J 26(7):1061–4 Al-Aqtum MT, Al-Qawasmeh MH (2001) Prevalence of colour blindness in young Jordanians. Ophthalmologica 215(1):39–42 Al-Awadi SA, Farag TI, Teebi AS, Naguib K, el-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN (1985) Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22(3):619–22 Al-Jaberi TM, El-Shanti H (2002) Diversity in polyp pathology and distribution of Familial Juvenile Polyposis Syndrome. Saudi Med J 23(3):328–31 Al-Maghribi H (2007) Congenital adrenal hyperplasia: problems with developmental anomalies of the external genitalia and sex assignment. Saudi J Kidney Dis Transpl 18(3):405–13 Almasri NM, Al Hamad M (2005) Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan. Breast Cancer Res 7(5):R598–604 Almasri NM, Al-Alami J, Faza M (2005) Bcl-2 gene rearrangement in Jordanian follicular and diffuse large B-cell lymphomas. Saudi Med J 26(2):251–5 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56(3):960–4 Al-Qudah AA (1998) Clinical patterns of neuronal migrational disorders and parental consanguinity. J Trop Pediatr 44(6):351–4 Al-Qudah AA, Tarawneh M (1998) Congenital muscular dystrophy in Jordanian children. J Child Neurol 13(8):383–6 Al-Rimawi HS, Al-Sheyyab M, Batieha A, El-Shanti H, Abuekteish F (1999) Effect of desferrioxamine in acute haemolytic anaemia of glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 101(3):145–8 Al-Rimawi HS, Jallad MF, Amarin ZO, Obeidat BR (2005) Hypothalamic-pituitary-gonadal function in adolescent females with beta-thalassemia major. Int J Gynaecol Obstet 90(1):44–7 Al-Rimawi HS, Abdul-Qader M, Jallad MF, Amarin ZO (2006) Acute splenic sequestration in female children with sickle cell disease in the North of Jordan. J Trop Pediatr 52(6):416–20 Al-Salem M (1990) Autosomal recessive ectopia lentis in two Arab family pedigrees. Ophthalmic Paediatr Genet 11(2):123–7 Al-Salem M (1991) Benign ocular manifestations of sickle cell anemia in Arabs. Indian J Ophthalmol 39(1):9–11

344

M. Dasouki and H. El-Shanti

Al-Salem M (1997) Leber’s congenital amaurosis in 22 affected members of one family. J Pediatr Ophthalmol Strabismus 34(4):254–7 Al-Salem M, Ismail L (1990) Ocular manifestations of sickle cell anaemia in Arab children. Ann Trop Paediatr 10(2):199–202 Al-Salem M, Rawashdeh N (1992) Pattern of childhood blindness and partial sight among Jordanians in two generations. J Pediatr Ophthalmol Strabismus 29(6):361–5 Al-Salem M, Rawashdeh N (1993) Consanguinity in north Jordan: prevalence and pattern. J Biosoc Sci 25(4):553–6 Al-Salem M, Arafat AF, Ismail L, Jaradat M (1996) Causes of blindness in Irbid, Jordan. Ann Saudi Med 16(4):420–3 Al-Sheyyab M, El Shanti H, Todd D, Shurman A (1996) Autosomal recessive lamellar ichthyosis and acute lymphoblastic leukemia. Eur J Hum Genet 4(2):105–7 Al-Sheyyab M, El-Shanti H, Ghariebeh N, Ektiesh F, Daoud AS (1998) Fanconi’s anemia and primary hypothyroidism. Ann Saudi Med 18(1):58–9 Al-Sheyyab M, Daoud AS, El-Shanti H (2000) Chediak–Higashi syndrome: a report of eight cases from three families. Indian Pediatr 37(1):69–75 Al-Sheyyab M, Jarrah N, Younis E, Shennak MM, Hadidi A, Awidi A, El-Shanti H, Ajlouni K (2001) Bleeding tendency in Wolfram syndrome: a newly identified feature with phenotype genotype correlation. Eur J Pediatr 160(4):243–6 Al-Shroof M, Karnik AM, Karnik AA, Longshore J, Sliman NA, Khan FA (2001) Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family. Mayo Clin Proc 76(12):1219–24 Al-Till M, Jarrah NS, Ajlouni KM (2002) Ophthalmologic findings in fifteen patients with Wolfram syndrome. Eur J Ophthalmol 12(2):84–8 Al-Till MI, Al-Bdour MD, Ajlouni KM (2005) Prevalence of blindness and visual impairment among Jordanian diabetics. Eur J Ophthalmol 15(1):62–8 Al-Wahadneh AM, Dahabreh MM (2006) Familial Mediterranean fever in children: a single centre experience in Jordan. East Mediterr Health J 12(6):818–23 Amarin VN, Akasheh HF (2001) Advanced maternal age and pregnancy outcome. East Mediterr Health J 7(4–5):646–51 Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H, Shiang R (2007) A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 81(4):673–83 Aqrabawi HE (2008) Facial cleft and associated anomalies: incidence among infants at a Jordanian medical centre. East Mediterr Health J 14(2):356–9 Arnaout MA (1992) Late-onset congenital adrenal hyperplasia in women with hirsutism. Eur J Clin Invest 22(10):651–8 Atoum MF, Al-Hourani HM (2004a) Comparison of some risk factors between non-familial and familial breast cancer females in Jordan. Saudi Med J 25(2):168–71 Atoum MF, Al-Hourani HM (2004b) Lifestyle related risk factors for breast cancer in Jordanian females. Saudi Med J 25(9):1245–8 Atoum MF, Al-Kayed SA (2004) Mutation analysis of the breast cancer gene BRCA1 among breast cancer Jordanian females. Saudi Med J 25(1):60–3 Awadallah S, Hamad M (2000) The prevalence of type II diabetes mellitus is haptoglobin phenotype-independent. Cytobios 101(398):145–50 Awidi AS (1992) Rare inherited bleeding disorders secondary to coagulation factors in Jordan: a nine-year study. Acta Haematol 88(1):11–3 Awidi A, Shannak M, Bseiso A, Kailani MA, Kailani MA, Omar N, Anshasi B, Sakarneh N (1999) High prevalence of factor V Leiden in healthy Jordanian Arabs. Thromb Haemost 81(4):582–4 Badria LF, Amarin ZO (2003) Does consanguinity affect the severity of pre-eclampsia? Arch Gynecol Obstet 268(2):117–20 Badria LF, Abu-Heija A, Zayed F, Ziadeh SM, Alchalabi H (2001) Has consanguinity any impact on occurrence of pre-eclampsia and eclampsia? J Obstet Gynaecol 21(4):358–60

11

Genetic Disorders in Jordan

345

Baranathan V, Stanford MR, Vaughan RW, Kondeatis E, Graham E, Fortune F, Madanat W, Kanawati C, Ghabra M, Murray PI et al (2007) The association of the PTPN22 620W polymorphism with Behcet’s disease. Ann Rheum Dis 66(11):1531–3 Barkawi M, Bashir N, Sharif L (1991) Sickle cell-thalassemia in a Jordanian family. Trop Geogr Med 43(1–2):94–9 Bashir N, Barkawi M, Sharif L (1992a) Sickle cell/beta-thalassemia in North Jordan. J Trop Pediatr 38(4):196–8 Bashir N, Barkawi M, Sharif L, Momani A, Gharaibeh N (1992b) Prevalence of hemoglobinopathies in north Jordan. Trop Geogr Med 44(1–2):122–5 Bassuk AG, Wallace RH, Buhr A, Buller AR, Afawi Z, Shimojo M, Miyata S, Chen S, GonzalezAlegre P, Griesbach HL et al (2008) A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum Genet 83(5):572–81 Berkovic SF, Mazarib A, Walid S, Neufeld MY, Manelis J, Nevo Y, Korczyn AD, Yin J, Xiong L, Pandolfo M et al (2005) A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping. Brain 128(Pt 3):652–8 Boehme DH, Shotar AO (1989) A complex deformity of appendicular skeleton and shoulder with congenital heart disease in three generations of a Jordanian family. Clin Genet 36(6): 442–50 Brautbar C, Amar A, Cohen N, Oksenberg J, Cohen I, Kahana E, Bloch D, Alter M, Grosse-Wilde H (1982) HLA-D typing in multiple sclerosis: Israelis tested with European homozygous typing cells. Tissue Antigens 19(3):189–97 Buchanan DJ, Rapoport S (1952) Chemical comparison of normal meconium and meconium from a patient with meconium ileus. Pediatrics 9(3):304–10 Chan AO, Soliman AS, Zhang Q, Rashid A, Bedeir A, Houlihan PS, Mokhtar N, Al-Masri N, Ozbek U, Yaghan R et al (2005) Differing DNA methylation patterns and gene mutation frequencies in colorectal carcinomas from Middle Eastern countries. Clin Cancer Res 11(23): 8281–7 Christodoulou K, Zamba E, Tsingis M, Mubaidin A, Horani K, Abu-Sheik S, El-Khateeb M, Kyriacou K, Kyriakides T, Al-Qudah AK et al (2000) A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12. Ann Neurol 48(6):877–84 Cook R, Hanslip A (1966) Mortality among offspring of consanguineous marriage in a rural area of East Jordan. J Trop Pediatr Afr Child Health 11(4):95–9 Corut A, Senyigit A, Ugur SA, Altin S, Ozcelik U, Calisir H, Yildirim Z, Gocmen A, Tolun A (2006) Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. Am J Hum Genet 79(4):650–6 Dahabreh M, Najada A (2009) Pulmonary alveolar microlithiasis in an 8-month-old infant. Ann Trop Paediatr 29(1):55–9 Daoud AS, Batieha A, Bashtawi M, El-Shanti H (2003) Risk factors for childhood epilepsy: a casecontrol study from Irbid, Jordan. Seizure 12(3):171–4 Daoud AS, Ajloni S, El-Salem K, Horani K, Otoom S, Daradkeh T (2004) Risk of seizure recurrence after a first unprovoked seizure: a prospective study among Jordanian children. Seizure 13(2):99–103 Eid SS, Rihani G (2004) Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in 200 healthy Jordanians. Clin Lab Sci 17(4):200–2 Eid SS, Shubeilat T (2005) Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR G677A among 594 thrombotic Jordanian patients. Blood Coagul Fibrinolysis 16(6):417–21 el-Hazmi MA, Warsy AS, al-Swailem AR (1995) The frequency of 14 beta-thalassemia mutations in the Arab populations. Hemoglobin 19(6):353–60 El-Shanti HE (2001) Familial Mediterranean Fever. Saudi Med J 22(2):104–9 El-Shanti HI (2003) Familial mediterranean Fever and renal disease. Saudi J Kidney Dis Transpl 14(3):378–85 El-Shanti H (2004) Further delineation of El-Shanti syndrome. Eur J Pediatr 163(12):761–2

346

M. Dasouki and H. El-Shanti

El-Shanti H, Al-Alami J (2002) The pattern of peripheral blood chromosomal abnormalities in Northern Jordan. Saudi Med J 23(12):1552–4 El-Shanti HI, Ferguson PJ (2007) Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–9 El-Shanti HE, Omari HZ, Qubain HI (1997) Progressive pseudorheumatoid dysplasia: report of a family and review. J Med Genet 34(7):559–63 El-Shanti H, Murray JC, Semina EV, Beutow KH, Scherpbier T, Al-Alami J (1998) Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Eur J Hum Genet 6(3):251–6 El-Shanti H, Al-Salem M, El-Najjar M, Ajlouni K, Beck J, Sheffiled VC, Stone EM (1999a) A nonsense mutation in the retinal specific guanylate cyclase gene is the cause of Leber congenital amaurosis in a large inbred kindred from Jordan. J Med Genet 36(11):862–5 El-Shanti HE, Daoud AS, Batieha A (1999b) A clinical study of a large inbred kindred with pure familial spastic paraplegia. Brain Dev 21(7):478–82 El-Shanti H, Lidral AC, Jarrah N, Druhan L, Ajlouni K (2000) Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am J Hum Genet 66 (4):1229–36 El-Shanti H, Ahmad M, Ajlouni K (2003) Alopecia universalis congenita, XY gonadal dysgenesis and laryngomalacia: a novel malformation syndrome. Eur J Pediatr 162(1):36–40 El-Shanti H, Daoud A, Sadoon AA, Leal SM, Chen S, Lee K, Spiegel R (2006a) A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev 28(6):353–7 El-Shanti H, Majeed HA, El-Khateeb M (2006b) Familial mediterranean fever in Arabs. Lancet 367(9515):1016–24 Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF et al (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82(1):57–72 Ferguson PJ, El-Shanti HI (2007) Autoinflammatory bone disorders. Curr Opin Rheumatol 19(5): 492–8 Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42(7):551–7 Gonzalez AM, Karadsheh N, Maca-Meyer N, Flores C, Cabrera VM, Larruga JM (2008) Mitochondrial DNA variation in Jordanians and their genetic relationship to other Middle East populations. Ann Hum Biol 35(2):212–31 Hadidi HF, Irshaid YM, Woosley RL, Idle JR, Flockhart DA (1995) S-mephenytoin hydroxylation phenotypes in a Jordanian population. Clin Pharmacol Ther 58(5):542–7 Hadidy AM, Jarrah NS, Al-Till MI, El-Shanti HE, Ajlouni KM (2004) Radiological findings in Wolfram syndrome. Saudi Med J 25(5):638–41 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67(6):511–6 Hamamy H, Al-Hait S, Alwan A, Ajlouni K (2007a) Jordan: communities and community genetics. Community Genet 10(1):52–60 Hamamy HA, Masri AT, Al-Hadidy AM, Ajlouni KM (2007b) Consanguinity and genetic disorders. Profile from Jordan. Saudi Med J 28(7):1015–7 Hamamy HA, Teebi AS, Oudjhane K, Shegem NN, Ajlouni KM (2007c) Severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility in two brothers: new syndrome? Am J Med Genet A 143(3):229–34 Hamed RM (2002) The spectrum of chronic renal failure among Jordanian children. J Nephrol 15(2):130–5 Hamed RM (2003) Congenital nephrotic syndrome. Saudi J Kidney Dis Transpl 14(3):328–35

11

Genetic Disorders in Jordan

347

Hamed RM, Shomaf M (2001) Congenital nephrotic syndrome: a clinico-pathologic study of thirty children. J Nephrol 14(2):104–9 Hamed RM, Tamimi S, Al-Shamayleh A, Kamal MF, Tarawneh M, Toffaha A (1998) Renal cysts and associated malformations in pediatric autopsy material. Ann Saudi Med 18(5):451–3 Hampshire DJ, Roberts E, Crow Y, Bond J, Mubaidin A, Wriekat AL, Al-Din A, Woods CG (2001) Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. J Med Genet 38(10):680–2 Handra-Luca A, Condroyer C, de Moncuit C, Tepper M, Flejou JF, Thomas G, Olschwang S (2005) Vessels’ morphology in SMAD4 and BMPR1A-related juvenile polyposis. Am J Med Genet A 138A(2):113–7 Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, Yassin OM, Nusier M, Walker S (2000) Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation. J Med Genet 37(2):95–101 Hasan MA, Batieha A, Jadou H, Khawaldeh AK, Ajlouni K (2001) Growth status of Jordanian schoolchildren in military-funded schools. Eur J Clin Nutr 55(5):380–6 Hattab FN, Amin WM (2005) Papillon-Lefevre syndrome with albinism: a review of the literature and report of 2 brothers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100(6):709–16 Hattab FN, Rawashdeh MA, Yassin OM, al-Momani AS, al-Ubosi MM (1995) Papillon-Lefevre syndrome: a review of the literature and report of 4 cases. J Periodontol 66(5):413–20 Hattab FN, al-Khateeb T, Mansour M (1996) Oral manifestations of severe short-limb dwarfism resembling Grebe chondrodysplasia: report of a case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81(5):550–5 Hattab FN, Yassin OM, Sasa IS (1998) Oral manifestations of Ellis-van Creveld syndrome: report of two siblings with unusual dental anomalies. J Clin Pediatr Dent 22(2):159–65 Hattab FN, Hazza’a AM, Yassin OM, al-Rimawi HS (2001) Caries risk in patients with thalassaemia major. Int Dent J 51(1):35–8 Hewitt C, Wu CL, Hattab FN, Amin W, Ghaffar KA, Toomes C, Sloan P, Read AP, James JA, Thakker NS (2004) Coinheritance of two rare genodermatoses (Papillon-Lefevre syndrome and oculocutaneous albinism type 1) in two families: a genetic study. Br J Dermatol 151 (6):1261–5 Hijazi SS, Abulaban A, Ammarin Z, Flatz G (1983) Distribution of adult lactase phenotypes in Bedouins and in urban and agricultural populations of Jordan. Trop Geogr Med 35 (2):157–61 Hiyasat D, Dehyyat MA, Ajlouni S, Mubaidin AF, Till M, Hadidi A, El-Shanti H, Ajlouni KM (2002) Cerebellar hypoplasia, hypergonadotrophic hypogonadism, retinitis pigmentosa, alopecia, microcephaly, psychomotor retardation, and short stature: "D-CHRAMPS syndrome". Eur J Pediatr 161(3):170–2 Hosseini-Maaf B, Hellberg A, Rodrigues MJ, Chester MA, Olsson ML (2003) ABO exon and intron analysis in individuals with the AweakB phenotype reveals a novel O1v-A2 hybrid allele that causes four missense mutations in the A transferase. BMC Genet 4:17 Hosseini-Maaf B, Smart E, Chester MA, Olsson ML (2005) The Abantu phenotype in the ABO blood group system is due to a splice-site mutation in a hybrid between a new O1-like allelic lineage and the A2 allele. Vox Sang 88(4):256–64 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV et al (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23(1):94–8 Irshaid YM, al-Hadidi HF, Rawashdeh NM (1993) Dextromethorphan O-demethylation polymorphism in Jordanians. Eur J Clin Pharmacol 45(3):271–3 Ismail SI, Sughayer MA, Al-Quadan TF, Qaqish BM, Tarawneh MS (2009) Frequency of t(14;18) in follicular lymphoma patients: geographical or technical variation. Int J Lab Hematol 31:535–545 Jaddou HY, Bateiha AM, Al-Khateeb MS, Ajlouni KM (2003) Epidemiology and management of hypertension among Bedouins in Northern Jordan. Saudi Med J 24(5):472–6

348

M. Dasouki and H. El-Shanti

Janaydeh M, Hamad M, Awadallah S (2004) The relationship between haptoglobin polymorphism and serum ceruloplasmin ferroxidase activity. Clin Exp Med 3(4):219–23 Janson S, Dawani H (1994) Chronic illness in preschool Jordanian children. Ann Trop Paediatr 14(2):137–44 Janson S, Jayakoddy A, Abulaban A, Gustavson KH (1990) Severe mental retardation in Jordanian children. A retrospective study. Acta Paediatr Scand 79(11):1099–1104 Jarrah NS, El-Shanti H, Shennak MM, Ajlouni KM (1999) A case of Wolfram syndrome in triplets: some newly recognized features. Ann Saudi Med 19(2):132–4 Jarrah N, El-Shanti H, Khier A, Obeidat FN, Haddidi A, Ajlouni K (2000) Familial disorder of sex determination in seven individuals from three related sibships. Eur J Pediatr 159(12):912–8 Jbour AK, Mubaidin AF, Till M, El-Shanti H, Hadidi A, Ajlouni KM (2003a) Hypogonadotrophic hypogonadism, short stature, cerebellar ataxia, rod-cone retinal dystrophy, and hypersegmented neutrophils: a novel disorder or a new variant of Boucher–Neuhauser syndrome? J Med Genet 40(1):e2 Jbour AS, Jarrah NS, Radaideh AM, Shegem NS, Bader IM, Batieha AM, Ajlouni KM (2003b) Prevalence and predictors of diabetic foot syndrome in type 2 diabetes mellitus in Jordan. Saudi Med J 24(7):761–4 Kakish KS (2001) Cystic fibrosis in Jordan: clinical and genetic aspects. Bahrain Med Bull 23(4):157–159 Kakish KS (2002) Cystic fibrosis and infantile hypertrophic pyloric stenosis: is there an association? Pediatr Pulmonol 33(5):404–5 Karadsheh NS (1993) Pyruvate kinase (PK) deficiency in Jordan. Haematologica 78(2):80–3 Karadsheh NS, Gelbart T, Schulten HJ, Efferth T, Awidi A (2005a) Relationship between molecular variants and clinical manifestions in twelve glucose-6-phosphate dehydrogenasedeficient patients in Jordan. Acta Haematol 114(2):125–6 Karadsheh NS, Moses L, Ismail SI, Devaney JM, Hoffman E (2005b) Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Jordan. Haematologica 90(12):1693–4 Khader Y, Bateiha A, El-Khateeb M, Al-Shaikh A, Ajlouni K (2007) High prevalence of the metabolic syndrome among Northern Jordanians. J Diabetes Complications 21(4):214–9 Khader Y, Batieha A, Ajlouni H, El-Khateeb M, Ajlouni K (2008) Obesity in Jordan: prevalence, associated factors, comorbidities, and change in prevalence over ten years. Metab Syndr Relat Disord 6(2):113–20 Khatib FA, Jarrah NS, Shegem NS, Bateiha AM, Abu-Ali RM, Ajlouni KM (2006) Sexual dysfunction among Jordanian men with diabetes. Saudi Med J 27(3):351–6 Khoury SA, Massad D (1992) Consanguineous marriage in Jordan. Am J Med Genet 43(5):769–75 Khoury SA, Massad DF (2000) Consanguinity, fertility, reproductive wastage, infant mortality and congenital malformations in Jordan. Saudi Med J 21(2):150–4 Kurdi-Haidar B, Mason PJ, Berrebi A, Ankra-Badu G, al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47(6):1013–9 Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R, Moisan JP (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet 31(3):239–40 Lees AJ, Singleton AB (2007) Clinical heterogeneity of ATP13A2 linked disease (Kufor-Rakeb) justifies a PARK designation. Neurology 68(19):1553–4 Madanat WY, Madanat AY (2008) Worsening of osteomalacia in a patient successfully treated for neuro-Behcet’s disease with infliximab. Clin Exp Rheumatol 26(4 Suppl 50):S128–9 Madanat WY, Prokaeva TB, Kotel’nikova GP, Alekberova ZS (1993) Endocarditis with left atrial thrombus formation in Behcet’s disease mimicking myxoma. J Rheumatol 20(11): 1982–4 Madanat W, Sharaiha Z, Khasawneh S, Zureikat H, Fayyad F (2003) Gastro-intestinal manifestations of Behcet’s disease. Adv Exp Med Biol 528:455–7 Mahafza WS (2004) Multiple enchondromatosis Ollier’s disease with two primary brain tumors. Saudi Med J 25(9):1261–3

11

Genetic Disorders in Jordan

349

Mahafza T, El-Shanti H, Omari H (2001) Raine syndrome: report of a case with hand and foot anomalies. Clin Dysmorphol 10(3):227–9 Mahasneh AA, Abdel-Hafiz SS (2004) Polymorphism of p53 gene in Jordanian population and possible associations with breast cancer and lung adenocarcinoma. Saudi Med J 25(11): 1568–73 Mahdi AH, al-Mashhadani SA, al-Nasser M (1991) Wolman’s disease in a Jordanian infant. Ann Trop Paediatr 11(3):305–8 Mahmoud IS, Sughayer MA, Mohammad HA, Awidi AS, EL-K MS, Ismail SI (2008) The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias. Br J Cancer 99(3):488–90 Majali H, Batieha AM, Jaddou HY, Khawaldeh A, Ajlouni KM (2003) Socio-economic discrepancies in growth status of Jordanian children in military-run schools at the turn of the twentieth century. Saudi Med J 24(5):548–9 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, al-Gharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115(5 Pt 1):730–4 Majeed HA, Rawashdeh M, el-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM (1999) Familial Mediterranean fever in children: the expanded clinical profile. QJM 92(6):309–18 Majeed HA, Al-Qudah AK, Qubain H, Shahin HM (2000a) The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum 30(2):138–43 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N (2000b) On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 137(3):441–2 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160(12):705–10 Majeed HA, El-Shanti H, Al-Khateeb MS, Rabaiha ZA (2002) Genotype/phenotype correlations in Arab patients with familial Mediterranean fever. Semin Arthritis Rheum 31(6):371–6 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34(6):813–8 Masri A, Hamamy H (2006) Canavan disease: a first case from Jordan. J Pediatr Neurol 4:143–146 Masri AT, Hamamy HA (2007) Clinical and inheritance profiles of hyperekplexia in Jordan. J Child Neurol 22(7):895–900 Masri AT, Bakri FG, Al-Hadidy AM, Musharbash AF, Al-Hussaini M (2006) Ataxia-telangiectasia complicated by craniopharyngioma–a new observation. Pediatr Neurol 35(4):287–8 Masri A, Badran E, Hamamy H, Assaf A, Al-Qudah AA (2008a) Etiologies, outcomes, and risk factors for epilepsy in infants: a case-control study. Clin Neurol Neurosurg 110(4):352–6 Masri A, Bakri FG, Al-Hussaini M, Al-Hadidy A, Hirzallah R, de Saint BG, Hamamy H (2008b) Griscelli syndrome type 2: a rare and lethal disorder. J Child Neurol 23(8):964–7 Medlej-Hashim M, Rawashdeh M, Chouery E, Mansour I, Delague V, Lefranc G, Naman R, Loiselet J, Megarbane A (2000) Genetic screening of fourteen mutations in Jordanian familial Mediterranean fever patients. Hum Mutat 15(4):384 Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G et al (2005) Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48(4):412–20 Middleton LT, Christodoulou K, Mubaidin A, Zamba E, Tsingis M, Kyriacou K, Abu-Sheikh S, Kyriakides T, Neocleous V, Georgiou DM et al (1999) Distal hereditary motor neuronopathy of the Jerash type. Ann NY Acad Sci 883:439–42 Milhavet F, Cuisset L, Hoffman HM, Slim R, El-Shanti H, Aksentijevich I, Lesage S, Waterham H, Wise C, SarraustedeMenthiere C et al (2008) The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat 29(6):803–8

350

M. Dasouki and H. El-Shanti

Mitchell SC, Zhang AQ, Barrett T, Ayesh R, Smith RL (1997) Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations. Pharmacogenetics 7(1):45–50 Myhre R, Steinkjer S, Stormyr A, Nilsen GL, Abu Zayyad H, Horany K, Nusier MK, Klungland H (2008) Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile Parkinsonism. BMC Neurol 8:47 Nabulsi A (1995) Mating patterns of the Abbad tribe in Jordan. Soc Biol 42(3–4):162–74 Najim al-Din AS, al-Kurdi A, Dasouki M, Wriekat AL, al-Khateeb M, Mubaidin A, al-Hiari M (1994) Autosomal recessive ataxia, slow eye movements and psychomotor retardation. J Neurol Sci 124(1):61–6 Nazer HM (1992) Early diagnosis of cystic fibrosis in Jordanian children. J Trop Pediatr 38(3): 113–5 Nusier M, Zhang Y, Yassin O, Hart TC, Hart PS (2002) Demonstration of altered splicing with the IVS3–1G –> a mutation of cathepsin C. Mol Genet Metab 75(3):280–3 Nusier M, Yassin O, Hart TC, Samimi A, Wright JT (2004) Phenotypic diversity and revision of the nomenclature for autosomal recessive amelogenesis imperfecta. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97(2):220–30 Nusier MK, Radaideh AM, Ababneh NA, Qaqish BM, Alzoubi R, Khader Y, Mersa JY, Irshaid NM, El-Khateeb M (2007) Prevalence of factor V G1691A (Leiden) and prothrombin G20210A polymorphisms among apparently healthy Jordanians. Neuro Endocrinol Lett 28(5):699–703 Obeidat BR, Khader YS, Amarin ZO, Kassawneh M, Al Omari M (2008) Consanguinity and Adverse Pregnancy Outcomes: The North of Jordan Experience. Matern Child Health J Qublan HS, Eid SS, Ababneh HA, Amarin ZO, Smadi AZ, Al-Khafaji FF, Khader YS (2006) Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 21(10):2694–8 Qublan H, Amarin Z, Dabbas M, Farraj AE, Beni-Merei Z, Al-Akash H, Bdoor AN, Nawasreh M, Malkawi S, Diab F et al (2008) Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb) 11(4):246–53 Radaideh AR, Nusier MK, Amari FL, Bateiha AE, El-Khateeb MS, Naser AS, Ajlouni KM (2004) Thyroid dysfunction in patients with type 2 diabetes mellitus in Jordan. Saudi Med J 25(8): 1046–50 Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J et al (2006) Hereditary Parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38(10): 1184–91 Rawashdeh MO, Majeed HA (1996) Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr 155(7):540–4 Rawashdeh M, Manal H (2000) Cystic fibrosis in Arabs: a prototype from Jordan. Ann Trop Paediatr 20(4):283–6 Rosenberg N, Hauschner H, Peretz H, Mor-Cohen R, Landau M, Shenkman B, Kenet G, Coller BS, Awidi AA, Seligsohn U (2005) A 13-bp deletion in alpha(IIb) gene is a founder mutation that predominates in Palestinian-Arab patients with Glanzmann thrombasthenia. J Thromb Haemost 3(12):2764–72 Roychoudhury AK, Nei M (1988) Human Polymorphic Genes: World Distribution. Oxford University Press, New York Sadiq MF, Huisman TH (1994) Molecular characterization of beta-thalassemia in north Jordan. Hemoglobin 18(4–5):325–32 Sadiq MF, Eigel A, Horst J (2001) Spectrum of beta-thalassemia in Jordan: identification of two novel mutations. Am J Hematol 68(1):16–22 Saha N (1985) Distribution of transferrin C subtypes among the Bedouin and non-Bedouin populations of Jordan. Hum Hered 35(5):341–2

11

Genetic Disorders in Jordan

351

Saleh H, Davrinche C, Charlionet R, Rivat C (1986) Alpha-1-antitrypsin phenotypes in a population of Jordan. Hum Hered 36(3):192–4 Sanchez-Velasco P, Karadsheh NS, Garcia-Martin A, Ruiz de Alegria C, Leyva-Cobian F (2001) Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations. Hum Immunol 62(9):901–9 Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM (2002) Effects of short term metformin administration on androgens in normal men. Saudi Med J 23(8):934–7 Shegem NS, Alsheek Nasir AM, Batieha AM, El-Shanti H, Ajlouni KM (2004) Effects of short term metformin administration on androgens in diabetic men. Saudi Med J 25(1):75–8 Srivastava T, Whiting JM, Garola RE, Dasouki MJ, Ruotsalainen V, Tryggvason K, Hamed R, Alon US (2001) Podocyte proteins in Galloway–Mowat syndrome. Pediatr Nephrol 16 (12):1022–9 Sughayer MA, Al-Khawaja MM, Massarweh S, Al-Masri M (2006) Prevalence of hormone receptors and HER2/neu in breast cancer cases in Jordan. Pathol Oncol Res 12(2):83–6 Taher BM, Ajlouni HK, Hamamy HA, Shegem NS, Madanat AY, Ajlouni KM (2004) Precocious puberty at an endocrine centre in Jordan. Eur J Clin Invest 34(9):599–604 Takemoto Y, Naruse T, Namba K, Kitaichi N, Ota M, Shindo Y, Mizuki N, Gul A, Madanat W, Chams H et al (2008) Re-evaluation of heterogeneity in HLA-B*510101 associated with Behcet’s disease. Tissue Antigens 72(4):347–53 Talafih K, Hunaiti AA, Gharaibeh N, Gharaibeh M, Jaradat S (1996) The prevalence of hemoglobin S and glucose-6-phosphate dehydrogenase deficiency in Jordanian newborn. J Obstet Gynaecol Res 22(5):417–20 Tamimi J, Madanat W (2003) Jordan friends of Behcet’s disease patients society. A fruit of joint efforts between doctors and patients. Adv Exp Med Biol 528:609–11 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research, and policy. Lancet 367(9515):970–1 Teebi AS, Dupuis L, Wherrett D, Khoury A, Zucker KJ (2004) Alopecia congenita universalis, microcephaly, cutis marmorata, short stature and XY gonadal dysgenesis: variable expression of El-Shanti syndrome. Eur J Pediatr 163(3):170–2 Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalcinkaya F, Ozen S, Majeed H, Ozdogan H et al (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 56(5):1706–12 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50(3):158–61 Verity DH, Vaughan RW, Madanat W, Kondeatis E, Zureikat H, Fayyad F, Kanawati CA, Ayesh I, Stanford MR, Wallace GR (1999a) Factor V Leiden mutation is associated with ocular involvement in Behcet disease. Am J Ophthalmol 128(3):352–6 Verity DH, Wallace GR, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, Fayyad F, Marr JE, Kanawati CA, Stanford MR (1999b) HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behcet’s disease. Tissue Antigens 54(3):264–72 Verity DH, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, Fayyad F, Marr JE, Kanawati CA, Wallace GR, Stanford MR (2000) Intercellular adhesion molecule-1 gene polymorphisms in Behcet’s disease. Eur J Immunogenet 27(2):73–6 Wahbeh AM, Ewais MH, Elsharif ME (2008) Spectrum of glomerulonephritis in adult Jordanians at Jordan university hospital. Saudi J Kidney Dis Transpl 19(6):997–1000 Wallace GR, Verity DH, Delamaine LJ, Ohno S, Inoko H, Ota M, Mizuki N, Yabuki K, Kondiatis E, Stephens HA et al (1999) MIC-A allele profiles and HLA class I associations in Behcet’s disease. Immunogenetics 49(7–8):613–7 Wallace GR, Kondeatis E, Vaughan RW, Verity DH, Chen Y, Fortune F, Madanat W, Kanawati CA, Graham EM, Stanford MR (2007) IL-10 genotype analysis in patients with Behcet’s disease. Hum Immunol 68(2):122–7 Wallerman O, Van Eeghen A, Ten Kate LP, Wadelius C (2003) Evidence for a second gene for primary microcephaly at MCPH5 on chromosome 1. Hereditas 139(1):64–7

352

M. Dasouki and H. El-Shanti

Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, al-Aboosi MM, el-Shanti H, Gitschier J (2001) Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet 68(4):1055–60 Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71(1):66–73 Williams DR, Hadeed A, al-Din AS, Wreikat AL, Lees AJ (2005) Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord 20(10):1264–71 Yang X, Ahmad T, Gogus F, Verity D, Wallace GR, Madanat W, Kanawati CA, Stanford MR, Fortune F, Jewell DP et al (2004) Analysis of the CC chemokine receptor 5 (CCR5) Delta32 polymorphism in Behcet’s disease. Eur J Immunogenet 31(1):11–4

Chapter 12

Genetic Disorders in Kuwait Nawal Makhseed

The Country and Population Kuwait is situated northeast of Saudi Arabia at the northern end of the Persian Gulf, south of Iraq (Fig. 12.1). The country’s total area is 17,820 km2, mainly flat desert with few oases. It is rich in oil, which constitutes the major source of wealth in Kuwait. Following the war to end the Iraqi occupation in 1991, the population has declined from more than two million to only 1.2 million because of the departure of many non-Kuwaiti residents, mainly the Palestinians, who constituted about 22% of the Kuwaiti population before the Iraqi occupation of Kuwait. The current population of Kuwait is estimated at 2,985 million. Of the total population, the Kuwaiti Nationals constitute 35%, other Arab nationals 22%, Asians 39%, and 4% are Bedoons, who are mostly Bedouins without determined citizenship. http://www.asiarooms.com/travel-guide/kuwait/kuwait-overview/kuwaitpopulation. html The Kuwaiti nationals can be divided into several groups. These groups reflect the tribal origins of the Kuwaiti society. The first tribe of settlers was the Anaza (led by the Sabah family) and the later settlers include the Bahar, Hamad, and Babtain families, originated in Nejd (central Arabia). Another group, the Kenaat (including the Mutawa family and its offshoot, the Saleh), came to Kuwait from Iraq and remain distinct from the Nejdi families. There are also few large families of Persian origin including the Behbahanis. The remaining citizens are few former Palestinians and other Arabs, the most being originally Bedouins who have been granted citizenship. The Bedouins are the nomadic Arabs of the desert who live on the fringes of the Arabian Peninsula, which includes parts of Kuwait, Saudi Arabia,

N. Makhseed Department of Pediatrics, Jahra Hospital, Ministry of Health, Kuwait e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_12, # Springer-Verlag Berlin Heidelberg 2010

353

354

N. Makhseed

Fig. 12.1 Map of Kuwait

Qatar, United Arab Emirates, Oman, Iraq, Jordan, and Syria as well as Negev and Sinai desert (Teebi 1994). Birth rate is about 21 per 1,000 (Population Bureau). Population growth rate has been around 3.4% in the last few years since the year 2000. Islam is the predominant religion among Kuwaitis, with more than 70% being Sunnite Muslims and the rest being Shite Muslims. In Kuwait it was estimated that 8–12.5% of all marriages contracted are polygamous (Chaleby 1985).

Genetic Services A small unit of Genetics was established in late 1960s but discontinued in 1970 because of the lack of qualified personal. The service was resumed as a weekly genetic clinic at Al-Sabah hospital, and in the late 1980s the Kuwait Medical Genetic Center (KMGC) was operational. It constituted clinical genetics section

12

Genetic Disorders in Kuwait

355

and cytogenetic laboratory. After 1983, community genetics clinics were developed. In 1993, Molecular genetics laboratory and Fluorescence in situ Hybridization (FISH) laboratory were added to the genetic center.

Consanguineous Marriages and Their Implications Al-Awadi et al. (1985b) found the rate of consanguineous mating was to be 54.3% with estimated population incidence rates from 52.9 to 55.7%. First-cousin marriages were the most common type, particularly paternal first cousins. Double firstcousin marriages also exist (Teebi 1994). The average inbreeding coefficient was 0.0219. This high rate is seen mostly among Bedouins as well as some wealthy families, for social, economic, and geographical factors. It was also found that other Arab communities living in Kuwait also have high rates of consanguinity according to studies conducted in Kuwait or in their countries of origin (Teebi 1994). Frequency of consanguineous marriages among Egyptians, and Jordanian, living in Kuwait was estimated to be 23.3 and 36.2% respectively (Al-Nassar et al. 1989). Radovanovic et al. (1999) studied the frequency, social correlates, and trend of consanguineous marriages. A questionnaire was administered to a representative sample of 482 households of Kuwaiti nationals from the most developed area (the Capital) and the least developed area (Jahra). It was concluded that the frequency of total first- and second-cousin marriages was much higher in Jahra governorate (42.1%) than in the Capital (22.6%). Over the last decade, the inbreeding has decreased in the Capital but not in Jahra. It was also found that Bedouin origin and year of marriage were the only variables significantly related to consanguinity.

Fertility Studies on the fertility rate in Kuwait conducted by different researchers from 1970 to 2004 showed a decline in the fertility rate in Kuwait as shown in (Table 12.1). Table 12.1 Fertility rates in Kuwait Year Total fertility rate 1970 7 1975 7.2 1980–1984 6.62 1985 6.5 1986 4.4 1990–1994 5.96 2000–2004 5.63 2007 3.58

References Kohli and Al-Omain (1993) Kohli and Al-Omain (1993) Courbage and Khlat (1993) Kohli and Al-Omain (1993) Kohli and Al-Omain (1993) Courbage and Khlat (1993) Courbage and Khlat (1993) Al-Kandari and Alshuaib (2007)

356

N. Makhseed

Al-Kandari (2007) studied the fertility and its relationship with socio-cultural factors in the Kuwaiti society. He concluded from a questionnaire administered to 7,749 married women who were 15–78 years of age that the fertility rate was 3.58 per woman. Fertility was higher among Sunni Muslim women, those of Bedouin ethnicity, and those in a consanguineous marriage. There was a significant negative relationship between fertility and respondents’ educational level, occupation, age at marriage, socioeconomic status, and type of marriage (consanguineous or not). There was a positive relationship between fertility and the respondents’ age and family income.

Genetic Disorders Reported From Kuwait Chromosomal Abnormalities Al-Naggar et al. (1999) studied the profile of chromosomal abnormalities at Al-Jahra Hospital region of Kuwait. This hospital was serving at that time an Arab population of 300,000, 80% of whom belong to the Bedouin community. The study population included 177 cases of chromosomal abnormalities diagnosed among 49,174 live births registered at the hospital from January 1983 to December 1989. Among the 177 cases with chromosomal abnormalities, 95% had numerical chromosomal abnormalities, and 5% had structural abnormalities. Of them, 145 cases had classic trisomy 21 with an incidence of 2.9/1,000 live births, 16 cases had trisomy 18 (0.3/1,000 live births), five cases had trisomy 13 (0.1/1,000 live births), one case had trilpoidy 69, XXY (0.02/1,000 live births), and one had Turner syndrome (0.05/1,000 live births). Nine cases with structural abnormalities were enumerated, and the incidence of each was 0.02/1,000 live births. Two cases of translocation trisomy 21 (0.04/1,000 live births) and three cases of cri-du-chat (0.06/1,000) were found. This study has shown that Bedouin had a double-fold increased risk of common trisomies and advanced maternal age was also a risk factor while the paternal age was an inconsistent risk factor.

Down Syndrome Al-Awadi et al. (1990) had shown during 7 years period, from 1980 to 1986, that there were 635 confirmed cases of Down syndrome at KMGC registry. Regular trisomy 21 was found in 96.2% of them, 1.9% had different translocation, 1.4% with mosaicism, and 0.5% had nonclassical karyotypes. These results were compared with major worldwide cytogenetic surveys of 17,738 Down syndrome cases. 92.9% were regular trisomy 21, 4.3% translocation, 2.2% mosaicism, and 0.5% nonclassical karyotype. Studies in Kuwait have shown a high incidence of Down syndrome (3.6/1,000) among highly inbred Bedouin community in the Jahra area of Kuwait, whereas in an area with a mixed Arab population, the incidence was

12

Genetic Disorders in Kuwait

357

1.7/1,000 live births. This was explained on the basis of possible gene effects on nondisjunction (Farag and Teebi 1988a). Alfi et al. (1980) reported that Down syndrome was four times more frequent among children of closely related parents. Another study in Kuwait (Naguib et al. 1989) suggested an association between consanguinity and occurrence of nondisjunction, although a single-gene defect was not observed. It was also reported in two studies that it is not uncommon among Bedouins in Kuwait to find examples of recurrent aneuploidies in the same family (Farag and Teebi 1988b). Recurrent regular trisomy 21 was reported in several unrelated inbred Bedouin families, the age of the mother in each of these families was less than 34 years, and this provides a further evidence of an aneuploidy gene effect among inbred populations (Farag and Krishna Murthy 1994; Quaife and AlGazali 1994). Trisomy 18 Naguib et al. (1987b) reported that the incidence of trisomy 18 in 1986 was 4.61/ 10,000, which is significantly higher than the international incidence as well as the incidence in previous years. The male-to-female sex ratio was 1:1.8, the median maternal age 32.5, and the median paternal age 40. Later, Naguib et al. (1999a, b) reported that the average Trisomy18 birth incidence rate was 8.95 per 10,000 live births based on 59 cases who were ascertained clinically and cytogenetically from 1994 to 1997. Trisomy 18 cases were mostly females with a male–female ratio of 1:2.1. Maternal age above 30 years was found to be a significant factor for Trisomy18, and such cluster of high prevalence may indicate a possible environmental and to a lesser extent, genetic predisposition to aneuploidy nondisjunction. Male Infertility Mohammed et al. (2007) conducted a study on 289 infertile men who had cytogenetic studies and molecular testing. Chromosomal anomalies and Y microdeletion were detected in 10.4% of them. The distribution of the chromosomal abnormalities found in the infertile men in Kuwait: 23 patients (8%) had sex chromosome abnormalities where 69% of them had Klinefelter or a variant of it, 13% had XXY syndrome, 8.7% were XX males, 4.4% had 45,X/46X, i(YP) karyotype, and 4.4% had 45, XY karyotype. Only seven patients of the total (2.6%) had Y-microdeletion in the AZF b and AZF c regions. Testicular biopsy was carried out in 31 azoospermic patients; five had Sertoli-cell-only syndrome and 26 had spermatogenic arrest. Alkhalaf et al. (2002) analyzed 118 infertile patients using cytogenetic analysis. The overall incidence of chromosomal abnormalities was 11%, with common chromosomal abnormalities detected in 12 patients. One of those was an infertile male with the karyotype 46,XY, del (21)(pter; q11.2). Krishna Murthy et al. (2002) reported that paternal balanced translocation t(1p;19p)(p32; q13) was associated with recurrent fetal loss.

358

N. Makhseed

Female Infertility Alkhalaf (2007) reported a novel chromosomal translocation, t(2;10) (p21;pl5), which was associated with increased chromosomal fragility in two young women with a history of early recurrent spontaneous abortions (7–10 weeks). However, the relationship between this novel translocation and DNA fragility was not well understood. Xp25 deletion was reported to be associated with infertility. Naguib et al. (1988) reported that a mother and two daughters with Xp25 deletion were fertile. Consistent inactivation of the deleted X chromosome in the proposita and, an early menopause in the mother, were noted.

Mental Retardation (MR) Farag et al. (1993a) conducted a 4-year clinicogenetic survey of 400 institutionalized mentally retarded (IQ < 50) patients in Kuwait. In 203 patients (50.75%), a constitutional disorder was found: chromosomal abnormality in 37 (9.25%); Mendelian disorders in 137 (34.5%); multiple congenital anomalies and mental retardation in 22 (5.55%); and central nervous system malformation in seven cases (1.75%). In 157 patients (39.35), a pre, peri, or postnatal cause was ascertained. No etiological diagnosis was detected in 40 patients (10%). Phenylketonuria was found to have a frequency between 1.6% and 1.865% among institutionalized mentally retarded patients (Teebi et al. 1987a).

Neural Tube Defects (NTD) El-Alfi et al. (1968) reported that the prevalence of anencephaly in Kuwait was high at 3.2/1,000 births among 4,625 deliveries at the Maternity hospital. Al-Awadi et al. (1984) reported 18 years later a marked decline in the prevalence of anencephaly to 1.33/1,000 births during 1983. The highest incidence (2.05/1,000 births) was among deliveries in Jahra hospital, 80% of the population served at this hospital belonged to the Bedouin community, and the lowest incidence (0.85/1,000 births) was among deliveries in Farwania hospital, which serves a mixed Arab and nonArab population, with only 15% belonging to Bedouin community. Meckel syndrome is an autosomal recessive form of neural tube defect anomalies, frequently diagnosed among neonates in Kuwait (Teebi 1994) with an incidence of 1:3,530 live births (Teebi et al. 1992). It is mostly ascertained among those of Bedouin ancestry. Farag et al. (1990) reported a variant of Meckel syndrome in a Bedouin family with five affected sibs lacking polydactyly. Other cases of Meckel syndrome were ascertained in a study of cleft lip with or without cleft palate (Naguib et al. 1989).

12

Genetic Disorders in Kuwait

359

Hematological Disorders The hemoglobinopathies are the commonest single-gene disorders known and are so common in some regions of the world that the majority of the population carries at least one genetic abnormality affecting the structure or synthesis of the hemoglobin molecule (Flint et al. 1993).

Sickle Cell Disease and Thalassemias Adekile (2001) reported the incidence of sickle cell trait to be at 3% of the Kuwaiti population. Marouf et al. (2002) reported that most commonly identified hemoglobinopathies were beta-thalassemia minor (14%), sickle cell trait (6%), sickle cell anemia (0.9%), S beta zero thal (0.8%), and S beta + thal (0.8%). Two rare hemoglobin variants, Hb DPunjab and Hb E, were encountered.

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD deficiency) In 1999, Samilchuk et al. reported that the frequency of G6PD-deficient genotypes was 4.5% (5.73% in males and 2.56% in females). Alfadhli et al. (2005) conducted a study to investigate the mutation spectrum of the G6PD gene among the Kuwaitis. Seventy-two men and seven women were screened for gene mutation. The results showed that G6PD Mediterranean (563C!T), and A- (202G!A,376A!G) genotypes were characterized as the most common variants among the G6PDdeficient population, representing 0.742 and 0.124 allele frequencies, respectively. The two previously described mutations, G6PD Chatham (1003G!A) and Aures (143T!C), were found at lower frequencies (0.101 and 0.034, respectively). The allele frequencies for these four G6PD variants among the randomly selected Kuwaitis were 0.035, 0.0074, 0.0046, and 0.0023 for Mediterranean, A-, Chatham, and Aures, respectively.

Endocrine Disorders Congenital Hypothyroidism There is no national newborn screening for congenital hypothyroidism in Kuwait. It is currently done at a low scale for newborns at three of the governmental hospitals. However, newborn screening is done for babies born at private hospitals in Kuwait. In one of the regional hospitals in Kuwait, 25 children were diagnosed on clinical grounds with congenital hypothyroidism from 1981 to 1987 (Daoud et al. 1989). The calculated incidence was 1:3,476 live births. Seven patients were

360

N. Makhseed

diagnosed in the first month, 6 in the following months, and 12 diagnosed after the age of 6 months. Thyroid scan was done for 13 patients, four had thyroid aplasia, three had ectopia, and six had thyroid in normal position.

Congenital Adrenal Hyperplasia (CAH) Lubani et al. (1990a) reported that in one hospital, 60 patients were diagnosed over a 10-year period (1978–1988). The prevalence of CAH was estimated to be 1:9,000 live births, which is higher than that reported from Europe and Canada. However, there was presumptive evidence of CAH resulting in the death of 20 other children, giving a prevalence of 1:7,000. There were more girls affected than boys with 68 and 32% of the total respectively. Seventy-five percent of the girls and 57.9% of the boys were salt losers. Biochemical analysis showed that 90% had 21-hydroxylase deficiency, 5% had 3-beta-hydroxy-steroid dehydrogenase deficiency, and 5% had 11-beta-hydroxylase deficiency.

Familial Hypophosphatemic Rickets (FHR) Lubani et al. (1990b) reported that 24 cases of FHR were diagnosed from 1982 to 1988, nine were diagnosed during screening of families with an index case. The average annual incidence was 0.2/1,000 live births. Age of onset ranged between 10 months and 14 years. Almost all patients presented with growth retardation and bowing of the legs. Those diagnosed early responded well to treatment; those diagnosed late had final height below the third centile.

Diabetes Mellitus Shaltout et al. (2002) has reported that the incidence of Type 1 diabetes in Kuwait is high compared with the neighboring Arab countries. Abdullah (2005) conducted an epidemiological study on type 1 diabetes among Arab children (<15 years of age) living in Arab and non-Arab countries. The study showed that the highest incidence is in Qatar and Kuwait, and the lowest in Oman and Jordan. From 2000 to 2002, Moussa et al. (2005) conducted a study to determine the prevalence of type 1 diabetes among 6–18-year old Kuwaiti children. The prevalence was 269.9 per 100,000 with no significant difference between males and females, with highest prevalence in the age group 10–13 years (347.3/100,000) and the lowest in the age group 6–9 years (182.6/100,000). There was no significant difference in prevalence between regions. Analysis of HLA-DQBI/DQA1 haplotypes from IDDM cases and controls revealed a significantly high frequency of haplotype DQA1*0301/ DQB1*0201 between Kuwaiti IDDM cases (49/78, 63%) and the controls (8/57, 14%) (Haider et al. 1999).

12

Genetic Disorders in Kuwait

361

Congenital Deafness The incidence of congenital hearing loss in Kuwait is not known. For the first time Al-Kandari and Alshuaib (2007) conducted a study to detect permanent hearing loss in a universal newborns hearing screening UNHS program. This was conducted on 200 healthy newborns and 15 babies at high risk for hearing loss. In the healthy newborn group, 1% had a profound sensorineural hearing loss, 1% with severe (70 dBnHL) sensorineural hearing loss, and 98% with normal hearing. In the highrisk group, 26.67% had profound sensorineural hearing loss, 20% had moderate (60 dBnHL) sensorineural hearing loss, and 53.33% had normal hearing level. It is evident from this study that the need for a UNHS program is crucial to diagnose hearing loss early in life and provide early treatment.

Major Congenital Anomalies Madi et al. (2005) investigated the incidence of major congenital abnormalities in 7,739 live and stillborn babies born in Al-Jahra Hospital in Kuwait from 2000 to 2001. Ninety-seven neonates were found to have major congenital malformations with an incidence of 12.5/1,000 births. Eleven percent of the 82 stillbirths had major anomalies. Of all babies, 49 (50.5%) had multiple congenital anomalies in the form of monogenic syndromes with an incidence of 2.7/1,000 births, chromosomal aberrations incidence of 2.2/1,000 births, sequences incidence of 0.4/1,000 births, associations incidence of 0.1/1,000 births, and unclassified multiple system anomalies incidence of 0.9/1,000 births. Forty-eight cases (49.5%) had isolated congenital malformation: cardiovascular anomalies incidence of 1.2/1,000 births, skeletal anomalies incidence of 0.9/1,000 births, central nervous system anomalies incidence of 1.6/1,000 births, gastrointestinal tract anomalies incidence of 0.8/1,000 births, and urogenital, skin, eye, and others with an incidence of 0.4/1,000 births. Consanguinity rate among their parents was 59%, which is higher than the general population rate of 52.9% (Al-Awadi et al. 1985b).

Inborn Errors of Metabolism (IEM) In Kuwait, the incidence of IEM remains unknown. There are scattered reports on various inborn errors of metabolism in Kuwait. Reavey and Yadav (1988) reviewed the results of amino acid analysis of 800 patients. Thirty-five patients with aminocidopathies were identified, which account for 4.4% of the patients. There were nine cases of PKU, one with benign hyperphenylalaninemia, seven cases of NKH, and five cases of Tyrosinemia, five

362

N. Makhseed

Table 12.2 Inborn errors of metabolism diagnosed/and or reported from Kuwait MIM# Disease References 1177000 Erythropoietic protophorphyria – 179060 PDH deficiency E1 Beta subunit – 201475 VLCAD – 214700 Ceroid storage disease – 215700 Citrullinemia Issa et al. (1988), Reavey and Yadav (1988), Madi et al. (1995) 219500 Cystathioninuria Yadav (1992) 220100 Cystinuria Reavey and Yadav (1988) 227810 Fanconi–Bickel syndrome – 229700 Fructose 1,6 diphosphatase Al-Raqum et al. (1994) deficiency 230000 Alpha-Fucosidosis Ismail et al. (1999) 230300 Gaucher disease type I Teebi (1994) 230500 Gm1 Gangliosidosis Teebi (1994) 231680 Glutaric aciduria type I Elsori et al. (2004) 232000 Propionic acidemia – 232200 Glycogen storage disease type Ia – 232300 Pompe disease – 232400 Classical galactosemia Teebi (1993), Teebi and Farag (1989b) 232500 Glycogen storage disease type IV – 235800 Histidinemia Al-Awadi et al. (1987b) 236200 Homocystinuria Reavey and Yadav (1988) 236250 Methylenetetrahydrofolate Al-Tawari et al. (2002) reductase deficiency 236490 Infantile systemic hyalinosis – 238750 Hyperlysinuria Yadav (1992) 239500 Hyperprolinemia Reavey and Yadav (1988) 243500 Isovaleric acidemia – 246450 HMG-CoA lyase deficiency – 248500 Alpha-mannosidosis – 248600 MSUD Reavy and Yadav (1988) 252500 Mucolipidosis type II Teebi (1994) 252800 Hurler’s and Hurler-Scheie Teebi (1994) syndrome 253200 Maroteaux-Lamy syndrome – 256550 Juvenile sialidosis – 257200 Niemann-Pick A Teebi (1994) 261600 Pheylketonuria Teebi et al. (1987a), Yadav et al. (1992), Mubashir et al. (1996) 272200 Multiple sulfatase deficiency Teebi (1994) 272750 Tay-Sachs syndrome Teebi (1994) 276600 Tyrosinemia type II Rehak et al. (1981) 276710 Tyrosinemia type I Reavey and Yadav (1988) 277410 Methylmalonic acidemia – 278300 Xanthinuria type I Fildes (1989) 309900 Hunter syndrome – 602079 Trimethylaminuria – 602473 Ethylmalonic aciduria Heberle et al. (2006) 650899 Non-ketotic hyperglycinemia Reavey and Yadav (1988) 606761 Malonic aciduria – 609016 LCAHD –

12

Genetic Disorders in Kuwait

363

Table 12.3 New syndromes and variants reported from Kuwait References MIM # Family Number origin of pt Autosomal dominant Teebi and Al-Saleh (1989b) 137130 Syrian 11 Teebi (1987) Stratton (1991) 145420 Iraqi 16

Al-Awadi et al. (1987) Naguib and Al-Awadi (1990)

Disease

Gastric sneezing Hypertelorism – Teebi type (brachycephalofrontonasal dysplasia)

188770

Kuwaiti

2

Hypoplastic Tibiae with postaxil polysyndactyly

Autosomal recessive Teebi et al. (1986b) Reardon et al. (1990)

200700 212135

Palestinian Kuwaiti

1 2

Lubani et al. (1991)

219721

Bedouin

2

Grebe-like chondrodysplasia Cardioskeletal syndrome, Kuwaiti type Cystic fibrosis with helicobacter gastritis, megaloblastic anemia and subnormal mentality Faciodigitogenital syndrome

Teebi et al. (1988b); 227330 Teebi et al. (1991) Naguib (1988), Teebi 239710 (1992) Farag and Teebi (1990a, b, c) 239711

Kuwaiti, 5+9 Bedouin Pakistani 3 Palestinian

4

Al-Awadi et al. (1985a)

241090

3+2

Teebi and Farag (1989a), Teebi et al. (1989b) Teebi et al. (1987b)

248110

Jordanian, Kuwaiti Palestinian

251260

Palestinian

8

Mousa et al. (1986)

271320

Bedouin

22

Al-Din et al. (1990)

271322

Palestinian

6

Farag et al. (1987)

271640

Syrian

3

Teebi (1991)

275595

Palestinian

2

Al-Awadi et al. (1985a, b), Teebi (1993), Farag et al. (1993a, b), RassRothchild et al. (1988) Teebi et al. (1989c) Al-Saleh and Teebi (1990)

276820

Palestina

2+1

Limb/pelvis-hypoplasia/ aplasia syndrome

277590 144200

Bedouin Kuwaiti

2 2

Weaver-like syndrome Palmoplantar keratoderma, epidermolytic recessive form 2 Kuwaiti 144200* (continued)

5

Hypertelorism, hypospadias, polysyndactyly syndrome Hypertelorism, hypospadias, tetralogy of Fallot syndrome Hypogonadism, primary, and partial alopecia Macrosomia with microphthalmia, lethal Microcephaly with normal intelligence Bedouin spastic ataxia syndrome Spinocerebellar degeneration with slow eye movements Spondyloepimetaphyseal dysplasia, a new variant Trigonobrachycephaly, bulbous bifid nose, micrognathia, and abnormalities of the hands

364 Table 12.3 (continued) References

N. Makhseed

MIM #

Teebi and Shaltout (1989), White et al. (unpublished) Teebi et al. (1986a)

_

Family origin Kuwaiti

Number of pt 1

Disease

_

Palestinian

3

Hypogonadotrophic hypogonadism, obesity, MR, and skeletal anomalies Nephrosis, minimal change

Awadalla et al. (1989)

_

Syrian

4

Craniofacial-hair-fingercaudal syndrome

Table 12.4 Mendelian inherited in man (MIM) based results of disorders reported in Kuwait References Disease/ syndrome MIM Farag et al. (1989) Acanthosis Nigricans AD 100600 Al-Mahmeed et al. (1989) Gorlin–Goltz syndrome AD 109400 Howard et al. (1993) Branchial Myoclonus with spastic paraparesis 113610 and Cerebllar ataxia (AD) Farag et al. (1993a) Sotos syndrome AD 117550 Al-Awadi et al. (1982) Cornelia de Lange’s syndrome AD 122470 Farag et al. (1993a) Crouzon carniofacial dysostosis AD 123500 Solute carrier Family 26, Member 3 126650 Sabry et al. (1996) Femoral-Facial syndrome AD 134780 Al-Awadi et al. (1985a) Fibrodysplasia ossificans progressiva AD 135100 Ghosh et al. (1993) Alpha thalassemia 141800 Manandhar et al. (1989) Familial hypercholestrolemia type IIA AD 143890 Al-Saleh and Teebi (1990) Palmoplantar Keratoderma Epidermolytic AD 144200 Teebi (1987) Hypertelorism, Teebi type AD 145240 Farag et al. (1993a) KBG syndrome AD 148050 Al-Awadi et al. (1994a) Palmoplantar keratoderma AD 148400 Gang (1994) Klippel–Trenaunay syndrome AD 149000 Kabarity et al. (1979) LEOPARD syndrome AD 151100 Farag et al. (1993a) Treacher Collins syndrome AD 154500 Farag et al. (1993a) Moebius’s syndrome AD 157900 Al-Saleh et al. (1993) Inflammatory linear verrucous epidermal nevus 163320 (ILVEN) (AD) Farag et al. (1993a) Noonan’s syndrome (AD) 163950 Farag et al. (1992b) Piebaldism (AD) 172800 Sabry et al. (1995) Poland syndrome (AD) 173800 Farag et al. (1993a) Sturge–Weber syndrome (AD) 185300 Al-Awadi et al. (1987) Hypoplastic tibiae and postaxial polysyndactyly (AD) 188770 Lubani et al. (1990a) Adrenal hyperplasia congenital due to 12 hydroxylase 201910 deficiency (AR) Farag et al. (1986b) Nonsyndromal anencephaly (AR) 206500 Teebi and Al-Awadi (1986) Progressive pseudorheumatoid arthropathy 208230 of childhood (AR) Reardon et al. (1993) Ataxia-Deafness-Retardation syndrome (AR) 208850 Farag and Teebi (1989) Bardet–Biedel syndrome 1990a (AR) 209900 Cardioskeletal syndrome, Kuwaiti Type (AR) 212135 Reardon et al. (1990) Madi et al. (1995) Joubert’s syndrome (AR) 213300 Kandil et al. (1993) Chediak–Hegashi syndrome (AR) 214500 Lubani et al. (1989) Chloride diarrhea, Familial (AR) 214700 Madi et al. (1995) Citrullinemia (AR) 215700 (continued)

12

Genetic Disorders in Kuwait

Table 12.4 (continued) References Heathcote et al. (2005) Farag et al. (1994c) Lubani et al. (1991)

365

Disease/ syndrome MIM Conotruncal malformations (AR) 217095 Cystic fibrosis (AR) 219700 Cystic fibrosis, helicobacter pylori-gastritis, 219721 megaloblastic anemia subnormal mentality (AR) Teebi (1994) Cystinuria (AR) 220100 Farag et al. (1994a) Diaphragm, unilateral Agenesis of Diaphragm 222400 defects, familial congenital (AR) Zaki et al. (1989) Anemia, dyserythropoietic congenital, Type I (AR) 224120 Farag and Schimke (1989) Ehlers–Danlos syndrome (AR) 225400 Teebi (1994) Werding–Hoffmann disease (AR) 226600 Teebi et al. (1988b), Teebi and Faciodigitogenital syndrome, Kuwaiti type (AR) 227330 Al Awadi (1991) Mohammed et al. (1994) Fanconi’s anemia (AR) 227650 Al-Raqum et al. (1994) Fructose 1,6-diphosphatase deficiency (AR) 229700 Teebi (1994) Gaucher’s disease type I (AR) 230300 Teebi (1994) GM1 gangliosidosis (AR) 230500 Kishawi et al. (1989) Hallermann–Streiff (AR) 234100 Farag et al. (1993a) Homcystinuria (AR) 236200 Teebi and Naguib (1988) Hydrocephalus (AR) 236600 Teebi et al. (1989a) Urofacial syndrome (AR) 236730 Yadav and Reavey (1988) Nonketotic hyperglycinemia (AR) 238300 Yadav and Reavey (1988) Hyperprolinemia (AR) 239510 Naguib (1988), Teebi (1992) Acrofrontofacionasal dysostosis, severe (AR) 239710 Mohan (1990) Indifference to pain (AR) 243000 Al-Awadi et al. (1983) Multiple intestinal atresia (AR) 243150 Al-Awadi et al. (1981) Apple-peel syndrome AR 243600 Abdel-Al et al. (1989) Kenny–Caffey syndrome, type I (AR) 244460 Hur et al. (2005) Keutel syndrome (AR) 245150 Hwa et al. (2007) Growth hormone insensitivity with 245590 immunodeficiency (AR) Farag and Teebi (1988a, b) Laurence–Moon syndrome (AR) 245800 Macrosomia with Microphthalmia, lethal (AR) 248110 Teebi et al. (1989a, b, c) Dubin and Teebi (1987) Primary hypomagnesemia (AR) 248250 Farah et al. (1997) Marinesco–Sjogern syndrome (AR) 248800 Barakat et al. (1986) Familial Mediterranean fever (AR) 249100 Farag et al. (1990) Meckel–Gruber syndrome (AR) 249800 Farag and Teebi (1990b) Spahr metaphyseal chondrodyslasia (AR) 250400 Sheriff and Hegab (1988) Microcephaly with chorioretinopathy (AR) 251270 Reardon et al. (1994), AlMicrocephaly & intracranial calcification (AR) 251290 Dabbous et al. (1998) Teebi and Al-Saleh (1989a) Clinical anophthalmia (AR) 251600 Farag and Teebi (1990a) Severe childhood autosomal recessive muscular 253700 dystrophy (SCARMD) AR Teebi (1994) Hurler’s & Hurler–Scheie syndromes (AR) 252800 Haider and Moosa (1997), Spinal muscular atrophy, Type I (AR) 253300 Haider et al. (2001) Haider and Moosa (1997), Spinal muscular atrophy, Type II (AR) 253550 Haider et al. (2001) Ismail et al. (1998) Insensitivity to pain, congenital, with anhidrosis (AR) 256800 Teebi (1994) Niemann–Pick, type A (AR) 257200 Farag and Teebi (1988a) Nondisjunction (AR) 257300 Abdel-Al et al. (1994) Osteopetrosis (AR) 259700 Osteopetrosis with renal tubular acidosis (AR) 259730 (continued)

366 Table 12.4 (continued) References Al-Kordi (1989), Ismail et al. (1997) Teebi et al. (1988a) Farag (1993) Teebi et al. (1987a), Usha et al. (1992) Zaki et al. (1993) Al-Hammouri et al. (1989) Teebi (1994) Naguib et al. (1987a, b) Kandil et al. (1994) Teebi (1990) Abdel-Hafez et al. (1983) Mousa et al. (1986) Al-Din et al. (1990) Farag et al. (1987) Teebi (1994) Farag et al. (1993a) Teebi and Shaltout (1989), Froster et al. (1993) Farag et al. (1994b) El-Badramany et al. (1995) Farag et al. (1993c) Teebi et al. (1989c) Farag et al. (1992a) Fildes (1989) Mullik et al. (1990) Mullik et al. (1989) Farag et al. (1993a) Gulati et al. (1988) Teebi et al. (1992) Selim (1974) El-Badramany et al. (1989) Farag et al. (1993a) Farag et al. (1993a) Farag et al. (1993a) Farag et al. (1993a) Farag et al. (1993a) Farag and Teebi (1990a) Farag et al. (1993a) Farag et al. (1993b) Farag et al. (1993b) Al-Torki et al. (1997b) Bose et al. (1996) Nanda et al. (2001) Farag and Teebi (1989) Ali 1970

N. Makhseed

Disease/ syndrome

MIM

Osteoporosis-pseudoglioma syndrome (AR) Persistent mullerian duct syndrome (AR) Phenylketonuria (AR)

259770 261500 261600

Laron’s syndrome (AR) Congenital erythropoietic porphyria (AR) Vitamin D – dependent rickets (AR) Pterygium syndrome (AR) Rhabdomyolysis, acute recurrent (AR) Robinow syndrome, autosomal recessive Peeling skin syndrome (AR) Bedouin spastic ataxia syndrome Bedouin spastic ataxia, II (AR) Spinocerebellar degeneration with slow eye movement (AR) Spondyloepimetaphyseal dysplasia, new variant (AR) Multiple sulfatases deficiency (AR) Tay-sachs disease (AR) Teebi–Shaltout syndrome (AR)

262500 263700 264700 265000 268200 268310 270300 271320

Spastic paraplegia 20, autosomal recessive (Troyer’s syndrome) Tyrosinemia type II (AR) Limb/pelvis-hypoplasia/ aplasia syndrome (AR) Weaver-like syndrome (AR) Wilson’s disease (AR) Xanthinuria, Type I (AR) Agammaglobulinemia (XL) Alport’s syndrome (XL) Coffin–Lowery syndrome (XL) Acardi’s syndrome (XL) Hypoparathyroidism (XL) Incontinenta pigmenti X-linked dominant Manic depressive illnes (XL) Renpenning’s syndrome (XL) Mental retardation (XL) Martin–Bell syndrome (XL) Mental retardation, skeletal dysplasia, abducent palsy (XL) Mental retardation/spastic diplegia (XL) Duchenne muscular dystrophy (XL) Rett’s syndrome (XL) Reifenstein’s syndrome (XL) Androgen receptor (testicular feminization syndrome) (XL) Lowry–Maclean syndrome (AD) Steroidogenic acute regulatory protein (AR) Extracellular matrix protein 1 (AR) Bardet–Biedl syndrome 5 (AR) Sickle cell anemia (AR)

271322 271640 272200 272750 272950 275900 276600 276820 277590 277900 278300 300300 301050 303600 304050 307700 308300 309200 309500 309530 309550 309620 309640 310300 312300 312750 313700

600252 600617 602201 603650 603903 (continued)

12

Genetic Disorders in Kuwait

Table 12.4 (continued) References Hwa et al. (2007) Al-Mulla et al. (2005, 2009), Amirrad et al. (2005) Griffith et al. (2008) Lerman-Sagie et al. (1996), Hadano et al. (2001) Zuliani and Hobbs (1990) Farag et al. (1994d), Wilkinson et al. (2005) Heathcote et al. (2005) (AD) autosomal dominant (AR) autosomal recessive (XL) X-linked

367

Disease/ syndrome Signal transducer and activator of transcription 5B, STAT5B (AR) BRCA1-ineracting protein 1; BRIP1 (AD)

MIM 604260

Pericenrtrin 2 mutation (Seckel syndrome ) (AR) Primary lateral sclerosis, Juvenile (AR)

605925 606353

Low density lipoprotein receptor (AD) Spastic paraplegia 26 (AR)

606945 609195

NK2, Drosophila, homolog of, 6; NKX2-6 (AR)

611770

605882

Table 12.5 Relatively common autosomal recessive disorders MIM Disease 249000 Meckel syndrome 201910, 202010 Congenital adrenal hyperplasia 141900 b thalassemia 220100 Cystinuria 209900 Bardet–Biedl syndrome 214700 Congenital chloride diarrhea 236200 Homocystinuria 237300 Carbamoyl phosphate synthase deficiency 249100 Familial Mediterranean fever 253700 Duchenne-like muscular dystrophy(SARCMD) 259730 Osteopetrosis, severe autosomal recessive 261600 Phenylketonuria 265000 Multiple pterygium syndrome 276710 Tyrosinemia type I 603470 Argininosuccinic aciduria 603903 (Sickle cell anemia) 605899 Non-Ketotic hyperglycinemia OMIM 226600 230300 230500 251200 251600 252500 252800 253200 257200 268800 272200 277900 278250 – – –

Disease Spinal muscular atrophy or Werdnig–Hoffmann disease Gaucher disease type I GM1 gangliosidosis Microcephaly Clinical anophthalmia Mucolipidosis type II Hurler and Hurler–Scheie syndromes Maroteaux–Lamy syndrome Niemann–Pick disease type B Sandhoff disease Multiple sulfatases deficiency Wilson’s disease Wrinkly skin syndrome Organic acidemias Lethal chondrodystrophies Undelineated neurodegenerative brain disorders

368

N. Makhseed

homocystinuria, four citrullinemia, two cystinuria, one hyperprolinemia and one maple syrup urine disease. The following is a list of inborn errors of metabolic disorders that have been reported from Kuwait as well as based on personal observation (Table 12.2).

New Syndromes and Variants It includes patients of Kuwaiti and non-Kuwaiti origin (Teebi 1994) (Table 12.3).

Other Disorders Reported from Kuwait The table indicates the list of genetic diseases that were reported in Kuwait as for OMIM (Table 12.4). Teebi (1994) and Teebi and Farag (1997) reported the following disorders as relatively common autosomal recessive disorders in Kuwait (Table 12.5).

References Abdel-Al YK, Auger LT, el-Gharbawy F (1989) Kenny–Caffey syndrome Case report and literature review. Clin Pediatr (Phila) 28(4):175–179 Abdel-Al YK, Shabani IS, Lubani MM, al-Ghawabi MA, Ibrahim MD, al-Mohtaseb S, Duodin KI (1994) Autosomal recessive osteopetrosis in Arab children. Ann Trop Paediatr 14(1):59–64 Abdel-Hafez K, Safer AM, Selim MM, Rehak A (1983) Familial continual skin peeling. Dermatologica 166:23–31 Abdullah MA (2005) Epidemiology of type I diabetes mellitus among Arab children. Saudi Med J 26(6):911–917 Adekile AD (2001) Sickle cell disease in Kuwait. Hemoglobin 25(2):210–225 Al-Awadi SA, Farag TI, Naguib K, Cuschieri A, Issa M (1981) Familial jejunal atresia with ‘apple-peel’ variant. J R Soc Med 74(7):499–501 Al-Awadi SA, Farag TI, Teebi AS, Devarjan LV (1982) Branchmann–de- Lange syndrome in an Arab girl. J Kwt Med Assoc 16:55–60 Al-Awadi SA, Farag TI, Cuschieri A, Naguib K, Teebi AS (1983) Autosomal recessive inheritance of intestinal atresia. J R Soc Med 76(5):434–435 Al-Awadi SA, Farag TI, Teebi AS, Naguib KK, El-Khalifa MY (1984) Anencephaly: disappearing in Kuwait? Lancet 2(8404):701–702 Al-Awadi SA, Farag TI, el-Khalifa MY, Al-Ansari AG (1985a) Fibrodysplasia ossificans progressiva. J R Soc Med 78(10):881–882 Al-Awadi SA, Moussa MA, Naguib KK, Farag TI, Teebi AS, el-Khalifa M, el-Dossary L (1985b) Consanguinity among the Kuwaiti population. Clin Genet 27(5):483–486 Al-Awadi SA, Naguib KK, Farag TI, Teebi AS (1987a) Hypoplastic tibiae with postaxial polysyndactyly: a new dominant syndrome? J Med Genet 24(6):369–372 Al-Awadi SA, Farag TI, Teebi AS, Naguib KK, Sundareshan TS, Murthy DS (1990) Down syndrome in Kuwait. Am J Med Genet (Suppl 7):87–88

12

Genetic Disorders in Kuwait

369

Al-Awadi SA, Abul Hassan SJ, Mohammed FM, Farag TI, Krishna Murthy DS, Al-Saleh QA, El-Saee L, Tayeh M, Sakr MF (1994a) Familial palmo-planter keratoderma, malignancy and sister chromatid exchanges. Gulf J Dermatol 1:40–43 Al-Awadi SA, Teebi AS, Farag TI, Naguib KK (1987b) Inherited metabolic disease in Kuwait: the need for a nationwide neonatal screening. In: Therrell BL (ed) Advances in neonatal screening. Amsterdam: Elsevier Science Publishers, pp 479–480 Al-Dabbous R, Sabry MA, Farah S, Al-Awadi SA, Simeonov S, Farag TI (1998) The autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease: report of another Bedouin family. Clin Dysmorphol 7(2):127–130 Al-Din AS, Al-Kurdi A, Al-Salem MK, Al-Nassar KE, Al-Zuhair A, Rudwan MA, Ayish I, Barghouti JA, Khaffaji S, Hamawi T (1990) Autosomal recessive ataxia, slow eye movements, dementia and extrapyramidal disturbances. J Neurol Sci 96(2–3):191–205 Alfadhli S, Kaaba S, Elshafey A, Salim M, Al-Awadi A, Bastaki L (2005) Molecular characterization of glucose-6-phosphate dehydrogenase gene defect in the Kuwaiti population. Arch Pathol Lab Med 129(9):1144–1147 Alfi OS, Chang R, Azen SP (1980) Evidence for genetic control of nondisjunction in man. Am J Hum Genet 32(4):477–483 Al-Hammouri MY, Al-Rashied AA, AL-Mazidi Z, Al-Saleh A (1989) Congenital erythropoietic porphyria. J Kwt Med Assoc 123:74–76 Ali SA (1970) Milder variant of sickle-cell disease in Arabs in Kuwait associated with unusually high level of foetal haemoglobin. Br J Haematol 19(5):613–619 Al-Kandari JM, Alshuaib WB (2007) Newborn hearing screening in Kuwait. Electromyogr Clin Neurophysiol 47(6):305–313 Al-Kandari YY (2007) Fertility and its relationship with sociocultural factors in Kuwaiti society. East Mediterr Health J 13(6):1364–1371 Al-Khalaf M (2007) Detection of a novel chromosomal translocation and chromosomal instability in women with recurrent abortions. J Reprod Med 52(9):810–814 Al-Khalaf M, Verghese L, Muharib N (2002) A cytogenetic study of Kuwaiti couples with infertility and reproductive disorders: short arm deletion of chromosome 21 is associated with male infertility. Ann Genet 45(3):147–149 Al-Kordi AM (1989) Osteopetrosis with renal tubular acidosis and cerebral calcification: carbonic anhydrase II deficiency syndrome. J Kw Med Assoc 23:200–204 Al-Mahmeed BE, Abbu-Mowais M, Al-Yassen IM (1989) Bilateral odontogenic keratocysts with partial manifestations of Gorlin–Goltz syndrome. J Kw Med Assoc 23:188–191 Al-Mulla F, Abdulrahman M, Varadharaj G, Akhter N, Anim JT (2005) BRCA1 gene expression in breast cancer: a correlative study between real-time RT-PCR and immunohistochemistry. J Histochem Cytochem 53(5):621–629 Al-Mulla F, Bland JM, Serratt D, Miller J, Chu C, Taylor GT (2009) Age-dependent penetrance of different germline mutations in the BRCA1 gene. J Clin Pathol 62(4):350–356 Al-Naggar RL, Madi SA, Tayel AM, Farag TI, Al-Awadi SA, Al-Ghnim MM, Abulhassan SJ, Sabry MA, Bastaki L (1999) Profile of chromosomal abnormalities in the al Jahra region of Kuwait. Med Princ Pract 8:167–172 Al-Nassar KE, Kelly CL, EL-Kazimi A (1989) Patterns of consanguinity in the population of Kuwait. Am J Hum Genet 45(Suppl 4):A0195 Al-Raqum FA, Al-Shagii W, Aboobacker KC, Al-Raahied AA (1994) Fructose 1, 6-diphosphatase deficiency: a case report on two brothers. J Kw Med Assoc 26:89–91 Al-Saleh QA, Teebi AS (1990) Autosomal recessive epidermolytic palmoplantar keratderma. J Med Genet 27:519–522 Al-Saleh QA, Nanda A, Hassab El-Naby HM, Sakr MFL (1993) Familial epidermal naevus (ILVEN). Int J Dermatol 32:1–3 Al-Tawari AA, Ramadan DG, Neubauer D, Heberle LC, Al Awadi F (2002) An early onset form of methylenetetrahydrofolate reductase deficiency: a report of a family from Kuwait. Brain Dev 24(5):304–309

370

N. Makhseed

Al-Torki NA, Abulhasan SJ, Sabry MA, AbdelRasool MA, Jameh IA, Al-Awadi SA (1997a) Saggital/coronal craniosynostosis associated with balanced reciprocal translocation [t(2;8) (2p16;8p22)] in an Arab girl. Am J Hum Genet 61(4):2174, Abstract Al-Torki NA, Sabry MA, Al-Awadi SA, Al-Tarkeit N (1997b) Lowry–Maclean syndrome with osteopenic bones and possible autosomal dominant inheritance in a Bedouin family. Am J Med Genet 73(4):491–492 Amirrad M, Al-Mulla F, Varadharaj G, John B, Saji T, Anim JT (2005) BRCA1 gene expression in breast cancer in Kuwait: correlation with prognostic parameters. Med Princ Pract 14(2):67–72 Awadalla NB, Teebi AS, Elzouki AY, Shaltout A (1989) Frequent relapser minimal change nephrosis: an unrecognized X-linked disorder? Eur J Pediatr 149(3):205–207 Barakat MH, Karnik AM, WA MH, El-Sobki NI, Fenech FF (1986) Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs–a study of 175 patients and review of the literature. Quart J Med 60:837–847 Bose HS, Sugawara T, Strauss JF III, Miller WL (1996) The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. New Eng J Med 335:1870–1878 Chaleby K (1985) Women of polygamous marriages in an inpatient psychiatric service in Kuwait. J Nerv Ment Dis 173(1):56–58 Courbage Y, Khlat M (1993) Structure et Accroissement de la Population dans Le Monde Arabe: Trendances Recentes. Conference Arabe sur la Population, Amman 4–8 April, 1993. Institut National d’Etudes Demographiques, Paris Daoud AS, Zaki M, Al-Saleh QA, Teebi AS, Al-Awadi SA (1989) Congenital hypothyroidism in Kuwait. J Trop Pediatr 35(6):312–314 Dubin KI, Teebi AS (1987) Primary hypomagnesemia. Eur J Pediatr 146:303–305 El-Alfi OS, Shaker YK, Shaath R, Abdel Salaam T (1968) Congenital malformations in Kuwait. J Kwt Med Assoc 2:99–108 El-Badramany MH, Farag TI, Al-Awadi SA, Hammad IM, Abdelkader A, Murthy DS (1989) Familial manic-depressive illness with deleted short arm of chromosome 21: coincidental or causal?. Br J Psychiatry 155:856–857 El-Badramany MH, Fawzy AR, Farag TI (1995) Familial Richner–Hanhart syndrome in Kuwait: 12-year clinical reassessment by a multidisciplinary approach. Am J Med Genet 60(5):353–355 Elsori HA, Naguib KK, Hammoud MS (2004) Glutaric aciduria type 1 in a Kuwaiti infant. East Mediterr Health J 10(4–5):680–684 Farag TI (1993) Familial persistent M€ ullerian duct syndrome in Kuwait and neighboring populations. Am J Med Genet 47(3):432–434 Farag IT, Krishna Murthy DS (1994) Multiple recurrence of trisomy 21 in two Bedouin famlilies: parental gonadal mosaicism or “aneuploidy’’ gene defect. Am J Hum Genet 3:A1851 Farag TI, Schimke RN (1989) Ehlers–Danlos syndrome: a new oculo-scoliotic type with associated polyneuropathy? Clin Genet 35(2):121–124 Farag TI, Teebi AS (1988a) Possible evidence for genetic predisposition to nondisjunction in man. J Med Genet 25(2):136–137 Farag TI, Teebi AS (1988b) Bardet–Biedl and Laurence–Moon syndromes in a mixed Arab population. Clin Genet 33(2):78–82 Farag TI, Teebi AS (1989) High incidence of Bardet Biedl syndrome among the Bedouin. Clin Genet 36(6):463–464 Farag TI, Teebi AS (1990a) Duchenne-like muscular dystrophy in the Arabs. Am J Med Genet 45:A936 Farag TI, Teebi AS (1990b) The second family with Spahr-type metaphyseal chondrodysplasia: autosomal recessive inheritance confirmed. Clin Genet 38(3):237–239 Farag TI, Teebi AS (1990c) Autosomal recessive inheritance of a syndrome of hypertelorism, hypospadias, and tetralogy of Fallot? Am J Med Genet 35(4):516–518 Farag TI, Krishna Murthy DS, Al-Awadi SA, Sundareshan TS, Al-Othman SA, Madi S, Redha MA (1986a) Robertsonian translocation t dic (14p;22p) with regular trisomy 21: A possible interchromosomal effect? Ann Genet 30(3):189–192

12

Genetic Disorders in Kuwait

371

Farag TI, Teebi AS, Al-Awadi SA (1986b) Nonsyndromal anencephaly: possible autosomal recessive variant. Am J Med Genet 24(3):461–464 Farag TI, Al-Awadi SA, Hunt MC, Satyanath S, Zahran M, Usha R, Uma R (1987) A family with spondyloepimetaphyseal dwarfism: a ‘new’ dysplasia or Kniest disease with autosomal recessive inheritance? J Med Genet 24(10):597–601 Farag TI, Teebi AS, Al-Awadi SA, El-Ramly MA (1989) Monozygotic twins condordant for Bardet-Biedl syndrome and benign acanthosis nigricans. Med Princip Pract 1:60–62 Farag TI, Usha R, Uma R, Madi SA, Al-Nagdy K, El-Badramany MH (1990) Phenotypic variability in Meckel–Gruber syndrome. Clin Genet 38(3):176–179 Farag TI, Al-Awadi SA, El-Badramany MH (1992a) Prevalence of Wilson’s disease among Bedouins. Am J Med Genet 29:943–944 Farag TI, El-Ramly MA, Sakr MF (1992b) A Bedouin kindred with 19 piebalds in 5 generations. Clin Genet 42(6):326–328 Farag TI, Al-Awadi SA, El-Badramary MH, Aref MA, Kasrawi B, Krishna Murthy DS, El-Khalifa MY, Yadav G, Marafie MJ, Bastaki L et al (1993a) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44(6):329–334 Farag TI, al-Awadi SA, Marafie MJ, Bastaki L, Al-Othman SA, Mohammed FM, Al-Suliman IS, Murthy DS (1993b) The newly recognised limb/pelvis-hypoplasia/aplasia syndrome: report of a Bedouin patient and review. J Med Genet 30(1):62–64 Farag TI, Al-Awadi SA, Marafie MJ, Bastaki L, Al-Othman SA, Mohammed FM, Al-Suliman IS, Murthy DS (1993c) The newly recognised limb/pelvis-hypoplasia/aplasia syndrome: report of a Bedouin patient and review. J Med Genet 30(1):62–64. Review Farag TI, Bastaki L, Marafie M, Al-Awadi SA, Krsz J (1994a) Autosomal recessive congenital diaphragmatic defects in the Arabs. Am J Med Genet 50(3):300–301 Farag TI, El-Badramary MH, Al-Sharkawy S (1994b) Toyer syndrome: report of the first “non-Amish” sibship and review. Am J Med Genet 53(4):383–385 Farag TI, Samilchuck E, Abul Hassan S, Al-Awadi SA, Kandil H, Madi SA, Al-Ghanem M (1994c) Cystic fibrosis in Kuwait and neighbouring populations. J Kwt Med Assoc 26:176–179 Farag TI, El-Badramany MH, Al-Sharkawy S (1994d) Troyer syndrome: report of the first ‘nonAmish’ sibship and review. (Letter). Am J Med Genet 53:383–385 Farah S, Sabry MA, Anim KAJ, JT QB, Al-Khatam S, Al-Busairi W, Hussein JM, Khan RA, Al-Awadi SA (1997) Marinesco–Sjogren syndrome in a Bedouin family. Acta Neurol Scand 96:387–391 Fildes RD (1989) Hereditary xanthinuria with severe urolithiasis occurring in infancy as renal tubular acidosis and hypercalciuria. J Pediat 115:277–280 Flint J, Harding RM, Boyce AJ, Clegg JB (1993) The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 6(1):215–262, Review Froster UG, Rehder H, Ho¨hn W, Oberheuser F (1993) Craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage (Teebi-Shaltout syndrome): clinical and autopsy findings. Am J Med Genet. 47(5):717–722 Gang RK (1994) Klippel–Trenaunay syndrome. J Kwt Med Assoc 26:78–80 Ghosh K, Shaqalaih A, Salman A, Hassanein AA (1993) Haemoglobinopathies in a large hospital in Kuwait. Haematologia (Budap) 25(3):185–190 Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, Al Sanna N, Saggar A, Hamel B, Earnshaw WC, Jeggo PA, Jackson AP, O’Driscoll M (2008) Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40 (2):232–236 Gulati RR, Bessiso MS, Hammouri MY, Al-Rashied AA (1988) Aicardi syndrome: a case report. J Kwt Med Assoc 22:197–199 Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, ShowguchiMiyata J, Okada Y, Singaraja R et al (2001) A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet 29:166–173, Note: Erratum: Nature Genet 29:352

372

N. Makhseed

Haider MZ, Moosa A (1997) Gene deletions in Arab patients with spinal muscular atrophy. J Child Neurol 12(5):310–313 Haider MZ, Shaltout A, Alsaeid K, Qabazard M, Dorman J (1999) Prevalence of human leukocyte antigen DQA1 and DQB1 alleles in Kuwaiti Arab children with type 1 diabetes mellitus. Clin Genet 56(6):450–456 Haider MZ, Moosa A, Dalal H, Habib Y, Reynold L (2001) Gene deletion patterns in spinal muscular atrophy patients with different clinical phenotypes. J Biomed Sci 8(2):191–196 Heathcote K, Braybrook C, Abushaban L, Guy M, Khetyar ME, Patton MA, Carter ND, Scambler PJ, Syrris P (2005) Common arterial trunk associated with a homeodomain mutation of NKX2.6. Hum Mol Genet 14:585–593 Heberle LC, Al Tawari AA, Ramadan DG, Ibrahim JK (2006) An early onset form of methylenetetrahydrofolate reductase deficiency: a report of a family from Kuwait. Brain Dev 28 (5):329–331 Howard RS, Greenwood R, Gawler J, Scaravilli F, Marsden CD, Harding AE (1993) A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation. J Neurol Neurosurg Psychiatr 56:977–981 Hur DJ, Raymond GV, Kahler SG, Riegert-Johnson DL, Cohen BA, Boyadjiev SA (2005) A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome. Am J Med Genet 135A:36–40 Hwa V, Camacho-Hubner C, Little BM, David A, Metherell LA, El-Khatib N, Savage MO, Rosenfeld RG (2007) Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm Res 68:218–224 Ismail EA, Abul Saad S, Sabry MA (1997) Nephrocalcinosis and urolithiasis in carbonic anhydrase II deficiency syndrome. Eur J Pediatr 156(12):957–962 Ismail EA, Al-Shammari N, Anim JT, Moosa A (1998) Congenital insensitivity to pain with anhidrosis: lack of eccrine sweat gland innervation confirmed. J Child Neurol 13:243–246 Ismail EA, Rudwan M, Shafik MH (1999) Fucosidosis: immunological studies and chronological neuroradiological changes. Acta Paediatr 88(2):224–227 Issa AR, Yadav G, Teebi AS (1988) Intrafamilial phenotypic variability in citrullinaemia: report of a family. J Inherit Metab Dis 11(3):306–307 Kabarity A, Al-Awadi SA, Farag TI (1979) Incomplete form of LEOPARD syndrome. J Kwt Med Assoc 13:213–230 Kandil HH, Al-Ghanem MM, Sarwat MA, Hassab AL, Nabi HM, Al-Awadi SA, Farag TI (1993) Chediak–Hegashi syndrome among Bedouins. Am J Hum Genet 53:A460 Kandil HH, Al-Ghanem MM, Al-Thallab FS, Farag TI (1994) Nonexertional familial paroxysmal rhabdomyolysis: report of five Bedouins sibs. Am J Hum Genet 55:A467 Kishawi AR, Malek AH, Al-Awadi SA, Teebi AS (1989) Hallermann–Streiff syndrome. J Kwt Med Assoc 23:80–81 Kohli KL, Al-Omain MH (1993) Fertility in Kuwait: 1970–1985. Genus 49:55–69 Krishna Murthy DS, Al-Torki NA, Bastaki L, Al-Ballol RI, Al-Awadi SA (2002) Paternal balanced translocation, t (1p;19q)associated with recurrent fetal loss-a case report. Am J Hum Genet 71:735, Suppl Abstracts # Lerman-Sagie T, Filiano J, Smith DW, Korson M (1996) Infantile onset of hereditary ascending spastic paralysis with bulbar involvement. J Child Neurol 11:54–57 Lubani MM, Doudin KI, Sharda DC (1989) Congenital chloride diarrhea in Kuwaiti children. Eur J Pediatr 148:333–336 Lubani MM, Issa AR, Bushnaq R, Al-Saleh QA, Dudin KI, Reavey PC, El-Khalifa MY, Manandhar DS, Abdul Al YK, Ismail EA et al (1990a) Prevalence of congenital adrenal hyperplasia in Kuwait. Eur J Pediatr 149(6):391–392 Lubani MM, Khuffash FA, Reavey PC, Sharda DC, Alshab TS (1990b) Familial hypophosphataemic rickets: experience with 24 children from Kuwait. Ann Trop Paediatr 10(4):377–381 Lubani MM, Al-Saleh QA, Teebi AS, Moosa A, Kalaoui MH (1991) Cystic fibrosis and Helicobacter pylori gastritis, megaloblastic anaemia, subnormal mentality and minor anomalies in two siblings: a new syndrome? Eur J Pediatr 50(4):253–255

12

Genetic Disorders in Kuwait

373

Madi SA, Al-Naggar RL, Al-Awadi SA, Bastaki LA (2005) Profile of major congenital malformations in neonates in Al-Jahra region of Kuwait. East Mediterr Health J 11(4):700–706 Madi SA, AL-Ghanemm MM, Farag TI, Samilchuck E (1995) Citrullinemia of three Bedouin sibs and review. Med Princ Pract 4:154–158 Manandhar DS, Farag TI, Hafez SA, Al-Awadi SA, Palkovic M, Hunt MCJ (1989) Familial hypercholesterolemia: is there a need for early detection and treatment. J Kwt Med Assoc 22:60–63 Marouf R, D’souza TM, Adekile AD (2002) Hemoglobin electrophoresis and hemoglobinopathies in Kuwait. Med Princ Pract 11(1):38–41 Mohammed FM, Krishna Murthy DS, Farag TI, Jain SJ, Hammad IM, Al-Rashied AA, Al-Awadi SA (1994) Chromosomal abnormalities in Fanconi anaemia. J Kwt Med Assoc 26(1):43–47 Mohammed F, Al-Yatama F, Al-Bader M, Tayel SM, Gouda S, Naguib KK (2007) Primary male infertility in Kuwait: a cytogenetic and molecular study of 289 infertile Kuwaiti patients. Andrologia 39(3):87–92 Mohan V (1990) Congenital insensitivity to pain. J Kwt Med Assoc 24:120–121 Mousa AR, Al-Din AS, Al-Nassar KE, Al-Rifai KM, Rudwan M, Sunba MS, Behbehani K (1986) Autosomally inherited recessive spastic ataxia, macular corneal dystrophy, congenital cataracts, myopia and vertically oval temporally tilted discs. Report of a Bedouin family – a new syndrome. J Neurol Sci 76(1):105–121 Moussa MA, Alsaeid M, Abdella N, Refai TM, Al-Sheikh N, Gomez JE (2005) Prevalence of type 1 diabetes among 6- to 18-year-old Kuwaiti children. Med Princ Pract 14(2):87–91 Mubashir MA, Farag TI, Al-Awadi SA et al (1996) Phenylketonuria in four Bedouin subs. Med Princ Pract 5:167–171 Mullik P, Said MA, Al-Rashied AA (1989) X-linked dominant inherited nephropathy: report of a kindred. J Kwt Med Assoc 23:433–438 Mullik P, Khalil ES, Al-Shayji W, Al-Rashied AA (1990) The spectrum of X-linked agammaglobulinemia. J Kwt Med Assoc 24:84–88 Naguib KK (1988) Hypertelorism, proptosis, ptosis, polysyndactyly, hypospadias and normal height in 3 sibs: a new syndrome? Am J Med Genet 29(1):35–41 Naguib KK, Al-Awadi SA (1990) Hypoplastic tibiae with postaxial polysyndactyly in two sibs: further conformation of a new syndrome. Am J Med Genet 35(4):588–589 Naguib KK, Teebi AS, Al-Awadi SA, Moosa A, Ali NR (1987a) Multiple pterygium syndrome in five Arab sibs. Ann Genet 30(2):122–125 Naguib KK, Al-Awadi SA, Marafie MJ, Al-Hijji SY (1987b) Trisomy 18 clustering in Kuwait. Clin Genet 32(6):379–382 Naguib KK, Sundareshan TS, Bahar AM, Al-Awadi SA, Jeryan LA, Hamdan MR (1988) Fertility with deletion Xq25: report of three cases; possible exceptions for critical region hypothesis. Fertil Steril 49:917–918 Naguib KK, Al-A-Awadi AS, Moussa MA (1989) Syndromal and nonsyndromal cleft lip with or without cleft palate in Kuwait. Ann Saudi Med 9:388–392 Naguib KK, Al-Awadi SA, Bastaki L, Moussa MA, Abulhassan SA, Tayel S, Murthy K (1999a) Clustering of trisomy 18 in Kuwait: genetic predisposition or environmental? Ann Saudi Med 19(3):197–200 Naguib KK, Al-Awadi SA, Moussa MA, Bastaki L, Gouda S, Redha MA, Mustafa F, Tayel SM, Abulhassan SA, Murthy DS (1999b) Trisomy 18 in Kuwait. Int J Epidemiol 28 (4):711–716 Nanda A, Alsaleh QA, Al-Sabah H, Ali AM, Anim JT (2001) Lipoid proteinosis: report of four siblings and brief review of the literature. Pediatr Dermatol 18(1):21–26 Quaife R, Al-Gazali LI (1994) A case of consanguineous parents with three living trisomy 21. Em Med J 12:150–153 Radovanovic Z, Shah N, Behbehani J (1999) Prevalence and social correlates to consanguinity in Kuwait. Ann Saudi Med 19(3):206–210

374

N. Makhseed

Raas-Rothschild A, Goodman RM, Meyer S, Katznelson MB, Winter ST, Gross E, Tamarkin M, Ben-Ami T, Nebel L, Mashiach S (1988) Pathological features and prenatal diagnosis in the newly recognised limb/pelvis-hypoplasia/aplasia syndrome. J Med Genet 25(10):687–697 Reardon W, Hurst J, Farag TI, Hall C, Baraitser M (1990) Two brothers with heart defects and limb shortening: case reports and review. J Med Genet 27(12):746–751 Reardon W, Wilson J, Cavanagh N, Baraitser M (1993) A new form of familial ataxia, deafness, and mental retardation. J Med Genet 30(8):694–695 Reardon W, Hockey A, Silberstein P, Kendall B, Farag TI, Swash M, Stevenson R, Baraitser M (1994) Autosomal recessive congenital intrauterine infection-like syndrome of microcephaly, intracranial calcification, and CNS disease. Am J Med Genet 52(1):58–65 Reavey PC, Yadav GC (1988) Aminoacidopathies: a review of 3 years experience of investigations in a Kuwait hospital. J Inherit Metab Dis 11(3):277–284 Reha´k A, Selim MM, Yadav G (1981) Richner-Hanhart syndrome (tyrosinaemia-II) (report of four cases without ocular involvement). Br J Dermatol 104(4):469–475 Sabry M, Al-Awadi SA, El-Alfi A, Gouda SA, Qazi NA, Farag TI (1995) Poland syndrome and associated dextrocardia in Kuwait. Med Princ Pract 4:121–126 Sabry MA, Obenbergerova D, Al-Sawan R, Saleh QA, Farah S, Al-Awadi SA, Farag TI (1996) Femoral hypoplasia-unusual facies syndrome with bifid hallux, absent tibia, and macrophallus: a report of a Bedouin baby. J Med Genet 33(2):165–167 Samilchuk E, D’Souza B, Al-Awadi S (1999) Population study of common glucose-6-phosphate dehydrogenase mutations in Kuwait. Hum Hered 49(1):41–44 Selim MM (1974) Incontinentia pigmentosa. J Kwt Med Assoc 8:65–72 Shaltout AA, Moussa MA, Qabazard M, Abdella N, Karvonen M, Al-Khawari M, Al-Arouj M, Al-Nakhi A, Tuomilehto J, El-Gammal A, Kuwait Diabetes Study Group (2002) Further evidence for the rising incidence of childhood Type 1 diabetes in Kuwait. Diabet Med 19(6):522–525 Sheriff SMM, Hegab S (1988) A syndrome of multiple fundal anomalies in siblings with microcephaly without mental retardation. Ophthalmic Surg 19:353–355 Stratton RF (1991) Teebi hypertelorism syndrome (brachycephalofrontonasal dysplasia) in a U.S. family. Am J Med Genet 39(1):78–80 Teebi AS (1987) New autosomal dominant syndrome resembling craniofrontonasal dysplasia. Am J Med Genet 28(3):581–591 Teebi AS (1990) Autosomal recessive Robinow syndrome. Am J Med Genet 35(1):64–68 Teebi AS (1991) Trigonobrachycephaly, bulbous bifid nose, macrostomia, micrognathia, acral anomalies, and hypotonia in sibs. Am J Med Genet 38(4):529–531 Teebi AS (1992) Naguib–Richieri–Costa syndrome: hypertelorism, hypospadias, and polysyndactyly syndrome. Am J Med Genet 44(1):115–117 Teebi AS (1993) Limb/pelvis/uterus-hypoplasia/aplasia syndrome. J Med Genet 30(9):797 Teebi AS (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31(3):224–233 Teebi AS, Al-Awadi SA (1986) Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J Med Genet 23(2):189–191 Teebi AS, Al-Awadi SA (1991) Kuwait type faciodigitogenital syndrome. J Med Genet 28(11):805 Teebi AS, Al-Saleh QA (1989a) Nonsyndromal microphthalmia. Clin Genet 35(4):311–312 Teebi AS, Al-Saleh QA (1989b) Autosomal dominant sneezing disorder provoked by fullness of stomach. J Med Genet 26(8):539–540 Teebi AS, Farag TI (1989a) Macrosomia, microphthalmia, and early rapid or sudden infant death: a new syndrome? Pediatrics 83(4 Pt 2):647–648 Teebi AS, Farag TI (1989b) New monogenic disorders in a mixed Arab population. Am J Hum Genet 45(Suppl 2):A66 Teebi AS, Farag TI (eds) (1997) Genetic disorders among Arab populations, Book. Oxford University Press, New York Teebi AS, Naguib KK (1988) Autosomal recessive nonsyndromal hydrocephalus. (Letter). Am J Med Genet 31:467–470

12

Genetic Disorders in Kuwait

375

Teebi AS, Shaltout AA (1989) Craniofacial anomalies, abnormal hair, camptodactyly, and caudal appendage. Am J Med Genet 33(1):58–60 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK (1986a) Hypogonadotropic hypogonadism, mental retardation, obesity and minor skeletal abnormalities: another new autosomal recessive syndrome from the Middle East. Am J Med Genet 24(2):373–378 Teebi AS, Al-Awadi SA, Opitz JM, Spranger J (1986b) Severe short-limb dwarfism resembling Grebe chondrodysplasia. Hum Genet 74(4):386–390 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK, El-Khalifa MY (1987a) Phenylketonuria in Kuwait and Arab countries. Eur J Pediatr 146(1):59–60 Teebi AS, Al-Awadi SA, White AG (1987b) Autosomal recessive nonsyndromal microcephaly with normal intelligence. Am J Med Genet 26(2):355–359 Teebi AS, Al-Awadi SA, Marafie MJ, Bushnaq RA, Satyanath S (1988a) Osteoporosis-pseudoglioma syndrome with congenital heart disease: a new association. J Med Genet 25(1):32–36 Teebi AS, Naguib KK, Al-Awadi S, Al-Saleh QA (1988b) New autosomal recessive faciodigitogenital syndrome. J Med Genet 25(6):400–406 Teebi AS, Farag TI, El-Khalifa MY, Besisso MS, Al-Ansari AG (1989a) Urofacial syndrome. Am J Med Genet 34(4):608 Teebi AS, Al-Saleh QA, Hassoon MM, Farag TI, al-Awadi SA (1989b) Macrosomia, microphthalmia, +/ cleft palate and early infant death: a new autosomal recessive syndrome. Clin Genet 36(3):174–177 Teebi AS, Sundareshan TS, Hammouri MY, Al-Awadi SA, Al-Saleh QA (1989c) A new autosomal recessive disorder resembling weaver syndrome. Am J Med Genet 33(4):479–482 Teebi AS, al Saleh QA, Odeh H (1992) Meckel syndrome and neural tube defects in Kuwait. J Med Genet 29(2):140 Usha R, Uma R, Farag TI, Girish Y, Al-Ghanim MM, Al-Najdi K, Al-Awadi SA, El-Badramany MH (1992) Late diagnosis of phenylketonuria in a Bedouin mother. Am J Med Genet 44 (6):713–715 Wilkinson PA, Simpson MA, Bastaki L, Patel H, Reed JA, Kalidas K, Samilchuk E, Khan R, Warner TT, Crosby AH (2005) A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet 42:80–82 (Letter) Yadav GC, Reavey PC (1988) Aminoacidopathies: a review of 3 years experience of investigations in a Kuwait hospital. J Inherit Metab Dis 11(3):277–284 Yadav G, Farag TI, Al-Awadi SA, Sam T, Marafie MJ, Bastaki L, Al-Khalifa MY, Kasrawi B, Wahba RA (1992) Aminoacidopathies among institutionalised mentally retarded in Kuwait. Clin Genet 42(4):212 Zaki M, Hassanein AA, Daoud AS, Al-Saleh Q (1989) Congenital dyserythropoietic anaemia in children: report of three cases from Kuwait. Ann Trop Paediat 3:161–164 Zaki M, Daoud AS, Ramadan DG (1993) Laron dwarfism in the Arabian Gulf: a report of a sibship. Ann Trop Paediatr 13(3):299–301 Zuliani G, Hobbs HH (1990) Dinucleotide repeat polymorphism at the 30 end of the LDL receptor gene. Nucleic Acids Res Jul 25;18(14):4300

Chapter 13

Genetic Disorders in Lebanon Vazken M. Der Kaloustian

Introduction Lebanon is one of the countries in the Arab World that developed services of medical genetics relatively early (Der Kaloustian et al. 1980). In this, it followed the developed countries in focusing attention on the chronically handicapped and on conditions such as congenital malformations, mental retardation, and hereditary metabolic disorders. The Lebanese form a population with a structure that favors the manifestation of a wide variety of common and rare genetic diseases (Table 13.1). In a review of all the admissions to the Pediatric Service of the American University Hospital in Beirut during 1961, 1966, and 1971, around 17% of the patients were found to suffer from a genetically caused or predisposed disorder (Der Kaloustian et al. 1980). This high prevalence of genetic diseases is favored by the high rate of consanguineous marriages in the country. Moreover, the wide variety may be the result of the mosaic of different ethnic communities that compose the Lebanese population (Naffah 1974). A rapid review of the geography, ethnography, and social structure of the country will help to understand the nature and origin of the genetic diseases in Lebanon, as well as their impact on the healthcare delivery systems.

The Country and Population Lebanon is a small country on the eastern shores of the Mediterranean (Fig. 13.1). It covers an area of 10,452 km2 and has a population of around three million. It is long and narrow, with a coastal area of a well-irrigated and cultivated plain. This area V.M. Der Kaloustian Emeritus Professor of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_13, # Springer-Verlag Berlin Heidelberg 2010

377

AR

●Alkalosis, hypokalemic, with hyperreninemia, aldosteronism, and normal juxtaglomerular apparatus Alkaptonuria

*108345 %606937

Lebanese Lebanese Druze

AR

Dhaini and Levy (2001) Me´garbane´ et al. (2001a) Delague et al. (2002)

Mahfouz et al. (2006) Teebi and Al-Awadi (1986)

þ107741 #208230

Lebanese

þ107730

Khachadurian and Abu-Feisal (1958), Deeb and Frayha (1976) Sabbagh et al. (2007b)

Baghdassarian and Tabbara (1975), Zahed et al. (2005) Barakat et al. (1986)

Tamouza et al. (2001) Soussou et al. (1974) Tamim et al. (2003) Sabbagh et al. (2007a)

#106300 207500

þ106180

*203500

#203100

#118450

El-Rassy et al. (2008)

Idriss and Der Kaloustian (1973), Der Kaloustian and Musallam (1975), Der Kaloustian et al. (1976) Najjar and Jarrah (1964) Delague et al. (2000b)

*201100

*240200 þ201910

References Khachadurian et al. (1971) Der Kaloustian et al. (1972b)

OMIM *200100 *201000

AR

MF AR or MF

Lebanese

AR

Angiotensin-converting enzyme gene polymorphism ●Ankylosing spondylitis, susceptibility to Anus, imperforate Apnea of prematurity ApoB-100 R3500Q mutation (not present in the Lebanese population) Apolipoprotein E Arthropathy, progressive, pseudorheumatoid of childhood Arylamine N-acetyltransferase ●Ataxia, cerebellar, congenital, with mental retardation, optic atrophy and skin abnormalities (gene at 15q24-q26)

Lebanese

AD

Druze

Lebanese Lebanese

AR AR

Addison’s disease Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency ●Alagille syndrome 1 (novel frameshift mutation in JAG1) Albinism

Table 13.1 Genetic diseases and traits reported in the Lebanese populationsA Disease Inheritance Communities with higher prevalence A-b-lipoproteinemia AR Jordanian Arab Acrocephalopolysyndactyly type AR Palestinian Muslim II – Carpenter syndrome Acrodermatitis enteropathica AR Lebanese Muslim and Christian

378 V.M. Der Kaloustian

Calcinosis, tumoral, with hyperphosphatemia ●Cardiogenital syndrome (Najjar syndrome) ●Cardiomyopathy, congestive, with hypergonadotropic hypogonadism (Malouf syndrome) Cardiomyopathy, familial hypertrophic Cataract, congenital Cataract, posterior polar Celiac disease ●Chondrodysplasia with multiple dislocations ●Chondrodysplasia with anomalies of multiple systems ●Charcot–Marie–Tooth disease (novel GDAP1 mutation) ●Charcot–Marie–Tooth disease, CMT4F (new CMT4 locus, periaxin gene, PRX)

Biliary malformation with renal tubular insufficiency Brown–Vialetto–Van Laere syndrome ●Bundle branch block, mapped at 19q13.1

Ataxia, cerebellar, congenital, with short stature (gene at 9q34-qter) Arypamine N-acety p transferase ●Ataxia telangiectasia ●Bardet–Biedl syndrome Bartter syndrome type 4, infantile, with sensorineural deafness (Hypokalemic saltlosing tubulopathy with chronic renal failure) Behc¸et syndrome *108345 #208900 #209900 #602522

%109650

Lebanese Lebanese

Lebanese

Lebanese Christian Lebanese Panethnic Lebanese Lebanese Lebanese Lebanese Muslim Shiite

AD AD

AR AR AR

AR

Lebanese Muslim Shiite

AR

Delague et al. (2000a) (continued)

De Sandre-Giovannoli et al. (2003)

Me´garbane´ et al. (2008b)

Malouf et al. (1985a) Baghdassarian and Tabbara (1975) Bidinost et al. (2006) Bitar et al. (1970), Hajjar et al. (1974) Me´garbane´ and Ghanem (2004)

Mikati et al. (1981) Najjar et al. (1970, 1984) Malouf et al. (1985b)

Me´garbane´ et al. (2000) Ste´phan (1954, 1974, 1978), De Meeus (1995), Ste´phan et al. (1997)

Bitar et al. (1986), Ghayad and Tohme (1995), Arayssi et al. (2008) Mikati et al. (1984)

Me´garbane´ et al. (1999a), Delague et al. (2001) Dhaini and Levy (2000) Bitar et al. (1969), Fares et al. (2004) Laurier et al. (2006) Jeck et al. (2001)

Genetic Disorders in Lebanon

#145900

*606598

#192600 *212500 #610623 116900

*140400 *211900 212120 212112

%211530 *113900

AR AD

AR

210550

Lebanese

%213200

Lebanese Maronite

AR

AR AR AR

AR

13 379

●Deafness, sensorineural, non-syndromic, DFNB13 ●Deafness, sensorineural, non-syndromic, DFNB21 with a-tectorin gene defect ●Deafness syndrome, branchiogenic De Sanctis-Cacchione syndrome ●Dermodistortive urticaria Diabetes insipidus

Deafness, sensorineural, non-syndromic, DFNB1 ●Deafness, sensorineural, non-syndromic, DFNB9. mutation in the OTOF gene

Lebanese

●Corneal dystrophy and perceptive deafness AR Cushing disease, familial ●Cystic fibrosis of the pancreas AR

#603629 %609166 *278800 125630 *125700

Lebanese Muslim Shiite Lebanese Muslim Sunnite Palestinian Muslim Panethnic

AR AR

Me´garbane´ et al. (2003c) Der Kaloustian et al. (1974a) Epstein and Kidd (1981) Najjar and Mahmud (1968)

Mustapha et al. (1999)

Mustapha et al. (1998)

*603681 %603098

AR

Chaib et al. (1996), Yasunaga et al. (1999)

Harboyan et al. (1971) Salti and Mufarrij (1981) Bitar and Idriss (1969); Desgeorges et al. (1997) Farra et al. (2008) Denoyelle et al. (1997)

Hennies et al. (2004) Me´garbane´ et al. (2001c)

De Sandre-Giovannoli et al. (2005), Delague et al. (2007) Naffah and Der Kaloustian (1975) Dudin et al. (1984), Mansour et al. (1984) Zahed et al. (2007) Rutland and de Longh (1990)

References

#601071

Lebanese Christian Maronite

Lebanese Muslim Sunnite

AR

#220290

*607817 217400 219090 #219700

#216550 605685

215518

OMIM *605725 #609311

AR

Lebanese

AR

Lebanese, various communities

Lebanese Lebanese

Lebanese AR AR

Chromosome 3 and 5 translocation Chromosome 5q12 deletion Chromosome (7)(p22.1pter) duplication ●Ciliary dyscoordination due to random ciliary orientation ●Cohen syndrome ●Cohen syndrome, cutis verticis gyrate and sensorineural deafness with VPS13B mutation

AR

●Charcot–Marie–Tooth disease, CMT4H Lebanese

Inheritance Communities with higher prevalence

Table 13.1 (continued) Disease

380 V.M. Der Kaloustian

223400 Lebanese Muslim Shiite and Sunnite, Christian Maronite and GreekOrthodox, Kurdish Muslim Lebanese Muslim Shiite Saudi Arabian Lebanese Lebanese

AR AR

AR AR XLR AR

Dyggve–Melchior–Clausen syndrome

●Ectodermal dysplasia, hidrotic, new form ●Ectodermal dysplasia and sensorineural deafness Ectodermal dysplasia, hypohidrotic (EDA1 mutation) ●Ectodermal dysplasia, hypohidrotic (new EDAR mutation) Ectopia lentis

Me´garbane´ et al. (2008c) Baghdassarian and Tabbara (1975) (continued)

*129600

Tomb et al. (2009)

Shammas et al. (1976, 1979), Shammas et al. (1979) Der Kaloustian et al. (1971) Der Kaloustian et al. (1987b) Mishalany et al. (1970, 1978), Der Kaloustian et al. (1974b) Naffah and Taleb (1974), Spranger et al. (1975), Naffah (1976), El Gouzzi et al. (2003), Neumann et al. (2006) Me´garbane´ et al. (1998) Mikaelian et al. (1970)

Me´garbane´ et al. (1999b).

Abboud et al. (1985)

Najjar et al. (1985)

Almawi et al. (2006)

Khachadurian and Somerville (1965), Hirbli et al. (1990) Stayoussef et al. (2009)

#224900

#305100

602401 224800

*223800

#246200

AR

*126300

Donohue syndrome (Leprechaunism) Down syndrome ●Duodenal atresia

AD

Lebanese

*249270

AR

AR

*222300

#125853

Panethnic AR

%222100

Panethnic

Diabetes mellitus, insulin-dependent (T1D, IDDM) Diabetes mellitus, non-insulin-dependent (T2D, NIDDM) Diabetes mellitus and insipidus, with optic atrophy and deafness (Wolfram syndrome) Diabetes mellitus, thiamine-dependent megalo-blastic anemia, and sensorineural deafness with deficient a-ketoglutarate dehydrogenase activity ●Diastrophic dysplasia, ‘broad boneplatyspondylic’ variant Distichiasis

%222100

Panethnic

Diabetes mellitus

13 Genetic Disorders in Lebanon 381

*612309

Lebanese Lebanese Lebanese, Greek Orthodox Lebanese Panethnic, with predominance in Armenians and Jews

Factor V R2 (H1299R) polymorphism ●Factor XI deficiency Factor XIII gene V34L mutation ●Familial Mediterranean fever or Paroxysmal polyserositis

Glaucoma, congenital Glucose-6-phosphate dehydrogenase deficiency Glycogenosis, hepatic

Fanconi anemia Fever, familial, lifelong, persistent Fibromatosis, juvenile hyaline Fructose-1,6-diphosphatase deficiency Fructosuria, nonalimentary Gilbert syndrome ●Gaucher disease type 1

#226700

*231300 *305900 þ232200

Panethnic Lebanese

AR

*227650 228400 *228600 *229700 þ229800 *143500 #230800

Panethnic

Maronite Lebanese

Lebanese

#134610

*612309 *264900 þ134570 #291100

AR LR

AR AR AR AR AR

AR

AR

AD

225360

AR AR AR Lebanese Lebanese

OMIM %601552

Inheritance Communities with higher prevalence AR Lebanese Druze

Table 13.1 (continued) Disease ●Ectopia lentis and distinctive craniofacial appearance Ehlers-Danlos syndrome, type IV-D Enterocolitis, necrotizing ●Epidermolysis bullosa, Epilepsy syndromes Factor V Leiden mutation Sulh et al. (1984) Me´garbane´ and Sayad (2007) Ayoub et al. (2005) Choueiri et al. (2001) Irani-Hakime et al. (2000), Taher et al. (2001) Zaatari et al. (2006) De Moerloose et al. (2004) Mahfouz et al. (2008) Reimann et al. (1954), Armenian and Khachadurian, 1973), Armenian and Uthman (1975) Khachadurian and Armenian (1974), Armenian (1982), Mansour et al. (2001), Medlej-Hashim et al. (2005), Jalkh et al. (2008), Sabbagh et al. (2008) Shahid et al. (1972) Herman et al. (1969) Fayad et al. (1987) Alexander et al. (1985) Khachadurian (1963) Bitar (1970) Shamseddine et al. (2004), El-Zahabi et al. (2007) Baghdassarian and Tabbara (1975) Taleb et al. (1964), Kurdi-Haidar et al. (1990), Usanga and Ameen (2000) Bitar and Takla (1971) Trioche et al. (1999)

References Shawaf et al. (1995), Haddad et al. (2001)

382 V.M. Der Kaloustian

Lebanese Lebanese Lebanese

Lebanese Christian

AD AD

AR AR

Various Lebanese communities

Lebanese, panethnic

Arab

AR AR

AR

HPA-1 platelet antigen alleles (1a and 1b) (see Integrin, beta-3, ITGB3) Hurler syndrome

Hydrocephalus ●Hypercholesterolemia, autosomal recessive; ARH Hypercholesterolemia, familial; FH ●Hypercholesterolemia, low-density lipoprotein receptor, Lebanese variant (LDLR, CYS660TER) ●Hyperlipoproteinemia, Type I Hyperoxaluria I

AR

Homocystinuria

●Glycogen storage disease I (novel mutation in the Glucose-6-phosphatase gene – W70X) Glycosuria, renal AR Gout Hallermann–Streiff syndrome ●Hearing loss, non-syndromic AR ●Hemoglobin Beirut Hemoblobin H disease HLA markers HLA complex class I and II antigen frequencies HLA, new HLA-B*27 allele (B*2719) – see above under ankylosing spondylitis Homocysteinemia and MTHFR polymorphisms

#238600 *259900

*144400 #606945

236600 #603813

252800

þ173470

*607093 þ236200

Abifadel et al. (2004) Traboulsi et al. (1985b) (continued)

Salam and Idriss (1964), Mossman et al. (1981) Abdul-Karim et al. (1964) Khachadurian and Uthman (1973), Garcia et al. (2001) Khachadurian (1964); Lehrman et al. (1987)

Baghdassarian and Tabbara (1975), Mamo and Tabbara (1976) Sabbagh et al. (2007c)

Sabbagh et al. (2008b)

#603174

141900 141850

Khachadurian and Khachadurian (1964) Bitar (1966) Baghdassarian and Tabbara (1975) Mustapha et al. (2001) Strahler et al. (1983), Blibech et al. (1986) Shahid et al. (1974) Serre et al. (1976, 1979) Abdelnoor et al. (2001)

*233100 138900 234100

13 Genetic Disorders in Lebanon 383

*147220 *243110 *243150 *243600 þ176261

Lebanese Lebanese Greek Orthodox and Shiite Lebanese Lebanese Lebanese Lebanese Muslim Sunnite

AR AR AR

AR AR

Lactose intolerance, adult Leber congenital amaurosis Leber optic atrophy ●Lentigines and nystagmus ●Lipodystrophy, congenital, generalized, type 2, Berardinelli–Seip syndrome type 2 Lipoid proteinosis

*247100 *154570

AD

Maltese-Lebanese Lebanese Muslim Sunnite

*223100 *20000 308905 150900 #269700

#612347 #156550 #218700

#604777 #261100

AR

AD AR

AR

Lebanese

*202500 *147000

Lebanese

AR

AR AR AR AR

%241090

Lebanese

AR ???

OMIM *240300

Inheritance Communities with higher prevalence AR

Kniest dysplasia Kocher–Debre´-Se´me´laigne syndrome

Table 13.1 (continued) Disease Hypoadrenocorticism with hypoparathyroidism and moniliasis Hypogonadism, hypergonadotropic, and partial alopecia Hypogonadism, hypogonadotropic, and alopecia Hypothyroidism, congenital Ichthyosis, lamellar, 3 Imerslund–Gr€asbeck syndrome without proteinuria Immunodeficiency, severe combined-1 Immunoglobulins IGHA2*M1 and IGHA2*M2 alleles Immunoglobulin lambda ●Interleukin-1, defective T-cell response to ●Intestinal atresia, multiple ●Jejunal atresia ●Jervell and Lange-Nielsen syndrome 2 (long-QT syndrome) Frayha et al. (1979) Najjar and Nachman (1965), Afifi et al. (1974) Loiselet and Jarjouhi (1974) Baghdassarian and Tabbara (1975) Baghdassarian and Tabbara (1975) Pipkin and Pipkin (1950) Salem et al. (1973), Najjar et al. (1975), Afifi et al. (1976), Magre´ et al. (2001) Newton et al. (1971); Zaynoun and Kurban (1974) Alexander et al. (1984)

Ghanem et al. (1988) Chu et al. (1984) Mishalany and Der Kaloustian (1971) Mishalany and Najjar (1968) Schulze-Bahr et al. (1997)

Mudawwar and Geha (1975) Soua et al. (1989)

Najjar et al. (1963); Najjar (1964) Lefe`vre et al. (2006) Ro¨ssler et al. (2003)

Al-Awadi et al. (1985), Me´garbane´ et al. (2003a) Salti and Salem (1979)

References Traboulsi et al. (1985a)

384 V.M. Der Kaloustian

Optic atrophy, congenital Ornithine aminotransferase deficiency ●Osseous dysplasia, severe short stature, multiple dislocations, delayed bone age Osteopetrosis

●Mannose-6-phosphate receptor recognition defect, Lebanese-type, phosphodiester glycosidase deficiency Maple syrup urine disease Marden-Walker syndrome Meckel syndrome ●Megarbane´ syndrome Mesomelic dysplasia, upper-limb Metaphyseal Spahr-type dysplasia (exclusion of RMRP and COL10A1 as candidate genes Methylenetetrahydrofolate reductase (MTHFR) ●Microcephaly, hypogonadotropic hypogonadism, short stature, and minor anomalies: a new syndrome Microphthalmia with myopia and corectopia Microphthalmos M€ ullerian structures, persistence of NAT1 genotypes ●Neuropathy, hereditary sensory and autonomic (novel mutation in HSN2) Night blindness with high-grade myopia Nystagmus, congenital ●Oculo–dento–osseous dysplasia ●Odontoonychodermal dysplasia

Lebanese

AR

Lebanese Muslim Shiite

AR AR

Lebanese Christian Maronites Lebanese

Syrian Muslim

AR

AR AR

Lebanese

AR

Souraty et al. (2007) (continued)

Der Kaloustian and Baghdassarian (1972) Baghdassarian and Tabbara (1975) Traboulsi et al. (1986a) Fadhil et al. (1983), Me´garbane´ et al. (2004), Adaimy et al. (2007) Baghdassarian and Tabbara (1975) Mitchell et al. (1988) Me´garbane´ (2007)

Genetic Disorders in Lebanon

#259700

258500 *238870

*257270 257400 257850 #257980

Rivie`re et al. (2004)

Panethnic

AR

#201300

Baghdassarian and Tabbara (1975) Baghdassarian and Tabbara (1975) Brook et al. (1973)

Almawi et al. (2004)

156900 *251600 *261550

Lebanese Christians and Muslims

Mikati et al. (1985)

*607093

Lebanese Shiite Lebanese

Mikati et al. (1982) Jaatoul et al. (1982) Naffah et al. (1972) Me´garbane´ et al. (2001b) Me´garbane´ and Ghanem (2005) Me´garbane´ et al. (2008a)

*251200

*248600 *248700 *249000 606527 %191440 250400

AR

AR AR AR AR AD AR

13 385

Rheumatoid arthritis

AR

Pseudoxanthoma elasticum Psychoses, affective Renal and urinary tract anomalies with chromosome aberrations Reticulosis, familial, histiocytic Retinitis pigmentosa Retinoblastoma AD

AR

AR

Prune belly syndrome Pseudocholinesterase deficiency

Pseudohermaphroditism, (pseudovaginal perineoscrotal Hypospadias,PPSH; 5-a-reductase SRD5A2 deficiency)

AR

AR

Inheritance AR XL AD AR AR AD

Phenylketonuria Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G polymorphism Porphyria, congenital erythropoietic Prolidase deficiency

●Ovarian failure, premature (POF1B) Parathyroid carcinoma, familial Pendred syndrome Pentosuria, essential Peutz–Jeghers syndrome

Table 13.1 (continued) Disease

Lebanese

Lebanese Christian

Lebanese, Muslim Shiite

Panethnic

Lebanese Christian Lebanese and Palestinian Muslim Sunnite Panethnic

Communities with higher prevalence Lebanese Lebanese Druze

#180300

*180200

*267700

*607306 *264800

#264600

Majdalani and Vassoyan (1974) Baghdassarian and Tabbara (1975) Baghdassarian and Tabbara (1975), Dudin et al. (1984b) Traboulsi et al. (1986b) Darwish and Armenian (1987)

Najjar et al. (1968) Khachadurian and Sutherland (1975) Barakat and Butler (1987)

Idriss et al. (1975) Der Kaloustian et al. (1982), Freij et al. (1984); Freij and Der Kaloustian (1986) Afifi et al. (1972b) Loiselet and Srouji (1968), Baraka et al. (1974) Hochberg et al. (1996)

#263700 þ170100

#100100 *272400

Salam (1963) Shammaa et al. (2008)

Lacombe et al. (2006) Frayha et al. (1972) Najjar (1963) Khachadurian (1962) Salem et al. (1972), Solh et al. (1983)

References

*261600 *173360

OMIM #259720 #300604 145000 *274600 *260800 *175200

386 V.M. Der Kaloustian

AR AR AR

AD

AR AR

AD AR AD AR

Palestinian Muslim

Lebanese Christian Maronite Panethnic

Lebanese Lebanese

Lebanese Christian Lebanese and Syrian Muslims

*119100

*106300 *248200 %603546 *272460 *186970 *272800 273150 187500 *273500

*252920 269000 *141900

Frayha and Nasr (1971) Baghdassarian and Tabbara (1975) Me´garbane´ et al. (2003b) Wiles et al. (1992) Ghanem et al. (1988), Buresi et al. (1989) Hechtman et al. (1989), Trop et al. (1992) Najjar et al. (1974) Der Kaloustian et al. (1985b) Taleb and Shahid (1967), Shahid et al. (1974), Chehab et al. (1987), Der Kaloustian et al. (1987a), Zahed and Bou-Dames (1997), Zahed et al. (2000); Qatanani et al. (2000), Makhoul et al. (2005) Der Kaloustian and Mnaymneh (1973) Barakat and Butler (1987) (continued)

Vincenti et al. (1973) Tabbara et al.(1973) Der Kaloustian et al. (1972a), Naffah (1973) Fuleihan et al. (1971) Der Kaloustian et al. (1981), Drousiotou et al. (2000) Mossman et al. (1983) Ben Ezra et al. (1982) Shahid and Abu Haydar (1962), Cabannes et al. (1965) Baghdassarian and Tabbara (1975), Sille´n et al. (1998); Kurban and Azar (1969) Akl et al. (1977), Nezarati et al. (2002) Der Kaloustian et al. (1985a)

Genetic Disorders in Lebanon

Tibial aplasia and ectrodactyly Turner syndrome

*270300 *270400 271310

AR

●Sjo¨gren–Larsson syndrome, mutation of nt941del3, ins21 ●Skin peeling, familial, continuous ●Smith–Lemli–Opitz syndrome ●Spinocerebellar degeneration with corneal dystrophy Spondylitis, ankylosing, juvenile Spondyloepimetaphyseal dysplasia Stargart macular degeneration Synspondylism, congenital T-cell antigen receptor, gamma subunit ●Tay–Sachs disease, juvenile Testes, rudimentary Tetralogy of Fallot with pulmonary atresia Thalassemia AD

#270200

AR AR AD

%180860 #268800

Sanfilippo disease, type B SC phocomelia syndrome Sickle-cell trait

Kurdish Lebanese Christian Maronite and Muslim Sunnite

AD AR

*307800 *180500 #180849

Russell–Silver syndrome Sandhoff disease

Syrian Muslim Sunnite Syrian

XLR AD

Rickets, vitamin D-resistant Rieger syndrome Rubinstein–Taybi syndrome

13 387

Lebanese Lebanese Syrian

AR AR XLR AR AR

Wolfram syndrome (DIDMOAD) Xanthinuria, hereditary

*301000

#277600

%206920

*277350 #277450

OMIM #276900 #276900 #276901 #276904

Faivre et al. (2002), Dagoneau et al. (2004) Bitar and Lightwood (1967), Parkman et al. (1978) Medlej et al. (2004) Frayha et al. (1973, 1977), Salti et al. (1976) Afifi et al. (1972a, b)

Traboulsi et al. (1984)

Saouda et al. (1998), DeAngelis et al. (2001) McLaren and Zekian (1971) Fregin et al. (2002)

References Baghdassarian and Tabbara (1975) Saouda et al. (1998)

Lebanese #222300 Lebanese Christian Maronite, Greek *278300 Orthodox, Muslim Shiite Xeroderma pigmentosum AR Palestinian Muslim, Syrian Muslim, *278700 Lebanese Christian A ● Represents a condition, a mutation, or a variant that was described first from Lebanon or in persons of Lebanese origin

Lebanese

Lebanese, Maronite

AR

AR

Usher syndrome type 1C

●Vitamin A metabolic defect ●Vitamin K-dependent clotting factor, hereditary combined deficiency of, second gene locus Waardenburg recessive microphthalmia syndrome ●Weill-Marchesani syndrome (ADAMTS10 mutations) Wiskott–Aldrich syndrome

AR

Inheritance Communities with higher prevalence

Table 13.1 (continued) Disease Usher syndrome Usher syndrome types I(USH1), II(USH2)

388 V.M. Der Kaloustian

13

Genetic Disorders in Lebanon

389

SYRIA

Tripoli

MT S

N

Zahlah

BA

NO

LE

Beirut

BA NO N

MT S

BE QA ’A

MEDITERRANEAN SEA

LE

SYRIA

TI

Saida

AN

Damascus

N

O

M

Tyre

T

R HE

EY

RK

TU

SYRIA

M

LEBANON

ISRAEL

JORDAN EGYPT

Fig. 13.1 Map of Lebanon. From Der Kaloustian et al. [1980]

widens in the north, forming the plain of the Akkar. In the south, it extends into the inland by low hills. A mountain ridge parallel to the sea (“the Lebanon”) limits the littoral. To the east of “the Lebanon” lies the Beqa’a Plateau, a fertile valley with agriculture on a large scale. Further to the east is the mountain ridge of “the AntiLebanon,” generally lower and much drier than “the Lebanon”. Syria borders Lebanon in the north, with the wooded hills of the Alawites; in the east are the Syrian Desert and the oasis of Damascus. The Israeli hills of Galilea lie on the southern borders. In the west, Lebanon is open to all the countries surrounding the Mediterranean through the harbors of Beirut, Saida (Sidon) and Trablos (Tripoli) (de Vaumas 1954).

390

V.M. Der Kaloustian

Ethnography of Lebanon The country has been a favored crossroads between Asia, Africa, and Europe since prehistoric times, and a place of encounter for people of very diverse ethnic origins. As a consequence, the present population of Lebanon presents with a wide genetic variety and comprises at least 17 ethno-religious communities. The earliest known settlements in Lebanon date back to 5000 BC. Later, for a period of 2,000 years, the Phoenician City States maintained a tributary relationship with the neo-Assyrian and neo-Babylonian empires. It was then conquered by the Achaemenid dynasty of Persia and turned into a satrapy. In the fourth century BC, it was occupied by the forces of Alexander the Great, who conquered Tyre in 332 BC followed by the Seleucids after his death. The Romans were next to conquer the region. Later, it was infiltrated by the Arab armies, and occupied for two centuries by the Crusaders (de Vaumas 1955). Finally, in the thirteenth century, it was invaded by the Ottoman Turks who ruled until the First World War. Following a short period under the French mandate, the country became independent in 1943. Christianity was introduced from neighboring Galilea soon after the time of Jesus of Nazareth. As for Islam, it was brought after the death of Muhammad, in the seventh century. The two principal demographic currents that have contributed to the population of the country throughout its history have been the Anatolian and Armenoid group, and the southeastern or Semitic group. In addition, the persecuted minorities of the surrounding regions have taken refuge in the Lebanese mountains. At the beginning of the first century AD, the greater part of the autochthonous population was Christian. In the fifth century, the Monophysite schism opposed the rural, Syriac-speaking populations to those of the cities, closer to Byzantium and following the Greek rites (Orthodox and not Monophysite). The Maronite community – presently the most numerous Christian community of Lebanon – was a group of Syriac-speaking peasants living in the valley of the Orontes in Syria. They were united by a monastic organization emanating from St. Maron. In the following centuries, owing to the insecurity prevailing in these regions, they moved southward and took refuge in the Lebanese mountains (de Vaumas 1955). An important portion of the local population was converted to Islam during the Arab conquests. In the seventh century AD, a Muslim branch, the Shiites, separated from Sunnites and moved to the fringes of the Arab empire in order to avoid the central government. Many of them settled on the high plateaus of Lebanon as early as the eighth century. The rural populations became, to a greater extent, Shiite, while the city dwellers, closer to the political authority, were Sunnite (de Vaumas 1955). In the eleventh century, dissident Shiite missionaries from Egypt converted tribes who took refuge in the central part of the Lebanese mountains and formed the Druze community, which is a religious isolate. At the end of the twelfth century, Saladdin helped the immigration and settlement of Kurds in Lebanon. A similar movement of Turks took place under the

13

Genetic Disorders in Lebanon

391

Ottoman Empire. Thus, Turkish and Kurdish elements mixed with the autochthones to form the present Sunnite community of the country. The Christian population of the coastal towns was culturally attached to Byzantium and was linked to the Orthodox at the time of the separation of the Oriental and Occidental churches. The Maronites, however, isolated in the mountainous areas, sought the protection of Westerners and were linked, quite early, with Rome (de Vaumas 1955). After the downfall of Byzantium, the Christians were obliged to seek the protection of the developing Western nations against Turkish despotism. Because of their ties with the West, various Christian communities developed “uniate” branches. Today, most communities with a “uniate” branch recognize the Pope, while the “orthodox” branch remains separate. The Armenian community is the most recent of the important Lebanese communities. The conversion to Christianity of this people of the region of Eastern Anatolia and the Caucasus started in the first century. This conversion is attributed to the apostles Bartholomew and Thaddeus, whence the name “Armenian Apostolic Church.” The Armenian Church is monophysite as opposed to the Byzantine Orthodox. And, all through its history of political and military turmoil, it has been eager to keep its independence. The Catholic and Protestant missions of the nineteenth and twentieth centuries created the Armenian Catholic and Protestant branches. Finally, the Turkish persecutions and genocide of the Armenians in 1915 pushed into Lebanon, between 1920 and 1940, two waves of immigrants belonging to all three Armenian religious communities: apostolic, catholic, and protestant. After the First World War, various political regimes created difficulties in the region and provoked new migrations into Lebanon. As a consequence, several new communities were founded. These were of little importance in terms of size, but they were nevertheless eager to keep their identity. Examples of these are the Syriacs and the Chaldeans, who came from Iraq.The Syriacs have a liturgical language that is the same as that of the Maronites, but their historical background is completely different. The influx of the newcomers continued in the middle of the twentieth century. The Palestinians and the Kurds, who took refuge in Lebanon as a result of political events in the region, still have an unsettled future. Nevertheless, they have their significant impact on the structure of the Lebanese population. The mosaic structure and the geographic distribution of the population of Lebanon are explained by this long history. The Sunnites live essentially in the four coastal towns: Beirut, Tripoli, Sidon, and Tyre. The Greek Orthodox and Greek Catholics, merchants or peasants, are spread in the cities and villages. The Maronites and the Druze are mostly in “the Lebanon” mountains, although the numerical increase of the Maronites has spread them elsewhere also. Traditional peasants, the Shiites, have been pushed to the periphery of the country, mostly to the dry hills of southern Lebanon. The Armenians are settled in the suburbs of Beirut and in villages in the Beqa’a valley, primarily Anjar. The Palestinians are mostly in camps in the outskirts of the major towns (Hitti 1967). Of the seven main communities of the country, the Shiites, Maronites, and Sunnites predominate

392

V.M. Der Kaloustian

numerically, followed by the Druze, Greek Orthodox, Greek Catholic, and Armenian communities, which are of medium numerical importance. The other groups (Jewish, Protestant, and different Eastern Christian communities) are smaller minorities. The Kurds and especially the Palestinians (who are mostly Sunnite Muslims), are numerically important, but are not considered as an integral part of Lebanon (Hitti 1967; Courbage and Fargues 1973).

The Genetic Traces of the Phoenicians The Phoenicians were traders in the Mediterranean Sea two to three thousand years ago. They established trading posts throughout the Mediterranean. Zalloua et al. (2008a), chose Phoenician-influenced sites on the basis of well-documented historical records and collected new Y-chromosomal data from six sites. They found that haplogroup J2 and six Y-STR haplotypes exhibited a Phoenician “signature” that contributed >6% to the modern Phoenician-influenced populations examined.

Y-Chromosome Diversity in Lebanon Nine hundred and twenty six Lebanese men were typed with Y-chromosomal SNP and STR markers. Male genetic variation within Lebanon was found to be more strongly structured by religious affiliation than by geographic origin. It was found that Y-haplogroup J*(J2) was more frequent in the putative Muslim source region (the Arabian Peninsula) than in Lebanon. It was also more frequent in Lebanese Muslims than Lebanese non-Muslims. Conversely, haplogroup R1b was more frequent in the putative Christian source region (Western Europe) than in Lebanon. It was also more frequent in Lebanese Christians than in Lebanese non-Christians. It is therefore suggested that the Islamic expansion from the Arabian Peninsula at the beginning of the seventh century AD introduced their lineages into the communities that later became the Lebanese Muslims, and the Crusaders in the eleventh to thirteenth centuries CE introduced the western European lineages into the Lebanese Christians (Zalloua et al. 2008b).

Consanguinity The degree of “genetic impermeability” varies widely according to the ethnic and religious groups. It is important to note that marriages are quite frequent between members of different Christian communities. In this respect, the Druze seem to be the most isolated group, even though Sunnites, Shiites, and Armenians also try to avoid marriage outside their own community. The prevalence of preferential patriarchal parallel-cousin marriage is recognized as a specific trait of the Arabs. This type of marriage has been so common that the

13

Genetic Disorders in Lebanon

393

popular name in Arabic for father-in-law is “uncle” (father’s brother), for motherin-law is “uncle’s wife” (wife of father’s brother), and for husband or wife is “uncle’s son” or “uncle’s daughter” (son or daughter of paternal uncle). In the studies of Khlat and Khudr (1984), the classical predominance of patrilateral parallel-cousin marriage is no longer evident in the most recent generations, which displays an equal preference for all types of cousin marriage. Harfouche (1965) studied the social structure of low-income families in Lebanon among three communities: Maronites, Sunnites, and Armenians. She found that the incidence of consanguineous marriage was highest among the Maronites (31%), second among the Sunnites (24%), and third among the Armenians (10%). Marriage between first cousins is common among Maronites and Sunnites, whereas among Armenians the rule is to avoid consanguineous marriages, especially between first cousins. In these three ethnic groups, the average rate of consanguineous marriages was 21%. A study of the general Lebanese population, by Loiselet et al. (1971), showed the highest incidence of consanguineous marriages to be among the Druze (41%), followed by the Shiites(28%), and the Sunnites (27%). The other groups (Maronites, Greek Orthodox, and Armenians) were found to have an incidence of 10%. The average incidence of consanguineous marriages in Lebanon according to this second study (Loiselet et al. 1971) was 18%. Since neither study is extensive, the different sampling methods may explain the differences in the details of the results. However, both studies lead to similar general conclusions about the extent of consanguinity. Khlat (1988a) has found that the overall cross-sectional proportion of consanguineous marriages in Lebanon is 25%. She has also shown, in a separate study, that the actual rate slightly declines with time and that this decline mainly reaches marriages between distant relatives, whereas the prevalence of first-cousin marriages remains relatively stable (Khlat et al. 1986; Khlat 1988b, c). Moreover, the perception of consanguineous marriages is still very positive in the population (Khlat et al. 1986) and the trend toward modernization in Beirut does not seem to weaken endogamy (Khlat and Halabi 1986).

Population Genetics Few major investigations have attempted to explore the genetic structure of the Lebanese population. One of these involved a study of dermatoglyphics (Naffah 1974), while the others investigated the types and distributions of certain genetic markers and protein variants (Lefranc et al. 1976).

Dermatoglyphics The dermatoglyphic studies that were carried out among the seven major communities of the Lebanese population pursued two aims: to compare anthropologically the different segments of the population and to obtain control data for the study

394

V.M. Der Kaloustian

of dermatoglyphics in congenital or hereditary anomalies (Naffah 1974). Dermatoglyphics have the advantage of being polygenic, which makes them more useful than monogenic traits in the study of relations between populations. On the basis of its dermatologic characteristics, and in spite of small and often insignificant variations between communities, the Lebanese population is, on the whole, quite homogeneous. Compared with others, there is a great similarity to the Mediterranean populations, especially those of the Near and Middle East. Although the general characteristics are those of a White population, certain peculiarities bring them closer to eastern Mongoloid populations. The Lebanese communities farthest from the average, according to their dermatoglyphic patterns, are the Armenians, the Shiites, and the Druze. The first two have the most Asian characteristics, while the last is closer to Western populations. No plausible explanation is available for these findings (Naffah 1974).

Genetic Markers and Protein Variants The different religious and ethnic communities of the country were considered to be relatively impermeable isolates because of the rarity of marriages between their members. The genetic distances were studied using random samples obtained from several laboratories for various medical analyses. The aim was to characterize the population as a whole and the differences between the communities composing it (Lefranc et al. 1976). The results of this study were similar to those of Naffah (1974) on dermatoglyphics. It was noted that, as a whole, the population of Lebanon is clearly Caucasian, but with certain Asian traits: a frequency of the B blood group (ABO system) higher than anywhere in Europe, a relative rarity of the Hp1 allele (haptoglobins) (Lalouel et al. 1976), and especially the presence of the haplotype Gm of the immunoglobulins, combining the Gm1 characteristic to the whole of Gm10, 11, 14, and 25 (Lefranc et al. 1976). The genetic distances between communities were calculated on the basis of the following seven markers: ABO, Rh, haptoglobins, Gc globulins, erythrocyte phosphatases, and Gm and Inv groups of immunoglobulins. The distances thus obtained are small in comparison with the distances measured between Mongolian and Caucasian communities (Lalouel et al. 1976). A study of the HLA system revealed no difference between the different communities of the country, except for the Armenians (Serre 1976).

Angiotensin-Converting Enzyme Gene Polymorphism (ACE; OMIM +106180) Angiotensin-converting enzyme (ACE) gene polymorphism insertion (I) or deletion (D) is linked to various functional effects and associated with common

13

Genetic Disorders in Lebanon

395

diseases. In a study by Sabbagh et al. (2007b) of the distribution of the genotypes of the ACE in the Lebanese population, the prevalence of the D/D, I/D, and I/I genotypes was found to be 39.1, 45.1, and 38.3%, respectively. In another study, Saab et al. (2007) found that the frequency of the I allele in the Lebanese population was 27% and the corresponding I/I genotype was at a frequency of 7.37%.

Arylamine N-acetyltransferase 1 (NAT1) Genotypes in a Lebanese Population (OMIM *108345) Chronic exposure to carcinogenic chemicals (e.g., cigarette smoke) does not inevitably lead to cancer. This fact initiated numerous studies aimed at understanding the basis for individual susceptibility. Epidemiologic studies suggested that genetic variation in the N-acetylation of aromatic amine carcinogens may present a predisposition or a resistance to these carcinogens. In this line, there was an increasing interest in NAT1 because of its potential roles in carcinogen metabolism and cancer risk. A polymerase chain reaction-restriction fragment length polymorphism genotype assay was used to determine the frequency of NAT1 alleles in a Lebanese population. Of 84 NAT1 alleles assayed, 56% were found to be NAT1*4. Alleles NAT1*3, *10, and *14 were found at frequencies of 0.036, 0.107, and 0.238, respectively. Nearly 50% of the population were heterozygous for a NAT1*14 allele. The high frequency of NAT1*14 in the Lebanese population, if confirmed, might be useful to determine if the occurrence of cancer or other disorders is associated in either a positive or negative manner with this allele (Dhaini and Levy 2000).

HLA Class I and II Allele Frequencies The frequencies of HLA class I and class II antigens differed among the various religious communities of the Lebanese population. The frequency of DR10 in the Druze was 26%, significantly higher than in other communities (0–8%). The frequency of B41 was similar in the Druze and Greek Orthodox (11–12%), and to a certain extent in the Shiites (5%), but higher than that in other communities (0–1%). The degree of similarity of the HLA frequencies among the various communities ranged from 77 to 96% (Abdelnoor et al. 2001). Frequencies of HLA polymorphisms were examined at the molecular level. HLA class II genotyping of DRB1 and DQB1 loci revealed that DRB1*1101, DRB1*0401 and DRB1*0301 were the three most common DRB1 alleles observed, with respective frequencies of 0.302, 0.164, and 0.096. In the DQB locus group, DQB1*0301 (with an allele frequency of 0.384) was highly predominant, followed by the DQB1*0501, DQB1*0201, and DQB1*0302, with respective allele frequencies of 0.199, 0.195, and 0.103 (Samaha et al. 2003).

396

V.M. Der Kaloustian

HPA-1 Platelet Antigen Alleles (Integrin, Beta-3; ITGB3; OMIM +173470) Human platelet antigen (PA) systems are involved in the development of cardiovascular diseases, alloimmunization, and the rejection of organ transplantation. HPA-1 is considered to be the most important antigenic system in the Caucasian population. In a study of the 1a and 1b alleles of HPA-1, Sabbagh et al. (2007c) observed that of the genotypes 1a/1a, 1a/1b, and 1b/1b, the most prevalent was 1a/1a (68.85%), followed by 1a/1b (30.24%), and 1b/1b (3.91%). The allelic frequencies for 1a and 1b were 0.81 and 0.19, respectively. The prevalence of the HPA-1b which is higher in the Lebanese population as compared with other ethnic groups may predispose to a higher risk of alloimmunization (Sabbagh et al. 2007c).

Immunoglobulins IGHA2*M1 and IGHA2*M2 Soua et al. (1989) found the frequencies of IGHA2*M1 and the IGHA2*M2 alleles to be 0.79 and 0.20, respectively in the Lebanese population.

Immunoglobulin l Constant Polymorphism of immunoglobulin l constant region (IGLC) genes was studied in French, Lebanese, and Tunisian populations (Ghanem et al. 1988). The human IGLC polymorphisms appear as EcoR1 restriction-fragment-length variations – 8, 13, 18 or 23 kb. These polymorphic fragments are related to a number of IGLC genes varying from six to nine per haploid genome. Family studies confirmed the allelic nature of four of the different EcoR1 restriction fragments observed. Frequencies of the corresponding alleles in French, Lebanese, and Tunisian populations were determined and compared. The decrease of the 8-kb fragment (allele A1) frequency and the increase of that of the 13-kb and 18-kb fragments (alleles A2 and A3) appeared to be correlated to an African Black contribution in the gene pool. This contribution was more important in Tunisia than in Lebanon.

Genetic Diseases in Lebanon Table 13.1 lists the genetic diseases reported from Lebanon. Some of these diseases are relatively more common than others, or are characteristic of the ethnic composition and the geographic situation of the country. This group of diseases includes familial paroxysmal polyserositis (familial Mediterranean fever–FMF), familial

13

Genetic Disorders in Lebanon

397

hypercholesterolemia (FH), hypothyroidism, the Dyggve–Melchior–Clausen syndrome, Sandhoff disease, juvenile Tay–Sachs disease, and various genetic hematologic diseases such as glucose-6-phosphate dehydrogenase deficiency, thalassemia major, and sickle-cell anemia. Moreover, a few rare conditions have been reported in the literature for the first time from Lebanon (Table 13.1).

Adrenal Hyperplasia, Congenital, 21-Hydroxylase Deficiency (OMIM +201910) Twenty-five unrelated Lebanese families with members affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydoxylase deficiency were tested for six point mutations, large deletions, gene conversion events, and duplications. In the classical forms, the most frequent mutation was that of a splice site in intron 2, accounting for 39% of the disease alleles. Gene conversion events accounted for 14% of the alleles. No large deletions were found. In the non-classical forms, the V281L mutations in exon 7 represent 86% of the tested alleles. The genotype–phenotype correlations were as expected (Delague et al. 2000b). The spectrum of mutations reflects the genetic diversity of the Lebanese population. However, no correlation could be noted between certain mutations and specific religious communities, except for the D8nt mutation, which was present only in the Christian Maronite group (Delague et al. 2000b).

Albinism, Oculocutaneous, Type 1 (OCA1; OMIM #203100) Thirty Lebanese subjects with oculocutaneous albinism were tested for the mutations in the tyrosinase gene. Mutations were found in 47%, while no mutation was identified in 53%. Fourteen different mutations were identified, of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B). Nine novel mutations were found. The new mutations for OCA1A were: cd84 T!G, Tyr!Stop; cd272 T!C, Trp!Arg; cd342 T!C, Asn!Asn; del15 bp IVS2; cd346 G!A, Gly!Glu; cd359 A!T, Gln!Leu. The new mutations for OCA1A were: cd360 A!G, Ser!Gly; del A cd402; cd433 A!G, Tyr!Cys (Zahed et al. 2005).

Ankylosing Spondylitis (OMIM #106300) A novel HLA-*B27 subtype was identified in a Lebanese patient suffering from ankylosing spondylitis. This variant differs from the common HLA-B*2705 at five nucleotype positions. These changes lead to three amino acid differences in the

398

V.M. Der Kaloustian

a2 domain: Thr to Ile at position 94, Leu to Ile at position 95, and Asn to Arg at position 97 (Tamouza et al. 2001).

Apnea of Prematurity The association of consanguinity with the incidence of apnea of prematurity was studied in Greater Beirut. The odds ratio of apnea of prematurity for first-degree consanguineous parents as compared with other marriages was 2.9. In addition to the recognized etiologic factors for apnea of prematurity, the authors suggested that genetic factors also play a role (Tamim et al. 2003).

Apolipoprotein E Gene Polymorphism (APOE, OMIM +107741) The Lebanese population showed similarities to earlier reported ApoE genotype distributions (high E3 allele frequency) but also peculiar differences to some Arab countries and other populations. The prevalence of genotypes E3/3, E3/4. and E2/3 was found to be 69, 26, and 22%, respectively, and 0.6% for each of E2/4 and E4/4 genotypes (Mahfouz et al. 2006).

Arthropathy, Progressive Pseudorheumatoid, of Childhood; PF (#208230) Wynne-Davies et al. (1982) reported fifteen patients with an inherited skeletal dysplasia, considerably more crippling than the usual form of spondylo-epiphyseal dysplasia tarda. Four of the patients were Arabs.This condition has a striking clinical resemblance to rheumatoid arthritis. However, in addition, it has platyspondyly and the radiological findings are different from those of rheumatoid arthritis. The authors present this as a new condition, but they also acknowledge that it may be the same as the case referred to by Maroteaux in 1974 as “les dysplasies spondylo-e´piphysio-me´taphysaires complexes.” The radiologic changes indicate bone dysplasia with flattened vertebral bodies. There is abnormality of the acetabular portion of the pelvis. There is also expansion of the ends of the proximal phalanges. Teebi and Al-Awadi (1986) reported a patient with these skeletal anomalies, born to double consanguineous Lebanese parents. They agreed with Wynne-Davis et al. that the condition most probably follows the autosomal recessive pattern of inheritance.

13

Genetic Disorders in Lebanon

399

Ataxia, Cerebellar, Autosomal Recessive 2 (SCAR2; OMIM %213200) Me´garbane´ et al. (1999a) described a family with children affected with nonprogressive autosomal recessive congenital cerebellar ataxia associated with short stature. Later, the disease locus was assigned to a 12.1 cm interval on chromosome 9q34-qter, between D9S67 and D9S312 (Delague et al. 2001).

Ataxia, Cerebellar, Autosomal Recessive 5 (SCAR5; OMIM %606937) Me´garbane´ et al. (2001a) reported a large inbred Lebanese Druze family with children affected by a new condition. This consisted of severe developmental delay, proportionate short stature, microcephaly, cerebellar spastic ataxia, cerebellar atrophy, optic atrophy, speech defect, and an abnormal osmiophillic pattern of the skin vessels. The gene was later mapped to chromosome 15q24-q26 (Delague et al. 2002).

Ataxia Telangiectasia (AT, OMIM #208900) Ataxia telangiectasia (AT) is a rare autosomal recessive disease characterized by progressive cerebellar ataxia, immunodeficiency, susceptibility to lymphoreticular malignancies, hypersensitivity to ionic radiation, and chromosomal instability. Two different mutations, were found in two Israeli Druze clans of Lebanese origin. One of the clans emigrated from Southeast Lebanon 500 years ago. In this clan, a point mutation was found at position 1339 (C!T), changing the codon at position 447 (CAG) to a stop codon (TAG). The other clan moved from the center of Lebanon 300–400 years ago. In this clan, deletions of GG and TACG were found, respectively, at positions 6,672 and 6,677 (Fares et al. 2004).

Bardet–Biedl Syndrome (BBS, OMIM #209900) SNP homozygosity mapping was performed in an extended consanguineous family living in a small Lebanese village. This led to the identification of a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above-mentioned mutation and another one in the same gene. No triallelism was found in this family (Laurier et al. 2006).

400

V.M. Der Kaloustian

Bartter Syndrome Type 4, Infantile, with Sensorineural Deafness (OMIM #602522) The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness (Bartter syndrome type 4) represents a genetic and clinical entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. The characteristic sign of the disease in these patients is the constant association with congenital hearing loss (Jeck et al. 2001).

Behc¸et Syndrome (OMIM %109650) Behc¸et syndrome is characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. In a study by Arayssi et al. (2008), polymorphisms of TNF (Tumor Necrosis Factor) alleles were not found to be associated with the clinical manifestations and the severity of the disease. The study confirmed the association of HLAB51 with Behc¸et syndrome and suggested an association between the 1031CC genotype and the disease in Lebanese patients.

Brown–Vialetto–Van Laere Syndrome (OMIM %211530) Brown–Vialetto–Van Laere syndrome is characterized by pontobulbar palsy, bilateral nerve deafness, cranial nerve disorders involving the motor components of the 7th and 9th to 12th cranial nerves and, less commonly, the spinal motor nerves and upper motor neurons. A large inbred Lebanese family was reported by Me´garbane´ et al. (2000) with four patients of both sexes. This strongly suggested autosomal recessive inheritance.

Cataract, Posterior Polar (CTPP4, OMIM #610623) Heterozygous and homozygous mutations in PITX3 were reported in a large Lebanese family by Bidinost et al. (2006). This was the first report of homozygous PITX3 mutations in humans. The phenotype of the two siblings who were homozygous for the C-terminal deletion of the gene was much more severe than that of the heterozygous family members. In addition to posterior polar cataracts, as in heterozygotes, the homozygotes had microphthalmia, blindness, and various neurologic manifestations as mental retardation, choreiform movements, decreased deep tendon reflexes of the lower extremities, and increased muscle tone.

13

Genetic Disorders in Lebanon

401

Charcot–Marie–Tooth Disease, Type CMT4A (OMIM #214400) A novel GDAP1 homozygous mutation was identified in a 9-year-old Lebanese girl with an autosomal recessive severe peripheral demyelinating phenotype (CMT4A) associated with axon loss. The affected girl carried a mutation in exon 5 (c.668T!A, leading to the substitution of the leucine 223 residue to a stop codon (p.L223X) (De Sandre-Giovannoli et al. 2003).

Charcot–Marie–Tooth Disease, CMT4F (OMIM # 214400) Delague et al. (2000a) reported a large inbred Lebanese family affected with autosomal recessive CMT4 in whom they excluded linkage to the already-known loci. Clinical features and the results of histopathologic studies confirmed that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype, known as CMT4F. MAG was excluded as a candidate gene.

Charcot–Marie–Tooth Disease, CMT4H (OMIM #609311) A new form of autosomal recessive demyelinating Charcot–Marie–Tooth neuropathy was identified in a Lebanese family (De Sandre-Giovannoli et al. 2005). The gene was mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11. A mutation was identified in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein). FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GP)-binding proteins (Rho GTPases) (Delague et al. 2007).

Chondrodysplasia with Multiple Dislocations Me´garbane´ and Ghanem (2004) reported the offspring of consanguineous parents, affected with left hip dislocation, dislocated knees, inguinal hernias, short long bones, pectus excavatum, dislocation of the radial heads, prominent joints, limitation of motion of the elbows, brachydactyly, genua valga, and pes planovalgus. They considered that the findings in their patient represented a newly recognized syndrome.

Chondrodysplasia with Multiple System Anomalies Me´garbane´ et al. (2008b) reported a consanguineous Lebanese family with a sib pair presenting with developmental delay, dysmorphic facial appearance, a narrow

402

V.M. Der Kaloustian

chest, a prominent abdomen, and short limbs. Differential diagnosis suggested to the authors that this is a new type of chondrodysplasia.

Cohen Syndrome (OMIM #216550) Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. Mutations were reported in the COH1 gene from various countries. Three siblings from Lebanon were also tested. Mutation c.9406-1G!T was identified. It affected the splice-acceptor site of intron 51. Direct sequencing of cDNA revealed that a cryptic splice site is activated in exon 52 and is used as the acceptor site instead of the mutant one in intron 51. The defective splicing leads to deletion of 16 exonic bases and results in a frameshift in the COH1 mRNA (Hennies et al. 2004).

Cohen Syndrome, Cutis Verticis Gyrate and Sensorineural Deafness (OMIM 605685, *607817) In 2001, Me´garbane´ et al. (2001b) described a syndrome in two brothers of a Lebanese family. They presented with microcephaly, cutis verticis gyrata, retinitis pigmentosa, cataracts, hearing loss, and mental retardation [OMIM 605685]. The parents did not give a history of consanguinity. They later discovered (Me´garbane´ et al. 2009) that both brothers had a homozygous novel splice site mutation in the VPS13B (COH1) gene. The mutation that they identified, c.9406-1G!C, affects the same nucleotide as an earlier described mutation associated with Cohen syndrome, c.9406-1G!T, but leads to a different nucleotide change. However, both nucleotide changes result in the same abnoramal splicing and the activation of a cryptic splice site near the 5’ end of exon 52, with a consecutive 16-bp frameshift deletion in the VPS13B mRNA.

Consanguinity and Birth Weight A study on 10,289 consecutive live-born singleton newborns admitted to eight hospitals in Beirut, Lebanon, during the years 2000 and 2001, revealed a statistically significant negative association between parental consanguinity and birth weight at each gestational age (Mumtaz et al. 2007).

13

Genetic Disorders in Lebanon

403

Consanguinity and Congenital Heart Malformations The association of isolated congenital heart defects with parental consanguinity was examined in 759 Lebanese patients with different types of defects. The subjects were patients of the Children’s Cardiac Registry Center (CCRC) at the American University of Beirut Medical Centrer. The proportion of first-cousin marriages among cardiac subjects was compared to that of the National Collaborative Perinatal Neonatal Network (NCPNN). The proportion of overall parental consanguinity and first-cousin matings among CCRC subjects (34.7 and 20.2%, respectively) were significantly higher than those reported by the NCPNN. A significantly higher rate of parental consanguinity was found in all categories of cardiac malformations, except lesions of the great vessels and coronary arteries (P < 0.05) (Nabulsi et al. 2003).

Consanguinity and Kidney Disease Nine hundred and twenty-five patients were surveyed in all of the dialysis centers of Lebanon. The etiology of the kidney disease was unknown in more than half of the patients. Consanguinity was present in the parents of 26% of them. More patients with consanguineous parents with unknown etiology of their renal disease were diagnosed, and dialysis was initiated before the age of 30, when compared with those whose parents were not consanguineous (45 vs. 33%(P < 0.02) and 42 vs. 27%(P < 0.01), respectively). Parental consanguinity-associated kidney diseases affected all religious communities, but particularly the Muslim and the Druze with 36 and 39%, respectively, versus 17% of the Christians (Barbari et al. 2003).

Cystic Fibrosis (CF, #219700; CFTR, *602421) Cystic fibrosis is considered to be rare in the Arab populations of the Middle East and little data had been reported until 1997 (Bitar and Idriss 1969). Twenty families were reported from Lebanon in 1979, with children affected with this condition. These were mainly from the Maronite, Greek Catholic, Greek Orthodox, Shiite, and Sunnite communities. A 50% rate of consanguineous marriages was found, independent of the community of origin. Screening of all the exons of the CFTR gene was performed. Ten different mutations were found for 87.5% of 32 unrelated CF alleles. These included two novel putative mutations: E672del and IVS21-28G!A. Three mutations, DF508 (37.5%), W1282X (15.6%), and N1303K (9.4%) accounted for 62.5% of the CF alleles. Moreover, during this study, two novel polymorphisms (IVS1a+17del5 and 2691T/C) were discovered (Desgeorges et al. 1997). Farra et al. (2008) described a novel mutation in two Lebanese Muslim siblings. This is a frameshift mutation 4016insG. It generates a stop codon instead of Arginine-1301.

404

V.M. Der Kaloustian

Deafness, Autosomal Recessive 1 (DFNB1, OMIM #220290) In a Lebanese family with DFNB1 deafness, the same mutation was detected in all the affected children on both Cx26 alleles. This was a deletion of a guanosine (G) in a sequence of six G extending from position 30 to 35 (position 1 being the first base of the initiator codon). This 30delG mutation creates a frameshift which results in a premature stop codon at nucleotide position 38 (Denoyelle et al. 1997). Mustapha et al. (2001) investigated 48 Lebanese pedigrees with non-syndromic recessive deafness. Of these, 37 were Muslims, ten were Christians, and one was Druze. Mutations were DFNB1, DFNB3, DFNB4, DFNB5, DFNB6, DFNB7, DFNB9, DFNB10, DFNB12, DFNB13, DFNB14, DFNB17, DFNB21, DFNB22. 7 families were not categorized. The details of the results are summarized in a table published in their paper. 30delG was the prevalent mutation in the GJB2 gene. Moreover, in a Christian Maronite family, they found affected subjects who were compound heterozygotes for two novel mutations. One of these was a missense mutation replacing arginine by histidine at codon 32 (R32H), and the other was an insertion of an adenine in position 291 (291insA), thus creating a stop codon (Mustapha et al. 2001).

Deafness, Autosomal Recessive 9 (DFNB9, OMIM #601071) Chaib et al. (1996) reported a new form of autosomal recessive non-syndromic deafness in a consanguineous Lebanese Muslim Sunnite family from an isolated village of Northern Lebanon. This gene named by the authors as DFNB6, maps to chromosome 2p23-22. However, it was noted that Fukushima et al. (1995) had already made this designation for another locus. Thus, various reliable sources and databases changed the name of this locus from DFNB6 to DFNB9. In all affected members of four unrelated Lebanese kindreds, Yasunaga et al. (1999) found a missense mutation in a novel human gene which they called otoferlin (OTOF; OMIM *603681). The mutation consisted of a homozygous T!A transversion at position 2,416 in exon 18 of the OTOF gene, causing a Tyr-to-stop substitution at codon 730.

Deafness, Autosomal Recessive 13 (DFNB13, OMIM %603098) Mustapha et al. (1998) reported a consanguineous Lebanese family with members affected with severe progressive sensorineural hearing loss. The family was Christian Maronite, from an isolated region in Northern Lebanon. Linkage analysis revealed a new locus [DFNB13], located in the chromosomal region 7q34-q36, between the markers D7S2468/D7S2505, on the proximal side, and D7S2439, on the distal side.

13

Genetic Disorders in Lebanon

405

Deafness, Autosomal Recessive 21 (DFNB21, OMIM #603629) Mustapha et al. (1999) reported a Lebanese family with members affected with severe sensorineural non-syndromic deafness. The family was Muslim Shiite. Linkage analysis revealed a new locus [DFNB21] located at 11q23-q25. The TECTA gene was already mapped to this site. This gene encodes a-tectorin, a protein with 2,155 amino acids, which is a component of the tectorial membrane. This gene is responsible for a dominant form of deafness, DFNA8/2. In this new family, sequence analysis of the TECTA gene revealed a G!A transition in the donor splice site (GT) of intron 9, which leads to a truncated protein of 971 amino acids. This established that a-tectorin mutations can be responsible for both dominant and recessive forms of deafness.

Deafness Syndrome, Branchiogenic (OMIM %609166) Me´garbane´ et al. (2003c) reported a Lebanese brother and sister with an apparently “new” syndrome presenting with congenital hearing loss, meatal atresia, preauricular tags and pits, branchial cysts or fistulae, strabismus, difficulty in opening the mouth wide, abnormal fifth fingers, short stature, learning disability, and patchy skin depigmentation in one. They belonged to the Muslim Sunnite community and were the offsprings of consanguineous parents. The father, his sister, and his halfbrother had unilateral auricular pits and/or branchial cysts and short stature. The authors concluded that this condition might be a new dominant branchiogenicdeafness syndrome.

Diabetes Mellitus (IDDM, T1D, OMIM %222100) In a study of HLA DRB1/DQB1 haplotypes on genetic susceptibilities to type 1 diabetes (T1D), it was found that in Lebanese subjects DRB1*030101, DRB1*130701, and DQB1*02201 were positively associated with T1D, and DRB1*110101, DQB1*030101, and DQB1*050101 were negatively associated with T1D (Stayoussef et al. 2009).

Diabetes Mellitus (NIDDM, T2D, OMIM #125853) In a study on patients from Bahrain and Lebanon, the association of HLA class II with type 2 diabetes (T2DM), DRB1*070101 and DQB1*0201 were found to be susceptibility-conferring haplotypes (Almawi et al. 2006).

406

V.M. Der Kaloustian

Dyggve–Melchior–Clausen Syndrome (OMIM #223800) Several families affected with this syndrome were reported from Lebanon (Naffah and Taleb 1974; Spranger et al. 1975; Naffah 1976). Three other patients of Lebanese origin affected with this condition were discovered in South Africa (Beighton 1978, 1990; Bonafede and Beighton 1978). This condition is evidently relatively more frequent in the Lebanese population. Lebanese patients showed two mutations in the DYM gene: IVS 3 194-1 G!A, and IVS 11 1252-1G!A (Thauvin-Robinet et al. 2002; El Ghouzzi et al. 2003; Paupe et al. 2004; Neumann et al. 2006).

Ectodermal Dysplasia, Hypohidrotic, X-Linked (XHED, OMIM #305100) Tomb et al. (2009) reported a Lebanese family with three male siblings affected with hypohidrotic ectodermal dysplasia. Molecular testing revealed a misssense mutation of codon 155.

Ectodermal Dysplasia, Hypohidrotic, Autosomal Recessive (OMIM #224900) Me´garbane´ et al. (2008c) reported a Lebanese patient with severe hypohidrotic ectodermal dysplasia and a novel homozygous mutation of the EDAR gene. The mutation was IVS9+1G!A. This mutation results in a total absence of the EDAR protein.

Ectopia Lentis, Spontaneous Filtering Blebs, Craniofacial Dysmorphism (OMIM %601552) Six members of a consanguineous Lebanese Druze family were reported with ectopia lentis and various craniofacial dysmorphisms. The ectopia lentis was associated with a variable degree of angle closure secondary to iridocorneal adhesions, patchy areas of atrophy in both irides, and avascular elevations of the bulbar conjunctiva. The craniofacial dysmorphisms consisted of downward slanting palpebral fissures, a large beaked nose, a triangular and retracted chin, and dental malocclusion. The pedigree was most compatible with autosomal recessive inheritance with pseudodominance (Shawaf et al. 1995).

13

Genetic Disorders in Lebanon

407

Later, in 2001, the same condition was reported in members of another Lebanese Druze family (Haddad et al. 2001).

Enterocolitis, Necrotizing Nexrotizing enterocolitis (NEC) is a multifactorial condition with various risk factors. A Lebanese consanguineous family was reported where three siblings presented with severe early and lethal enterocolitis (Me´garbane´ and Sayad 2007). In 1974, Fried and Vure reported an Ashkenazi Jewish family, in which three of four children with consanguineous parents died within a few weeks after birth of severe enterocolitis. Although a common environmental origin of the disease cannot be dismissed, consanguinity in both families suggests a disease with autosomal recessive inheritance.

Epidermolysis Bullosa, Junctional (EBJ), Herlitz Type (OMIM #226700) Two female newborns, born to two first-degree consanguineous couples, presented a lethal form of EBJ. The two patients were homozygous for a new missense mutation of LAMA3 gene (exon 32:4300 insA), encoding the a3 subunit of laminin-5. The resulting mRNA, rapidly degraded, results in an extremely reduced synthesis of a3 polypeptide, truncated in its C-terminal domain (Ayoub et al. 2005).

Epilepsy Syndromes In a study in Lebanon on various epilepsy syndromes based on the criteria of the International League Against Epilepsy classification, it was concluded that genetic factors are important not only in idiopathic epilepsies and febrile seizures, but also in cryptogenic and symptomatic epilepsies (Choueiri et al. 2001).

Factor V Leiden (F5, OMIM *612309) Factor V Leiden is the most common genetic risk factor for deep venous thrombosis (DVT). In the Eastern Mediterranean countries, a high prevalence of factor V Leiden mutation was reported in healthy individuals (7–14%) with the highest

408

V.M. Der Kaloustian

frequency in Lebanon (14%); among patients with DVT, 40% had a factor V Leiden mutation. Positive family history was statistically associated with an increased risk for factor V Leiden mutation (Irani-Hakime et al. 2000; Taher et al. 2001). Moreover, a recently identified polymorphism, HR2 (His1299Arg), was reported to be a possible risk factor for the development of venous thromboembolism. The prevalence of factor V R2 (H1299R) polymorphism was also studied in the Lebanese population (Zaatari et al. 2006). Of a total of 125 controls studied, 13 (10.4%) had the HR2 haplotype, 11 (8.8%) were heterozygous (R1/R2), and two (1.6%) were homozygous (R2/R2).

Factor XI Deficiency (OMIM *264900) A new mutation of the F11 gene was reported for the first time. The patient was a Lebanese woman from the Greek-Orthodox community, who was found to have a prolonged activated partial thromboplastin time (aPTT) in her preoperative workup (de Moerloose et al. 2004).

Factor XIII, A1 (F13A1; OMIM +134570) Factor XIIIa gene (F13A1) V34L polymorphism was studied in 205 healthy unrelated Lebanese individuals (Mahfouz et al. 2008). The prevalence of wild type, heterozygous, and homozygous genotypes was found to be 74.2, 22.4, and 3.4%, respectively. The data in this study serve as a baseline for future investigations of the prevalence of Factor XIIIa V34L polymorphism in association with cardiovascular diseases.

Familial Mediterranean Fever (FMF) – Famillial Paroxysmal Polyserositis (FPP) – “Armenian” or “Periodic” disease (OMIM #249100) This genetic disorder, affecting primarily people of Mediterranean origin, was originally reported from Lebanon by Reimann et al. (1954). It occurs mainly in Armenians and Sephardic Jews (Schwabe and Peters 1974), but is present also among Arabs, Turks, Ashkenazi Jews, and other Mediterranean populations. Khachadurian and Armenian (1974) reported 120 cases of FPP from Lebanon. In their series, there was a predominance of Armenians; 53% of their patients were Armenian, 34% Muslim Arabs, 9% Christian Arabs, and 4% Syriacs. In another series of 72 patients, Naffah et al. (1975) found the Armenians to represent 45% of all cases. These are very high proportions, since the Armenians

13

Genetic Disorders in Lebanon

409

represent only around 8% of the population of the country. Around 25% of their patients were Christian Arabs and 25% Muslim Arabs (21% Shiites and 4% Sunnites); 4% of the cases were of Kurdish origin. No case was found among the Druze community. In both series (Khachadurian and Armenian 1974; Naffah et al., 1975), published from Lebanon, the incidence of amyloidosis is very low and the average survival is longer, suggesting that the disorder in Armenians is distinct from that in Sephardic Jews (Sohar et al. 1967; Schwabe and Peters 1974). Pras et al. (1992), and Fischel-Ghodsian et al. (1992), found that the FMF gene maps to 16p in all ethnic groups, including Armenians, and Ashkenazi and nonAshkenazi Jews. Studying 14 Armenian and nine non-Ashkenazi Jewish families with FMF, Sohat et al. (1992) found linkage to the a-globin complex on 16p in both groups, with no evidence for genetic heterogeneity either between or within the groups. Mansour et al. (2001) tested Lebanese patients for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G!C), M6801 (G!A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2. Mutations were detected in patients belonging to all communities, including the Maronite, Greek Orthodox, Greek Catholic, Syriac, and Shiite. The most frequent mutations were M694V and V726A (27 and 20% of the total alleles, respectively). The M694I, E148Q, and M6801 mutations accounted for 9, 8, and 5%, respectively. Each one of the K695R, E167D and F479L mutations were observed once. All the remaining mutations were not encountered. Thirty-three of the alleles did not carry any of the studied mutations. Over 50 mutations have been identified in MEFV, in 640 Lebanese patients studied by Medlej-Hashim et al. (2005). The percentages of the various mutations were as follows: M694V (30.3%), V726A (19.4%) M694I (12.8%), M680I (7.4%), E148Q (8.3%), R761H (3.1%), rare mutations (2.3%), and undetermined (16.4%) Rare mutations include the R653H, K659R, A744S, S108R, E167D, E148V, and T177I. Three novel mutations, T177I, S108R, and E474K, were also identified in the Lebanese population (Medlej-Hashim et al. 2005). Haplotype analysis of Lebanese FMF patients was performed using four microsatellite loci to study founder effects for the five most frequent mutations within the MEFV gene (M694V, M694I, V726A, and E148Q). The results suggested that each of these mutations have probably arisen from unique mutation events and that the carrier chromosomes derived from a common ancestor. The estimated ages of the most recent common ancestor for each of the five mutations were 7,000, 8,500, 15,000, 23,000, and 30,000 years for M694V, M694I, V726A, M680I, and E148Q, respectively. These results confirmed that Muslim sub-populations (Shiites and Sunnites), as well as Christian ones, including Armenians who were formerly settled in the southeastern part of Asia Minor (Cilicia), are all derived from an ancient common ancestral population (Jalkh et al. 2008). In another study, Sabbagh et al. (2008a) reported that five of the most common mutations, M694V, E148Q, V726A, M694I, and M6801(G/C), accounted for 26.1, 22.2, 21.3, 9.6, and 7.7%, respectively. The A744S, F479L, R761H, and I692del were found in 2.9% of the patients. P369S and M680I (G/A) were present in 1.2%

410

V.M. Der Kaloustian

of the patients. K695R was absent. This spectrum of MEFV mutations revealed a higher degree of heterogeneity in this population than others. Considering the relatively high frequency of the E148Q, the authors questioned whether it is a mutation rather than a polymorphism.

Gaucher Disease, Type I (OMIM #230800) Gaucher disease type I is caused by a mutation in the glucocerebrosidase (GBA) gene. A previously unidentified mutation (L371V) was reported in a Lebanese family (Shamseddine et al. 2004). In another Lebanese family compound heterozygosity was reported in two patients. The two mutations were a rare one, 259T (R48W), and a more common one, L444P (El-Zahabi et al. 2007).

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: Favism (OMIM +305900) This acute hemolytic disease occurs in Lebanon because of the presence of a relatively high number of persons with G6PD deficiency and because fava beans are an important element of the Lebanese cuisine. In 1964, Taleb et al. studied the blood of 548 Lebanese men. They found 17 cases of G6PD deficiency, representing around 3.09% of the general population. Of 105 Druze and 36 Armenians tested in this series, none had the deficiency. This may be explained by the fact that both of these population groups have lived for centuries in mountainous areas, away from malarial endemicity. In spite of the absence of the deficiency in these two groups, because of the small number of individuals tested, the differences in incidence between the communities were not statistically significant. G6PD Mediterranean has a change from cytosine to thymine, at position 563 (in exon 6), which causes a change from serine to phenylalanine in the amino acid at position 188 (Vulliamy et al. 1988). There is a second silent mutation of TAC to TAT at codon 437 in exon 11 (C to T at nucleotide 1311). This mutation is a polymorphism. Beutler and Kuhl (1990) studied the distribution of the nucleotide polymorphism C1311T in diverse populations. Only one of 22 male subjects from Mediterranean countries, who had the G6PD Mediterranean-563T genotype, had a C at nucleotide 1311. In contrast, G6PD Mediterranean-563T males from the Indian subcontinent had the usual C at nucleotide 1311. Beutler and Kuhl (1990) interpreted these findings as suggesting that the same mutation at nucleotide 563 arose independently in Europe and in Asia. Similar studies were performed by Kurdi-Haidar et al. (1990) in 21 unrelated individuals with G6PD Mediterranean from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Israel. All but one had the 563

13

Genetic Disorders in Lebanon

411

mutation and, of these, all but one had the C-to-T change at nucleotide 1311. Among 24 unrelated persons of Middle Eastern origin with normal G6PD activity, four had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. Kurdi-Haidar et al. (1990), concluded that most Middle Eastern subjects with the G6PD Mediterranean phenotype have the same mutation as that found in Italy, that the silent mutation is an independent polymorphism in the Middle East, with a frequency of about 0.13, and that the mutation leading to the G6PD Mediterranean deficiency probably arose on a chromosome that already carried the silent mutation. In 2000, Usanga and Ameen found the percentage of G6PD deficiency among Lebanese males to be 2.13%.

Glycogen Storage Disease I (OMIM +232200) Trioche et al. (1999) reported a patient affected with glycogen storage disease I, born to a father of Lebanese origin and a French mother. She was compound heterozygote for mutations W70X and T108I. The father carried the W70X mutation. With this, there is a 288G!A transversion resulting in the creation of a premature stop codon at codon 70. This mutation abolishes a Bsr I restriction site.

Heart Block, Familial, Type IB (PFHB1B, OMIM %604559) Edouard Ste´phan, in 1954, was the first to report a bundle branch block in three members of the same family. He then published several other papers (Ste´phan 1974, 1978; Ste´phan et al. 1997) on this large Lebanese kindred, and designated the disorder as “hereditary bundle branch defect (HBBD).” The gene was mapped by de Meeus et al. (1995) at 19q13.3, narrowing the critical region to a 13-cM interval.

Heart Defects, Congenital A molecular study of congenital heart defects in Lebanese patients revealed that there is a differential duplication of an intronic region in the NFATC1 gene in patients with ventricular septal defect, suggesting that NFATC1 is a potential VSD-susceptibility gene (Yehya et al. 2006). The independent effect of consanguinity on the prevalence of congenital heart defects was investigated in newborns admitted to nine hospitals located in Beirut, and members of the NCPNN. Infants born to first-cousin marriages had a 1.8 times higher risk of having a CHD diagnosed at birth compared to those born to unrelated

412

V.M. Der Kaloustian

parents. In particular, first-cousin marriage was a significant risk factor for ventricular septal defect, atrial septal defect, hypoplastic left heart, and single ventricle. No association was found with d-transposition of the great arteries, coarctation, pulmonary atresia, atrioventricular septal defect, and tetralogy of Falllot (Yunis et al. 2006).

Hypercholesterolemia, Familial, FH (OMIM #143890) Khachadurian and his collaborators (Khachadurian 1964, 1968, 1972; Khachadurian and Uthman 1973) studied 31 families with 52 patients fulfilling the criteria for the homozygous form of FH. The high incidence of conasanguineous marriages in Lebanon is partly responsible for the large number of homozygous cases encountered. The frequency of homozygotes is 10 times higher than in other parts of the world. It was on the basis of these studies in Lebanon that Khachadurian, in 1964, first established the existence of homozygous FHC. Lehrman et al. (1987) analyzed the nature of the low-density lipoprotein receptor (LDLR) gene mutation present in high frequency in Lebanon. They demonstrated that the mutation involves a shortening of the receptor protein in three of its five domains: the region of clustered 0-linked carbohydrates, the membrane-spanning region, and the cytoplasmic tail. The defect was considered to be due to a single nucleotide substitution in the gene, creating a premature termination codon at amino acid 660, thus eliminating 180 residues from the mature protein. The termination codon occurred in the middle of a cysteine-rich sequence that is part of the domain homologous to the epidermal growth factor precursor (LDLR, CYS660TER). Lehrman et al. (1987) refer to this mutation as “the Lebanese allele.” The mutation creates a new restriction site, permitting diagnosis by Southern blotting of genomic DNA. Oppenheim et al. (1991) found the “Lebanese” allele in five Israeli–Arab kindreds with hypercholesterolemia. Figueiredo et al. (1992) analyzed ten Brazilian families with patients affected with hypercholesterolemia. They found the Lebanese allele in five families.

Hypercholesterolemia, Autosomal Recessive; ARH (OMIM #603813) A rare autosomal recessive form of hypercholesterolemia (ARH), that clinically resembles FH but is not due to mutations in the LDLR gene, was described by Khachadurian and Uthman in 1973. The patients affected with this condition have markedly impaired LDLR function in the liver, but normal or slightly reduced function in the cultured fibroblasts (Garcia et al. 2001).

13

Genetic Disorders in Lebanon

413

The ARH locus was mapped to a 1-cM interval on chromosome 1p35 and mutations were identified in a gene encoding a putative adaptor protein (ARH). This protein has a tissue-specific role in LDLR function, and is required in the liver but not in fibroblasts (Garcia et al. 2001).

Hyperhomocysteinemia (OMIM #603174) and MTHFR (OMIM *60793) Certain mutations in the MTHFR (5,10-methylenetetrahydrofolate reductase) gene may result in homocysteinemia. A study by Sabbagh et al. (2008b) in Lebanon on the two most common MTHFR polymorphisms of C677T and A1298C revealed that for C677T the prevalence of the C/C, C/T, and T/T genotypes was 65.3, 30.8, and 3.9%, respectively. The overall carrier rate was 34.6% and the allelic frequency was 0.19. The A1298C genotypic prevalence of A/C, A/A, and C/C was 50.2, 25.9, and 23.9%, respectively. The overall carrier rate was 74.14% and the allelic frequency was 0.49. This study revealed that the Lebanese population has the highest prevalence of the MTHFR A1298C polymorphism.

Hyperlipoproteinemia, Type I (OMIM #238660) Hyperlipoproteinemia Type I is a rare autosomal recessive disorder. It is associated with repeated episodes of abdominal pain, recurrent pancreatitis, eruptive xanthomatosis, hepatosplenomegaly, and lipemia retinalis. This condition is caused by a deficiency of the lipoprotein lipase. LPL is the gene coding for this enzyme. A novel mutation in the LPL gene causing hyperchylomicronemia with recurrent hepatitis was reported in two Lebanese probands. The mutation was in exon 5. Both patients were homozygous for the 776A!T mutation, resulting in the D174V substitution (Abifadel et al. 2004).

Hypogonadism, Hypergonadotropic, with Partial Alopecia (OMIM %241090) In 1985, Al-Awadi et al. observed two Lebanese sisters with hypergonadotropic hypogonadism and partial alopecia. The hair was present only in the center of the scalp. One of the sisters had streak ovaries, and the other did not have gonads. The parents were first cousins once removed. In 2003, Me´garbane´ et al. (2003a) reported from Lebanon two sisters with primary hypergonadotropic hypogonadism, microcephaly, flat occiput, congenital

414

V.M. Der Kaloustian

partial alopecia with abnormal hair structure, m€ ullerian hypoplasia, and absent or streak ovaries. The parents were first cousins.

Hypogonadism, Hypogonadotropic, with Alopecia Salti and Salem (1979) reported a Lebanese family in which several members, both female and male, had hypogonadism with partial alopecia. Studies in three affected members have revealed that the hypogonadism is of the hypogonadotropic type. The parents are consanguineous and the condition most probably follows an autosomal recessive pattern of inheritance.

Hypothyroidism In 1963, Najjar et al. reported 47 hypothyroid children from 42 families living in an area in Lebanon where goiter is endemic. Three important differences from sporadic cretinism in nonendemic areas were found: There was a low incidence of athyreosis, the sex ratio failed to show the usual predominance of females, and the rate of consanguinity and familial incidence were high.

Ichthyosis, Lamellar, 3 (OMIM #604777) In a Lebanese patient with lamellar ichthyosis type 3, a mutation was identified in the CYP4F22 gene. This was a 980delC, resulting in a frameshift (Lefe`vre et al. 2006).

Imerslund–Gr€ asbeck Syndrome (IGS, OMIM #281100) Selective malabsorption of the intrinsic factor and vitamin B12/cobalamin (cbl) complex is known as Imerslund–Gr€asbeck syndrome. The disease is due to mutations in the CUBN gene, encoding cubilin. Four children of one family from Lebanon have been reported (Ro¨ssler et al. 2003).

Jervell and Lange–Nielsen Syndrome 2 (JLNS2, OMIM #612347) The Jervell and Lange–Nielsen syndrome is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death. It is a heterogeneous condition, with genes mapped at 11p15.5 (JLNS1) and 21q22.1-p22.2 (JLNS2). JLNS2 is due to mutations in the KCNE1 gene

13

Genetic Disorders in Lebanon

415

(OMIM+176261) which encodes a transmembrane protein involved in the activity of a potassium channel. Schulze-Bahr et al. (1997) found mutations in the KCNE1 gene in the members of a Lebanese family affected with JLNS2.

Lipodystrophy, Congenital, Generalized, Type 2 (BSCL2, Berardinelli–Seip Type 2, OMIM #269700) Congenital generalized lipodystrophy type 2, or Berardinelli–Seip syndrome, is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. The first patients from Lebanon were published in 1973 and 1975 (Salem et al. 1973; Najjar et al.1975). A new gene locus, BSCL2, linked to 11q13, was identified in Lebanese and Norwegian patients. All the Lebanese patients were found to be homozygous for the same mutation. This is a 5-bp deletion in exon 4, which shifts the reading frame after amino acid 105, introducing a premature stop codon at position 111 (Magre´ et al. 2001).

Mannose-6-Phosphate Receptor Recognition Defect: Lebanese Type (OMIM %154570) Five healthy individuals belonging to three generations of a Lebanese family were found to have highly elevated plasma lysosomal enzyme levels inherited as a dominant Mendelian trait. The same enzymes were within normal limits in other extracellular fluids. The physicochemical properties of the elevated plasma enzymes were different from those of both control and I-cell disease, while the pattern and extent of elevation was similar to that found in mucolipidoses II and III. Secretion of lysosomal hydrolases into cell media by fibroblasts from one of the individuals was increased two to seven times more that that from controls (Alexander et al. 1984). Mannose-6-phosphate receptors in fibroblasts of the same individual were found to be functioning normally, but the cells had only half-normal levels of phosphodiester glycosidase activity. Pynocytosis of b-hexosaminidase (hexB) secreted by these fibroblasts into Sandhoff’s disease fibroblasts was 18% of control. The apparent KD for binding of these hexB to man-6-P receptors was 3.7 109 M compared to 1.25 109 M for control enzyme. Treatment of this abnormal hex B with exogenous placental phosphodiester glycosidase increased its binding to man-6-P receptors threefold. Secretion rates of seven lysosomal enzymes from these fibroblasts were, on average, twice as great as rates measured for two I-cell disease heterozygote fibroblast lines. The results suggest that these fibroblasts are heterozygous for phosphodiester glycosidase deficiency (Alexander et al. 1986).

416

V.M. Der Kaloustian

Me´garbane´ Syndrome (OMIM 606527) Two brothers with short face, beaked nose, flat nasal bridge, flat philtrum, bilateral ptosis, joint laxity and dislocation, hernias, and severe psychomotor retardation were reported by Me´garbane´ et al. (2001b). Their parents were first-cousin Iraqi Muslims. The authors suggested that this condition was most likely inherited as an autosomal recessive.

Mesomelic Dysplasia, Upper-Limb (OMIM %191440) Me´garbane´ and Ghanem (2005) reported a Lebanese boy with upper-limb mesomelic dysplasia. The father was also affected. This is the second report of this condition in the literature. It was first reported by Fryns et al. in 1988.

Methylenetetrahydrofolate Reductase (MTHFR): C677T Mutation (OMIM *607093) The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene plays a role in precipitating mild hyperhomocysteinemia, and is a risk factor for vascular thrombosis. The frequency of this mutation among 589 healthy Lebanese subjects was investigated. The prevalence of the mutated homozygous (T/T) and heterozygous (C/T) C677T MTHFR genotypes was 11.04 and 39.73%, respectively, giving an allele frequency of 0.309. The prevalence of the T/T genotype was similar with respect to gender. However, a higher prevalence was noted among Christian (13.08%) compared to Muslim (7.66%) subjects (P < 0.001). Moreover, heterogeneity in its distribution was seen in the different Lebanese provinces, and was directly related to the Christian/Muslim composition of each province (Almawi et al. 2004).

Neuropathy, Hereditary Sensory and Autonomic, Type II (OMIM #201300) Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by proximal and distal sensory loss caused by the reduction or absence of peripheral sensory nerves. This condition is due to mutations in the HSN2 gene. Screening of this gene in an HSAN type II Lebanese family showed a 1-bp deletion mutation found in a homozygous state in all affected individuals (Rivie`re et al. 2004).

13

Genetic Disorders in Lebanon

417

Odontoonychodermal Dysplasia (OMIM #257980) Odontoonychodermal dysplasia is a condition characterized by dry hair, severe hypodontia, a smooth tongue with reduced fungiform and filiform papillae, keratoderma of the palms and soles, hyperkeratosis of the skin, and onychodysplasia. This condition was first reported from Lebanon (Fadhil et al. 1983). Other cases and variants were also reported later, from Lebanon and elsewhere (Zirbel et al. 1995; Arnold et al. 1995; Me´garbane´ et al. 1998, 2004). In 2007, Adaimy et al. reported three consanguineous Lebanese Muslim Shiite families that included six individuals affected with this condition. They identified the same c.697G!T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients.

Osseous Dysplasia with Severe Short Stature, Multiple Dislocations, and Delayed Bone Age Two Lebanese children with consanguineous parents were reported with anisospondyly, absence of ossification of the odontoid apophysis, fusion of the neural arches of the cervical vertebrae, partial agenesis of the coccyx, abnormal and subluxated radial heads, bilateral dislocation of the hips, dysplastic acetabulae, hypoplasia of the femoral heads, short femoral necks, short long bones with thin diaphyses, widening of the medullary canal and thinning of the cortical one, slightly enlarged metaphyses, and diffuse osseous demineralization. The bone age was delayed (Me´garbane´ and Ghanem 2004; Me´garbane´ 2007).

Osteopetrosis, Autosomal Recessive (OPTB1, TCIRG1, OMIM #259700 and OPTB5, OSTM1, OMIM #259720) Four Lebanese families were reported, with children of consanguineous parents, affected with osteopetrosis (Souraty et al. 2007). The clinical findings included failure to thrive, a prominent forehead, exophthalmia, optic atrophy, neurological manifestations, hepatosplenomegaly with elevated hepatic enzymes and acid phosphatase, anemia, thrombocytopenia, hypocalcemia, and an early fatal outcome (Souraty et al. 2007). Mutations were identified in two genes: the T-cell immunoregulator-1 (TCIRG1) and the osteopetrosis-associated transmembrane protein 1 (OSTM1). Analysis of the TCIRG1 gene revealed two different types of mutations in the probands of two of these Lebanese families. A homozygous deletion of a single nucleotide was found in exon 7 at nucleotide 4668 of the gene. This lead to a frameshift starting at codon 235 and premature termination after 43 extraneous amino acids

418

V.M. Der Kaloustian

5(1235fs 43). In the third Lebanese family, the proband was homozygous for the G to C change at position +5 of the donor splice site of intron 5 (IVS5 + 5-exon skipping). The proband of the fourth family showed a single point mutation in exon 1, leading to a nonsense mutation (80433T!A, C12X) [Souraty et al. 2007].

Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles In a study on the PAI-1 gene in the Lebanese population, it was found that the 4G/ 5G genotype was the most prevalent (45.6%), followed by 5G/5G (36.9%), and 4G/ 4G (17.5%). Compared to other ethnic communities, the Lebanese population was found to have a relatively high prevalence of the rare 4G allele, which may predispose this population to develop cardiovascular diseases and other thrombotic disorders (Shammaa et al. 2008).

Premature Ovarian Failure with POF1B Mutation (OMIM #300604) In five sisters of a Lebanese family, affected with premature ovarian failure, Lacombe et al. (2006) identified a point mutation in the POF1B gene, localized in exon 10. The substitution of a nucleotide (G!A) at position 1,123 results in an arginine!glutamine mutation of the protein sequence at position 329 (mutation R329Q).

Pseudohermaphroditism (Pseudovaginal Perineoscrotal Hypospadias) Eight patients with male pseudohermaphroditism were reported from a large Muslim Shiite village in Southern Lebanon, with a high rate of consanguinity. The affected individuals had 5-a-reductase deficiency (5aRD). They had a 46,XY chromosomal pattern. At birth, they had an external female phenotype, bilateral testes, and normal male internal genitalia. There is masculinization at puberty, followed by a change in gender role. Molecular studies revealed a homozygous point mutation in exon 1, with a T!A substitution, leading to a leucine to glutamine (Leu-Gln) substitution at position 55 (Hochberg et al. 1996).

Sandhoff Disease (OMIM #268800) ) Out of 11 cases clinically diagnosed in Lebanon as infantile Tay–Sachs disease, nine were enzymatically diagnosed to be affected with Sandhoff disease. The presence of

13

Genetic Disorders in Lebanon

419

this condition was noted to be particularly in the Christian Maronite and Muslim Sunnite communities (Der Kaloustian et al. 1981). Thus, the frequency of the mutation for this disease is thought to be significantly higher in Lebanon than elsewhere. In Lebanese Maronites living in Cyprus, a novel mutation (a deletion of A at nt76) was found (Hara et al. 1994). Population screening in Cyprus revealed a high frequency of nt76 mutation carriers in the Maronite community. However, no mutation was identified in two Sunnite Muslim obligate carriers and eight Maronite individuals who were designated biochemically as carriers but were negative for both the nt76 and IVS8 nt5 mutations (Drousiotou et al. 2000).

Sickle-Cell Anemia (OMIM #603903) and Thalassemia Major (OMIM+141900) Cabannes et al. (1965) studied 3,000 Lebanese individuals and uncovered nine HbS heterozygotes. These consisted of one Maronite, one Greek Orthodox, four Shiites, and three Sunnites. No case was found among the Armenian and Druze communities. The same study showed the presence of the b-thalassemia trait in many regions and communities of Lebanon. The incidence of this trait is 2%, with slight variation from one group to the other. Dabbous and Firzli (1968) reviewed their 10-year experience in the Pediatric Hematology Clinic of the American University Hospital in Beirut, and noted that the sickling phenomenon was present almost exclusively in Muslim patients. Although the total admissions represented 49% Muslims and 51% Christians, all the patients affected with sickle-cell disease were Muslims. Out of 49 patients with sickle cells, eight had sickle-thalassemia, 17 had sickle-cell trait, and 25 had siclkecell anemia. Nineteen were Lebanese, seven Syrian, fourteen Palestinian, five Saudi Arabian, two Bahraini, and two Qatari. The authors (Dabbous and Firzli 1968) think that the sickle-cell gene was introduced in the country in the thirteenth and fourteenth centuries, when the various Muslim groups from the neighboring areas settled in the coastal towns west of Mount Lebanon proper, while the majority of the Christian and Druze withdrew to find shelter at higher altitudes in the mountains. It is of interest to note that malaria (until its eradication in the 1950s) was known to occur at low altitude in Lebanon, and endemic foci existed in the coastal plains and inner plateau, the same areas inhabited by the Muslims in general. Thus, it seems most likely that the preponderance of the HbS gene in Muslims is due to its introduction into the country by Muslim settlers in the fourteenth and fifteenth centuries, and its persistence and propagation in these communities to the malaria that existed in the regions inhabited by Muslims. Even though all subjects with sickle-cell disease (SCD) have the same singlebase-pair mutation, the severity of the clinical and hematological manifestations is extremely variable. A study examined for the first time in Lebanon the correlation

420

V.M. Der Kaloustian

between the clinical manifestations of SCD and the b-globin gene haplotypes. Most reported haplotypes were found in the population, with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels, into three groups (Group A: HbF < 5%; Group B: HbF between 5 and 15%; and Group C: HbF >15%), the highest levels of HBF were associated with the most severe clinical cases. These results suggested that fetal hemoglobin levels are one of the parameters that affect the severity of SCD (Inati et al. 2003). Taleb et al. (1969) published a study on hemoglobinopathies in Lebanon. They found six cases of sickle-cell anemia (four Lebanese), 13 cases of b-thalassemia major (all Lebanese), and one case of sickle-thalassemia (Lebanese). Shahid et al. (1974) described a family in which four siblings had HbH disease. Both parents were Sunnite Muslims and originated from a small village in Southern Lebanon. Strahler et al. (1983) found, from a Lebanese source and by reverse-phase high-performance liquid chromatography, a hemoglobin with substitution of valine by alanine at position 126 of the b-globin chain. They named it hemoglobin Beirut. Later, Blibech et al. (1986) found the same hemoglobin in an Algerian family. Patients with b-thalassemia from a Lebanese population with a high rate of consanguineous marriages were studied by Chehab et al. (1984). The clinical course of the anemia suggests that this population consists of the severe Mediterranean type; 23 unrelated homozygous b-thalassemia patients investigated for globin synthetic ratios consisted of 18 b+ and 5 b with a non-a/a range of 0.158–0.465 and 0.25–0.41, respectively. The percentage of Gg chains in HbF was determined for 21 of these patients and a mean value of 59% Gg-chain content was found. A study by Chehab et al. (1987) of the molecular lesions of b-thalassemia in Lebanon revealed the presence of eight different mutations in 25 patients. The IVS1 position 110 mutation predominated with a frequency of 62% and was almost invariably associated with Mediterranean chromosome haplotype I. Five other mutations commonly found in the Mediterranean area occurred with frequencies of 2–8%. In addition, a G!C substitution in IVS1 position 5 was demonstrated in a patient with Mediterranean haplotype II. A new mutation at codon 29 was found in two other patients with haplotype II. A study by Zahed et al. (1997), suggested that thalassemia was most frequent among the Sunnite Muslims, followed by the Shiite Muslims and the Maronites. The most frequent mutation was IVSI-110 (40%), followed by other common Mediterranean mutations (IVSI-1, IVSII-1, IVSI-6). The most heterogeneous religious group seemed to be the Sunnite Muslims, with 13 mutations, while only two mutations were detected among the Christian Maronites. No mutation was found among the Armenians. Another study by Zahed et al. (2000) on the molecular basis of b-thalassemia revealed a very important degree of heterogeneity. Eighteen different mutations were identified among a total of 277 chromosomes. There was evidence of clustering of certain mutations in particular geographic regions or among specific religious

13

Genetic Disorders in Lebanon

421

groups. Seventy-two of the patients were Muslims and the Sunnite Muslims were the most heterogeneous at the molecular level. While the most common mutations were found in all religious groups, they found that IVSI-5 (G!C) and cd8(-AA) were exclusive to the Sunnite. They also reported that two mutations were exclusive to the Shiites. These were cd30 (G!C) and cd29 (C!T). Haplotype analysis revealed 11 different haplotypes. The five most common mutations were each found on two different haplotypes. Some mutations had a particular geographic distribution. For example, cd29 was mainly found in the Beqa’a valley, cd30 was found in Southern Lebanon (Zahed et al. 2000), while 290 bp del was found in the Shiites in Beirut and 88 was found among the Druze in Mount Lebanon (Makhoul et al. 2005). Both studies revealed similar findings by haplotype analysis of the mutant b-globin gene (Zahed et al. 1997, 2000). Moreover, they identified a rare 5’ subhaplotype (haplotype 12, previously reported in South Africa and Asia) linked to IVSI-110 in three unrelated Maronite individuals. The great majority of the Lebanese chromosomes with the IVS-I-110 mutation are associated with the RFLP haplotype I and sequence haplotype HT1. This is probably the ancestral structure from which the mutation first emerged. The remainder of the IVS-I-110 alleles are linked to the 50 subhaplotype 12 RFLP haplotype and/or HTR sequence haplotype (Zahed et al. 2002). Approximately one-third of thalassemic patients in Lebanon have thalassemia intermedia. In these patients three factors were analyzed: mild b-globin gene, mutations, deletions in the a-globin gene, and the presence of a polymorphism for the enzyme Xmn I in the Gg-promoter region. It was found that the most important contributing factor is the b-genotype: 68% of these patients have a mild b+ mutation (IVSI-6, cd29, 88 or 87), while 26% of the patients are positive for the Xmn I polymorphism associated with increased production of HbF, which showed a strong linkage to particular mutations (IVSII-1, cd8 and cd30) (Qatanani et al. 2000). In a thalassemic patient with a mild phenotype, a mutation was reported representing the insertion of a G nucleotide at codons 8/ 9 [(+G)AAG-TCT(Lys-Ser)!AAG-G-TCT(beta0)] of the beta-globin gene (Zalloua et al. 2003). Six (IVS-I-110, IVS-I-1, IVS-I-6, IVS-II-1, cd5, and C!T substitution at cd29) out of 20 b-globin defects identified accounted for more than 86% of the total. The Sunnite Muslims presented the greatest heterogeneity with 16 different mutations. The Shiite Muslims followed with 13 mutations, and the Maronites, who represented 11.9% of all b-thalassemia subjects, carried seven different mutations. The Druze were found to have six different mutations. One of these mutations, the rare b+ promoter mutation of C!T at position 88, seemed to be unique for this religious group (Makhoul et al. 2005). Zahed and Bou-Dames (1997) published the results of interviews of 83 couples at risk for a hemoglobin disorder, mostly b-thalassemia, in an effort to evaluate their attitude regarding first-trimester prenatal diagnosis. Fifty-nine percent were in favor, 23% were uncertain, and 18% were opposed, because of their religious

422

V.M. Der Kaloustian

convictions against termination of pregnancy. Another important factor influencing their choice was the cost of the test.

Sjo¨gren–Larsson Syndrome (SLS, OMIM #270200) Sjo¨gren–Larsson syndrome is an autosomal recessive disorder, presenting with congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. It is caused by mutations in the gene encoding fatty aldehyde dehydrogenase (FALDH), located on 17p11.2. Sequence analysis of the gene in a Lebanese family with affected persons revealed a homozygous in-frame deletion of three Cs and an insertion of 21 bp at nucleotide position 941 (nt941del3, ins21) (Sille´n et al. 1998). This mutation has been found previously in a family of mixed European origin (De Laurenzi et al. 1996).

Smith–Lemli–Opitz syndrome (SLOS, OMIM #270400) Smith–Lemli–Opitz syndrome is a multiple congenital anomalies/mental retardation syndrome. The condition is due to the deficient activity of the enzyme 7-dehydrocholesterol (7-DHC) reductase. Akl et al. (1977) reported a patient with bilateral focal renal dysplasia. Siblings affected with this condition and with consanguineous parents of Syrian-Lebanese origin were reported, with a novel mutation in the DHCR7 gene. The patients were homozygotes for a missense mutation, causing a C!T transition at position 1,649 in exon 9, substituting a leucine for a proline residue (P467L) (Nezarati et al. 2002).

Spondyloepimetaphyseal Dysplasia with Multiple Dislocations (OMIM %603546) Me´garbane´ et al. (2003b) reported a new Lebanese patient with spondyloepimetaphyseal dysplasia with multiple dislocations, and reviewed the literature.

Tay–Sachs Disease, juvenile (OMIM #272800) Hechtman et al. (1989) evaluated the expression of the hexosaminidase isozymes in fibroblast cell lines obtained from two siblings of Lebanese Christian origin who presented with juvenile-onset Tay–Sachs disease. In the normal control fibroblasts,

13

Genetic Disorders in Lebanon

423

the a-subunit of hexosaminidase A (Hex A) is synthesized as a 67-kDa precursor, which is cleaved in lysosomes to a mature 54-kDa peptide. The patient’s fibroblasts were capable of synthesizing the 67-kDa precursor but failed to convert it to the mature subunit. The a-subunit precursor synthesized by the cells of the patients could not be phosphorylated, nor was the patient’s a-subunit precursor secreted into the medium in response to NH4Cl, which caused accumulation of both a- and b-subunit precursor in the medium of the normal control fibroblasts. The patients had 0.32 and 0.36% of HexA-associated cleaving activity, compared to normal control fibroblasts, whereas this percentage is less than 0.016% for infantile Tay–Sachs disease fibroblasts. The occurrence of this form of Tay–Sachs disease in Lebanon in three unrelated Lebanese immigrant families in Canada, together with the fact that the grandparents of the unrelated probands come from villages in both the northern and the southern regions of Lebanon, lead the authors (Hechtman et al. 1989) to speculate that a gene causing juvenile-onset Tay–Sachs disease may not be infrequent in Lebanon. Again, in a Lebanese proband with juvenile-onset Tay–Sachs disease Trop et al. (1992) found, by direct sequencing of PCR products, a G!A transition at nucleotide749 in exon 7. The mutation caused a glycine-to-aspartic acid change at amino acid 250. Boustany et al. (1991) found in a Lebanese Maronite patient with the juvenile form of Tay–Sachs disease a specific mutation in the heterozygous state. The mutation consisted of a G!A transition at nucleotide 1511 of the a-chain of hexosaminidase A, resulting in substitution of histidine for arginine at position 504. Cultured fibroblasts synthesized an a-subunit that could acquire mannose 6-phosphate and be excreted, but which failed to associate with the b-subunit to form the enzymatically active heterodimer (Paw et al. 1990).

Usher Syndrome Type 1C (USH1C, OMIM #276904) Usher syndrome is the most common form of inherited deafness associated with retinitis pigmentosa. It is heterogeneous, both clinically and genetically. On the basis of the clinical phenotype, it is classified into three main types: USH1, USH2, and USH3. USH1 is the most genetically heterogeneous, with at least eight loci (Ahmed et al. 2003). Linkage analysis of seven Lebanese families with Usher syndrome revealed that two were of type I (USH1) and five with type II (USH2). The seventh was of the USH1C type (Saouda et al. 1998). Patients with USH1C and residing in New England were studied and their haplotypes compared. One patient had haplotypes found in previously reported USH1C Acadian families residing in south-western Louisiana. One patient was Lebanese-American (DeAngelis et al. 2001). The latter had the same haplotype as a previously reported USH1C family residing in Lebanon (Saouda et al. 1998).

424

V.M. Der Kaloustian

Vitamin K-Dependent Clotting Factors, Deficiency of (Familial Multiple Coagulation Factor Deficiency, FMFD, OMIM #277450) Familial multiple coagulation factor deficiency is a very rare disorder with only 14 cases described in the literature by 2002 (Fregin et al. 2002). Clinical symptome of the disease are episodes of intracerebral hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. Clinical details of a Lebanese and a German family were presented with a suggestion of autosomal recessive inheritance (Oldenburg et al. 2000). The same group reported a second gene locus to the centromeric region of chromosome 16 (Fregin et al. 2002). Previously, a missense mutation in the g-glutamyl carboxylase gene was found to cause combined deficiency of all vitamin K-dependent blood coagulation factors (Brenner et al. 1998).

Weill–Marchesani Syndrome, Autosomal Recessive (WMS; OMIM #277600) Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities. This condition presents with clinical homogeneity, but with both autosomal recessive and autosomal dominant inheritance. Faivre et al. (2002) reported in two consanguineous families (a Lebanese and a Saudi Arabian) linkage of the autosomal recessive variety of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. In 2004, Dagoneau et al. (2004) reported null mutations in the gene encoding ADAMTS10 in the Lebanese and Saudi Arabian families. The nucleotide change in the Lebanese family resulted in a nonsense mutation (R237X) with 709C!T/ 709C!T.

Wolfram Syndrome (DIDMOAD, WFS1, OMIM #222300) Wolfram syndrome (WFS) is a rare hereditary heterogeneous neurodegenerative disorder. It is also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). Thirty-one Lebanese patients, all derived from consanguineous marriages, were studied. Even though the accurate prevalence of this condition is not established in this study, it was suggested that it is much more prevalent in the Lebanese than in other populations, possibly because of the high rate of consanguinity. WFS1 gene mutations were detected in three families (23.5%), with two different putative mutations. No abnormalities were detected in the mitochondrial DNA (Medlej et al. 2004).

13

Genetic Disorders in Lebanon

425

Delivery of Care to Patients with Genetic Diseases and Genetic Programs Genetic counseling and care to patients with genetic diseases were provided by two genetics units, both located in Beirut and founded in 1968. The first of these, The National Unit of Human Genetics was at the American University Medical Centre. It had facilities for clinical genetics, cytogenetics, biochemical genetics, and prenatal diagnosis. A multidisciplinary consultant staff provided genetic counseling in a genetics clinic and consultations on the wards. The second unit comprised cytogenetics and biochemical genetics laboratories at the Faculty of Medicine, St. Joseph University, Beirut (Faculte´ de Me´decine, Universite´ St. Joseph, Beyrouth) as well as at the Genetics Clinic of the Hoˆtel Dieu de France Hospital in Beirut. These two units catered not only to patients from various regions of Lebanon, but also to those from countries of the Middle East. Both units benefited from the effective support of a governmental agency, the Lebanese National Council for Scientific Research (LNCSR). They both had a productive scientific period, with a substantial number of publications. The unit at the American University of Beirut had also programs for M.Sc. and Ph.D. in human genetics, and a fellowship program in clinical genetics. Unfortunately, because of the Lebanese civil war, the two units were dismantled to a great extent, keeping only a skeleton of services, mostly in Cytogenetics. In the phase of reconstruction of the country during the past two decades, both universities are making special efforts to reorganize their genetic services and give them high priority. Fortunately, these efforts lead to the production of a new generation of very capable and productive specialists with outstanding contributions, and a marked presence in the region and internationally. The Cytogenetics Laboratory at the American University of Beirut Medical Center (AUBMC) is the only laboratory in Lebanon that performs prenatal diagnosis of chromosome abnormalities (Eldahdah et al. 2007).

References Abboud MR, Alexander D, Najjar SS (1985) Diabetes mellitus, thiamine-dependent megaloblastic anemia, and sensorineural deafness associated with deficient alpha-ketoglutarate dehydrogenase activity. J Pediatr 107:537–541 Abdelnoor AM, Abdelnoor M, Heneine W, Khauli R, Kobeissy F, Mansur S, Malak R, Sharara H (2001) Major histocompatibility complex class I and II antigen frequencies in selected groups of Lebanese. Transplant Proc 33:2839–2840 Abdul-Karim R, Iliya F, Iskandar G (1964) Consecutive hydrocephalus: report of two cases. Obstet Gynecol 24:376–378 Abifadel M, Jambart S, Allard D, Rabe`s J-P, Varret M, Derre´ A, Chouery E, Salem N, Junien C, Ayde´nian H, Boileau C (2004) Identification of the first Lebanese mutation in the LPL gene and description of a rapid detection method. Clin Genet 65:158–161

426

V.M. Der Kaloustian

Adaimy L, Chouery E, Me´garbane´ H, Mroueh S, Delague V, Nicholas E, Belguith H, de Mazancourt P, Me´garbane´ A (2007) Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am J Hum Genet 81:821–828 Afifi AK, Der Kaloustian VM, Mire JJ (1972a) Muscular abnormality in xeroderma pigmentosum. J Neurol Sci 17:435–442 Afifi AK, Rebeiz J, Mire J, Andonian SJ, Der Kaloustian VM (1972b) The myopathology of the prune belly syndrome. J Neurol Sci 15:153–166 Afifi AK, Najjar SS, Mire-Salman J, Bergman RA (1974) The myopathology of the Kocher– Debre´–Se´me´laigne syndrome. Electromyography, light and electron-microscopy study. J Neurol Sci 22:445–470 Afifi AK, Mire-Salman J, Najjar S (1976) The myopathology of congenital generalized lipodystrophy, light and electron microscopic observation. Johns Hopkins Med J 39(Suppl):61–68 Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER (2003) The molecular genetics of Usher syndrome. Clin Genet 63:431–444 Akl KF, Khudr GS, Der Kaloustian VM, Najjar SS (1977) The Smith–Lemli–Opitz syndrome. Report of a case with bilateral focal renal dysplasia. Clin Pediatr 16:665–668 Al-Awadi SA, Farag TI, Teebi AS, Naguib K, El-Khalifa MY, Kelani Y, Al-Ansari A, Schimke RN (1985) Primary hypogonadism and partial alopecia in three sibs with mullerian hypoplasia in the affected females. Am J Med Genet 22:619–622 Alexander D, Assaf M, Khudr A, Haddad I, Barakat A (1985) Fructose-1, 6-diphosphatase deficiency: diagnosis using leukocytes and detection of heterozygotes with radiochemical and spectrophotometric methods. J Inherit Metab Dis 8:174–177 Alexander D, Dudin G, Talj F, Bitar F, Deeb M, Khudr A, Abboud M, Der Kaloustian VM (1984) Five related Lebanese individuals with high plasma lysosomal hydrolases: a new defect in mannose-6-phosphate receptor recognition? Am J Hum Genet 36:1001–1014 Alexander D, Deeb M, Talj F (1986) Heterozygosity for phosphodiester glycosidase deficiency: a novel human mutation of lysosomal enzyme processing. Hum Genet 73:53–59 Almawi WY, Finan RR, Tamim H, Daccache JL, Irani-Hakime N (2004) Differences in the frequency of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene among the Lebanese population. Am J Hematol 76:85–87 Almawi WY, Wakim-Ghorayeb SF, Arekat MR, Najm P, Keleshian SH, Al-Sayed N, Blanchon B, Samaha HR, Irani-Hakime N (2006) Association of selective HLA class II susceptibilityconferring and protective haplotypes with type 2 diabetes in patients from Bahrain and Lebanon. Clin Vaccine Immunol 13:1296–1298 Arayssi TK, Hamdan AR, Touma Z, Shameseddeen W, Hourani HB, Farra CG (2008) TNF polymorphisms in Lebanese patients with Behc¸et’s disease. Clin Exp Rheumatol 26(4 suppl 50):S130–131 Armenian H (1982) Genetic and environmental factors in the aetiology of familial paroxysmal polyserositis. An analysis of 150 cases from Lebanon. Trop Geogr Med 34:183–187 Armenian HK, Khachadurian AK (1973) Familial paroxysmal polyserositis. Clinical and laboratory findings in 120 cases. J Med Liban 26:605–614 Armenian HK, Uthman SM (1975) Familial paroxysmal polyserositis (FPP). J Med Liban 28:439–442 Arnold WP, Merks MAW, Steijlen PM (1995) Variant of odontoonychodermal dysplasia? Am J Med Genet 59:242–244 Ayoub N, Tomb R, Charlesworth A, Meneguzzi G (2005) E´pidermolyse bulleuse jonctionnelle. Identification d’une nouvelle mutation dans 2 familles libanaises. Ann Dermatol Venereol 132:550–553 Baghdassarian SA, Tabbara KF (1975) Childhood blindness in Lebanon. Am J Ophthalmol 79:827–830 Baraka A, Bikhazi G, Abu-Haidar G (1974) Succinylcholine block in a patient with atypical serum cholinesterase. Middle East J Anaesthesiol 4:53–59

13

Genetic Disorders in Lebanon

427

Barakat AY, Butler MG (1987) Renal and urinary tract abnormalities associated with chromosome aberrations. Int J Pediatr Nephrol 8:215–226 Barakat AY, Francis YK, Mufarrij AA (1986) Hypokalemic alkalosis, hyperreninemia, aldosteronism, normal blood pressure and normal juxtaglomerular apparatus – a new syndrome of renal alkalosis. Int J Pediatr Nephrol 7:99–100 Barbari A, Stephan A, Masri M, Karam A, Aoun S, El Nahas J, Bou Khalil J (2003) Consanguinity-associated kidney disease in Lebanon: an epidemiological study. Mol Immunol 39:1109–1114 Beighton P (1978) Inherited disorders of the skeleton. Churchill-Livingstone, Edinburgh, pp 50–52 Beighton P (1990) Dyggve–Melchior–Clausen syndrome. J Med Genet 27:512–515 Ben Ezra D, Abulafia H, Maftzir G, Yatziv S, Paez J, Zelikovitch A (1982) Radial aplasia, chromosomal aberration, and anterior chamber cleavage manifestations in two siblings. Birth Defects Orig Artic Ser 18:571–575 Beutler E, Kuhl W (1990) The NT 1311 polymorphism of G6PD: G6PD Mediterranean mutation may have originated independently in Europe and Asia. Am J Hum Genet 47:1008–1012 Bidinost C, Matsumoto M, Chung D, Salem N, Zhang K, Stockton DW, Khoury A, Megarbane A, Bejjani B, Traboulsi EI (2006) Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities. Invest Ophthal Vis Sci 47:1274–1280 Bitar E (1966) La goutte au Liban. J Med Liban 19:235–241 Bitar E, Ghayad E, Ghoussoub K, Sinno W, Chams H, Khoury A, Baloglou P, Kallab K, Halaby C, Chemaly R et al (1986) Behc¸et’s disease: A propos of 32 cases. Rev Rhum Mal Osteoartic 53:621–624 Bitar JG (1970) Unconjugated hyperbilirubinemia (Gilbert’s syndrome). J Med Liban 23:485–489 Bitar JG, Idriss H (1969) Cystic fibrosis of the pancreas. J Med Liban 22:181–185 Bitar JG, Lightwood R (1967) The Wiskott-Aldrich syndrome associated with mucoviscidosis in the same patient. J Pediatr 71:123–126 Bitar JG, Takla R (1971) Hepatic glycogenoses. J Med Liban 24:483–490 Bitar J, Khalife´ R, Matta C, Najjar S, Tawil H (1969) Ataxia telangiectasia. J Med Liban 22:187–190 Bitar JG, Salem AA, Nasr AT (1970) Celiac disease in the Middle East. J Med Liban 23: 423–444 Blibech R, Mrad H, Kastally R, Brissart MA, Potron G, Arous N, Riou J, Blouquit Y, Bardakdjian J, Lacombe C, Rosa J, Galacteros F (1986) Hemoglobin Beirut (alpha 2 beta 2 (126) val-to-ala) in an Algerian family. Hemoglobin 10:651–654 Bonafede RP, Beighton P (1978) The Dyggve–Melchior–Clausen syndrome in adult siblings. Clin Genet 14:24–30 Boustany RM, Tanaka A, Nishimoto J, Suzuki K (1991) Genetic cause of a juvenile form of Tay–Sachs disease in a Lebanese child. Ann Neurol 29:104–107 Brenner B, Sa´nchez-Vega B, Wu S-M, Lanir N, Stafford DW, Solera J (1998) A missense mutation in g-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 12:4554–4559 Brook CG, Wagner H, Zachmann M, Prader A, Armendares S, Frenk S, Aleman P, Najjar SS, Slim MS, Genton N, Bozie C (1973) Familial occurrence of persistent M€ ullerian structures in otherwise normal males. Br Med J 1:771–773 Buresi C, Ghanem N, Huck S, Lefranc G, Lefranc M-P (1989) Exon duplication and triplication in the human T-cell receptor gamma constant region genes and RFLP in French, Lebanese, Tunisian, and Black African populations. Immunogenetics 29:161–172 Cabannes R, Taleb N, Ghorra F, Schmitt-Beurrier A (1965): Etudes des types he´moglobiniques dans la population du Liban. Nouv Rev Fr Hematol 5:851–856

428

V.M. Der Kaloustian

Chaib H, Place C, Salem N, Chardenoux S, Vincent C, Weissenbach J, El-Zir E, Loiselet J, Petit C (1996) A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome 2p22-23. Hum Mol Genet 5:155–158 Chehab FF, Khouri FP, Deeb SS (1984) Globin synthetic ratios in homozygous beta-thalassemia patients from Lebanon. Hemoglobin 8:151–162 Chehab FF, Der Kaloustian V, Khouri FP, Deeb SS, Kan YW (1987) The molecular basis of betathalassemia in Lebanon: application to prenatal diagnosis. Blood 69:1141–1145 Choueiri RN, Fayad MN, Farah A, Mikati MA (2001) Classification of epilepsy syndromes and role of genetic factors. Pediatr Neurol 24:37–43 Chu ET, Rosenwasser LJ, Dinarello CA, Rosen FS, Geha RS (1984) Immunodeficiency with defective T-cell response to interleuken 1. Proc Natl Acad Sci USA 81:4945–4949 Courbage Y, Fargues P (1973) La situation de´mographique au Liban. Publications de l’Universite´ Libanaise, Beyrouth Dabbous IA, Firzli SS (1968) Sickle cell anemia in Lebanon. Its predominance in Mahommedans. Z Morphol Anthropol 59:225–231 Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Me´garbane´ A, Alswaid A, Dolfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 75:801–806 Darwish M, Armenian HK (1987) A case-control study of rheumatoid arthritis in Lebanon. Int J Epidemiol 16:420–424 DeAngelis MM, McGee TL, Keats BJB, Slim R, Berson EL, Dryja TP (2001) Two families from New England with Usher syndrome type 1C with distinct haplotypes. Am J Ophthalmol 131:355–358 De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Teinert PM, Compton JG, Markova N, Rizzo WB (1996) Sjo¨gren–Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet 12:52–57 De Meeus A, Stephan E, Debrus S, Jean M-K, Loiselet J, Weissenbach J, Demaille J, Bouvagnet P (1995) An isolated cardiac conduction disease maps to chromosome 19q. Circ Res 77:735–740 De Moerloose P, Germanos-Haddad M, Boehlen F, Neerman-Arbez M (2004) Severe factor XI deficiency in a Lebanese family: identification of a novel missense mutation (Trp501Cys) in the catalytic domain. Blood Coagul Fibrinolysis 15:269–272 De Sandre-Giovannoli A, Chaouch M, Boccaccio I, Bernard R, Delague V, Grid D, Vallat JM, Le´vy N, Me´garbane´ A (2003) Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and spicing mutations. J Med Genet 40:e87 De Sandre-Giovannoli A, Delague V, Hamadouche T, Chaouch M, Krahn M, Boccaccio I, Maisonobe T, Chouery E, Jabbour R, Atweh S, Grid D, Me´garbane´ A, Le´vy N (2005) Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11. J Med Genet 42:260–265 De Vaumas E (1954) Le Liban, Etude de Ge´ographie Physique. Firmin-Didot, Paris De Vaumas E (1955) La re´partition confessionnelle au Liban et l’e´quilibre de l’Etat Libanais. Rev Ge´ogr Alp 42:511–603 Deeb Z, Frayha RA (1976) Multiple vacuum discs: an early sign of ochronosis. Radiologic findings in two brothers. J Rheumatol 3:82–87 Delague V, Bareil C, Tuffery S, Bouvargnet P, Chouery E, Koussa S, Maisonobe T, Loiselet J, Me´garbane´ A (2000a): Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene. Am J Hum Genet 67:236–243 Delague V, Souraty N, Khallouf E, Tardy V, Chouery E, Halaby G, Loiselet J, Morel Y, Me´garbane´ A (2000b) Mutational analysis in Lebanese patients with congenital adrenal hyperplasia due to a deficit in 21-hydroxylase. Horm Res 53:77–82

13

Genetic Disorders in Lebanon

429

Delague V, Bareil C, Bouvagnet P, Salem N, Chouery E, Loiselet J, Me´garbane´ A, Claustres M (2001): Nonprogressive autosomal recessive ataxia maps to chromosome 9q34-9qter in a large consanguineous Lebanese family. Ann Neurol 50:250–253 Delague V, Bareil C, Bouvagnet P, Salem N, Chouery E, Loiselet J, Me´garbane´ A (2002): A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24q26 in a large consanguineous Lebanese Druze family. Neurogenetics 4:23–27 Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Me´garbane´ A, Haase G, Le´vy N (2007) Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive CharcotMarie-Tooth type 4H. Am J Hum Genet 81:1–16 Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl H-HM, Middleton A, Houseman MJ, Dode´ C, Marlin S, Boulila-ElGaed A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E´, Aubois A, Joannard A, Levilliers J, Garabe´dian E´-N, Mueller RF, McKinlay Gardner RJ, Petit C (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexion 26 gene. Hum Mol Genet 12:2173–2177 Der Kaloustian VM, Baghdassarian SA (1972) The autosomal recessive variety of congenital stationary night-blindness with myopia. J Med Genet 9:67–69 Der Kaloustian VM, Mnaymneh WA (1973) Bilateral tibial aplasia with lobster-claw hands. A rare genetic entity. Acta Paediatr Scand 62:77–78 Der Kaloustian VM, Musallam SS (1975) Treatment of acrodermatitis enteropathica with oral zinc sulfate. Letter to the editor. Pediatrics 55:744 Der Kaloustian VM, Kronfol NM, Takla R, Habash A, Khazin A (1971) Leprechaunism. Am J Dis Child 122:442–445 Der Kaloustian VM, Afifi AK, Sinno AA, Mire J (1972a) The Rubinstein–Taybi syndrome. Am J Dis Child 124:897–902 Der Kaloustian VM, Sinno AA, Nassar SI (1972b) Acrocephalopolysyndactyly, type II (Carpenter’s syndrome). Am J Dis Child 124:716–718 Der Kaloustian VM, De Weerd-Kastelein EA, Kleijer WJ, Keijzer W, Bootsma D (1974a) The genetic defect in the De Sanctis–Cacchione syndrome. J Invest Dermatol 63:392–396 Der Kaloustian VM, Slim MS, Mishalany HG (1974b) Familial congenital duodenal atresia. Pediatrics 54:118 Der Kaloustian VM, Musallam SS, Sanjad SA, Murib A, Hammad WD, Idriss ZH (1976) Oral treatment of acrodermatitis enteropathica with zinc sulfate. Am J Dis Child 130: 421–423 Der Kaloustian VM, Naffah J, Loiselet J (1980) Genetic diseases in Lebanon. Am J Med Genet 7:187–203 Der Kaloustian VM, Khoury MJ, Hallal R, Idriss ZH, Deeb ME, Wakid NW, Haddad FS (1981) Sandhoff disease: a prevalent form of infantile Gm2 gangliosidosis in Lebanon. Am J Hum Genet 33:85–89 Der Kaloustian VM, Freij BJ, Kurban AK (1982) Prolidase deficiency: an inborn error of metabolism with major dermatological manifestations. Dermatologica 164:293–304 Der Kaloustian VM, Jarudi NI, Khoury MJ, Afifi AK, Bahuth NB, Deeb ME, Shammas J, Mikati MA (1985a) Familial spinocerebellar degeneration with corneal dystrophy. Am J Med Genet 20:325–339 Der Kaloustian VM, Ratl H, Malouf J, Hatem J, Slim M, Tomeh A, Khouri J, Kutayli F (1985b) Tetralogy of fallot with pulmonary atresia in siblings. Am J Med Genet 21:119–122 Der Kaloustian VM, Khudr A, Firzli S, Dabbous I (1987a) Psychosocial and economic profile of a sample of families with thalassemic children in Lebanon. J Med Genet 24:772–777 Der Kaloustian VM, Masri R, Khudr A, Talj F, Libbus B, Nabulsi M, Khouri FP (1987b) Down syndrome in two siblings with 47, XY,+21 and 46, XY/46, XY,-21,+t(21q;21q). Hum Genet 75:97

430

V.M. Der Kaloustian

Desgeorges M, Me´garbane´ A, Guittard C, Carles S, Loiselet J, Damaille J, Claustres M (1997) Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet 100:279–283 Dhaini HR, Levy GN (2000) Arylamine N-acetyltransferase 1 (NAT1) genotypes in a Lebanese population. Pharmacogenet Genomics 10:79–83 Drousiotou A, Stylianidou G, Anastasiadou V, Christopoulos G, Mavrikiou E, Georgiou T, Kalakoutis G, Oladimeji A, Hara Y, Suzuki K, Furihata K, Ueno I, Ioannou PA, Fensom AH (2000) Sandhoff disease in Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community. Hum Genet 107:12–17 Dudin G, Alexander D, Talj F, Deeb M, Musallam S, Der Kaloustian VM (1984a) Interstitial deletion of band q12 of chromosome 5. Clin Genet 25:455–456 Dudin G, Traboulsi E, Khouri F, Der Kaloustian VM (1984b) Hereditary retinoblastoma and 13qmosaicism. Cytogenet Cell Genet 38:235–237 El Ghouzzi V, Dagoneau N, Kinning E, Thauvin-Robinet C, Chemaitilly W, Prost-Squarcioni C, Al-Gazali LI, Verloes A, Le Merrer M, Munnich A, Trembath RC, Cormier-Daire V (2003) Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve–Melchior– Clausen syndrome. Hum Mol Genet 12:357–364 Eldahdah LT, Ormond KE, Nassar AH, Khalil T, Zahed LF (2007) Outcome of chromosomally abnormal pregnancies in Lebanon: obstetricians’ roles during and after prenatal diagnosis. Prenat Diagn 27:525–534 El-Rassy I, Bou-Abdallah J, Al-Ghadban S, Bitar F, Nemer G (2008) Absence of NOTCH2 and Hey2 mutations in a familial Alagille syndrome case with a novel frameshift mutation in JAG1. Am J Med Genet 146A:937–939 El-Zahabi LM, Makarem J, Habbal Z, Otrock ZK, Taher A, Shamseddine A (2007) Gaucher disease: different clinical manifestations associated with a rare muttion (R48W) in a Lebanese family. Mol Genet Metab 91:402–404 Epstein PA, Kidd DD (1981) Dermo-distortive urticaria: an autosomal dominant dermatologic disorder. Am J Med Genet 9:307–315 Fadhil M, Ghabra TA, Deeb M, Der Kaloustian VM (1983): Odontoonychodermal dysplasia: a previously apparently undescribed ectodermal dysplasia. Am J Med Genet 26:123–131 Faivre L, Me´garbane´ A, Alswaid A, Zylberberg L, Aldohayan N, Campos-Xavier AB, Bacq D, Legeai-Maller L, Bonaventure J, Munnich A, Cormier-Daire V (2002) Homozygosity mapping of a Weill–Marchesani syndrome locus to chromosome 19p13.3-p11.2. Hum Genet 110: 366–370 Fares F, Ran SA, David M, Zelnik N, Hecht Y, Khairaldeen H, Lerner A (2004) Identification of two mutations for ataxia telangiectasia amon the Druze community. Pren Diagn 24:358–362 Farra C, Medawar R, Mroueh S, Souaid M, Cabet F, Awwad J (2008) Cystic fibrosis: a new mutation in the Lebanese population. J Cyst Fibros 7:429–432 Fayad MN, Yacoub A, Salman S, Khudr A, Der Kaloustian VM (1987) Juvenile hyaline fibromatosis: two new patients and review of the literature. Am J Med Genet 26:123–131 Figueiredo MS, Dos Santos JE, Alberto FL, Zago MA (1992): High frequency of the Lebanese allele of the LDLr gene among Brazilian patients with familial hypercholesterolemia. J Med Genet 29:813–815 Fischel-Ghodsian N, Bu X, Oztas S, Prezant TR, Danon Y, Shohat T, Rotter JI, Shohat M (1992) The gene for familial Mediterranean fever maps to the short arm of chromosome 16 in both Armenians and non-Ashkenazi Jews. Am J Hum Genet 41(Suppl):A187 Frayha R, Nasr F (1971) Juvenile ankylosing spondylitis. J Med Liban 24:401–409 Frayha RA, Nassar VH, Dagher F, Salti IS (1972) Familial parathyroid carcinoma. J Med Liban 25:299–309 Frayha RA, Salti IS, Abu Haidar GI, Al-Khalidi U, Hemady K (1973) Hereditary xanthinuria and xanthine urolithiasis: an additional 3 cases. J Urol 109:871–873 Frayha RA, Salti IS, Arnaout A, Khachadurian A, Uthman SM (1977) Hereditary xanthinuria. Report of three patients and short review of the literature. Nephron 19:328–332

13

Genetic Disorders in Lebanon

431

Frayha R, Melhem R, Idriss H (1979) The Kniest (swiss cheese cartilage) syndrome. Description of a distinct arthropathy. Arthritis Rheum 22:286–289 Fregin A, Rost S, Wolz W, Krebsova A, Muller CR, Oldenburg J (2002) Homozygosity mapping of a second gene locus for hereditary combined deficiency of vitamin K-dependent clotting factors to the centromeric region of chromosome 16. Blood 100:3229–3232 Freij BJ, Der Kaloustian VM (1986) Prolidase deficiency. A metabolic disorder presenting with dermatologic signs. Int J Dermatol 25:431–433 Freij BJ, Levy HL, Dudin G, Mutasim D, Deeb M, Der Kaloustian VM (1984) Clinical and biochemical characteristics of prolidase deficiency in siblings. Am J Med Genet 19:561–571 Fried K, Vure E (1974) A lethal autosomal recessive entero-colitis of early infancy. Clin Genet 6:195–196 Fryns J-P, Hofkens G, Fabry G, Van Den Berghe H (1988) Isolated mesomelic shortening of the forearm in father and daughter: a new entity in the group of mesomelic dysplasias. Clin Genet 33:57–59 Fukushima K, Ramesh A, Srisailapathy CRS, Ni L, Wayne S, O’Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RIS, Smith RJH (1995) An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p – DFNB6. Genome Res 5:305–308 Fuleihan DS, Der Kaloustian VM, Najjar SS (1971) The Russell–Silver syndrome. Report of three siblings. J Pediatr 78:654–657 Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292:1394–1398 Ghanem N, Dariavach P, Bensama M, Chibani J, Lefranc G, Lefranc MP (1988) Polymorphism of immunoglobulin lambda constant region genes in populations from France, Lebanon and Tunisia. Exp Clin Immunogenet 5:186–195 Ghayad E, Tohme A (1995) Behc¸et disease in Lebanon. J Med Liban 43:2–7 Haddad R, Uwaydat S, Dakroub R, Traboulsi EI (2001) Confirmation of the autosomal recessive syndrome of ectopia lentis and distinctive craniofacial appearance. Am J Med Genet 99:185–189 Hajjar ET, Vincenti F, Salti IS (1974) Gluten-induced enteropathy. Osteomalacia as its principal manifestation. Arch Intern Med 134:565–566 Hara Y, Ioannou P, Drousiotou A, Stylianidou G, Anastasiadou V, Suzuki K (1994) Mutation analysis of a Sandhoff disease patient in the Maronite community in Cyprus. Hum Genet 94:136–140 Harboyan G, Mamo J, Der Kaloustian V, Karam F (1971) Congenital corneal dystrophy with progressive sensorineural hearing loss. Arch Ophthalmol 85:27–32 Harfouche JK (1965) Social structure of low income families in Lebanon. Khayat’s, Beirut, p 41 Hechtman P, Boulay B, Bayleran J, Andermann E (1989) The mutation mechanism causing juvenile-onset Tay-Sachs disease among Lebanese. Clin Genet 35:364–375 Hennies HC, Rauch A, Seifert W, Schumi C, Moser E, Al-Talj E, Tariverdian G, Chrzanowska KH, Krajewska-Walasek M, Rajab A, Giugliani R, Neumann TE, Eckl KM, Karbasiyan M, Reis A, Horn D (2004) Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am J Hum Genet 75:138–145 Herman RH, Overhold EL, Hagler L (1969) Familial life-long persistent fever of unknown origin responding to dexamethasone and uronic acids. Am J Med 46:142–153 Hirbli KI, Aboujaoude´ JH, Ghorra FS, Barakat-el-Khoury WM (1990) Pre´valence et incidence du diabe`te sucre´ au Liban. Diabe`te Me´tab 16:479–483 Hitti PK (1967) Lebanon in history – from the earliest times to the present, 3rd edn. McMillan, London Hochberg Z, Chayen R, Reiss N, Falik Z, Makler A, Munichor M, Farkas A, Goldfarb H, Ohana N, Hiort O (1996) Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5a-reductase 2 deficiency. J Clin Endocrinol Metab 81:2821–2827 Idriss ZH, Der Kaloustian VM (1973) Acrodermatitis enteropathica. Clin Pediatr 12:393–395

432

V.M. Der Kaloustian

Idriss ZH, Najjar SS, Der Kaloustian VM, Shammaa M (1975) Congenital erythropoietic porphyria. Am J Dis Child 129:701–702 Inati A, Taher A, Bou Alawi W, Koussa S, Kaspar H, Shbaklo ZPA (2003) b-globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in Lebanon. Eur J Haematol 70:79–83 Irani-Hakime N, Tamim H, Kreidy R, Almawi WY (2000) The prevalence of factor V R506Q mutation-Leiden among apparently healthy Lebanese. Am J Hematol 65:45–49 Jaatoul NY, Haddad NE, Khoury LA, Afifi AK, Bahuth NB, Deeb ME, Mikati MA, Der Kaloustian VM (1982) The Marden–Walker syndrome. Am J Med Genet 11:259–271 Jalkh N, Ge´nin E, Chouery E, Delague V, Medlej-Hashim M, Idrac C-A, Me´garbane´ A, Serre J-L (2008) Familial Mediterranean fever in Lebanon: founder effects for different MEFV mutations. Ann Hum Genet 73:41–47 Jeck N, Reinalter SC, Henne T, Marg W, Mallmann R, Pasel K, Vollmer M, Klaus G, Leonhardt A, Seyberth HW, Konrad M (2001) Hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness. Pediatrics 108:e5 Khachadurian AK (1962) Essential pentosuria. Am J Hum Genet 14:249–255 Khachadurian AK (1963) Nonalimentary fructosuria. Pediatrics 32:455–457 Khachadurian AK (1964) The inheritance of essential familial hypercholesterolemia. Am J Med 37:402–407 Khachadurian AK (1968) Migratory polyarthritis in familial hypercholesterolemia (type II hyperlipoproteinemia). Arthritis Rheum 11:385–393 Khachadurian AK (1972) A general review of clinical and laboratory features of familial hypercholesterolemia (type II hyperbetalipoproteinemia). In: Proceedings of the 19th Colloqium. Peeters protides of the biological fluids. Pergamon Press, 1971 Khachadurian A, Abu Feisal K (1958) Alkaptonuria. Report of a family with severe cases in four successive generations, with metabolic studies in one patient. J Chronic Dis 7:455–465 Khachadurian AK, Armenian HK (1974) Familial paroxysmal polyserositis (familial Meditrerranean fever). Incidence of amyloidosis and mode of inheritance. Birth Defects Orig Artic Ser 10 (4):62–66 Khachadurian AK, Khachadurian LA (1964) The inheritance of renal glycosuria. Am J Hum Genet 16:189–194 Khachadurian AK, Somerville I (1965) Diabetes mellitus in Lebanon. A retrospective clinical study of 560 patients. J Chronic Dis 18:1309–1315 Khachadurian AK, Sutherland JV (1975) Affective psychoses in Lebanon. J Med Liban 28:159–167 Khachadurian AK, Uthman SM (1973) Experience with homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab 15:132–140 Khachadurian AK, Freyha R, Shamma’a MM, Baghdassarian SA (1971) A-b-lipoproteinemia and colour-blindness. Arch Dis Child 46:871–873 Khlat M (1988a) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Khlat M (1988b) Consanguineous marriages in Beirut: time trends, spatial distribution. Soc Biol 35:324–330 Khlat M (1988c) Social correlates of consanguineous marriages in Beirut: a population-based study. Hum Biol 60:541–548 Khlat M, Halabi S (1986) Modernization and consanguineous marriage in Beirut. J Biosoc Sci 18:489–495 Khlat M, Khudr A (1984) Cousin marriages in Beirut, Lebanon. Is the pattern changing? J Biosoc Sci 16:369–373 Khlat M, Halabi S, Khudr A, Der Kaloustian VM (1986) Perception of consanguineous marriages and their genetic effects among a sample of couples from Beirut. Am J Med Genet 25:299–306 Kurban AK, Azar HA (1969) Familial continuous skin peeling. Br J Dermatol 81:191–195

13

Genetic Disorders in Lebanon

433

Kurdi-Haidar B, Mason PJ, Bereebi A, Ankra-Badu G, Al-Ali A, Oppenheim A, Luzzatto L (1990) Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet 47:1013–1019 Lacombe A, Lee H, Zahed L, Choucair M, Muller J-M, Nelson SF, Salameh W, Vilain E (2006) Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet 79:113–119 Lalouel JM, Loiselet J, Lefranc G, Chaiban D, Chakhachiro L, Rivat L, Rapartz C (1976) Genetic differentiation among Lebanese communities. Acta Anthropogenet 1:15–33 Laurier V, Stoetzel C, Muller J, Thibault C, Corbani S, Jalkh N, Salem N, Chouery E, Poch O, Licaire S, Danse JM, Amati-Bonneau P, Bonneau D, Me´garbane´ A, Mandel JL, Dolifus H (2006) Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism. Eur J Hum Genet 11:1195–1203 Lefe`vre C, Bouadjar B, Ferrand V, Tadini E, Me´gharbane´ A, Lathrop M, Prud’homme JF, Fischer J (2006) Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet 15:767–776 Lefranc G, Loiselet J, Rivat L, Ropartz C (1976) Gm, Km and ISf allotypes in the Lebanese population. Acta Anthropogenet 1:34–45 Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, Russell DW, Goldstein JL (1987): The Lebanese allele at the low density lipoprotein receptor locus. Nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem 262:401–410 Loiselet J, Jarjouhi L (1974) L’intole´rance au lactose chez l’adulte Libanais. J Med Liban 27:339–350 Loiselet J, Srouji G (1968): Re´partition de la cholineste´rase mutant parmi les communaute´s libanaises. Comparaison avec la re´partition d’autres ge`nes. Ann Genet 11:152–156 Loiselet J, Karayacouboglu J, Boustany N, Khouri R (1971) Les lipides sanguins chez un groupe de jeunes Libanais. J Med Liban 24:311–328 Magre´ J, Dele´pine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L, Sobel E, Papp J, Meier M, Me´garbane´ A, BSCL Working Group, Lathrop M, Capeau J (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370 Mahfouz RAR, Sabbagh AS, Zahed LF, Mahfoud ZR, Kalmoni RF, Otrock ZK, Taher AT, Zaatari GS (2006) Apolipoprotein E gene polymorphism and allele frequencies in the Lebanese population. Mol Biol Rep 33:145–149 Mahfouz RAR, Sabbagh AS, Shammaa DMR, Otrock ZK, Zaatari GS, Taher AT (2008) Factor XIII gene V34L mutation in the Lebanese population: Another unique feature in this community? Mol Biol Rep 35:375–378 Majdalani E, Vassoyan J (1974) A propos d’une observation de lymphohistiocytose familiale he´mophagique. Arch Fr Pediatr 31:297–302 Makhoul NJ, Wells RS, Kaspar H, Shbaklo H, Taher A, Chakar N, Zalloua PA (2005) Genetic heterogeneity of beta thalassemia in Lebanon reflects historic and recent population migration. Ann Hum Genet 69:55–66 Malouf J, Alam S, Kanj H, Mufarrij A, Der Kaloustian VM (1985a) Hypergonadotropic hypogonadism with congestive cardiomyopathy: an autosomal recessive disorder? Am J Med Genet 20:483–489 Malouf J, Ratl H, Der Kaloustian VM (1985b) Apical hypertrophic cardiomyopathy in a father and daughter. Am J Med Genet 22:75–80 Mamo JG, Tabbara KF (1976) Homocystinuria in Lebanon. J Med Liban 24:473–482 Mansour AM, Traboulsi EI, Khawwam E, Dudin GE, Der Kaloustian VM (1984) Eye findings in interstitial deletion of band q12 of chromosome 5. Ophthalmic Paediatr Genet 4:117–119 Mansour I, Delague V, Cazeneuve C, Dode´ C, Chouery E, P^echeur C, Medlej-Hashim M, Salem N, El Zein L, Levan-Petit I, Lefranc G, Goossens M, Delpech M, Amselem S, Loiselet J, Grateau E,

434

V.M. Der Kaloustian

Me´garbane´ A, Naman R (2001) Familial Mediterranean fever in Lebanon: mutation spectrum, evidence of cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694I mutations. Eur J Hum Genet 9:51–55 McLaren D, Zekian B (1971) Failure of enzymatic clearance of beta-carotene: the cause of vitamin A deficiency in a child. Am J Dis Child 121:278–280 Medlej R, Wasson J, Baz P, Azar S, Salti I, Loiselet J, Permutt A, Halaby G (2004) Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population. J Clin Endocrinol Metab 89:1656–1661 Medlej-Hashim M, Serre J-L, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G, Me´garbane´ A (2005) Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet 48:412–420 Me´garbane´ A (2007) Osseous dysplasia with severe short stature, multiple dislocations, and delayed bone age: report on a second Lebanese patient. Am J Med Genet 143A:1782–1787 Me´garbane´ A, Ghanem I (2004) A newly recognized chondrodysplasia with multiple dislocations. Am J Med Genet 130A:107–109 Me´garbane´ A, Ghanem I (2005) Severe autosomal dominant upper-limb mesomelic dysplasia: report of a second family. Clin Genet 68:567–569 Me´garbane´ A, Sayad R (2007) Early lethal autosomal recessive enterocolitis: report of a second family. Clin Genet 71:89–90 Me´garbane´ A, Noujeim Z, Fabre M, Der Kaloustian VM (1998) New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet 75:196–199 Me´garbane´ A, Delague V, Salem N, Loiselet J (1999a) Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family. Am J Med Genet 87:88–90 Me´garbane´ A, Haddad FA, Haddad-Zebouni S, Achram M, Eich G, Le Merrer M, Superti-Furga A (1999b) Homozygosity for a novel DTDST mutation in a child with a ‘broad bone-platyspondylic’ variant of diastrophic dysplasia. Clin Genet 56:71–76 Me´garbane´ A, Desguerres L, Rizkallah E, Delague V, Nabbut R, Barois A, Urtizberea A (2000) Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family. Am J Med Genet 92:117–121 Me´garbane´ A, Delague V, Ruchoux MM, Rizkallah E, Maurage CA, Viollet L, Rouaix-Emery N, Urtizberea A (2001a) New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family. Am J Med Genet 101:135–141 Me´garbane´ A, Ruchoux MM, Loeys B, Ayoub N, Nuytinck L (2001b) Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome. Am J Med Genet 104: 221–224 Me´garbane´ A, Waked N, Chouery E, Moglabey YB, Saliba N, Mornet E, Serre JL, Slim R (2001c) Microcephaly, cutis verticis gyrata of the scalp, retinitis pigmentosa, cataracts, sensorineural deafness, and mental retardation in two brothers. Am J Med Genet 98:244–249 Me´garbane´ A, Gannage´-Yared MH, Khalife´ AA, Fabre M (2003a) Primary hypergonadotropic hypogonadism, partial alopecia, and m€ ullerian hypoplasia: report of a second family with additional findings. Am J Med Genet 119A:214–217 Me´garbane´ A, Ghanem I, Le Merrer M (2003b) Spondyloepimetaphyseal dysplasia with multiple dislocations, leptodactylic type: report of a new patient and review of the literature. Am J Med Genet 122A:252–256 Me´garbane´ A, Rassi S, Chouery E, Delague V, de Nanclares P, Leal G, Tabet M, Castano L, Loiselet J (2003c) A new dominant branchiogenic-deafness syndrome with internal auditory canal hypoplasia and abnormal extremities. Am J Med Genet 120A:276–282 Me´garbane´ H, Haddad M, Delague V, Renoux J, Boehm N, Me´garbane´ A (2004) Further delineation of the odonto-onycho-dermal dysplasia syndrome. Am J Med Genet 129A:193–197

13

Genetic Disorders in Lebanon

435

Me´garbane´ A, Chouery E, Ghanem I (2008a) A multiplex family with possible metaphyseal Spahr-type dysplasia and exclusion of RMRP and COL10A1 as candidate genes. Am J Med Genet 146A:1865–1870 Me´garbane´ A, Dagher R, Melki I (2008b) Sib pair with previously unreported skeletal dysplasia. Am J Med Genet 146A:2916–2919 Me´garbane´ H, Cluzeau C, Bodemer C, Freitag S, Chalabi-Atallah M, Me´garbane´ A, Smahi A (2008c) Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet 146A:2657–2662 Me´garbane´ A, Slim R, N€ urnberg G, Ebermann I, N€ urnberg P, Bolz HJ (2009) A novel VPS13B mutation in two brothers with Cohen syndrome, cutis verticis gyrate and sensorineural deafness. Eur J Hum Genet 17(8):1076–1079 Mikaelian DO, Der Kaloustian VM, Shahin NA, Barsoumian VM (1970) Congenital ectodermal dysplasia with hearing loss. Arch Otolaryngol 92:85–89 Mikati MA, Melhem RE, Najjar SS (1981) The syndrome of hyperostosis and hyperphosphatemia. J Pediatr 99:900–904 Mikati MA, Dudin G, Der Kaloustian VM, Benson PF, Fensom AH (1982) Maple syrup urine disease with increased intracranial pressure. Am J Dis Child 136:642–643 Mikati MA, Barakat AY, Sulh HB, Der Kaloustian VM (1984) Renal tubular insufficiency, cholestatic jaundice, and multiple congenital anomalies – a new multisystem syndrome. Helvet Paediatr Acta 39:463–471 Mikati MA, Najjar SS, Sahli IF, Melhem RE, Mansour S, Der Kaloustian VM (1985) Microcephaly, hypergonadotrophic hypogonadism, short stature, and minor anomalies: a new syndrome. Am J Med Genet 22:599–608 Mishalany HG, Der Kaloustian VM (1971) Familial multiple level intestinal atresia: report of two siblings. J Pediatr 79:124–125 Mishalany HG, Najjar FB (1968) Famillial jejunal atresia. Three cases in one family. J Pediatr 73:753–755 Mishalany HG, Der Kaloustian VM, Ghandour MH (1970) Familial congenital duodenal atresia. Pediatrics 46:629–634 Mishalany HG, Idriss ZH, Der Kaloustian VM (1978) Pyloroduodenal atresia (diaphragm type): an autosomal recessive disease. Pediatrics 62:419–420 Mitchell GA, Brody LC, Looney J, Steel G, Suchanek M, Dowling C, Der Kaloustian V, Kaiser-Kupfer M, Valle D (1988) An initiator codon mutation in ornithine-d-aminotransferase causing gyrate atrophy. J Clin Invest 81:630–633 Mossman J, Patrick AD, Fensom AH, Tansley LR, Benson PF, Der Kaloustian VM, Dudin G (1981) Correct prenatal diagnosis of a Hurler fetus where amniotic fluid cell cultures were of maternal origin. Prenat Diagn 1:121–124 Mossman J, Young EP, Patrick AD, Fensom AH, Ellis M, Benson PF, Der Kaloustian VM (1983) Prenatal tests for Sanfilippo disease type B in four pregnancies. Prenat Diagn 3:347–350 Mudawwar F, Geha R (1975) Severe combined immunodeficiency in Lebanon. J Med Liban 28:467–476 Mumtaz G, Tamim H, Kanaan M, Khawaja M, Khogali M, Wakim G, Yunis K (2007) Effect of consanguinity on birth weight for gestational age in a developing country. Am J Epidemiol 165:742–752 Mustapha M, Chardenoux S, Nieder A, Salem N, Weissenbach J, El-Zir E, Loiselet J, Petit C (1998) A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36. Eur J Hum Genet 6:245–250 Mustapha M, Well D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, Loiselet J, Petit C (1999) An a-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet 8:409–412 Mustapha M, Salem N, Delague V, Chouery E, Ghassibeh M, Rai M, Loiselet J, Petit C, Me´garbane´ A (2001) Autosomal recessive non-syndromic hearing loss in the Lebanese

436

V.M. Der Kaloustian

population: prevalence of the 30delG mutation and report of two novel mutations in the connexion 26 (GJB2) gene. J Med Genet 38(10):E36 Nabulsi MM, Tamim H, Sabbagh M, Obeid MY, Yunis KA, Bitar FF (2003) Parental consanguinity and congenital heart malformations in a developing country. Am J Med Genet 116A:342–347 Naffah J (1973) Rubinstein–Taybi syndrome with ring E chromosome. Abstract, 4th International Conference on Birth Defects, Vienna Naffah J (1974) Dermatoglyphics and flexion creases in the Lebanese population. Am J Phys Anthropol 41:391–409 Naffah J (1976) The Dyggve–Melchior–Clausen syndrome. Am J Hum Genet 28:607–614 Naffah J, Der Kaloustian VM (1975): Un remaniement complexe inte´ressant les chromosomes 3 et 5 chez un enfant polymalforme´. Ann Ge´ne´t 18:121–124 Naffah J, Taleb N (1974) Deux nouveaux cas de syndrome Dyggve-Melchior-Clausen avec hyperplasie de l’apophyse odontoı¨de et compression spinale. Arch Fr Pe´diatr 31:985–992 Naffah J, Ghosn G, Gharios N (1972) A propos de trois nouveaux cas dans une meˆme fratrie du syndrome de Meckel ou dysence´phalie splanchnokystique de Gr€ uber. Arch Fr Pe´diatr 23:109–1081 Naffah J, Bitar E, Nasr W, Khoury K (1975) Etude ge´ne´tique de la polyse´rite paroxystique familiale – 72 cas. Nouv Presse Me´d 4:1031–1033 Najjar S (1963) Pendred’s syndrome in two families living in an endemic goiter area. Br Med J 5348:31–33 Najjar SS (1964) Hypothyroidism in children from an endemic goiter area. J Pediatr 64:372–380 Najjar SS, Jarrah A (1964) Pigmentation in Addison’s disease. Am J Dis Child 107:198–201 Najjar SS, Mahmud J (1968) Diabetes insipidus and diabetes mellitus. J Pediatr 73:251–253 Najjar SS, Nachman HS (1965) The Kocher-Debre´-Se´me´laigne syndrome:hypothyroidism with muscular “hypertrophy. J Pediatr 66:901–908 Najjar SS, Yunoszai K, Der Kaloustian VM (1963) Hypothyroidism in children. A review of 47 cases. J Med Liban 16:181–186 Najjar SS, Farah FS, Kurban AK (1968) Tumoral calcinosis and pseudoxanthoma elasticum. J Pediatr 72:243–247 Najjar SS, Der Kaloustian VM, Nassif SI (1970) Genital anomaly, mental retardation, and cardiomyopathy: a new syndrome? J Pediatr 83:286–288 Najjar SS, Takla RJ, Nassar VH (1974) The syndrome of rudimentary testes: occurrence in five siblings. J Pediatr 84:119–122 Najjar SS, Salem GM, Idriss ZH (1975) Congenital generalized lipodystrophy. Acta Paediatr Scand 64:273–279 Najjar SS, Der Kaloustian VM, Ardati KO (1984) Genital anomaly and cardiomyopathy: a new syndrome. Clin Genet 26:371–373 Najjar SS, Saikaly MG, Zaytoun GM, Abdelnoor A (1985) Association of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The Wolfram or DIDMOAD syndrome. Arch Dis Child 60:823–828 Neumann LM, El Ghouzzi V, Paupe V, Weber H-P, Fastnacht E, Leenen A, Lyding S, Klusmann A, Mayatepek E, Pelz J, Cormier-Daire V (2006) Dyggve–Melchior–Clausen syndrome and Smith–McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith–McCort dysplasia. Am J Med Genet 140A:421–426 Newton FH, Rosenberg RN, Lampert PW, O’Brien JS (1971) Neurological involvement in Urback–Wiethe’s disease (lipoid proteinosis): a clinical, ultrastructural, and chemical study. Neurology 21:1205–1213 Nezarati MM, Loeffler J, Yoon G, MacLaren L, Fung E, Snyder F, Utermann G, Graham GE (2002) Novel mutation in the D-sterol reductase gene in three Lebanese sibs with Smith–Lemli–Opitz (RSH) syndrome. Am J Med Genet 110:103–108 Oldenburg J, von Brederlow B, Fregin A, Rost S, Wolz W, Eberl W, Eber S, Lenz E, Schwaab R, Brackmann HH, Effenberger W, Harbrecht U, Schurgers LJ, Vermeer C, M€ uller CR (2000)

13

Genetic Disorders in Lebanon

437

Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb Haemost 84:937–941 Oppenheim A, Friedlander Y, Dann EJ, Berkman N, Pressman Schwartz S, Leitersdorf E (1991) Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at the low density lipoprotein receptor gene locus and by an additional independent major factor. Hum Genet 88:75–84 Parkman R, Rappeport J, Geha R, Belli J, Cassady R, Levey R, Nathan DG, Rosen FS (1978) Complete correction of the Wiskott–Aldrich syndrome by allogenic bone marrow transplantation. N Engl J Med 298:921–926 Paupe V, Gilbert T, Le Merrer M, Munnich A, Cormier-Daire V, El Ghouzzi V (2004) Recent advances in Dyggve–Melchior–Clausen syndrome. Mol Genet Metab 83:1–59 Paw BH, Moskowitz SM, Uhrhammer N, Wright N, Kaback MM, Neufeld EF (1990) Juvenile Gm2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the a-subunit of b-hexosaminidase. J Biol Chem 265:9452–9457 Pipkin AC, Pipkin SB (1950) A pedigree of generalized lentigo. J Hered 4:79–82 Pras E, Aksentijevitch I, Gruberg L, Below JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326(23):1509–1513 Qatanani M, Taher A, Koussa S, Naaman R, Fisher C, Rugless M, Old J, Zahed L (2000) b-thalassaemia intermedia in Lebanon. Eur J Haematol 64:237–244 Reimann HA, Moadie´ J, Semerjian S, Sahyoun PF (1954) Periodic peritonitis – heredity and pathology. Report of seventy-two cases. J Am Med Assoc 154:1254–1259 Rivie`re J-B, Verlaan DJ, Shekarabi M, Lafrenie`re RG, Be´nard M, Der Kaloustian VM, Shbaklo Z, Rouleau GA (2004) A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family. Ann Neurol 56:572–575 Ro¨ssler J, Breitenstein S, Havers W (2003) Late onset of Imerslund–Gr€asbeck syndrome without proteinuria in four children of one family from the Lebanon. Eur J Pediatr 162:808–809 Rutland J, de Longh RV (1990) Random ciliary orientation: a cause of respiratory tract disease. N Engl J Med 323:1681–1684 Saab YB, Gard PR, Overall AD (2007) The geographic distribution of the ACE II genotype: a novel finding. Genet Res 89:259–267 Sabbagh AS, Daher RT, Otrock ZK, Abdel Khalek RN, Zaatari GS, Mahfouz RA (2007a) ApoB-100 R3500Q mutation in the Lebanese population: prevalence and historical review of the literature. Mol Biol Rep 34:267–270 Sabbagh AS, Otrock ZK, Mahfoud ZR, Zaatari GS, Mahfouz RAR (2007b) Angiotensin-converting enzyme gene polymorphism and allele frequencies in the Lebanese population: prevalence and review of the literature. Mol Biol Rep 34:47–52 Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2007c) Gene frequencies of the HPA-1 platelet antigen alleles in the Lebanese population. Transfus Med 17:473–478 Sabbagh AS, Ghasham M, Abdel Khalek R, Greije L, Shammaa DMR, Zaatari GS, Mahfouz RA (2008a) MEFV gene mutations spectrum among Lebanese patients referred for Familial Mediterranean Fever work-up: experience of a major tertiary care center. Mol Biol Rep 35:447–451 Sabbagh AS, Mahfoud Z, Taher A, Zaatari G, Daher R, Mahfouz RA (2008b) High prevalence of MTHFR gene A1298C polymorphism in Lebanon. Genet Test 12:75–80 Salam M (1963) Phenylketonuria in a child from the Middle East. Am J Dis Child 105:102–103 Salam M, Idriss H (1964) Infantile amaurotic familial idiocy and gargoylism in siblings. Pediatrics 34:658–663 Salem GM, Salti IS, Abu Haydar FR (1972) Peutz–Jeghers syndrome: report of two cases from Lebanon associated with endocrine abnormalities. J Med Liban 25:475–480 Salem G, Najjar SS, Zeynoun ST, Farah FS (1973) Lipodystrophy. J Med Liban 26:259–267 Salti IS, Mufarrij IS (1981) Familial Cushing disease. Am J Med Genet 8:201–204 Salti IS, Salem Z (1979) Famillial hypogonadotropic hypogonadism with alopecia. Can Med Assoc J 121:428–430

438

V.M. Der Kaloustian

Salti I, Kattuah N, Alam S, Wehby V, Frayha R (1976) The effect of allopurinol on oxypurine excretion in xanthinuria. J Rheumatol 3:201–204 Samaha H, Rahal EA, Abou-Jaoude M, Younes M, Dacchache J, Hakime N (2003) HLA class II allele frequencies in the Lebanese population. Mol Immunol 39:1079–1081 Saouda M, Mansour A, Bou Moglabey Y, El Zir E, Mustapha M, Chaib H, Nehme´ A, Me´garbane´ A, Loiselet J, Petit C, Slim R (1998) The Usher syndrome in the Lebanese population and further refinements of the USH2A candidate region. Hum Genet 103:193–198 Schulze-Bahr E, Haverkamp W, Wedekind H, Rubie C, Ho¨rdt M, Borggrefe M, Assmann G, Breithardt G, Funke H (1997) Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous. Hum Genet 100:573–576 Schwabe AD, Peters RS (1974) Familial Mediterranean fever in Armenians: analysis of 100 cases. Medicine 53:453–462 Serre JL (1976) L’apport de l’e´tude des syste`mes HLA dans la description de la re´alite´ anthropobiologique des communaute´s libanaises. The`se de 3e`me cycle, Universite´ Paris VII Serre JL, Lefrance G, Loiselet J, Jacquard H (1979) HLA markers in six Lebanese religious subpopulations. Tissue Antigens 14:251–255 Shahid M, Abu Haydar N (1962) Sickle cell disease in Syria and Lebanon. Acta Haematol 27:268–273 Shahid MJ, Khouri FP, Ballas SK (1972) Fanconi’s anaemia: report of a patient with significant chromosomal abnormallities in bone marrow cells. J Med Genet 9:474–478 Shahid MJ, Khouri FP, Sahli IF (1974) Haemoglobin H disease and thalassaemia. J Med Genet 11:275–279 Shammaa DMR, Sabbagh AS, Taher AT, Zaatari GS, Mahfouz RAR (2008) Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population. Mol Biol Rep 35:453–457 Shammas HF, Tabbara KF, Der Kaloustian VM (1976) Atypical serum cholinesterase in a family with congenital distichiasis. J Med Genet 13:514–515 Shammas HF, Tabbara KF, Der Kaloustian VM (1979) Distichiasis of the lids and lymphedema of the lower extremities: a report of ten cases. J Pediatr Ophthalmol Strabismus 16:129–132 Shamseddine A, Taher A, Fakhani S, Zhang M, Scott R, Habbal MZ (2004) Novel mutation, L371V, causing multigenerational Gaucher disease in a Lebanese family. Am J Med Genet 125A:257–260 Shawaf S, Noureddin B, Khouri A, Traboulsi EI (1995) A family with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. Ophthalmic Genet 16:163–169 Shohat M, Bu X, Shohat T, Fischel-Ghodsian N, Magal N, Nakamura Y, Schwabe AD, Schlezinger M, Danon Y, Rotter J (1992) The gene for familial Mediterranean fever in both Armenian and non-Ashkenazi Jews is linked to the a-globin complex on 16p: evidence for locus homogeneity. Am J Hum Genet 51:1349–1354 Sille´n A, Anton-Lamprecht I, Braun-Quentin C, Kraus CS, Sayli BS, Ayuso C, Jagell S, K€ uster W, Wadelius C (1998) Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjo¨gren–Larsson syndrome. Hum Mutat 12:377–384 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 43:227–253 Solh HM, Azoury RS, Najjar SS (1983) Peutz–Jeghers syndrome associated with precocious puberty. J Pediatr 103:593–595 Soua Z, Ghanem N, Ben Salem M, Lefranc G, Lefranc M-P (1989) Frequencies of the human immunoglobulins IGHA2*M1 and IGHA2*M2 alleles corresponding to the A2m(1) and A2m (2) allotypes in the French, Lebanese. Tunisian and Black African populations. Nucleic Acids Res 17:3625 Souraty N, Noun P, Djambas-Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Me´garbane´ A (2007) Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis. Eur J Med Genet 50:188–199

13

Genetic Disorders in Lebanon

439

Soussou I, Der Kaloustian VM, Slim MS (1974) Familial imperforate anus: report of a family. Dis Colon Rectum 17:562–564 Spranger J, Maroteaux P, Der Kaloustian VM (1975) The Dyggve–Melchior–Clausen syndrome. Radiology 114:415–421 Stayoussef M, Benmansour J, Al-Jenaidi FA, Nemr R, Ali ME, Mahjoub T, Almawi WY (2009) Influence of common and specific HLA-DRB1/DQB1 haplotypes on genetic susceptibilities of three distinct Arab populations to type 1 diabetes. Clin Vaccine Immunol 16:136–138 Ste´phan E (1954) Bloc auriculo-ventriculaire chez trois membres d’une meˆme famille. Rev Med Moyen Orient 11:246–248 Ste´phan E (1974) Familial atrioventricular block. Letter to the editor. JAMA 228:697 Ste´phan E (1978) Hereditary bundle branch system defect. Survey of a family with 4 affected generations. Am Heart J 95:89–95 Ste´phan E, de Meeus A, Bouvagnet P (1997) Hereditary bundle branch defect: right bundle branch blocks of different causes have different morphologic characteristics. Am Heart J 133:249–256 Strahler JR, Rosenbloom BB, Hanash SM (1983) A silent, neutral substitution detected by reversephase high-performance liquid chromatography: hemoglobin Beirut. Science 221:860–862 Sulh HM, Steinmann B, Rao VH, Dudin G, Zeid JA, Slim M, Der Kaloustian VM (1984) EhlersDanlos syndrome type IV D: an autosoomal recessive disorder. Clin Genet 25:278–287 Tabbara KF, Khouri FP, Der Kaloustian VM (1973) Rieger’s syndrome with chromosomal anomaly. Can J Ophthalmol 8:488–491 Taher A, Khalil I, Shamseddine A, El-Ahdab F, Bazarbachi A (2001) High prevalence of factor V Leiden mutation among healthy individuals and patients with deep venous thrombosis in Lebanon: is the Eastern Mediterranean region the area of origin of this mutation? Thromb Haemost 86:723–724 Taleb N, Shahid M (1967) Les ane´mies me´diterrane´ennes (thalasse´mies). J Med Liban 20:127–139 Taleb N, Loiselet J, Ghorra F, Sfeir A (1964): Sur la de´ficience en glucose-6-phosphate de´shydroge´nase dans les populations autochtones du Liban. C R Acad Sci (Paris) 258:5749–5751 Taleb N, Loiselet J, Macaron C (1969) Aspects de la sicklane´mie au Liban. J Med Liban 22:551–558 Tamim H, Khogali M, Beydoun H, Melki I, Yunis K (2003) Consanguinity and apnea of prematurity. Am J Epidemiol 158:942–946 Tamouza R, Mansour I, Bouguacha N, Klayme S, Djouadi K, Laoussadi S, Azoury M, Dulphy N, Ramasawmy R, Krishnamoorthy R, Toubert A, Naman R, Charron D (2001) A new HLA-B*27 allele (B*2719) identified in a Lebanese patient affected with ankylosing spondylitis. Tissue Antigens 58:30–33 Teebi AS, Al-Awadi SA (1986) Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. J Med Genet 2:189–191 Thauvin-Robinet C, El Ghouzzi V, Chemaitilly W, Dagoneau N, Boute O, Viot G, Me´garbane´ A, Sefiani A, Munnich A, Le Merrer M, Cormier-Daire V (2002) Homozygosity mapping of a Dyggve–Melchior–Clausen syndrome gene to chromosome 18q21.1. J Med Genet 39: 714–717 Tomb R, Soutou B, Zalloua P (2009) Dysplasie ectodermique anhidrotique familiale: une mutation rare du ge`ne EDA1. Anhidrotic ectodermal dysplasia. Report of a rare mutation in EDA1. Ann Dermatol Ve´ne´re´ol 136:28–31 Traboulsi EI, Nasr AM, Fahd SD, Jabbour NM, Der Kaloustian VM (1984) Waardenburg’s recessive anophthalmia syndrome. Ophthalmic Paediatr Genet 4:13–18 Traboulsi EI, Azar DT, Jarudi N, Der Kaloustian VM (1985a) Ocular findings in the candidiasisendocrinopathy syndrome. Am J Ophthalmol 99:486–487 Traboulsi EI, el-Baba F, Barakat AY, Faris BM (1985b) The retinopathy of primary hyperoxaluria. Retina 5:151–153 Traboulsi EI, Faris BM, Der Kaloustian VM (1986a) Persistent hyperplastic primary vitreous and recessive oculo-dento-osseous dysplasia. Am J Med Genet 24:95–100

440

V.M. Der Kaloustian

Traboulsi EI, Jurdi-Nuwayhid F, Frangieh GT, Der Kaloustian VM (1986b) Retinoblastoma in Lebanon. Ophthalmic Paediatr Genet 7:29–34 Trioche P, Francoual J, Chalas J, Capel L, Bernard O, Labrune P (1999) Identification of three novel mutations (Q54P, W70X and T108I) in the glucose-6-phosphatase gene of patients with glycogen storage disease type Ia. Mutation in Brief #256. Online. Hum Mutat 14:91 Trop I, Kaplan F, Brown C, Mahuran D, Hechtman P (1992) A gly 250-to-asp substitution in the a-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a LebaneseCanadian family. Hum Mutat 1:35–39 Usanga EA, Ameen R (2000) Glucose-6-phosphate dehydrogenase deficiency in Kuwait, Syria, Egypt, Iran, Jordan and Lebanon. Hum Hered 50:158–161 Vincenti F, Hajjar ET, Salti IS (1973): Tumerous hyperparathyroidism in hypophosphatemic vitamin D-resistant rickets. J Med Liban 26:583–594 Vulliamy TJ, D’Urso M, Battistuzzi G, Estrada M, Foulkes NS, Martini G, Calabro V, Poggi V, Giordano R, Town M, Luzzatto L, Persico MG (1988) Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci USA 85:5171–5175 Wiles CR, Taylor TF, Sillence DO (1992) Congenital synspondylism. Am J Med Genet 42:288–95 Wynnes-Davies R, Hall C, Ansell BM (1982) Spondylo-epiphyseal dysplasia tarda with progressive arthropathy: a ‘new’ disorder of autosomal recessive inheritance. J Bone Joint Surg 64B:442–443 Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C (1999) A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 21:363–369 Yehya A, Souki R, Bitar F, Nemer G (2006) Differential duplication of an intronic region in the NFATC1 gene in patients with congenital heart disease. Genome 49:1092–1098 Yunis K, Ghina M, Bitar F, Chamseddine F, Kassar M, Rashkidi J, Ghaith M, Tamim H (2006) Consanguineous marriage and congenital heart defects: a case-control study in the neonatal period. Am J Med Genet 140A:1524–1530 Zaatari GS, Otrock ZK, Sabbagh AS, Mahfouz RAR (2006) Prevalence of factor V R2 (H1299R) polymorphism in the Lebanese population. Pathology 38:442–444 Zahed L, Bou-Dames J (1997) Acceptance of first-trimester prenatal diagnosis for the haemoglobinopathies in Lebanon. Prenat Diagn 17:423–428 Zahed L, Talhouk R, Saleh M, Abou-Jaoudeh R, Fisher C, Old J (1997) The spectrum of b-thalassemia mutations in the Lebanon. Hum Hered 47:241–249 Zahed L, Quatanani M, Nabulsi M, Taher A (2000) b-thalassemia mutations and haplotype analysis in Lebanon. Hemoglobin 24:269–276 Zahed L, Demont J, Bouhass R, Trabuchet G, H€anni C, Zalloua P, Perrin P (2002): Origin and history of the IVS-I-110 and codon 39 beta-thalassemia mutations in the Lebanese population. Hum Biol 74:837–84 Zahed L, Zahreddine H, Noureddine B, Rebeiz N, Shakar N, Zalloua P, Haddad F (2005) Molecular basis of oculocutaneous albinism type ! in Lebanese patients. J Hum Genet 50: 317–319 Zahed L, Pramparo T, Farra C, Mikati M, Zuffardi O (2007) A patient with duplication (7) (p22.1pter) characterized by array-CGH. Am J Med Genet 143A:168–171 Zalloua PA, Aoun E, Koussa S, Asfahani WS, Taher A (2003) The codons 8/9(+G) mutation found for the first time in the Lebanese population. Hemoglobin 27:1–5 Zalloua PA, Platt DE, El Sibai M, Khalife J, Makhoul N, Haber M, Xue Y, Izaabel H, Bosch E, Adams SM, Arroyo E, Lo´pez-Parra AM, Aler M, Picornell A, Ramon M, Jobling MA, Comas D, Bertranpetit J, Wells RS, Tyler-Smith C, and the Genographic Consortium (2008a) Identifying genetic traces of historical expansions: Phoenician footprints in the Mediterranean. Am J Hum Genet 83:633–642 Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE, Royyuru AK, Herrera RJ, Soria Hernanz DF, Blue-Smith J, Wells RS, Comas D, Bertranpetit J, Tyler-Smith C,

13

Genetic Disorders in Lebanon

441

Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE, Royyuru AK, Herrera RJ, Soria Hernanz DF, Blue-Smith J, Wells RS, Comas D, Bertranpetit J, Tyler-Smith C, and the Genographic Consortium (2008b) Y-chromosomal diversity in Lebanon is structured by recent historical events. Am J Hum Genet 82:873–882 Zaynoun ST, Kurban AK (1974) Lipoid proteinosis. J Med Liban 90:85–90 Zirbel GM, Ruttum MS, Post AC, Esterly NB (1995) Odonto-onycho-dermal dysplasia. Br J Dermatol 133:797–800

Chapter 14

Genetic Disorders in Libya Tawfeg Ben-Omran

The Country Libya is a Mediterranean North African country (Fig. 14.1). The country stretches along the northeast coast of Africa between Tunisia and Algeria on the west and Egypt on the east; to the south are Sudan, Chad, and Niger. Libya’s coastline is about 1,770 km with an estimated surface area of 1,775,500 km2. About 93% of the land is desert or semi-desert. Tripoli (the capital) is the country’s major city. For most of Libyan history, Libyans have been subjected to varying degrees of foreign control. In antiquity, the Phoenicians, Carthaginians, Greeks, Romans, Vandals, and Byzantines ruled all or parts of Libya. Although the Greeks and Romans left impressive ruins at Cyrene, Leptis Magna, and Sabratha, only little remains today to testify the presence of these ancient cultures. The Arabs conquered Libya in the seventh century A.D. In the following centuries, most of the people adopted Islam, the Arabic language, and the culture. The Ottoman Turks conquered the country in the sixteenth century. Libya remained part of their Empire until the Italian invasion in 1911, and after years of Libya’s resistance, incorporated Libya as its fourth coastal colony. In 1934, Italy adopted the name “Libya” (used by the Greeks for all of North Africa except Egypt) as the official name of the colony, which consisted of the provinces of Cyrenaica, Tripolitania, and Fezzan. Libya declared its independence on December 24, 1951; it was the first country to achieve independence through the United Nations as the Kingdom of Libya, and retained this status till September 1, 1969; since then it has been ruled by a Revolution Council led by the leader Muammar el-Qaddafi.

T. Ben-Omran Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation and Weill Cornell Medical College, Doha-Qatar e‐mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_14, # Springer-Verlag Berlin Heidelberg 2010

443

444

T. Ben-Omran

Fig. 14.1 Map of Libya

Libya’s economy still depends mainly upon exported crude oil. After the first major oil discovery in 1959, Libya had become one of the major oil-exporting countries resulting in rapid expansion in the economy. Libyans are generally affluent with the highest per capita income in Africa.

The Population Libya has a relatively small population. Ninety percent of the people live in less than 15% of the land, primarily along the cost. According to the census conducted in 1984, the total population of Libya is 3.7 million. However, due to an impressive decline in the mortality rate coupled with the continuation of a high birth rate, as well as the country’s strong economic performance in the late 1970s, fuelling an influx of contracting and services staff as well as expatriate professionals, there was a rapid increase in population. Recently, according to 2008 estimates, the total population of Libya was 6.18 million, with 39% of the population below the age of 15. More than half of the population is urban; most of them live in the coastal area in the main cities, namely Tripoli (2.4 million) and Benghazi (0.75 million). The estimated birth rate is 25.6 births per 1,000 populations (158,000 births per annum). Approximately 98.3% of all births are in health establishments. Infant mortality rate is 17.6 per 1,000 live births; under-five mortality is 20.1 per 1,000 population, with a growth rate of 1.83%. Life expectancy at birth is 72.5 years. Libyans are primarily a mixture of Arabs and Berbers. Small Tebou and Touareg tribal groups in southern part of Libya lead nomadic or semi-nomadic lives.

14

Genetic Disorders in Libya

445

Genetic Services Although Libya has made a considerable progress in the prevention and elimination of infectious diseases, genetic disorders remain a major health problem in the country. The burden of these disorders is largely underestimated by healthcare authorities; this is because of a lack of published studies. In addition, there is a lack of data for some of the most common genetic disorders as most available studies are hospital-based; hence the lack of well-designed epidemiological studies. The first Genetic Clinic in Libya was established in the main Children Hospital in Benghazi in 1982, along with a small diagnostic cytogenetic laboratory in histology department, at the Faculty of Medicine. Between 1982 and 1985, over 400 patients with various genetic disorders had been registered in this clinic. Currently, most patients with genetic disorders are seen by different pediatric subspecialties (mainly endocrinologists, neonatologists, and neurologists etc) in the main children hospitals (mainly in Tripoli and Benghazi). There are very limited diagnostic facilities for genetic and metabolic disorders. Most samples are currently sent to one of two laboratories in Germany and France.

Consanguinity It is estimated that 48.4% of marriages in Libya are consanguineous; 30% of the total marriages are between first cousins (Broadhead and Sehgal 1981). The Libyan population is characterized demographically by large family size (6.1 children) and high birth rates. The high rate of consanguineous marriages in Libya gives rise to an inbred population in particular isolated areas in the Green and Nafossa mountains, as well as oases in southern part of Libya with increased risk of autosomal recessive disorders. Polygamy is not uncommon in Libya however it is not advocated by Libyan law.

Genetic Disorders Reported from Libya In general, the magnitude of genetic disorders and birth defects in Libya is underestimated. In a study by Mir et al. (1992), congenital anomalies were present in 2.38% of all infants. A recent study by Singh and al-Sudani (2000) showed the incidence of major congenital anomalies (MCAs) to be 7.4 per 1,000 live births and 9.3 per 1,000 total births. The incidence of perinatal death in births with MCAs was 49.1% as against 2.7% for all births. Gahukamble et al. (2002) conducted a retrospective analysis of the records of newborns with gastrointestinal atresias over a 16-year period. This showed that more than 25% of patients with atresias had atresias that were genetically influenced. In addition, Gahukamble et al. (2003) reported an unusual occurrence of foregut atresias in two consecutive siblings and a pair of monozygous twins.

446

T. Ben-Omran

Chromosomal Disorders Down syndrome incidence in Libya was found to be 1:517 live births (Verma et al. 1990; Khan 1992). Cytogenetically, about 96% were regular trisomy 21. The relatively high incidence was attributed in part to late maternal age. The mean age was 35.62 years, and 82.0% of mothers were over 30 years. The existence of genetic factors predisposing to nondisjunction was not excluded as a contributing factor.

Disorders of the Central Nervous System (CNS) Benamer (2007) reviewed all publications related to the incidence and prevalence of neurological disorders including neurogenetic disorders in Libya (Table 14.1). This study highlighted that neurogenetic disorders are a common health problem and represented a significant portion of all neurological disease burden in the country (13% of the total estimated neurological cases: 1,566 cases). This can be attributed to the demographic structure of the Libyan population (similar to other many Arabic countries).

Neural Tube Defects (NTD) In a study by Kishan et al. (1985), a total of 48,974 births (live and still births) were studied (between 1982 and 1984) for Neural Tube Defects (NTD). There were 32 cases of anencephaly with an incidence of 0.65 per 1,000 live births. Associated Central Nervous System (CNS) malformations were observed in 12 cases (37.5%). There were 18 cases of spina bifida with an incidence of 0.36 per 1,000 live births.

Table 14.1 Reported neurogenetic disorders in Libya MIM # Disease/Syndrome 208900 Ataxia telangiectasia 123400 Creutzfeldt-Jakob disease 212895 Early onset cerebellar ataxia with retained tendon reflexes 229300 Friedreich’s ataxia 118200 Hereditary sensory and motor neuropathy 270685 Hereditary spastic paraplegia 182600 164500 Late onset cerebellar ataxia Motor neuron disease Muscular dystrophy 253300 Spinal muscular atrophy

Reference Sridharan et al. (1985) Radhakrishnan et al. (1988a, b) Sridharan et al. (1985) Sridharan et al. (1985) Radhakrishnan et al. (1988a, b) Sridharan et al. (1985) Sridharan et al. (1985) Radhakrishnan et al. (1986) Radhakrishnan et al. (1987) Radhakrishnan et al. (1988a, b)

14

Genetic Disorders in Libya

447

Hereditary Ataxias Sridharan et al. (1985) performed a study over a 2-year period between 1982 and 1984. He found 52 cases with various types of hereditary ataxias and paraplegia. Hereditary Spastic Paraplegia was diagnosed in 24 patients (12 males and 12 females) from 10 families. Autosomal recessive inheritance was found in 15 patients from 6 families (8 males and 7 females). Early Onset Cerebellar Ataxia with Retained Tendon Reflexes (MIM 212895) was diagnosed in 13 patients (6 males and 7 females) from 9 families. One family was diagnosed with Late Onset Cerebellar Ataxia with retinal pigmentary degeneration with autosomal dominant inheritance. Friedreich Ataxia (MIM 229300) was diagnosed in three patients. Ataxia Telangiectasia (MIM 208900) was diagnosed in one patient. This study showed the approximate prevalence of hereditary ataxia and paraplegia of 4.8/100,000 population.

Neuromuscular Disorders In a study (from 1983 to 1985) Radhakrishnan et al. (1987) found 34 cases with Duchenne muscular dystrophy (MIM 310200), 19 with limb girdle muscular dystrophy (MIM 253600), and 4 with facioscapulohumeral muscular dystrophy (MIM 158900). In addition, they found 41 cases with hereditary motor and sensory neuropathy (MIM 118200) and 3 cases with opthalmoplegia-plus (chronic progressive external opthalmoplegia and skeletal muscle involvement). The overall prevalence was estimated to be approximately 13.2/100,000 population. Richard et al. (2008) studied 23 families with congenital myasthenic syndrome originating from Libya, Tunisia, Algeria, and Morocco. Direct sequencing of the acetylcholine receptor epsilon subunit gene (CHRNE) was performed. The epsilon1293insG mutation was identified in 14 families (about 60% of the initial 23). This study concluded that epsilon1293insG mutation is likely to be derived from an ancient single founder mutation in the North African population.

Spinal Muscular Atrophy (SMA) (MIM 253300) Radhakrishnan et al. (1988a, b) reported 24 patients with Spinal Muscular Atrophy (SMA) (13 males and 11 females, age between 20 days and 45 years) among 519,000 subjects from a study carried over 4 years (1983–1986). There were 6 patients with infantile form with an incidence 1/12,500 live births/year, 12 with chronic childhood form (prevalence 2.3/100,000 population), and 6 with adultonset type (prevalence 1.2/100,000 population). The incidence is much lower than that in the Arabian Peninsula.

448

T. Ben-Omran

Hereditary Hematological Disorders Since ethnically Libyan population represents a mixture of African Negroes and South Mediterranean racial types, it is expected to find both sickle cell anemia and thalassemia in Libya. Jain (1983) studied 1,350 Libyan individuals visiting two University Hospitals in Benghazi (1978–1979) searching for hemoglobinopathies and Glucose-6-phosphate dehydrogenase deficiency (G6PD). G6PD was found in 147 individuals (10.8%), 16 were homozygous for beta-thalassemia (1.2%), 130 were heterozygous for betathalassemia (9.6%), homozygozity for sickle cell anemia in 5 individuals (0.36%), 61 with sickle cell trait (4.5%), and only 3 had sickle cell-thalassemia (0.2%).

Inborn Errors of Metabolism (IEM) and Lysosomal Storage Disorders The prevalence of this group of disorders in Libya is underestimated, partly due to the lack of a national neonatal screening program as well as the lack of clinical and diagnostic facilities for inborn errors of metabolism (IEM). In addition, most clinicians lack awareness of IEM especially in rural areas and there is no system for appropriate referrals or regular follow-up for this group of patients. There are some selective screening programs existing in Libya: for example, all infants of diabetic mothers are screened for congenital hypothyroidism, any infant with cataract would be screened for galactosemia, and all infants with positive family history of IEM are screened as well for similar diseases. From a recent study (unpublished data) to estimate the cost-effectiveness of establishing a neonatal screening program for phenylketonuria (PKU) in Libya, the estimated incidence of IEM in Libya is shown in Table 14.2. In a recent retrospective study by Eldeep et al. (2009). In this study 1503 (856 neonates and 647 children) patients were admitted to the pediatric intensive care unit Elkhadra Children Hospital in Tripoli. Inborn errors of metabolism account for Table 14.2 The estimated incidence of endocrine/IEM in Libya

MIM# 201910 230400 243500 251000

261600 606054 276700

Disorder Congenital hypothyroidism Congenital adrenal hyperplasia Galactosemia Glycogen storage disease Isovaleric acidemia Methylmalonic acidemia Mitochondrial disorders Nonketotic hypoglycemia Phenylketonuria Propionic acidemia Tyrosinemia Urea cycle defects

Estimated incidence 1:4,000 1:5,000 1:1,000 1:130,000 1:130,000 1:40,000 1:70,000 1:130,000 1:7,000 1:40,000 1:50,000 1:50,000

14

Genetic Disorders in Libya

449

3% of total admissions. The total number of deaths was 136 patients (71 neonates & 65 children). The main cause of death among all admissions was congenital anomalies (38%) followed by IEM (36%). Phenylketonuria (MIM 261600) Since newborn screening has not been established yet in Libya, most patients come to attention in late infancy or childhood because of developmental delay or frank mental retardation. Elrfifi et al. (unpublished data) reported 19 patients (7 males, 12 females) with classical PKU. Most cases were product of consanguineous marriage with 4 families have 2 affected children each. The mean age of diagnosis was 28 months (ranging from 7 months to 9 years). The mean phenylalanine level at diagnosis was 1200 mmol/L (ranging from 600–2400 mmol/L). All late treated patients presented with developmental delay, in addition to developmental delay 3 had eczema, 5 patients presented with athetotic movements in the upper limbs, only one female patient diagnosed at 9 years had convulsion. The authors concluded that quality of life and IQ can be improved in late diagnosed and treated patients with PKU who continue on phenylalanine-restricted diet. Tyrosinemia type I (MIM 276700) There are 14 cases with tyrosinemia type I (personal observation with Dr. Alobaidy), among whom 11 are doing well on NTBC treatment, three died. Lysosomal Storage Disorders There are 31 patients diagnosed with Gaucher disease. Between 1997 and 2006, seven patients were diagnosed from Benghazi (personal observation with Dr. Shembesh). Two mutations (L444P and N370S) were found. Another 11 patients with Gaucher disease (personal communication with Dr. Zarroug) diagnosed at Tripoli Medical Center (age ranges from 18 months to 17 years), including 2 young ladies (23 and 24 years of age). In addition to Gaucher disease, there are nine patients with MPS type 1 (three with Hurler and six with Hurler-Scheie) and one family with three children affected with MPS type II. All patients receiving enzyme replacement therapy are doing well. Fabry disease seems less commonly seen in Libya with only two patients diagnosed at Tripoli medical center (personal communication with Dr. Shebani) possibly an under-diagnosed condition.

Familial Hypercholesterolemia Sheriff et al. (1994) reported Libyan family with hypercholesterolemia and increased high-density lipoprotein cholesterol in Plasma. The family with 11

450

T. Ben-Omran

members, of which 9, including both parents, 5 sons, and 2 daughters, show a marked increase in high density lipoprotein (HDL) cholesterol alone with low plasma concentrations of triglycerides. They concluded that the marked increase in HDL cholesterol possibly linked to a decrease in heparin-releasable hepatic lipase activity.

Endocrine Disorders Congenital Hypothyroidism A recent study (unpublished data) showed an estimated incidence of congenital hypothyroidism of 1:4,000 (Table 14.2).

Insulin-dependent Diabetes Mellitus Kadiki and Roaeid (2002) studied the incidence of insulin-dependent diabetes mellitus (IDDM) in children up to14 years old in Benghazi (based on prospective registration of IDDM new cases for the period 1991–2000). A total of 276 (males 117 and females 159) new cases were ascertained with apparent female preponderance. The average annual incidence per year was 7.8/100,000 population. There was an increase in incidence rate over that reported for the period 1981–1990 (7.8 vs. 7.0). It was concluded from this study that IDDM is probably the commonest chronic disease of childhood in Libya.

Genodermatosis Xeroderma Pigmentosum (XP MIM 278720) Khatri et al. (1999) studied the clinical profile of 42 cases with Xeroderma Pigmentosum (XP) (23 girls and 19 boys from 29 families) between 1981 and 1994. Consanguinity was seen in 92.8% (39 of 42), and 57% (24 of 42) were first cousins. The incidence of XP was approximately 15–20 per million of the population as against the worldwide incidence of approximately 4 per million. This study concluded that XP has a relatively high incidence in Libya. Similar high incidence has also been reported in Egypt, Tunisia, and other Arab countries. It is characterized by high percentage of consanguinity in parents of the patients, female preponderance, early onset of initial manifestations, severe ocular and oral lesions in a high percentage of patients, and early death. The malignant skin tumors seen were squamous cell carcinoma in 23 patients, basal cell carcinoma in 17 patients, and basosquamous carcinoma in 2 patients.

14

Genetic Disorders in Libya

451

Lipoid proteinosis (MIM 247100) Lipoid proteinosis is an autosomal recessive disorder associated with variable scarring and infiltration of skin and mucosae. It is caused by loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Chan et al. (2003) reported a 10-year-old boy with lipoid proteinosis from a consanguineous family. Molecular studies showed a homozygous nonsense mutation (Q32X) in exon 2 of the ECM1gene. DNA analysis from the affected individual’s five siblings revealed that four were heterozygous carriers.

Congenital Sensorineural Deafness Lucotte (2007) studied the prevalence of carriers for 35delG mutation in the connexin 26 gene (MIM 121011) in seven populations from the Mediterranean area, including Libya, and compared the mutation in 17 other published populations in the same area. The study revealed a prevalence of the 35delG mutation is 1/41 in Libya. Otman and Abdelhamid (2005) reported a 36-year-old African man born in the Southern part of Libya with Waardenburg syndrome type 2 (MIM 247100). He presented with congenital deafness and white forelock, variable-sized hypopigmented, depigmented patches and hyperpigmented islands within the areas of hypomelanosis affecting the upper parts of the trunk, both arms and forearms. Shembesh et al. (1986) reported three Libyan children from one consanguineous family with the syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD, MIM 222300). Two children presented with diabetic ketoacidosis, while one was discovered during screening of the family.

Miscellaneous Disorders/Syndromes Other published disorders/syndromes or those through personal observation are included in Table 14.3.

Comments It is obvious from the available data that genetic and congenital disorders are common in Libya, in particular, recessively inherited disorders. This is attributed to several factors, similar in most Arab countries, including large family size, high maternal and paternal age, and high rate of consanguinity (nearly 30% of Libyan youth advocate consanguinity: from The Pan Arab Population and Family Health

452

T. Ben-Omran

Table 14.3 Other published disorders/syndromes, or through personal observation MIM # Disease/Syndrome Reference Autosomal recessive Ehlers Danlos syndrome (type I) Banerjee et al. (1988) 123400 Creutzfeldt-Jakob disease Radhakrishnan et al. (1988a, b) 225500 Ellis-van Creveld syndrome Personal observation 231070 Geroderma osteodysplastica Newman et al. (2008) 176670 Hutchinson-Gilford progeria syndrome Khalifa (1989) 249000 Meckel-Gruber syndrome Mehabresh (unpublished) 277700 Werner’s syndrome Radhakrishnan et al. (1991)

Project Report in 2008), in addition to the lack of public health preventive measures toward congenital and genetically determined disorders and inadequate genetic services and antenatal health care. There is discrepancy between the magnitudes of genetic and congenital disorders and the currently available genetic services if exist. Libyan healthcare system may use the available infrastructure in establishing different preventive measures, for example establishing a national neonatal screening program. It is recommended to establish specialized genetic and metabolic preventive services at least for now in the main pediatric hospitals in Tripoli Benghazi and Zawia as first step, in addition to implementing different strategies for the prevention of genetic and metabolic disorders within the primary healthcare system, some efforts being introduced privately in Musrata city (personal communication). Also, we emphasize on education through school health, mass media and educational campaigns to raise awareness of the public and decision makers toward introducing different preventive programs, similar to some Arab countries, which include: l

l

l

Premarital and preconception screening and counseling for common inherited disorders including hemoglobinopathies and common autosomal recessive conditions in the country Newborn screening for metabolic disorders and congenital hypothyroidism as well as for clinically detected conditions Prenatal screening for chromosome abnormalities, like Down syndrome, and congenital malformations such as NTD

References Banerjee G, Agarwal RK, Shembesh NM, Mauhoub Mansoor El (1988) Missed diagnosis, Ehlers Danlos syndrome – masquerading as primary muscle disease. Postgrad Med J 64:126–127 Benamer HT (2007) Neurological disorders in Libya: an overview. Neuroepidemiology 29:143–149 Broadhead RL, Sehgal KC (1981) Consanguinity and congenital abnormalities in East Libya. Garyounis Med J 4:3–5 Chan I, El-Zurghany A, Zendah B, Benghazil M, Oyama N, Hamada T, McGrath JA (2003) Molecular basis of lipoid proteinosis in a Libyan family. Clin Exp Dermatol 28:545–548

14

Genetic Disorders in Libya

453

Eldeep A, Benyones R, Dougman K, Esahli H (2009) A five years review of admission patterns and outcomes in a pediatric intensive care unit in Elkhadra hospital. Jamahiriya Medical Journal 9(3):205–209 Elrfifi K, Zeglam A, Ben-Omran T, Aboureyana F, Al-Hmadi S. Intelligence quotient (IQ) of late treated phenylketonuric patients: Is brain damage still preventable? (Unpublished) Gahukamble DB, Adnan AR, Al-Gadi M (2002) Atresias of the gastrointestinal tract in an inbred, previously unstudied population. Pediatr Surg Int 18:40–42 Gahukamble DB, Adnan AR, Al Gadi M (2003) Distal foregut atresias in consecutive siblings and twins in the same family. Pediatr Surg Int 19:288–292 Jain RC (1983) Abnormal haemoglobin, thalassaemia and G-6-PD deficiency in Libya. Br J Haematol 54:154–155 Kadiki OA, Roaeid RB (2002) Incidence of type 1 diabetes in children (0–14 years) in Benghazi Libya (1991–2000). Diabetes Metab 28:463–467 Khalifa MM (1989) Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin Genet 35:125–132 Khan MA (1992) Development outcome of Down’s syndrome in eastern Libya. Indian J Med Sci 46:268–274 Khatri ML, Bemghazil M, Shafi M, Machina A (1999) Xeroderma pigmentosum in Libya. Int J Dermatol 38:520–524 Kishan J, Soni AL, Elzouki AY, Mir NA (1985) Neural tube defects. Indian Pediatr 22:545–547 Lucotte G (2007) High prevalences of carriers of the 35delG mutation of connexin 26 in the Mediterranean area. Int J Pediatr Otorhinolaryngol 71:741–746 Mehabresh MI, Benseriti GA. Meckel-Gruber like syndrome with (Encephalocele, nephrocalcinosis congenital hearth disease-VSD and no polydactyly). Elfath children-hospital, BenghaziLibya Mir NA, Galczek WC, Soni A (1992) Easily identifiable congenital malformations in children: survey of incidence and pattern in 32, 332 live born neonates. Ann Saudi Med 12:366–371 Newman WG, Clayton-Smith J, Metcalfe K, Cole R, Tartaglia M, Brancati F, Morara S, Novelli A, Liu X, Siminovitch KA, Mundlos S, Tassabehji M, Black GC (2008) Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24. Am J Med Genet A 146A:3034–3037 Otman SG, Abdelhamid NI (2005) Waardenburg syndrome type 2 in an African patient. Indian J Dermatol Venereol Leprol 71:426–427 Radhakrishnan K, Mousa ME (1988) Creutzfeldt-Jakob disease in Benghazi, Libya. Neuroepidemiology 7:42–43 Radhakrishnan K, Ashok PP, Sridharan R, Mousa ME (1986) Descriptive epidemiology of motor neuron disease in Benghazi, Libya. Neuroepidemiology 5:47–54 Radhakrishnan K, el-Mangoush MA, Gerryo SE (1987) Descriptive epidemiology of selected neuromuscular disorders in Benghazi, Libya. Acta Neurol Scand 75:95–100 Radhakrishnan K, Thacker AK, Maloo JC (1988a) A clinical, epidemiological and genetic study of hereditary motor neuropathies in Benghazi, Libya. J Neurol 235:422–424 Radhakrishnan K, Thacker AK, Maloo JC, Gerryo SE, Mousa ME (1988b) Descriptive epidemiology of some rare neurological diseases in Benghazi, Libya. Neuroepidemiology 7:159–164 Radhakrishnan K, Maloo JC, Thacker AK, Mousa ME (1991) Werner’s syndrome: a Libyan family with nine affected members. Ann Saudi Med 11:712–715 Richard P, Gaudon K, Haddad H, Ammar AB, Genin E, Bauche´ S, Paturneau-Jouas M, M€ uller JS, Lochm€uller H, Grid D, Hamri A, Nouioua S, Tazir M, Mayer M, Desnuelle C, Barois A, Chabrol B, Pouget J, Koenig J, Gouider-Khouja N, Hentati F, Eymard B, Hantaı¨ D (2008) The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 9:1967–1972 Shembesh NM, Sehgal KC, el-Mauhoub M, Elzouki AA (1986) DIDMOAD syndrome in a Libyan family. Ann Trop Paediatr 6:47–50 Sheriff DS, El Fakhri M, Ghwarsha K (1994) Libyan family with hypercholesterolemia and increased high-density lipoprotein cholesterol in plasma. Clin Chem 40(12):2313–2316

454

T. Ben-Omran

Singh R, al-Sudani O (2000) Major congenital anomalies at birth in Benghazi, Libyan Arab Jamahiriya, 1995. East Mediterr Health J 6:65–75 Sridharan R, Radhakrishnan K, Ashok PP, Mousa ME (1985) Prevalence and pattern of spinocerebellar degenerations in northeastern Libya. Brain 108:831–843 Verma IC, Mathews AR, Faquih A, el-Zouki AA, Malik GR, Mohammed F (1990) Cytogenetic analysis of Down syndrome in Libya. Indian J Pediatr 57:245–248

Chapter 15

Genetic Disorders in Morocco Abdelaziz Sefiani

The Country and Population Morocco is a North African country with a population of nearly 35 million and an area about 710,000 km2. Morocco has international borders with Algeria in the East, the Mediterranean sea in the North, and Mauritania in the South. The Berbers were the earliest known inhabitants of Morocco; they have inhabited the country since the earliest recorded time. Through the centuries, Berbers have mixed with many other ethnic groups: the Phoenicians, Carthaginians, Romans (first century BC), Vandals (fifth century AD), Byzantines (sixth century), and finally the Arabs who began bringing their civilization in the seventh century. This admixture of populations grew richer by the African migration from the South. Contrary to many Arab countries, Morocco was not under the Ottoman rule. On religious grounds, Morocco is homogeneous Sunnite Muslim ethnic group (>99%) with a Jewish minority. In 1948, approximately 265,000 Jews lived in Morocco; most of them left the country for Palestine. The Jewish population is currently down to 4,000. The beginning of the twentieth century knew different migration waves of Moroccans toward countries of the North. Currently nearly three million Moroccans live outside the country, mainly in Europe. These populations benefit from the health and research structures of the host countries, allowing the identification of several hereditary diseases and gene mutations in patients from Moroccan origin.

A. Sefiani Department of Medical Genetics, National Institute of Heath/University Mohammed V Souissi, Rabat 27, Avenue Ibn Batouta, BP 769, 11400, Rabat, Morocco e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_15, # Springer-Verlag Berlin Heidelberg 2010

455

456

A. Sefiani

Genetic Services In Morocco, like other developing countries, malformations and genetic disorders are an important cause of morbidity and mortality, but the interest for genetic diseases is relatively recent. The Moroccan Health policy focused for many years on infectious diseases and malnutrition diseases. To date, a large number of genetic disorders were reported in the Moroccan population, in particular those which do not require high specialized biological investigations for their diagnosis. In the 1980s, molecular genetic data in some patients became available. For the majority of these diseases, the prevalence was not available. The first medical genetic centers were set up at the end of the 1990s and genetics was recognized as individualized medical specialty and new field medical practice in 1996. This chapter presents genetic diseases reported in Moroccan patients, for which, molecular data are available; most of them are indexed in the Moroccan Human Mutation Database at the address: http://www.sante.gov.ma/Departements/INH/MoHuMuDa

Consanguinity and Genetic Diseases in Morocco Morocco is one of the Mediterranean countries where consanguineous marriages are still frequent. It is an integral part of the cultural and social life. This contributes to morbidity and mortality of newborns and apparently increases prevalence of recessive genetic disorders and congenital malformations. The prevalence of consanguinity in Morocco reported to date varies in the range of 19.81–28.00% (Bouazzaoui 1994; Hami et al. 2006; Cherkaoui et al. 2006; Talbi et al. 2007). These studies were mainly limited to one region or reflect the activity of a specific medical center. A recent national study conducted by Jaouad et al. (2009) estimates the prevalence of consanguinity in Morocco to be 15.25% with a mean inbreeding coefficient of 0.0065. The rate of consanguineous marriage in 176 families reported in this study with autosomal recessive (AR) diseases was 59.09%.

Chromosomal Abnormalities The type and the frequency of the chromosomal anomalies in Morocco are not different from what is described elsewhere. According to a study carried out between 1993 and 2006 in the Department of Medical Genetics (DGM) of the Moroccan National Institute of Health, among the 3,778 cases studied for cytogenetics disorders, 1,133 (29.98%) had chromosomal abnormalities (unpublished data). The most common clinical reasons for performing cytogenetic investigations were suspected Down’s syndrome (23.66%), recurrent miscarriage (13.84%), short stature (7.49%), and dysmorphic features with developmental delay (7.38%). The frequency of Down’s syndrome in Moroccan population with abnormal

15

Genetic Disorders in Morocco

457

chromosomes is similar to that of other surveys. This could be attributed to its easy detection at the clinical level. Concerning structural chromosomal aberrations, translocation was the most common followed by deletion, marker chromosome, and ring chromosome in the order of frequency. Some balanced chromosomal anomalies discovered in Moroccan patients had a scientific interest. The translocation t(3;10)(p24;q32) reported in a large consanguineous Moroccan family was associated in homozygote state with recessive microcephaly, micropolygyria and corpus callosum agenesia. The breakpoint disturbs the EOMES gene, which leads to this new AR syndrome (Baala et al. 2007). A der(22;22)(q10;10q) was associated with an unexpected fertility in a Moroccan man which confirms that paternal uniparental disomy 22 has no clinical consequences (Ouldim et al. 2008).

Genetic Disorders in Morocco Neurosensorial Diseases Hearing Loss Nonsyndromic sensorineural hearing loss is mainly AR. Despite extensive genetic heterogeneity, the gene that encodes connexin 26, GJB2 (DFNB1) has been recognized to account for a large proportion of cases of nonsyndromic AR deafness. Like other Mediterranean populations, GJB2 35delG was found to be the most frequent mutation in Moroccan hearing-impaired children. This mutation was responsible for almost half of the hearing loss among Moroccan patients (Ratbi et al. 2007a). This finding underlines the advantages of a systematic search for this mutation among deaf children when environmental causes are considered irrelevant. The identification of this genetic anomaly signs the etiologic diagnosis of deafness, which allows a relevant genetic advice, and a better treatment of patients. Glaucoma Two AR mutations c.4339delG and p.Gly61Glu of CYP1B1, the gene encoding cytochrome P450 1B1, were reported by Belmouden et al. (2002) in Moroccan patients. Juvenile and adult primary glaucoma are characterized by autosomal dominant inheritance. Many loci are known. The mutation p.Thr377Met in myocilin gene (MYOC) was reported in one Moroccan patient by Melki et al. (2003). The phenotype associated with mutation in MYOC is highly variable even within the same kindred, ranging from normal through ocular hypertension to severe open angle glaucoma. The same author reported the homozygous mutation p.Met98Lys of OPTN in three families. Primary Open Angle Glaucoma secondary glaucomas arise as a consequence of disease or abnormality either elsewhere in the eye or in other systems: secondary

458

A. Sefiani

causes of childhood glaucoma: anterior segment disorders such as aniridia, neurofibromatosis type 1, Sturge-Weber syndrome. Secondary causes of juvenile and adult glaucoma such as: nail patella syndrome, Marfan syndrome, homocystinuria.

Retinitis Pigmentosa The mode of inheritance of Retinitis pigmentosa (RP) is determined by family history. RP can be inherited in an autosomal dominant, AR or X-linked manner. X-linked RP can be either recessive, affecting males only, or dominant, affecting both males and females; females are always more mildly affected. Some digenic and mitochondrial forms have also been described. At least 35 different genes or loci are known to cause nonsyndromic RP. Ebermann et al. (2007) found a homozygous mutation of MERTK gene in one Moroccan family. Therapy with vitamin A palmitate may slow retinal degeneration but is not recommended for those under age 18 years and should be routinely monitored in women of childbearing age because of potential teratogenic effects. Use of UV-A and UV-B blocking sunglasses is recommended. Diamox therapy may reduce cystoid macular edema. CPF 550 lenses may increase eye comfort by reducing glare and adaptation time from light to dark. Various other optical aids include magnifiers, closed-circuit television, and high-intensity, wide-beam flashlights.

Leber Congenital Amaurosis It is generally inherited as an AR trait but some autosomal dominant families have been described. There is genetic heterogeneity with more than nine genes identified. These genes are expressed preferentially in the retina or in the retinal pigment epithelium. Their putative functions are quite diverse and include retinal embryonic development (CRX), photo-receptor cell structure (CRB1), phototransduction (GUCY2D), protein trafficking (AIPL1, RPGRIP1), and vitamin A metabolism (RPE65). Mutations of many of these genes were reported in Moroccan population (see Table 15.1), in particular a recurrent mutation c.387delC (p.Asn129fsX165) of GUCY2D Aboussair et al. (2010).

Neuromuscular Diseases Dystrophinopathies Both X-linked recessive Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) diseases are caused by dystrophin deficiency in skeletal and heart muscles, leading to progressive necrosing lesions. The dystrophin gene is located in Xp21.2; it encodes several isoforms. The clinical diagnosis can be confirmed by

15

Genetic Disorders in Morocco

Table 15.1 Genetic diseases with gene mutations reported in Moroccan patients Disease Gene Achalasia Addisonianism Alacryma syndrome AAAS Analbuminenia ALB Apolipoprotein E APOE Arterial tortuosity syndrome SLC2A10 Ataxia with vitamin E deficiency Alpha-TTP gene Atrial-septal-defect with atrioventricular conduction NKX2-5 defects Autism Chromosomal aberration Bare lymphocyte type I TAP2 Bare lymphocyte type I SLC2A10 Bare lymphocyte type II, complementation group D RFXAP b-Thallassemia HBB Bloom syndrome DNA helicase RecQ Cataract congenital cerulean type 3 CRYGD Chanarin-Dorfman syndrome CGI-58 Charcot-Marie-tooth disease, axonal, type 2B RAB7 Charcot-Marie-tooth disease, axonal, type 2B1 LMNA Charcot-Marie-tooth disease, axonal, type 4C SH3TC2 Charcot-Marie-tooth disease type 4A GDAP1 Charcot-Marie-tooth disease type 4B2 SBF2 Charcot-Marie-tooth disease X-linked CX32 Colorectal adenomatous polyposis AR MYH Cone-rode dystrophy 3 ABCA4 Congenital adrenal hyperplasia, due to 21-hydroxylase CYP21A2 deficiency Congenital disorder of glycosylation type IIe COG7 Creutzfeld-Jakob disease PRNP Cystic fibrosis CFTR D-Bifunctional protein deficiency HSD17B4 Deafness, autosomal recessive 59 PJVK Deafness, neurosensory, autosomal recessive GJB2 Diabetes mellits type A insuline- resistance INSR Diamond-Blackfan anemia RPS19 DGS Di-Georges syndrome Dyggve-Melchior-Clausen syndrome Dymeclin Ectodermal dysplasia, anhidrotic EDAR Ectodermal dysplasia, anhidrotic AAAS Ectodermal dysplasia, anhidrotic EDARADD Epidermolysis pillosa with pyloric atresia ITGB4 Epilepsy, myoclonic, unverricht and lundborg CSTB Fabry disease GLA Facioscapulohumeral muscular dystrophy FSHMD1A Factor V deficiency F5 Factor XI deficiency F11 Familial hypercholesterolemia LDLR Familial hyperchilomicronemia LPL Familial mediterranean fever MEFV Fragile X mental retardation syndrome FMR1 Fructose 1-6 bipphosphatase deficiency FBP1 Furamase deficiency FH

459

OMIM 6¼ 231550 103600 107741 208050 277460 108900 209850 604571 208050 209920 141900 210900 608983 275630 600882 605588 601596 214400 604563 302800 608456 604116 201910 608779 123400 219700 261515 610220 220290 610549 105650 188400 223800 224900 231550 224900 226730 254800 301500 158900 227400 264900 144010 238600 249100 300624 229700 606812 (continued)

460 Table 15.1 (continued) Disease g-glutamylcysteine synthetase Deficiency, hemolytic anemia due to Glaucoma 1, open angle A Glaucoma 3, primary congenital A Glaucoma, primary open angle Goldberg-Shprintzen megacolon syndrome Goldberg-Shprintzen syndrome Growth hormone-releasing hormone receptor deficiency Hemochromatosis Hemophilia A Hereditary spastic paraplegia Huntington disease-like Hurler syndrome Ichthyosis lamellar type 2 Incontinencia pigmenti Infertility associated with multi-tailed spermatozoa and large heads Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Leber congenital amaurosis Lipodystrophy, congenital generalized, type 1 Lowe-oculo-cerebro-renal syndrome Lysinuric protein intolerance 3-M syndrome Malignant hyperthermia Mental retardation, X-linked Mental retardation, X-linked 3-Methylglutoconic aciduria type 1 Microcephaly polymicrogyria corpus collosum agenesis Mitochondrial DNA depletion syndrome Morquio syndrome A Mowat-Wilson syndrome Mucopolysaccharidosis type IIIC Multiple endocrine neoplasia type IIA Muscular dystrophy, Becker type Muscular dystrophy, congenital merosin-deficient Muscular dystrophy, Duchenne type Muscular dystrophy, limb-girdle type 2C LGMD2C Muscular dystrophy, limb-girdle type 2D LGMD2D Mycobacterium tuberculosis, susceptibility to infection by Nephrosis congenital, type 1 Neuropathy hereditary with spastic paraplegia Niemann-Pick disease type B Noonan syndrome Oculocutaneous albinism type 1 Ommen Otospondylomegaepiphyseal dysplasia Papillon-Lefevre syndrome

A. Sefiani

Gene GCLC

OMIM 6¼ 230450

MYOC CYP1B1 OPTN EDNRB KIAA1279 GHRHR HFE F8C SPG7 JPH3 IDUA ABCA12 NEMO AURKC

137750 231300 137760 235730 609367 139191 235200 306700 600584 606438 607014 601277 308300 243060

AIPL1 GUCY2D RPGRIP1 LCA6 RPE65 AGPAT2 OCRL SLC7A7 CUL7 RYR1 PQBP1 TM4SF2 AUH TBR2 RRM2B GALNS ZFHX1B HGNSAT RET Dystrophin LAMA2 Dystrophin SCGC SGCA IL12RB1

604393 204000 605446 604537 204100 608594 309000 222700 231520 145600 300463 300210 250950 604615 251880 253000 235730 252930 171400 300376 607855 310200 253700 608099 209950

NPHS1 Cct5 SMPD1 PTPN11 TYR RAG 1 COL11A2 CTSC

256300 256840 607616 163950 203100 603554 215150 245000 (continued)

15

Genetic Disorders in Morocco

Table 15.1 (continued) Disease Parkinson disease 8 Parkinson disease autosomal recessive juvenile Persistant Mullerian duct syndrome type I Phosphoglycerate deshydrogenase deficiency Polycystic kidney disease, autosomal recessive Prader-Willi syndrome Protease inhibitor 1 a-1 antitrypsin deficiency Retinitis pigmentosa Retinitis punctata albescens Retinal cone dystrophy Rett syndrome Schindler disease Short stature, idiopathic, autosomal Sjogren-Larsson syndrome Spastic paraplegia 7, autosomal recessive Spinal muscular atrophy type I Spinal muscular atrophy type II Spinal muscular atrophy type III Spinal muscular atrophy type IV Stickler syndrome, autosomal recessive Thiopurine S-methyl transferase Thromboembolism susceptibility due to factor V Leiden Ullrich congentital muscular dystrophy Usher syndrome type IB Vitamin D-dependent rickets type II Walker-Warburg syndrome Williams-Beuren syndrome Xeroderma-pigmentosum/cockayne syndrome complex Xeroderma-pigmentosum/cockayne syndrome complex

461

Gene LRRK2 PARK2 AMH PHGDH

OMIM 6¼ 607060 600116 261550 601815

FCYT SNRPN SERPINA1 MERTK RLBP1 KCNV2 MECP2 NAGA GHSR FALDH SPGT SMN1 SMN1 SMN1 SMN1 COL9A1 TPMT F5 COL6A3 Myosin VIIA VDR POMT2 ELN XPG XPC

263200 176270 107400 604705 136880 610356 312750 609241 604271 270200 607259 253300 253550 253400 271150 120210 187680 227400 254090 276900 277440 236670 194050 133530 278720

several methods. Creatine phosphokinase levels are 50–200-fold (DMD) or 10–35fold (BMD) above standard values. Muscular biopsy shows dystrophic features (necrotic and regenerative fibers). Immunohistochemical studies show a total absence of dystrophin (DMD) or altered quantity and/or quality (BMD). Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. In a previous study carried out by Sbiti et al. (2003b), the frequency of deletions in Moroccan DMD/BMD patients was about 51.3%. All these deletions were clustered in the two known hot-spots regions, and in 81% of cases were detected in the region from exon 43 to exon 52. These findings are comparable to those reported in other studies.

Limb-Girdle Muscular Dystrophy The mode of inheritance of limb-girdle muscular dystrophy (LGMD) is mainly AR. Elkerch et al. (2001) showed that nearly 50% of the Moroccan LGMD is due to the mutation del521T of SGCG gene (LGMD2C), with a maghrebin founder effect, as

462

A. Sefiani

has been previously shown in Tunisian and Algerian families. Few families have been reported with mutations of SGCA gene responsible of LGMD2D (personal unpublished data).

Congenital Muscular Dystrophy Approximately 50% of Congenital muscular dystrophy (CMD) is caused by complete merosin deficiency; diagnosis is made by detection of complete merosin deficiency on immunostaining of muscle biopsy and abnormal white matter signal on MRI after 4 months of age. Molecular genetic testing allows for genetic confirmation of some forms of CMD. The CMDs are inherited in an AR manner with the exception of Ullrich CMD, for which autosomal dominant inheritance have been reported. Allamand and Guicheney (2002) reported a homozygous mutation of LAMA2 in Moroccan patient with congenital merosin-deficient muscular dystrophy.

Facioscapulohumeral Muscular Dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is inherited in an autosomal dominant manner. Approximately 70–90% of individuals have inherited the disease-causing deletion from a parent, and approximately 10–30% of affected individuals have FSHD as the result of a de novo deletion. It is diagnosed by a molecular genetic test showing a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4. Molecular genetic testing detects about 95% of affected individuals. FSHD is probably relatively prevalent in Morocco, but up today only two large Moroccan families were reported with molecular abnormalities (personal unpublished data).

Spinal Muscular Atrophy The SMN1 (survival motor neuron 1) gene is the primary disease-causing gene. Approximately 95–98% of individuals with a clinical diagnosis of Spinal muscular atrophy (SMA) lack exon 7 of SMN1 gene. Approximately 2–5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1. Targeted mutation analysis is used to detect deletion of exon 7 of SMN1 by a PCR and artificial restriction site creation. In Moroccan population, a previous study conducted by Bouhouche et al. (2003) showed a high incidence of SMN1 gene deletion in adult-onset SMA Moroccan patients. Among 54 suspected SMA patients (types I–IV), all of Moroccan origin, Sbiti et al. (2003a) found the exon 7 of the SMN1 gene homozygously absent in 100% of type I, 90% of type II, 74% of type III and 80% of type IV SMA patients (Bouhouche et al. 2007a).

15

Genetic Disorders in Morocco

463

Sbiti et al. from the DGM at INH Rabat have used the SMA genetic test to investigate 50 patients with unknown etiology of congenital hypotonia. The deletion of SMN1 gene was found in 16 patients (32%) Unpublished data. Charcot-Marie-Tooth Disease Charcot-Marie-Tooth (CMT) with AR inheritance is a heterogeneous group of inherited motor and sensory neuropathies. Bouhouche et al. (2007b) reported a novel mutation 233C >T in the GDAP1 gene, that was associated with a common haplotype suggesting a Moroccan founder mutation. They reported also patients with CMT2B1 disease that had the mutation 298C > T in the LMNA gene (Bouhouche et al. 2007a). The GDAP1 gene has been associated with both demyelinating and axonal phenotypes; Azzedine et al. (2003) reported already described S194X and a novel R310Q mutation in this gene. X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary motor and sensory neuropathy caused by mutations in the connexin 32 gene (Cx32). Meggouh et al. (1998) reported the first de novo mutation 499delG of the Cx32 gene in a Moroccan patient. Hereditary Spastic Paraplegia Hereditary spastic paraplegia (HSP) may be transmitted in an autosomal dominant manner, an AR manner, or an X-linked recessive manner. At least 35 different genes/loci are associated with HSP. Molecular genetic testing is available on a clinical basis for some types of HSP. Elleuch et al. (2006) reported a dominant frameshift mutation of SPG7 in a Moroccan patient.

Hematological Diseases Haemoglobinopathies are a result of an abnormal structure of the hemoglobin molecule, affecting one of the globin chains. This group of disease is most common in African populations, the Mediterranean basin, and Southeast Asia. Among this group, thalassemia, which is probably the most common single gene disorder worldwide, has a high incidence in the Moroccan population, even though it has not been fully characterized in this country. Thalassemia Mutation/haplotype study of the gene encoding the hemoglobin subunit b (HBB) has been performed on the Moroccan population. Six major mutations were found: Cd 39 (C > T) c.118C > T, Cd 8 (-AA) c.-25_26delAA, IVSI-6T > C c.92+6T > C,

464

A. Sefiani

IVSI-1G > A c.92+1G > A, Cd 6 (-A) c.-20delA, -29(A > G) c.-79 A > G, accounting for 75% of the 86 independent chromosomes studied (Lemsaddek et al. 2003). These data are consistent with the geographical location of the country and historical links with both the Mediterranean and the Sub-Saharan Africa communities. Based on these results, a genetic testing of the HBB gene has been set up to detect the major Moroccan mutations, and it is useful for genetic counseling, presymptomatic diagnosis of at-risk family members and possibly prenatal diagnosis.

Sickle Cell Anemia The term sickle cell disease encompasses a group of symptomatic disorders associated with mutations in the HBB gene and defined by the presence of hemoglobin S (Hb S). The other forms of sickle cell disease result from co-inheritance of Hb S with other abnormal globin beta chain variants, the most common forms being sickle-hemoglobin C disease (Hb SC) and two types of sickle b-thalassemia (Hb S b+-thalassemia and Hb S b+-thalassemia). Other globin beta chain variants such as D-Punjab and O-Arab also result in sickle cell disease when co-inherited with Hb S. HBB sequence analysis may be used following mutation analysis if it is uninformative or as the primary test to detect mutations associated with b-thalassemia hemoglobin variants. Sicke cell anemia is frequent in Morocco but to date, molecular studies in the Moroccan population have only been done on a few cases.

Hemophilia Hemophilia A and B are clinically undistinguishable. The factor VIII gene located in chromosome Xq28, involved in Hemophilia A, shows in 45% of patients an inversion occurring in intron 22 responsible of the gene disruption. A study by Belmahi et al. (1997) showed that among 11 patients studied, 5 had the inversion of intron 22. The same author reported a study performed in 10 Moroccan families with 47 women at risk to be carriers (Belmahi et al. 2001). Among them 27 wished to know her statute and the study found that only 12 were carriers. Other mutations are predominantly point mutations with about 5% being large or small deletions and insertions. Approximately 2% of patients with severe phenotype of hemophilia A do not have a detectable mutation of factor VIII gene. Detection of women carriers of the mutation is essential for genetic counseling.

G6PD Deficiency This deficit is most prevalent in Africa (affecting up to 20% of the population), but is common also around the Mediterranean (4–30%). Even if G6PD deficiency seems frequent in Morocco, there is no recent data available for the real frequency of this disease or the gene mutations in the Moroccan patients.

15

Genetic Disorders in Morocco

465

Endocrine and Metabolic Diseases Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) is an AR disease. It has been revealed that the 21-OH gene (CYP21A2) and its non functional pseudogene (CYP21A1P) are located on chromosome 6 (6p21.3), sharing a high homology of about 98%. Most of the mutations causing 21-hydroxylase deficiency result from intergenic recombinations between CYP21A2 and closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for 5–10% of 21-hydroxylase deficiency alleles. Abid et al. (2008) reported that the mutation IVS2-13A/C > G of CYP21A2 gene was the most common mutation in Morocco and the p.I172N was associated with the simple virilizing form (Elleuch et al. 2006). The p.Q318X was the second most frequent mutation with a regional distribution: the mutation was especially detected (75%) in patients from the midland of Morocco (Fez). A novel p.L353R mutation was associated with the p.V281L mutation on the same chromosome in one patient at homozygous state.

Familial Hypercholesterolemia Familial hypercholesterolemia (FH) is caused by mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B gene (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. There is a heterogeneous mutational spectrum of FH in Morocco. El Messal et al. (2003) and Chater et al. (2006) identified in Moroccan patients four mutations previously described (C113R, D151, P664L, C690S), five new mutations (C25X, G266C, 313+5G > T, A480E, D558A) and two large specific deletions (FH Morocco-1 and FH Morocco-2) in the LDLR gene.

Mucopolysaccharidosis Alif et al. reported a recurrent mutation p.Pro533Arg of the gene IDUA in Moroccan patients with Mucopolysaccharidosis (MPS) I (Alif et al. 2000); this mutation, which is rare in Europeans, was identified in 92% of mutant alleles. The predominance of this mutation could permit the screening of healthy heterozygotes and genetic counseling for families of Moroccan descent. MPS IIIC is caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: a-glucosaminide Nacetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. The gene encoding this enzyme is HGSNAT. Recurrent mutation c.(318+1G > A;794C > A) in this gene, was found in three unrelated Moroccan patients and a Spanish patient (Hrebcek et al. 2006). Besides adding new data on the molecular spectrum of MPS IIIC, the

466

A. Sefiani

results obtained in this study will allow carrier detection and prenatal molecular diagnostics with great benefits for the Sanfilippo families. Furthermore, having detected that c.(318 + 1G > A;794C > A) is a recurrent mutation, alleles might be of great epidemiological relevance. As there is no known consanguinity among the patients studied here, c.(318 + 1G > A;794C > A) may represent a founder mutation in the context of the Moroccan population, which, if confirmed, should render the mutation a primary target in molecular studies of MPS IIIC in Morocco.

Dermatologic Diseases Xeroderma Pigmentosum Cells from individuals with Xeroderma pigmentosum (XP) with defective nucleotide excision repair are hypersensitive to killing by UV in comparison to normal cells. XP is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V). Mutations in XPA and XPC account for approximately 50% of XP. Sarasin et al. (2007) studied 32 XP patients mostly from North Africa, and found that XPC mutations were present in 28 probands. They identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 81% of XPC patients from North Africa. Haplotype analysis of the XPC gene demonstrated a common founder effect for this mutation in the Mediterranean region. XPC appears to be the major disease-causing gene concerning XP in Morocco. Since this unique XPC mutation is responsible for a huge proportion of XP cases, these data will help to set up a first simple XP molecular test, at least, in North Africa.

Hypohydrotic/Anhydrotic Ectodermal Dysplasia Kabbaj et al. (1998) studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an AR trait. Fourteen family members, both males and females, were affected and they all had a common ancestor. Linkage analysis by homozygosity mapping permits to find out that dominant and recessive HED are localized to the same chromosomal region which is 2q11-q13 (Kabbaj et al. 1998). The study of another large Moroccan family with autosomal dominant HED by Baala et al. (1999) mapped the disease gene to chromosome 1q42.2–q43, and identified a novel missense mutation in the death domain (DD) of EDARADD gene (c.335T4G, p.Leu112Arg) (Bal et al. 2007). The functional consequences of the dominant (p.Leu112Arg) mutation were studied knowing that EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). They demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation. These results

15

Genetic Disorders in Morocco

467

confirm that NF-kB activation is impaired in HED and support the role of EDARADD DD as a downstream effector of EDAR signaling.

Incontinentia Pigmenti The diagnosis of Incontinencia Pigmenti (IP) is based on clinical findings and molecular genetic testing of IKBKG (NEMO), the only gene known to be associated with IP. A deletion that removes exons 4 through 10 of IKBKG is present in about 80% of probands. Tnacheri Ouazzani et al. (2007) reported a case of deletion of gene NEMO in an infant girl aged 2 months who had typical skin lesions associated with severe impairment of her left eye.

Cancer Genetics Breast Cancer Several founder mutations are common in specific populations: 185delAG mutation of BRCA1 and 6174delT mutation of BRCA2 in Ashkenazi Jewish women. The 185delAG was reported in one Moroccan family suffering from breast cancer with no Jewish ancestries known (personal unpublished data). Most missense mutations in BRCA1/2 are of uncertain significance. Reference to websites such as the Breast Cancer Information Core (BIC) database may help with interpretation. Other autosomal dominant cancer-predisposing syndromes with an increased risk of breast cancer include: Peutz-Jeghers syndrome (gastrointestinal hamartomas, mucocutaneous pigmentation, and predisposition to gastrointestinal, breast and other cancers), Li-Fraumeni syndrome (soft tissue sarcomas, lung cancer and adreno-cortical carcinoma), Cowden syndrome (which is associated with macrocephaly, tricholemmomas, mucosal neuromas), ataxia telangiectasia (heterozygous carriers are at 3.6-fold risk of breast cancer).

Colorectal Cancer Until recently, familial adenomatous polyposis was considered to be solely due to autosomal dominant inheritance of germline mutations in the APC gene at 5q22.2. But there is emerging evidence that a significant proportion of attenuated FAP cases are due to AR inheritance of mutations in MUTYH (MYH), a DNA repair gene involved in the repair of oxidation damage, at 1p34.1. Early estimates are that, about 25% of those with >9 adenomas and no evidence of dominant family history are due to MUTYH mutations. Homozygous mutations p.Tyr165Cys of MYH and 1186_1187insGG were reported in Moroccan patients with attenuated polyposis.

468

A. Sefiani

Multiple Endocrine Neoplasia Type 2 This autosomal dominant cancer predisposition syndrome is characterized by the association of medullary thyroid cancer (MTC) and phaeochromocytoma. It is caused by activating germline mutations in the RET protooncogene. Multiple Endocrine Neoplasia Type 2 (MEN2) is subdivided into three subtypes, MEN2A, MEN2B, and familial MTC, all with a high risk of MTC arising in the C-cells of the thyroid. Ainahi et al. (2006) and Benazzouz et al. (2006) reported three MEN2 Moroccan families with the heterozygous mutation p.Cys634Tyr.

Familial Mediterranean Fever The Familial Mediterranean Fever is an autosomal recessive hereditary disease. The responsible gene MEFV is encoding the protein marenostrin or pyrin which play an essential role in the regulation of the inflammatory reactions. MEFV gene contains ten exons and most of the mutations have been found on the last exon. Up to date, 152 mutations and polymorpisms have been reported in, where V726A, M694V, M694I, M680I and E148Q are the most common mutations. Identification of MEFV gene mutations is an important step to have a firm diagnosis, to establish a genetic counseling, and to improve management and treatment of patients. Familial Mediterranean Fever (FMF) predominantly affects populations living in the Mediterranean region, with two common mutations: M694V and M694I. Belmahi et al. (2006) determined the mutational spectrum in Maghrebins patients with FMF; the most frequent MEFV mutations in this cohort were M694V and M694I. These mutations account for different proportions of the MEFV mutations in Algerian (5%, 80%), Moroccon (49%, 37%), and Tunisian (50%, 25%) patients. M694I mutation is specific to the Arab population from Maghreb. Other rare mutations were observed: M680L, M680I, A744S, V726A, and E148Q. We estimated the frequency of MEFV mutation carriers among the Arab Maghrebian population at around 1%, which is significantly lower than in non-Ashkenazi Jews, Armenians or Turks.

Cystic Fibrosis Over 1,500 CFTR sequence changes have been described, F508del being the most frequent mutation, along with geographic and ethnic variations in their distribution and frequency. Little is known about the spectrum and frequency of CFTR gene mutations in Moroccan patients; some data are available on cystic fibrosis (CF) in Moroccan patients living in Europe. Ratbi et al. (2008) carried out a preliminary study by screening healthy Moroccan individuals for 32 CFTR gene mutations. Two subjects were heterozygous for F508del and eight others for the (T)5 variant

15

Genetic Disorders in Morocco

469

(Ratbi et al. 2008). The prevalence of CF in Morocco would then range from 1/1,680 to 1/4,150 considering the effect of consanguinity for other mutations would further increase. The mutation 1811+1.6kbG > A was also reported in consanguineous Moroccan family (personal unpublished data). A Moroccan male having infertility by congenital bilateral absence of the vas deferens had CFTRdup11_13 in one allele and the (T)5 variant in the other one (Ratbi et al. 2007b). These findings indicate that the Moroccan population is at risk for CF and CFTR-related disorders.

Infertility Associated with Multi-tailed Spermatozoa and Large Heads One or more of abnormalities of sperm count, motility, or morphology is found in almost 90% of infertile males. An important proportion of the cases is believed to have a genetic component, yet few causal genes have been identified so far. A previous study by Dieterich et al. (2007), demonstrated that a homozygous mutation c.144delC in the Aurora Kinase C gene (AURKC) led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype observed in Moroccan patients. This founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. The absence of AURKC causes male infertility owing to the production of largeheaded multiflagellar polyploid spermatozoa. In another study, Dieterich et al. (2009), a carrier frequency of 1/50 was established on individuals from the Maghreb, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. Acknowledgments The author wishes to express his appreciation to Dr. Imane Cherkaoui Jaouad, Dr. Siham Chafaı¨ Elalaoui, Dr. Laila Rifai and Prof. Ilham Ratbi who have helped immeasurably in the preparation of this chapter.

References Abid F, Tardy V, Gaouzi A, El Hessni A, Morel Y, Chabraoui L (2008) CYP21A2 gene mutation analysis in Moroccan patients with classic form of 21-hydroxylase deficiency: high regional prevalence of p.Q318X mutation and identification of a novel p.L353R mutation. Clin Chem Lab Med 46(12):1707–1713 Aboussair N, Berahou A, Perrault I, Elalaoui SC, Megzari A, Rozet JM, Kaplan J, Sefiani A (2010) First North African observation of Leber congenital amaurosis secondary to CEP290 gene mutation. J Fr Ophtalmol (in press) Ainahi A, Kebbou M, Timinouni M, Benabdeljalil N, Fechtali T, Oufara S, El Antri S (2006) Study of the RET gene and his implication in thyroid cancer: Morocco case family. Indian J Cancer 43:122–126

470

A. Sefiani

Alif N, Hess K, Straczek J, Sebbar S, Belahsen Y, Mouane N, Abkari A, Nabet P, Gelot MA (2000) Mucopolysaccharidosis type I in Morocco: clinical features and genetic profile. Arch Pediatr 7 (6):597–604 Allamand V, Guicheney P (2002) Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet 10(2):91–94 Azzedine H, Ruberg M, Ente D, Gilardeau C, Pe´rie´ S, Wechsler B, Brice A, LeGuern E, Dubourg O (2003) Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord 13(4): 341–346 Baala L, Hagj Rabia S, Zlotogora J, Kabbaj K, Chhoul H, Munnich A, Lyonnet S, Sefiani A (1999) Both recessive and dominant forms of anhidrotic/hypohydrotic ectodermal dysplasia map to chromosome 2q11-13. Am J Hum Genet 64:651–653 Baala L, Briault S, Etchevers HC, Laumonnier F, Natiq A, Amiel J, Boddaert N, Picard C, Sbiti A, Asermouh A, Attie´-Bitach T, Encha-Razavi F, Munnich A, Sefiani A, Lyonnet S (2007) Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet 39(4):454–456 Bal E, Baala L, Cluzeau C, El Kerch F, Ouldim K, Hadj-Rabia S, Bodemer C, Munnich A, Courtois G, Sefiani A, Smahi A (2007) Autosomal dominant anhidrotic ectodermal dysplasia at the EDARRAD locus. Hum Mutat 28:703–709 Belmahi L, Viemont M, Benouachane T, M’seffer-Alaoui F, Delpech D, Sefiani A (1997) Recherche des inversions du ge`ne F8c dans l’he´mophilie A au Maroc: a` propos de 11 cas. Rev Mar Rhuma 8:64–70 Belmahi L, Benouchane T, Viemont M, Maani K, Hadj Khalifa H, M’Seffer Alaoui F, Delpech M, Sefiani A (2001) Sept. Carriers detection in hemophilia A, about 27 cases. Maroc Medical, tome 23, n 3 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode´ C (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329(2):71–74 Belmouden A, Melki R, Hamdani M, Zaghloul K, Amraoui A, Nadifi S, Akhayat O, Garchon HJ (2002) A novel frameshift founder mutation in the cytochrome P450 IBI (CY1BI) gene is associated with primary congenital glaucoma in Morocco. Clin Genet 62 (4):334–339 Benazzouz B, Chraı¨bi A, Doghmi Y, El Bacha S, Boutayeb S, Kadiri A, Hilal L (2006) Characterization of RET proto-oncogene C634Y mutation in a Moroccan family with multiple endocrine neoplasia type 2A. Ann Endocrinol 67:21–26 Bouazzaoui N (1994) Consanguinity and public health in Morocco. Bulletin de l’Acade´mie Nationale de Me´decine 178:1013–1025 Bouhouche A, Benomar A, Birouk N, Bouslam N, Ouazzani R, Yahyaoui M, Chkili T (2003) High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients. J Neurol 250(10):1209–1213 Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D, Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R, LeGuern E (2007a) Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families. Brain 130(Pt 4):1062–1075 Bouhouche A, Birouk N, Benomar A, Ouazzani R, Chkili T, Yahyaoui M (2007b) A novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families. Can J Neurol Sci 34(4):421–426 Chater R, Aı¨t Chihab K, Rabe`s JP, Varret M, Chabraoui L, El Jahiri Y, Adlouni A, Boileau C, Kettani A, El Messal M (2006) Mutational heterogeneity in low-density lipoprotein receptor gene related to familial hypercholesterolemia in Morocco. Clin Chim Acta 373 (1–2):62–69

15

Genetic Disorders in Morocco

471

Cherkaoui M, Baali A, Larrouy G, Sevin A, Boe¨tsch G (2006) Consanguinity, fertility of couples and mortality of children in the high Atlas population (commons of Anougal and Azgour, Marrakesh, Morroco). Int J Anthropol 20:199–206 Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M, Perrin J, Martinez D, Se`le B, Jouk PS, Ohlmann T, Rousseaux S, Lunardi J, Ray PF (2007) Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 39 (5):661–665 Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, Prisant N, Zoghmar A, Guichaoua MR, Koscinski I, Kharouf M, Noruzinia M, Nadifi S, Sefiani A, Lornage J, Zahi M, Viville S, Se`le B, Jouk PS, Jacob MC, Escalier D, Nikas Y, Hennebicq S, Lunardi J, Ray PF (2009) The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum Mol Genet 18(7):1301–1309 Ebermann I, Walger M, Scholl HP, Charbel Issa P, L€ uke C, N€ urnberg G, Lang-Roth R, Becker C, N€urnberg P, Bolz HJ (2007) Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction. Hum Mutat 28(6):571–577 El Messal M, Aı¨t Chihab K, Chater R, Vallve´ JC, Bennis F, Hafidi A, Ribalta J, Varret M, Loutfi M, Rabe`s JP, Kettani A, Boileau C, Masana L, Adlouni A (2003) Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene. J Hum Genet 48(4):199–203 Elkerch F, Sbiti A, Azibi K, Leturcqu F, Boudouma M, Kaplan JC, Sefiani A (2001) La gammasarcoglycanopathie par la mutation del521T au Maroc. a` propos de 20 cas. Rev Magh Pe´diat 11 (4):189–192 Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A (2006) Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia. Neurology 66(5):654–659 Hami H, Soulaymani A, Mokhtari A (2006) Endogamy, isonymy and consanguinity in the region of the Gharb-Chrarda-Be´ni Hssen (Morocco). Antropo Revista de Antropologia fisica 11:223–233. www.didac.ehu.es/antropo Hrebcek M, Mrazova L, Seyrantepe V, Durand S, Roslin NM, Noskova L et al (2006) Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C Syndrome). Am J Hum Genet 79:807–819 Jaouad IC, Elalaoui SC, Sbiti A, Elkerch F, Belmahi L, Sefiani A (2009) Consanguineous marriages in Morocco and the consequence for the incidence of autosomal recessive disorders. J Biosoc Sci 41(5):575–581 Kabbaj K, Baala L, Chhoul H, Sefiani A (1998) Autosomal recessive anhidrotic ectodermal dysplasia in a large Moroccan family. J Med Genet 35:1043–1044 Lemsaddek W, Picanco I, Seuanes F, Mahmal L, Benchekroun S, Khattab M, Nogueira P, Osorio-Almeida L (2003) Spectrum of Thalassemia mutations and HbF levels in the heterozygous Moroccan population. Am J Hematol 73:161–168 Meggouh F, Benomar A, Rouger H, Tardieu S, Birouk N, Tassin J, Barhoumi C, Yahyaoui M, Chkili T, Brice A, LeGuern E (1998) The first de novo mutation of the connexin 32 gene associated with X linked Charcot-Marie-Tooth disease. J Med Genet 35(3):251–252 Melki R, Idhajji A, Driouiche S, Hassani M, Boukabboucha A, Akhayat O, Garchon H, Belmouden A (2003) Mutational analysis of the Myocilin gene in patients with primary open-angle glaucoma in Morocco. Ophthalmic Genet 24(3):153–160 Ouldim K, Sbiti A, Natiq A, El-Kerch F, Cherkaoui S, Sefiani A (2008) Unexpected fertility and paternal UPD 22. Fertil Steril 90(5):2013.e13–2013.e15 Ratbi I, Hajji S, Ouldim K, Aboussair N, Feldmann D, Sefiani A (2007a) The mutation 35delG of the gene of the connexin 26 is a frequent cause of autosomal-recessive non-syndromic hearing loss in Morocco. Arch Pediatr 14(5):450–453 Ratbi I, Legendre M, Niel F, Martin J, Soufir JC, Izard V, Costes B, Costa C, Goossens M, Girodon E (2007b) Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod 22(5):1285–1291

472

A. Sefiani

Ratbi I, Ge´nin E, Legendre M, Le Floch A, Costa C, Cherkaoui-Deqqaqi S, Goossens M, Sefiani A, Girodon E (2008) Cystic fibrosis carrier frequency and estimated prevalence of the disease in Morocco. J Cyst Fibros 7(5):440–443 Sarasin A, Bourillon A, Bourrat E, Armier J, Pham D, Blanchet-Bardon C, Khadir K, Zghal M, Robert CC, Grandchamp B, Stary A, Benchikhi H, Soufir N (2007) Mutation avec effet fondateur dans le Xeroderma Pigmentosum du groupe C chez les malades d’Afrique du Nord: l’espoir d’un diagnostic pre´natal et pre´symptomatique simplifie´ (communication orale). Ann Dermatol Venereol 134:7S1–7S70 Sbiti A, Arazam A, Sefiani A (2003a) Le diagnostic mole´culaire des amyotrophies spinales infantiles et son inte´reˆt dans les hypotonies conge´nitales au Maroc: a` propos de 32 cas. Rev Maghr Pe´diatr 13:129–133 Sbiti A, El Kerch F, Sefiani A (2003b) Analysis of dystrophin gene deletions by multiplex PCR in Moroccan patients. J Biomed Biotechnol 2:158–160 Talbi J, Khadmaoui A, Soulaymani A, Chafik A (2007) Study of consanguinity in Moroccan population. Influence on the profile of health. Antropo Revista de Antropologia fisica 15:1–11. www.didac.ehu.es/antropo Tnacheri Ouazzani B, Guedira K, Dali H, Laghmari M, Ibrahimy W, Daoudi R, Sefiani A, Chakir M, Jiddane M, Mohcine Z (2007) Incontinentia pigmenti: a case study. J Fr Ophtalmol 30(8):e24

Chapter 16

Genetic Disorders in Oman Anna Rajab

The Country and Population Oman is situated in the southeast of the Arabian Peninsula along the east coast of the Persian Gulf and its territory being 309,500 km2. It has its borders with United Arab Emirates to the North, Saudi Arabia to the West and Yemen to the South West. After the accession of His Majesty Sultan Qaboos Bin Said in 1970, Oman opened the doors wide to the modern world. Since 1970, progress has been extremely rapid. Schools, roads, hospitals, electricity and telecommunications have been brought to the remotest regions. Main sources of Oman’s income are oil, gas, fisheries, agriculture, industry and tourism. The National census (2006) showed that the total population was 1,850,000. In general, the Omani population is characterized by a rapid rate of growth, large family size with an average of seven children per family. Oman was one of the fastest growing nations with natural population growth of 3.7% per year during 1980–1993. After a comprehensive birth-spacing campaign was started, the population growth dropped to less than 2% per year. Oman is generally considered a very young nation (See Population pyramid Fig. 16.1). There are eight main geographical areas in Oman referred to as “Manataq” which are further divided into districts referred as “Walayat” (see Fig. 16.2 Map of Oman).

Oman History The earliest archeological evidence of settlements in Oman dates back to about 12,000 BC, towards the end of the Ice Age. The tribes that took possession of Arabia in the beginning of the New Era were composed of two main stocks. One of these A. Rajab Consultant Clinical Geneticist, Genetic Unit, Ministry of Health, Sultanate of Oman e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_16, # Springer-Verlag Berlin Heidelberg 2010

473

474

A. Rajab 80 + 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 15-19 10-14 5-09 0-04 10%

8%

6%

4%

2%

00%

2%

Males

4%

6%

8%

10%

Females

Fig. 16.1 Population pyramid of Omani nationals (2007)

stocks was Kahtan (Bani Hina), who colonized the Yemen and moved up north into Oman territories after the collapse of the Mareb dam in Yemen in fifth century AD. The other was Adnan (Bani Ghafir, descended from Ismael) who occupied the northern part of Arabian Peninsula (Carter 1982). In history, Bani Hina and Bani Ghafir have been opponents and have been competing for the territories for pastures and watering places. Later on, more Arab tribes (Northern Arabs) came from Iraq and settled in the north of Oman. Oman’s sailors and merchants traded from one end of the monsoon to the other, from China to East Africa as far back as the eighth century AD and forged their ways in ancient times to the markets of India and the distant shores of China. For centuries, Muscat was an important place of trade with India, Red Sea and East Africa. As Oman lies on the cross-roads between the East and the West, mixing

16

Genetic Disorders in Oman

475

Fig. 16.2 Map of Oman

with populations from neighboring Asian and African countries occurred because of immigration, trade, introduction of slaves and mercenaries.

Medical and Genetic Services in Oman In the past 30 years, Oman has witnessed remarkable social and economic growth, which is best reflected in the well-organized and efficient health care system. There has been a significant decrease in the incidence of communicable diseases and in the mortality and morbidity rates of infants and children under 5 years (Fig. 16.3). In the past, the scale of the problem of congenital/genetic disorders was hidden in the high infant mortality because most affected infants died without being diagnosed. Now, the majority are diagnosed and provided with best possible management. As a result, the number of surviving affected children increases by the annual

476

A. Rajab 100 80 60 40

IMR U5 SBR

20 0 1980

1985

1990

1995

2000

2005

Fig. 16.3 Changes in infant mortality rates (IMR), mortality under 5 years (U5) and Stillbirth (SBR) at 5-year intervals observed during the past 25 years (1980–2005) from the Ministry of Health information system data

birth cohort causing a considerable burden on the health-care services (Alwan and Modell 1997). Conditions with high lethality in perinatal period may be underrepresented as well as conditions seen in specialized clinics such as deafness, blindness, dermatological, orthopedic, neurological, psychiatric and numerous genetic diseases presenting outside of pediatric age group. The Ministry of Health in Oman is wishing to promote the potential benefits of the genomic advances for the health of Omani population, considering the context of the added value of the genetic technology to health-care delivery and recognizing the urgent need for the application of genomics in the Sultanate of Oman. High level of consanguinity (Rajab and Patton 2000) and the presence of genetic isolates create favorable circumstances for genetic studies. Specialized National Genetic Health Center is under construction in the capital city of Muscat and is expected to open its doors in 2010. Emphasis in Oman is on community genetic services which combine the skills of community medicine and medical genetics. The community approach is an accepted policy in Oman, and the approach for an early identification and prevention of genetic disease is aimed to be applied for the population at risk. Genetic Services in Oman are in the process of being incorporated into Primary Health Care. Educational packages and advocacy sessions delivered regularly to increase population genetic literacy. The first Community Genetic service in Oman was established in 1999 as National Program for the control genetic blood disorders. It is an integrated strategy combining the best possible patient care as a first objective coupled with community education, high-risk population screening and genetic counseling. Clinical genetic services in Oman commenced from 1993, cytogenetic laboratory from year 2000 and molecular genetic services were established in 2007.

Genetic Disorders in Oman Hospital-based data on genetic disease was collected in Oman from 1990 and presented in Tables 16.3–16.12. The number of diagnosed condition was notably

16

Genetic Disorders in Oman

477

growing over years parallel to the improvement in diagnostic expertise and growth of diagnostic capacity. It is understood that, before comprehensive care became available, the illness and death of the children may have been attributed to other causes. As an example, limited access to detailed studies of various metabolic defects such as mitochondrial and glycosulation defects may be the cause of underdiagnosis and may not be a reflexion of disease rarity (Bappal et al. 2001).

Chromosomal Rearrangements Chromosomal rearrangements in 28.3% of 1,800 pediatric samples were studied in Cytogenetic Laboratory of Ministry of Health (Goud et al. 2005) with trisomies, tetrasomies and monosomies, translocations, autosomal aneploidies in the order of frequency. The birth prevalence of Down syndrome in Oman was 1:350 live births during 2000–2008 (Rajab et al. unpublished).

Single Gene Defects Autosomal Recessive Diseases Autosomal recessive conditions are by far the commonest and remain the major contributors to childhood morbidity, mortality and handicap (Tables 16.1–16.10). The complexity of dealing with autosomal recessive disorders is that it sums to a large number when a large variety of rare disorders are put together. The birth prevalence of various recessive disorders is largely unknown. The figures of recessive disorders frequently ascertained in pediatric practice derived from 1993–2002 hospital-based data presented in Table 16.1 (Rajab et al. 2005a, b). Some of the genetic conditions in Oman are confined to a common population group and reflect their ethnic and genetic diversity. It is evident from Fig. 16.4 that a number of autosomal recessive conditions could be placed on the map reflecting the places of residence of specific population groups.

Hemoglobinopathies Hemoglobin disorders represent highest population prevalence for single genes reflecting natural selection due to advantage for survival in heterozygous state against malaria. In Oman, the estimated birth prevalence of infants with hemoglobin disorders is 3.5–4.7/1,000 (Daar et al. 1998; Rajab and Patton 1997; Rajab and Patton 1999; White et al. 1993). Around 10% of Omani nationals are carriers of gene of sickle-cell anemia (OMIM 6039030), 2–3% carry the gene of b-thalassaemia (OMIM 141900) and 45% are carriers of a-thalassaemia (OMIM 141800).

478

A. Rajab Table 16.1 Commonly ascertained autosomal recessive diseases in Oman among 420,000 live births (1993–2002) Autosomal recessive diseases No of patients born 1993–2002 Spinal muscular atrophy (Wernig-Hoffman 56 disease) Congenital adrenal hyperplasia 55 Polycystic kidneys 34 Cystic fibrosis 32 Primary microcephaly 31 Renal tubular acidosis 28 Congenital nephrotic syndrome (Finish type) 25 Nesidoblastosis 24 Apple-peel bowel syndrome 21 Zellweger syndrome 19 Metachromatic leukodystrophy 18 Congenital generalized lipodystrophy 18 Ellis–Van creveld syndrome 18 Scwartz–Jampel syndrome 15 Bardet–Biedl syndrome 14 Robinow syndrome 12 Oculocutaneous albinism 14 Epidermolysis bullosa 15 Galactosialidosis 9 Cerebro-oculo-musculo-skeletal syndrome 9 Meckel-Gruber syndrome 9 Carbohydrate-deficient glycoprotein syndrome 8 Mucopolysacharidoses 8 Rajab et al. 2005a, Community Genet (8):27–30 Copyright permission from S. Karger AG, Basel 28.05.2005

the Sultanate of Observed incidence 1 in 10,000 birth 1 in 10,000 birth 1 in 12,000 birth 1 in 15,000 birth 1 in 15,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 20,000 birth 1 in 25,000 birth 1 in 25,000 birth 1 in 25,000 birth 1 in 30,000 birth 1 in 30,000 birth 1 in 35,000 birth 1 in 30,000 birth 1 in 30,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth 1 in 50,000 birth

Currently, about 400 patients with thalassaemia major and 3,000 affected with various sickle cell disorders reside in the Sultanate. The birth prevalence of hemoglobin disorders are presented in Table 16.2.

Inborn Errors of Metabolism Various groups of metabolic diseases were observed in hospital practice (Bappal et al. 2001; Joshi et al. 2002; Joshi and Venugopalan 2007).Metabolic endocrinipathies, disorders of aminoacids, organic acids and long-chain fatty acids, various lysosomal storage disorders and mitochondrial cytopathies, observed in hospital practice, are presented in Table 16.3.

Neurogenetic Disorders A number of handicapping genetic disorders observed included microcephalic syndromes, syndromes with brain structural anomalies, neuronal migration defects,

16

Genetic Disorders in Oman

479

RS = Robinow Syndrome CAH = Congenital Adrenal Hyperplasia CGL = Congenital Generalised Lipodystrophy CDGS = Carbohydrate-Deficient Glycoprotein Syndrome MGS = Meckel-Gruber Syndrome

EVC = Ellis Van Creveld Syndrome SC-J = Schwartz Jampel Syndrome GS = Galactosialidosis BBS = Bardet-Biedl Syndrome

Fig. 16.4 Geographical areas of oman representing high density of (90% of cases) autosomal recessive conditions. Rajab et al. 2005a, b Community Genet (8):27–30. Copyright permission from S. Karger AG, Basel 28.05.2005

Table 16.2 Birth prevalence of b-chain disorders in Oman (Rajab and Patton 1999) Region Total birth AS (%) No. AS b-thal No. Total % Total No. of 1989–1992 trait b-thal b-thal trait b-thal trait (%) trait and AS and AS Musandam 2,174 14.3 311 5.4 117 19.7 428 Dakhliya 22,107 14.3 3,161 3.3 730 17.6 3,891 North 15,076 13.3 2005 2.4 362 15.7 2,367 Sharqiya Dhahir 13,712 11.0 1,508 3.3 452 14.3 1,961 Capital 30,339 9.1 2,761 4.2 1,274 13.3 4,035 South Bathna 26,551 10.0 2,655 2.2 584 12.2 3,239 South 14,059 8.5 1,195 3.5 492 12 1,687 Sharqiya North Batna 37,347 5.6 2,091 4.5 1,681 10.1 3,772 Dhufar 12,053 0 0 0 0 0 0 Wustah 2,110 0 0 0 0 0 0 Total

175,538

8.9

15,688

3.2

5,692

12.2

21,380

480

A. Rajab

Table 16.3 Inborn errors of metabolism from hospital data Disorder OMIM Metabolic endocrinopathies Congenital adrenal hyperplasia 201910, 202110, 107910 Metabolic rickets 277440, 264700, 600785, 241520 Apparent mineralocorticoids excess 218030 Nesidioblastosis 256450 Maple syrup urine disease 248600 Tyrosinaemia 276700 Dihydropterin synthetase deficiency 261640 Homocystinuria 236200 Glutaric aciduria 231670, 231680 Organic acidurias Propionic 606054 Isovaleric 243500 Lysosomal storage disorders Mucopolysaccharidoses 607014, 607015, 252300 Multiple sulphatase deficiency 272200 Mucolipidosis I and II 256500 and 256550 Glycogen storage diseases 232200, 230800, 232400, 232300, 232700 Galactosialidosis 256540 GM1–Gangliosidodis 230500 Long-chain fatty acid oxidation defects Zellweger Syndrome 214100 Refsum disease 266500 Mitochondrial diseases Kearns-Sayre syndrome 530000 Congenital lactic acidosis Bappal et al. 2001 Pyruvate carboxylase deficiency 266150 pyruvate dehydrogenase deficiency 208800 Abnormality of fatty alcohol metabolism Sjogren–Larsen syndrome 270200

neurodegenerative diseases, seizure disorders and neuromuscular disorders (Table 16.4).

Osteodysplasias and Spondylodysplasias Various diseases of bone, skeletal dysplasias and chondrodysplasias from hospitalbased registry are presented in Table 16.5.

Diseases Affecting Kidneys, Liver and Gut Various types of cystic renal dysplasias, congenital nephropathies, renotubular disorders and disorders affecting liver and gut are presented in Table 16.6.

16

Genetic Disorders in Oman

481

Table 16.4 Genetic diseases with neurologic dysfunction, brain structural defects and neuromuscular disorders Disorder OMIM Nonsyndromic mental retardation 249500 Syndromes with mirocephaly Primary microcephaly 608716, 251200 Lethal microcephaly Rajab et al. 2007a, b Microcephaly with pontocerebellar hypoplasia Rajab et al. 2003 Cohen microcephaly 216550 Microcephalic Primordial Dwarfism 210710 Syndromes with brain malformations and poor outcome Walker–Warburg syndrome 236670 Pena–Shokeir syndrome 214150 Meckel–Gruber syndrome 249000 Fryns syndrome 220950 Jouber syndrome 213300 Conditions with regression/ neurologic deficit/seizures Baten’s disease 256730 Tay–Sach’s disease 272800 Niemann–Pick’s disease 257220 Leukodystriophies 251100, 254200, 264090 Progressive myoclonic epilepsy 310370 Hereditary spastic paraplegia 270800 Hyperekplexia 149400 Genetic form of cerebral palsy Rajab et al. 2006 Neuromuscular disorders Spinal muscular dystrophies 253300, 253400, 253900 Congenital myopathies 255310, 161100, 601462 Charcot–Marie–Tooth neuropathy 214400 Facioscapulohumeral dystrophy 158900 Limb girdle muscular dystrophies 608099, 160500, 253601

Table 16.5 Skeletal dysplasias and diseases affecting bone structure Condition Asphyxiating thoracic dystrophy EllisVan–Creveld syndrome Hypochondrogenesis Grebe chondrodysplasia Robinow syndrome Spondyloepiphyseal dysplasia Omani type 3-M dwarfism (Dolichospondylic Dysplasia) Osteogenesis Imperfecta Pycnodysostosis Bamatter syndrome Osteopetrosis

OMIM 208500 225500 200610 200700 268310 608637 273750 610195 265800 231070 259700

Immunodeficiencies and Chromosomal Instability Syndromes Various syndromes with defects of immune system and DNA repair observed in Oman are presented in Table 16.7.

482

A. Rajab Table 16.6 Disease affecting kidneys, liver and gut Apple-peel bowel syndrome Infantile polycistic kidneys Focal segmental glomerulosclerosis Finish type congenital nephrosis Steroid-resistant nephrotic syndrome Nephronophtysis Cystinosis Hyperoxaluria Distal renal tubular acidosis Bartter syndrome Familiar intrahepatic cholestasis Crigler-Najjar syndrome type I Wilson disease

243600 263200 603278 256300 600995 256100, 602088 219800 259900 602722 607364 211600 218800 277900

Table 16.7 Diseases with impaired immunity and increased chromosomal fragility Immunodeficiencies and chromosomal instability OMIM Ataxia-telangiectasia 208900 Bloom syndrome 210900 Chronic granulomatous disease 233700 Common variable immunodeficiency 240500 Cyclic neutropenia 610738 Hemophagocytic lymphohistiocytosis type 1 267700 Fanconi anemia 227650 Nijmegen syndrome 251260 SCID 102700 Xeroderma pigmentosusm 278700

Table 16.8 Dematological diseases Dematological disorders Epidermolysis bullosa Hypohydrotic ectodermal dysplasia Lamellar ichthyosis Ichthyosis congenita

OMIM 226700, 226670 224900 242300 242500

Genodermatoses Common dermatological conditions observed in Oman are presented in Table 16.8.

Diseases Affecting Vision and Hearing Diseases associated with visual and hearing deficit represented in Table 16.9.

16

Genetic Disorders in Oman Table 16.9 Congenital blindness and deafness Congenital blindness and deafness Optic atrophy Congenital nonsyndromic sensoryneural deafness (Simsek et al. 2001) Leber congenital amaurosis Usher syndrome

483

OMIM 258500 220290 204000 276900

Miscellaneous Recessive Disorders Table 16.10 Table 16.10 Various autosomal recessive diseases from hospital records Autosomal recessive disorders OMIM Bardet–Biedl syndrome 209900 Congenital insensitivity to pain with anhydrosis 256800 Congenital generalized lipodystrophy 269700, 608594, 608154 Cutis laxa with growth and developmental delay 219200 Escobar syndrome 265000 Long Q-T syndrome 152427 Neonatal progeroid syndrome 271900 Oculocutaneous albinism 606952 Schwartz–Jampel syndrome 255800

Autosomal Dominant Conditions Table 16.11 Table 16.11 Autosomal dominant disorders Disorder Achondroplasia Adult polycystic kidney disease Allagille syndrome Craniosynostoses, acrocephalosyndactily Deafness congenital nonsyndromic Epidermolysis bullosa simplex Fanconi renotubular syndrome Hereditary angioedema Huntington’s chorea Hyper-IgE syndrome Neurofibromatosis Sotos syndrome Spinocerebellar ataxia Tuberous Sclerosis

OMIM 100800 601313 118450 101400 600965 131800 134600 106100 143100 147060 162200 117550 117360 191100

484

A. Rajab Table 16.12 X-linked conditions observed in Oman Disorder Anhydrotic ectodermal dysplasia Alport syndrome Bruton agammaglobulinaemia Hemophilia A Hemophilia B Duchenne muscular dystrophy Lissencephaly (LIS 4A) OTC deficiency Testicular feminization Syndrome X-linked forms of mental retardation

OMIM 305100 301050 300300 306700 306900 310200 300121 311250 300068 300624, 312750, 301040

X-Linked Conditions The commonest X-linked condition in Oman is G6PD deficiency found in 28% of males and 12% females (Daar and Pathare 2006). In a majority of Omanies, G6PD deficiency is benign (Daar et al. 1996; White et al. 1993) which suggest that asymptomatic forms A+ and B+ G6PD types predominate. Neonatal jaundice and hemolytic crises are seen in a small proportion of patients, mainly in Northern parts of Oman (Table 16.12).

Novel Phenotypes and Variants, and Novel Genotypes Two novel forms of lipodystrophy have been described in Omani families. The fist was a novel phenotype of congenital generalized lipodystrophy with effect on both, skeletal and nonskeletal muscle with the locus mapped to 9q (Rajab et al. 2002; Heathcote et al. 2002). Apart from generalized Lipodystrophy, there were reduced exercise tolerance, percussion myotonia and nonskeletal muscle hyperthrophy, such as hypertrophic pyloric stenosis, prominent veins (phlebomegaly), hyperthrophy of urethers, tonque, esophagus and myocardium (Rajab et al. 2010). The second novel form of Congenital Generalized Lipodystrophy with deafness was described in three Omani children with low birth weight, short stature, retarded bone age, tendency to fractures, striated metaphyses, sensorineural deafness and delayed cognitive development (Rajab et al. 2003). The recognized features of Bernadinelli-Seip lipodystrophy such as abnormalities of lipids and insulin, hepatosplenomegaly, acanthosis and hirsutism were not found. Microcephaly, a lethal form of prenatal onset was described in four siblings in an Omani family (Rajab et al. 2007a). Gene found in Amish families with lethal microcephaly was excluded. Low birth-weight, disproportionately small head, fetal distress, apnoea, seizures and facial features reminiscent of Amish microcephaly were noted. Brain imaging revealed a simplified gyral pattern with normal to

16

Genetic Disorders in Oman

485

slightly thinned cortical gray matter, thin corpus callosum, mild brainstem and cerebellar hypoplasia. All patients died within hours to weeks after birth following severe apnoea attacks and central hypoventilation. A new form of Escobar variant with pursed mouth, creased tongue, ophthalmologic features and scoliosis was described in children from Oman and was found to be acetylcholine receptor pathway mutations explaining various fetal akinesia deformation sequence disorder (Rajab et al. 2005b, Michalk et al. 2008). Another phenotype of arthrogryposis type Escobar from Oman presenting at birth with severe contractures are found to be prenatal myasthenia caused by disruption of the acetylcholine receptor fetal subunit (Hoffmann et al. 2006). An autosomal recessive form of spastic cerebral palsy with wicrocephaly and mental retardation have been reported in two interrelated sibships presenting with mental retardation and spasticity. The phenotypic features were resembling such of cerebral palsy following birth asphyxia with no history of birth asphyxia in any of the patients (Rajab et al. 2006).Genetic study is underway for suggestive linkage to the locus of hereditary spastic paraplegia. Extensive Brain Calcifications in two interrelated Omani families were described in eight children manifesting autosomal recessive genetic disorder (Rajab et al. 2009). Brain imaging revealed extensive scattered calcifications of basal ganglia and cortex, similar to Aicardi–Goutieres Syndrome (AGS) or “Coats’ Plus” syndrome. However, the clinical features in the present families diverge substantially from these two syndromes. Growth delay, mild developmental delay and poor school performance were present in all the affected individuals, but progressive deterioration of neurological function was not apparent, nor were there significant cortical white matter disease or retinopathy. Genome-wide linkage and fine-mapping analyses indicate a genetic locus for this disorder on Chromosome 2 with a LOD score of 6.17. In all, the Chromosome 2 locus is novel and the clinical presentation displays features distinguishing the disorder from either Coats’ or AGS, making this a new variant or possibly a new disorder of inherited brain calcification. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11–21 was described in three siblings with postnatal microcephaly, mental retardation, optic atrophy, seizures, spasticity and growth failure. A simplified frontal gyral pattern with cerebellar hypoplasia, corpus callosum and midbrain hypoplasia was found on MRI scan (Rajab et al. 2003). A novel type of spondyloepiphyseal dysplasia was described in nine individuals from two consanguineous sibships (OMIM 608637) missence mutation in C6ST-1 gene R304Q (Rajab et al. 2004; Tiele et al. 2004). The clinical features include near to normal length at birth, short stature with final height of 110–130 cm, severe shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia and normal intelligence osteoarthropathy and spinal involvement resulted in physical handicap in early adulthood, and female patients were disabled earlier than males. Comparison of these patients with other skeletal dysplasias suggests that they represent a previously undescribed variant of spondyloepiphyseal dysplasia.

486

A. Rajab

Positional cloning and a gene of Autosomal Recessive Robinow syndrome were first discovered in a study of Omani patients (Afzal et al. 2000a, b). It is allelic to dominant brachydactily type B, and caused by mutation of ROR2. Scwartz–Jampel Syndrome (chondrodystrophic myotonia) in an Omani family with three affected created a base for genetic study with identification of SJS locus to chromosome 1p36 and the discovery of perlecan, the major proteoglycan of basement membranes being altered in patients with Schwartz–Jampel syndrome (Nicole et al. 1995, 2000). Geroderma osteodysplastica patients from Oman (OMIM 231070) were described. Subsequent analysis of SCYL1BP1 in three Omani GO patients from families reported by Rajab et al. (2008) identified homozygosity for a 2-bp deletion in exon 1 of the SCYL1BP1 gene, affecting the deduced methionine start codon (Hennies et al. 2008). Protein blot analysis of fibroblast lysate from the Omani patient revealed complete absence of SCYL1BP1, indicating a loss-of-function effect. Wrinkly skin syndrome (autosomal recessive cutis laxa) multicenter study included patients from Oman (Rajab et al. 2008). Impaired glycosylation caused by mutations in the vesicular H+ATPase subunit ATP6V0A2 was detected in Omani families. (Kornak et al. 2008). Cohen syndrome is a disorder described in Finland characterized by microcephaly, mental retardation, unique facial features, neutropenia and ophthalmologic findings. A novel mutations of the COH1 gene in an Omani familywere found (Hennies et al. 2004; Mochida et al. 2004), providing the evidence that COH1 is responsible for Cohen syndrome in a wide geographic distribution. Hemophagocytic Lymphohistiocytosis type 1 studies in Oman were performed in Sultan Qabus University. Mutations in FHL1 gene (Del 9q 21.5-22; Pro 89!Thr, Arg225!Pro; trp374!stop codon; 50delT; mutation L17X; 12 bp inframe deletion (codon 284–287); Pro188!leu; Thr173!met change) were found in Omani families (Ohadi et al. 1999; Muralitharan et al. 2005, 2007). Hypopituitarism and hypoglycaemia in an Omani family in three affected children was found to have novel LHX3 mutation (Rajab et al. 2008). They also were of short stature, short neck, osteopenia, soft hyperelastic skin, hypermobile joints, spinal vertebral anomalies, deep palmar and plantar creases, learning difficulties and sensorineural deffness. Three M syndrome (DOLICHOSPONDYLIC DYSPLASIA) (OMIM 273750) from Omani families was studied with the identification of a new aminocaid change in exon 23 (Q1469R) on 6p 21.1 (Huber et al. 2009) Bardet–Biedl syndrome families from Oman were enrolled in the multicenter study with identification of FLJ23560 as BBS10 on chromosome 12q21.2 (White et al. 2007). The original phenotype of Bardet–Biedl syndrome with nephrosis, severe brain malformations and early lethality was observed (unpublished data). Allopecia universalis congenita (OMIM 203655) in Omani families was found to map to 8p21.2 with mutation 2776+1, G.A in exon 12 (Cichon et al. 1998). Grebe acromesomelic dysplasia (OMIM 200700) mutations were studied in Omani families with identification of a new deletion of G1144 on chromosome 20q11.2 (Al-Yahyaee et al. 2003)

16

Genetic Disorders in Oman

487

New mutation of the gene regulating factor X function was found in Omani family with bleeding disorder. Familial CRM+ FX deficiency was found to be from impaired prothrombinase activity of factor X (Gly381Asp Factor X) (Pinotti et al. 2003). Paroxysmal nonkinesigenic dyskinesia (OMIM 118800) in Omani family was studied with identification of a novel mutation (c.20C>T: A7V; c.26C>T: A9V) of Myofibrillogenesis regulator 1 gene (MR-1) (Hempelmann et al. 2006). Spinal muscular atrophy (OMIM 553300) study conducted at Sultan Qabus University identified deletions of exons 5,6,7 and 8 on chromosome on 5q12.2q13.3 in Omani families (Simsek et al. 2003; Haider et al. 2001).

Comment As children with handicapping genetic disorders now survive, the population of patients on long-term therapy has steadily expanded causing a considerable burden on the health-care and social services. National strategies for the prevention and management of disorders and birth defects can be defined according to the epidemiological situation, local needs and priorities, as well as available resources. Few important adjustments in health-care delivery are being implemented based on availability of medical genetic expertise, comprehensive genetic diagnostic laboratory services, and genetic and genomic research. In addition, integrated support to the families affected by genetic illness, education in genetic health, and continuous medical education on medical genetics and ethics would be required for medical and paramedical professionals. The challenge faced by public health geneticists is to define novel prevention strategies ethically compatible with the cultural background and social circumstances and religious beliefs of the population, and the legal system of the country. The prime objective of genetic service is to maximize the chances for every couple to have a healthy child, and to offer early and proper management for the affected individual.

References Afzal AR, Rajab A, Fenzke CD, Oldridge M, Elanko N, Ternes-Pereira E, Tuysuz B, Murday V, Patton MA, Wilkie A, Jeffery S (2000a) Recessive Robinow syndrome, allelic to dominant brachydactily type B, is caused by mutation of ROR2. Lett Nat Genet 25(4):419–422 Afzal AR, Rajab A, Fenske C, Crosby A, Lahiri N, Ternes-Pereira E, Murday VA, Houlston R, Patton MA, Jeffrey S (2000b) Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22. Hum Genet 106(3):351–354 Alwan AA, Modell B (1997) Community control of genetic and congenital disorders. EMRO technical publications series 24. World Health Organisation Regional Office for the Eastern Mediterranean. (218 pp) ISBN 92-9021-220-9. ISSN 1020-0428

488

A. Rajab

Al-Yahyaee SAS, Al-Kindi MN, Habbal O, Kumar DS (2003) Clinical and molecular ana´lysis of Grebe acromesomelic dysplasia in an Omani family. Am J Med Genet 121A:9–14 Bappal B, George M, Nair R, Khusaiby SA, De Silva V (2001) Factitious hypoglycemia: a tale from the Arab world. Pediatrics 107(1):180–181 Carter JRL (1982) Tribes of Oman, 1st edn. Peninsula Publishing, London Cichon S, Anker M, Vogt IR, Rohleder H, P€ utzst€ uck M, Hillmer A, Farooq SA, Al-Dhafri KS, Ahmad M, Haque S, Rietschel M, Propping P, Kruse R, No¨then MM (1998) Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum Mol Genet 7(11):1671–1679 Daar S, Vulliamy TJ, Kaeda J, Mason PJ, Luzzatto L (1996) Molecular characterization of G6PD deficiency in Oman. Hum Hered 46(3):172–176 Daar S, Hussein HM, Merghoub T, Krishnamoorthy R (1998) Spectrum of beta-thalassemia mutations in Oman. Ann N Y Acad Sci 850:404–406 Daar S, Pathare AV (2006) Combined therapy with desferrioxamine and deferiprone in betathalassemia major patients with transfusional iron overload. Ann Hematol 85(5):315–319 Goud MT, Harassi S, Al-Khalili S, Salmani KK, Al-Busaidi SM, Rajab A (2005) Incidence of chromosomal abnormalities in the Sultanate of Oman. Saudi Med J 26(12):1951–1957 Haider MZ, Moosa A, Dalal H, Habib Y, Reynold L (2001) Gene deletion patterns in spinal muscular atrophy patients with different clinical phenotypes. J Biomed Sci 8(2):191–196 Heathcote K, Rajab A, Magre J, Syrris P, Besti M, Patton M, Delepine M, Lathrop M, Capeau J, Jeffery S (2002) Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. Diabetes 51(4):1291–1293 Hempelmann A, Kumar S, Muralitharan S, Sander T (2006) Myofibrillogenesis regulator 1 gene (MR-1) mutation in an Omani family with paroxysmal nonkinesigenic dyskinesia. Neurosci Lett 402(1–2):118–120 Hennies HC, Rauch A, Seifert W, Schumi C, Moser E, Al-Taji E, Tariverdian G, Chrzanovska KH, Krajevska-Walasek M, Rajab A, Guigliani R, Neumann TE, Eckl KM, Karsbasyan M, Reis A, Horn D (2004) Allelic heterogeneity in the COH1 gene explain clinical variability in Cohen syndrome. Am J Hum Genet 75:138–145 Hennies HC, Kornak U, Zhang H, Egerer J, Zhang X, Seifert W, K€ uhnisch J, Budde B, N€atebus M, Brancati F, Wilcox WR, M€ uller D, Kaplan PB, Rajab A, Zampino G, Fodale V, Dallapiccola B, Newman W, Metcalfe K, Clayton-Smith J, Tassabehji M, Steinmann B, Barr FA, N€ urnberg P, Wieacker P, Mundlos S (2008) Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat Genet 40(12):1410–1412 Hoffmann K, M€uller JS, Stricker S, Megarbane A, AnnaRajab TH, Lindner MC, Chouery E, Adaimy L, IsmatGhanem VD, Boltshauser E, Talim B, Horvath R, Robinson PN, Lochm€ uller H, H€ubner C, Mundlos S (2006) Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal subunit. Am J Hum Genet 79:303–312 Huber C, Delezoide AL, Guimiot F, Baumann C, Malan V, Le Merrer M, Da Silva DB, Bonneau D, Chatelain P, Chu C, Clark R, Cox H, Edery P, Edouard T, Fano V, Gibson K, GillessenKaesbach G, Giovannucci-Uzielli ML, Graul- Neumann LM, van Hagen JM, van Hest L, Horovitz D, Melki J, Partsch CJ, Plauchu H, Rajab A, Rossi M, Sillence D, Steichen-Gersdorf E, Stewart H, Unger S, Zenker M, Munnich A, Cormier-Daire V (2009) A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet 17(3):395–400 Joshi SN, Hashim J, Venugopal P (2002) Pattern of inborn errors of metabolism in an Omani population of the Arabian Peninsula. Ann Trop Paediatr 22(1):93–96 Joshi SN, Venugopalan P (2007) Clinical characteristics of neonates with inborn errors of metabolism detected by Tandem MS analysis in Oman. Brain Dev 29(9):543–546 Kornak U, Reynders E, Dimopoulou A, Van Reeuwijk J, Fischer B, Rajab A, Budde B, N€ urnberg P, Foulquier F, ARCL Debre´-type Study Group, Lefeber D, Urban Z, Gruenewald S, Annaert W, Brunner HG, van Bokhoven H, Wevers R, Morava E, Matthijs G, Van Maldergem L, Mundlos S (2008) Impaired glycosylation and cutis laxa caused by mutations in the vesicular H(+)ATPase subunit ATP6V0A2. Nat Genet 40:32–34

16

Genetic Disorders in Oman

489

Michalk A, Stricker S, Becker J, Rupps R, Pantzar T, Miertus J, Botta G, Naretto VG, Janetzki C, Yaqoob N, Ott CE, Seelow D, Wieczorek D, Fiebig B, Wirth B, Hoopmann M, Walther M, Ko¨rber F, Blankenburg M, Mundlos S, Heller R, Hoffmann K (2008) Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 82(2):464–476 Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D, Kosaki K, Noruzinia M, Sarda P, Ishihara J, Bodell A, Apse K, Walsh CA (2004) Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet 41(6):e87 Muralitharan S, Al Lamki Z, Dennison D, Christie BS, Wali YA, Zachariah M, Romana M, Bayoumi R, Krishnamoorthy R (2005) An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression. Am J Hematol 78(1):59–63 Muralitharan S, Wali YA, Dennison D, Lamki ZA, Zachariah M, Nagwa EB, Pathare A, Krishnamoorthy R (2007) Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic omani patients. Am J Hematol 82(12):1099–1102 Nicole S, Ben Hamida C, Beighton P, Bakouri S, Belal S, Romero N, Viljoen D, Ponsot G, Sammoud A, Weissenbach J, Fardeau M, Ben Hamida M, Fontaine B, Hentati F (1995) Localization of the Schwartz-Jampel syndrome (SJS) locus to chromosome 1p34–p36.1 by homozygosity mapping. Hum Molec Genet 4:1633–1636 Nicole S, Davoine C-S, Topaloglu H, Cattolico L, Barral D, Beighton P, Ben Hamida C, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B (2000) Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz-Jampel syndrome (chondrodystrophic myotonia). Nature Genet 26:480–483 Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, Kinsey S, Rhodes M, Layton DM (1999) Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 64(1):165–171 Pinotti M, Camire RM, Baroni M, Rajab A, Marchetti G, Bernardi F (2003) Impaired prothrombinase activity of factor X Gly381Asp results in severe familial CRM+ FX deficiency. J Tromb Haemost 89:243–248 Rajab A, Patton M (1997) Major factors determining frequncies of haemoglobinopathies in Oman. Letter to the editor. Am J Med Genet 71:240–242 Rajab A, Patton M (1999) Development and use of a national haemoglobinopathy register in Oman. Letter to the editor. Community Genet 2:47–48 Rajab A, Patton M (2000) A study of consanguinity in the Sultanate of Oman. Ann Hum Biol 3:321–326 Rajab A, Heathcote K, Joshi S, Jeffery S, Patton M (2002) Heterogeniety or congenital generalised lipodystrophy in seventeen patients from Oman. Am J Med Genet 110:219–225 Rajab A, Khaburi M, Spranger S, Kunze J, Spranger J (2003a) Congenital generalized lipodystrophy, mental retardation, deafness, short stature, and slender bones: a newly recognized syndrome? Am J Med Genet 121A:271–276 Rajab A, Mochida GH, Hill A, Ganesh V, Bodell A, Riaz A, Grant PE, ShugartYY WCA (2003b) A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology 60:1664–1667 Rajab A, Kunze J, Mundlos S (2004) Spondyloepipheseal dysplasia omani type: a new recessive type of SED With progressive spinal involvement. Am J Med Genet 126A:413–419 Rajab A, Bappal B, Al-Shaikh H, Al-Khusaibi S, Mohammed AJ (2005a) Common autosomal recessive diseases in Oman derived from a hospital-based registry. Community Genet 8:27–30 Rajab A, Hoffmann K, Ganesh A, Sethu AU, Mundlos S (2005b) Escobar variant with pursed mouth, creased tongue, ophthalmologic features and scoliosis in 6 children from Oman. Am J Med Genet 134A:151–157 Rajab A, Yoo S-Y, Abdulgalil A, Kathiri S, Ahmed R, Moshida GH, Adria Bodell A, Barkovich J, Walch CA (2006) An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation. Am J Med Genet 140A:1504–1510

490

A. Rajab

Rajab A, Manzini MC, Mochida GH, Walsh CA, Ross ME (2007a) A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143(23):2761–2767 Rajab A, Manzini C, Mochida G, Walsh C, Ross E (2007b) A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A 143(23): 2761–2767 Rajab A, Kornak U, Budde BS, Hoffmann K, Jaeken J, N€ urnberg P, Mundlos S (2008) Geroderma osteodysplasticum hereditaria and wrinkly skin syndrome in 22 patients from Oman. Am J Med Genet A 146A:965–976 Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT (2009a) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17(14):2150–2159 Rajab A, Aldinger KA, El-Shirbini HA, Dobyns WB, Ross ME (2009b) Recessive developmental delay, small stature, microcephaly and brain calcifications with locus on chromosome 2. Am J Med Genet A 149A(2):129–137 Rajab A, Al-Harasi S, Neitzel H, Sperling K. Down syndrome in The Sultanate of Oman (in preparation) Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, L€utzkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M (2010) Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PloS Genetics 6(3):e1000874 Simsek M, Al-Wardy N, Al-Khayat A, Shanmugakonar M, Al-Bulushi T, Al-Khabory M, Al-Mujeni S, Al-Harthi S (2001) Absence of deafness-associated connexin-26 (GJB2) gene mutations in the Omani population. Hum Mutat 18(6):545–546 Simsek M, Al-Bulushi T, Shanmugakonar M, Al-Barwani HS, Bayoumi R (2003) Survival motor neuron (SMN) genes for molecular allele-specific amplification of exon 7 in the diagnosis of spinal muscular atrophy. Genet Test 7(4):325–327 Tiele H, Sakano M, Kitagawa K, Rajab A, Hohne W, Ritter H, Leschik G, Nurnberg P, Mundlos S (2004) Loss of chonroitin 6-0-sulfotransferase-1 function result in severe human chondrodysplasia with progressive spinal involvement. PNAS 101(27):10155–10160 White JM, Christie BS, Nam D, Daar S, Higgs DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 White DR, Ganesh A, Nishimura D, Rattenberry E, Ahmed S, Smith UM, Pasha S, Raeburn S, Trembath RC, Rajab A, Macdonald F, Banin E, Stone EM, Johnson CA, Sheffield VC, Maher ER (2007) Autozygosity mapping of Bardet-Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10. Eur J Hum Genet 15(2):173–178

Chapter 17

Genetic Disorders Among the Palestinians Bassam Abu-Libdeh and Ahmad Said Teebi

History of Palestine The land of Palestine is among the most storied and fought-over parts of the world. Having drawn together in city-states, one of which was Jericho, the Canaanites were the earliest known inhabitants of Palestine, with roots there extending as far back as the third millennium BC. Located at the intersection of routes connecting three continents, Asia, Africa, and Europe, Palestine became a natural meeting place, as well as a battleground, for culture and religious influences from Syria, Mesopotamia, Egypt, and Asia Minor. Although the Hebrews, Semitic tribes from Mesopotamia, began to steadily immigrate into Palestine after the fourteenth century BC, it was not until around 1125 BC, more than 150 years after Moses led his people out of serfdom in Egypt, that they finally defeated the Canaanites. A more formidable opponent to the Hebrews proved to be the Philistines, who had established an independent state on the southern coast of Palestine and controlled the Canaanite town of Jerusalem. Owing to their military superiority, they soundly defeated the Israelites around 1050 BC. The Union of the Israelite tribes under King David, however, enabled the Hebrews to defeat the Philistines approximately 50 years later and assimilate with the Canaanites. After David’s death in 922 BC, the kingdom was divided into two sections, Israel, which fell to Assyria in 722 BC, and Judah, which fell to Babylonia in 586; as a result, Jerusalem was destroyed and most of the Jews were exiled. Not long afterward, however, Cyrus the Great of Persia conquered Babylonia and allowed the Jews to return, permitting them significant autonomy in the process. Persian rule was eventually ended when Alexander the Great of Macedonia took the region in 333 BC. After his successors’ attempts to impose Hellenistic (Greek) culture and religion, the Jews revolted three

B. Abu-Libdeh (*) Associate Professor of Pediatrics & Genetics, Al-Quds Medical School, Chief of Pediatrics & Genetics, Makassed Islamic Charitable Hospital, Jerusalem, Israel e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_17, # Springer-Verlag Berlin Heidelberg 2010

491

492

B. Abu-Libdeh and A.S. Teebi

times between 141 BC and AD 135; the last of these insurrections ultimately resulted in Jews being banned from Jerusalem. Judea was renamed Syria Palistina. A period of prosperity followed in which most of the population became Hellenized and Christianized. Roman rule ended when Arab armies invaded Palestine and captured Jerusalem in AD 638, beginning 1,300 years of Muslim presence in what became to be known as Filastin. Palestine was holy to the Muslims because it was their first qiblah (the direction they face when praying) and because the prophet Mohammad was believed to have been nocturnally transported there from Mecca and to have been consequently ascended to heaven from the area thought to be the place of Solomon’s Temple, where the Dome of the Rock was later built. Although the Muslims guaranteed security and allowed religious freedom to all inhabitants of the region, the majority converted to Islam and adopted Arab culture. Palestine enjoyed, along with the rest of the Muslim empire at the time, a golden age of science, art, philosophy, and literature. Muslims continued in this renaissance until the empire, Palestine included, declined under the Mamelukes. It was also under the Mamelukes that the period of greatest turbulence overtook Palestine. During the eleventh century AD, various religious leaders in Europe spurred an uprising to conquer the “Holy Land” from the Muslims. Although the Crusades were at first dominated by religious aims, worldly motives such as capturing land and expanding trade also played a part. The Crusades were played out in eight major campaigns; the cast of victors and possessors of land changed frequently. The most severe damage to the Christian cause was inflicted by Saladin, a Muslim warrior and sultan of Egypt, who in the Third Crusade regained for his empire the stronghold of Jerusalem, a triumph the Christians were unable to reverse after the end of these wars. The Ottoman Turks then defeated the Mamelukes in the thirteenth century and ruled Palestine until 1917. The country was divided into districts, which were mainly administered by the Arab Palestinians. The Christian and Jewish communities were allowed a large measure of autonomy nevertheless. After a period of stagnation under the Ottoman Empire, the region was revitalized economically and socially in the nineteenth century by growing European interest in new markets and land. The rise of European nationalism, and especially of anti-Semitism during the 1880s, encouraged Jews living in Europe to seek reinstitution in Palestine or “the Promised Land.” Zionism was thus born. Aided by the Arabs, the British captured Palestine from the Turks in 1917–1918. In the Balfour Declaration of 1917, Britain promised the Jews, whose help was needed in World War I, a Jewish “national home” in Palestine, even though Palestinian Arabs made up more than 95% of the population at the time. Helped by large-scale immigration between the two world wars, the state of Israel was established on May 14, 1948. The West Bank, including East Jerusalem, was put under the control of neighboring country Jordan, while Egypt took command of the Gaza Strip. However, these two territories were both captured by Israel in 1967. The war resulted in the displacement of 60–70% of the Palestinians, whose number in diaspora is now estimated to be 5 million, scattered to neighboring countries, mainly Jordan. Later on, they spread to other countries, particularly the Arabian Gulf states and North America. Their number in Israel is

17

Genetic Disorders Among the Palestinians

493

Fig. 17.1 Map of old Palestine including present-day Israel and the Palestinian territories of West Bank and Gaza, and Jordan

1.1 millions and 3.7 millions in Palestinian Territories of the West Bank and Gaza (Palestinian Central Bureau of Statistics 2003) The Palestinians have maintained their identities and the desire to return to their homeland. The Oslo accord of 1993 resulted in the establishment of a Palestinian autonomy in the Palestinian territories of the West Bank and Gaza. Historical data are summarized from Mattar (1993), Bram and Dickey (1993), and Harden (1962).

494

B. Abu-Libdeh and A.S. Teebi

Consanguinity and Family Patterns According to the latest statistics of the Palestinian Central Bureau of Statistics, consanguinity is generally high among Palestinians. In general, around 50% of total marriages are consanguineous with little variation between the West Bank and Gaza Strip, with 43.4% and 49.3%, respectively. There has been no significant decline in this rate between the years 2000 and 2006 in spite of the public education and media campaign to discourage this kind of marriage (Fig. 17.2). This can be attributed to political, economic, and social factors that play a major role in deciding the type of marriage (Palestinian Central Bureau of Statistics 2009). A study from Israel (Freundlich and Hino 1984) conducted among the Arab rural population in the western Galilee showed unusually high overall figures (39%). They were highest in the Druze population (49%), lower among Muslims (40%), and still lower among Christians (29%). The most common type of consanguineous marriage was that between first cousins, particularly paternal first cousins. A study by Jaber et al. (1994) from Israel also showed an overall prevalence of consanguineous mating of 44.3%, with an average family inbreeding coefficient of 0.0192. The study group represented Arabs from urban, suburban, and rural areas with an average inbreeding coefficient of 0.01625, 0.01794, and 0.01958, respectively. First-cousin marriage constituted more than 50% of all consanguineous marriages. In the village of Taybe near Tel-Aviv, one of the largest and most developed Arab villages in Israel, consanguineous mating was apparent in 236 families out of 610 families randomly chosen (Jaber et al. 1992). Most of these were first-cousin-type marriages (170 families). In this study (Jaber et al. 1992) a significant increase in the incidence of malformation was noted in relation to the closeness of the parental relationship. For an index-case group, the prevalence of major malformations was 5.8% in the product of intervillage marriage, 8.3% in the intravillage nonrelated

60%

Percentage

50% 40%

West Bank Gaza

30% 20% 10% 0% 2000

2004 Year

2006

Fig. 17.2 Consanguineous marriages percentage in the West Bank and Gaza

17

Genetic Disorders Among the Palestinians

495

marriages, 15.1% in a distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriage ( p < 0.001). Palestinian families generally prefer large numbers of children. The average number of offspring per woman in the West Bank and Gaza was 7.8 (Courbage and Khlat 1993). The small family unit (parents and children) maintains strong ties with extended family, from which they obtain support and pride. The typical Palestinian village includes several clans (called hamula, pl. hamayil) with patrilineal structure. Each individual carries and uses at least four names: the first name, the father’s name, the paternal grandfather’s name, and the family name. It is usually possible to trace kinship using the father’s first name (Lewitter et al. 1983). One finds an excess of popular names that relate to Islamic (Mohammad, Ahmad, etc.) or Christian (Jiryis, Hanna, Butros, etc.) traditions.

Genetic Markers and Polymorphism The genetic profile of Palestinians was studied for the first time by Arnaiz-Villena et al. (2001) by using human leukocyte antigen (HLA) gene variability and haplotypes. The comparison with other Mediterranean populations by using neighborjoining dendrograms and correspondence analysis reveals that Palestinians are genetically very close to Jews and other Middle East populations, including Turks (Anatolians), Lebanese, Egyptians, Armenians, and Iranians. Hammer et al. used haplotypes constructed from Y-chromosome markers to trace the paternal origins of the Jewish Diaspora. A set of 18 biallelic polymorphisms was genotyped in 1,371 males from 29 populations, including 7 Jewish (Ashkenazi, Roman, North African, Kurdish, Near Eastern, Yemenite, and Ethiopian) and 16 non-Jewish groups from similar geographic locations. They concluded that Jewish and Middle Eastern non-Jewish populations share a common pool of Y-chromosome biallelic haplotypes (Hammer et al. 2000). Mitochondrial DNA haplotypes were studied in the Jews and Arabs (Ritte et al. 1993). Results showed little differentiation with only Ethiopian Jews distinguishable. The remaining groups were genetically similar to Europeans. The genetic similarity of Palestinians to the Jordanians is well illustrated in studies of taste reaction to phenylthiourea (Omari 1986b), serum protein polymorphisms (Cleve et al. 1992; Nevo et al. 1993), color vision (Omari 1986a), tongue curling and folding (Omari 1986a), mid-digital hair (Omari 1986b), and ridge count and other dermato-glyphic parameters (Omari 1985, 1991, 1992, 1993). No significant differences were found between Jordanians and Palestinians (West Bank versus East Bank of Jordan River) in regard to blood groups (Omari 1986a). Data from this study are compared to those of a study on the Druze community from northern Israel (Nevo 1988). The blood group markers are similar among Jews and Arabs and have little, if any, African admixture (Banerjee et al. 1981; Omari 1986a). Of note is the high incidence of the O allele (Saha and Banerjee 1986). Gc allele frequencies were also similar for

496

B. Abu-Libdeh and A.S. Teebi

Arab Druze and Muslims; the gene frequencies reported were as follows: Gc1F 0.1212 and 0.223, Gc1S 0.602 and 0.544, and Gc2 0.186 and 0.231, respectively (Cleve et al. 1978; Nevo and Cleve 1983). While the Druze are believed to have separated from other Muslims some eight centuries ago, the gene frequencies suggest that there has been no significant genetic divergence between the two communities. The frequency of alleles of a-1 antitrypsin in Palestinian was found to be different from that reported in European populations (Nevo et al. 1982). The latter work also includes a description of a new allele, PiV-S.

Genetics Disorders Among the Palestinians Only a few population epidemiological studies were conducted to discover the incidence of congenital malformations and genetic disorders among Palestinians. Similar to other Arabs (Teebi 1994), the Palestinians apparently have increased frequencies of congenital malformation and autosomal recessive disorders. This became more evident with the decreasing load of infections and nutritional problems. There is also as apparent high frequency of new autosomal recessive disorders and variants among Palestinians. The high frequency of autosomol recessive disorders at large is partly explained by the high rate of consanguinity, which also explains the high frequency of monogenic disorders in mentally retarded individuals from Palestine (Janson et al. 1990). In this study, parental consanguinity in cases of severe mental retardation was 67.5% (Janson et al. 1990) compared to 50% in the general population. In the mixed Arab population of Kuwait, genetic causes accounted for over 50% of cases of mental retardation (Farag et al. 1993).

Chromosomal Abnormalities The only cytogenetics laboratory in Palestine is located at Makassed Hospital in Jerusalem. It was established in 1996 and since then till 2008, 3,704 peripheral blood samples were processed for chromosome analysis for different indications. The most frequent abnormality detected was trisomy 21 followed by sex reversal, Turner syndrome and Klinefelter syndrome. Table 17.1 summarizes these patterns (Abu-Libdeh, unpublished data).

Common Autosomal Recessive Disorders Reported Among Palestinians Hemoglobinopathies Several autosomal recessive disorders are reported or observed to be highly prevalent in the general population. Hemoglobinopathies, mainly b Thalassemais (thal) are prevalent among Palestinians and represent a potentially preventable national

17

Genetic Disorders Among the Palestinians

497

Table 17.1 Patterns of cytogenetic abnormalities on peripheral blood samples of Palestinians undergoing karyotyping at the cytogenetic laboratory at Makassed Hospital in Jerusalem between 1996 and 2008 Total Abn Trio Trio. Trio. Trans KF TS Sex Bal Others samples 21 18 13 DS Synd revers Trans 1996 169 31 17 1 2 1 1 0 6 1 2 1997 232 46 27 1 3 1 3 2 2 2 5 1998 268 50 28 1 2 0 5 5 5 2 2 1999 257 53 35 2 1 1 3 2 4 1 4 2000 265 48 24 5 0 0 5 4 7 0 3 2001 240 40 22 0 1 2 1 4 5 2 3 2002 196 39 23 1 0 1 3 2 7 2 0 2003 279 56 33 4 0 0 1 9 8 1 0 2004 291 61 36 2 1 0 4 6 5 2 5 2005 384 82 44 4 2 1 3 6 20 2 0 2006 365 56 38 3 3 1 3 2 0 2 4 2007 350 57 39 2 0 0 2 2 4 3 5 2008 408 72 60 3 3 1 2 1 0 1 1 Total 3704 691 426 29 18 9 36 45 73 21 34 Abn ¼ abnormal samples, Trio 21 ¼ trisomy 21, Trio 18 ¼ trisomy 18, Trio 13 ¼ trisomy 13, Trans. DS ¼ translocation Down syndrome, KF Synd ¼ Klinefelter syndrome, TS ¼ Turner syndrome, Sex revers ¼ Sex reversal, Bal Trans ¼ balanced translocation

health problem. The frequency of the b-thal trait among Muslim and Christian Palestinians and Bedouins is variable and ranges between 3% and 4% and up to more than 10% in some areas (Filon et al. 1994, 1995). Carrier screening performed on 1,650 secondary school students from Gaza for b thal showed an overall frequency of 4.3% (Sirdah et al. 1998). The frequency of b thal in the microcytic subjects was 27.1%. Assuming a carrier frequency of 4% in the general population, then the incidence is estimated at 1/2,500. This incidence has been declining over the last decade, mainly because of the mandatory premarital thalassemia screening that was adopted on May 2000 (Younis 2006). One additional factor for the decline was the introduction of an active antenatal diagnosis program for thalassemia at Makassed Hospital in Jerusalem. During the period of Jan/1999–Jul/2005, 25 cases of homozygous b thalassemia were diagnosed antenatally with subsequent termination of the pregnancy according to the wishes of the parents (Ayesh et al. 2005a). In 1990, there were 21 new cases affected with thalassemia, rising to 33 cases in 1995. In the year 2000, the number was 16, falling to 7 in 2003 and 5 in 2004 (Younis 2006). Marked genetic heterogeneity was observed among Palestinians, among whom 17 mutations were detected (Darwish et al. 2005; Ayesh et al. 2005a, b) Most of the detected mutations are the Mediterranean type, as seen in neighboring countries. The four most common mutations with their relative frequencies were as follows: IVSI-110 (22.2%), IVSI-6 (13.6%), Cd37 (12%), and IVSI-I (9.7%) (Ayesh et al. 2005a,b). Darwish et al. (2005) reported that IVSI-6 was the most common mutation with a frequency of 28.7% among their patient population. However, their sample was not representing the whole population (Suheil Ayesh, personal communication). Other studies have shown slight differences in the relative frequencies of the most common mutations with IVSI-110 being the most

498

B. Abu-Libdeh and A.S. Teebi

common and accounting for 37.5% of all b thal alleles in Gaza (Filon et al. 1995). The IVS1-110 mutation is the most prevalent mutation in Lebanon and Egypt, accounts for 22% of the b-thal alleles in Israel and is present in both Kurdish Jews and Arabs (Filon et al. 1994). In Bedouins, most of the b-thal gene mutations were found in those who live in malarial regions near the Huleh and Jazreel valleys in northern Israel. A unique poly-A deletion (AATAAAA – A), accounting for 2.5% of all mutations in Gaza, has not been reported in any other country (Filon et al. 1995). A new b-hemoglobin variant, Hb Taybe, named for the Arab village of Taybe, was reported (Galacteros et al. 1994). This hemoglobin (a 38 or 39 THR deleted) is silent in the hetorozygote state and produces severe hemolytic anemias in the homozygous form. HbS and HbO-Arabs are present in several large Palestinian kindred in the ArabIsraeli village of Jesser El-Zarka (Rachmilewitz et al. 1985). This village traces its ancestry to immigrants from Jordan, the West Bank city of Nablus, and the south of Sudan. One Jewish family and eight Palestinian Arab families were found to have the Benin haplotype of the b-globin gene and the ninth family had the CAR haplotype (Central African Republic) (Rund et al. 1990).

Familial Mediterranean Fever One other relatively common disease is Familial Mediterranean Fever (FMF) and the incidence among Palestinians was estimated to be at least 1:2,000 (Barakat et al. 1989; Majeed and Barakat 1989; Said et al. 1992). Such a high incidence is close to that observed in Armenians and Sephardic Jews (Sohar et al. 1967). The spectrum of mutations and genotypes in the pyrin gene in Palestinian FMF patients is similar to that among other patients in neighboring countries. The five most frequent mutations are M694V (49%), V726A (16.7%), M694I (11.9%), E148Q (8.5%), and M680I (4.4%) that account for 90% of all detected mutations. The remaining nine mutations (P369S, R408Q, A744S, M680Ib, R653H, 695R, E167D, F479L, and R761H) were much less represented and had frequencies <2.6% each (Ayesh et al. 2005a).

Cystic Fibrosis Cystic fibrosis (CF) is another relatively common genetic disorder. Reports from Israel suggest a high incidence among Palestinians (Katznelson 1978, 1982). Observations from Kuwait indicate apparent high frequencies of CF among Palestinians and Jordanians (Issa et al. 1988). Data from Israel showed that the DF508 mutation accounts for 22–25% of CF chromosomes in Palestinians versus 32.5% in Ashkenazi Jews; these can be compared to the 70% figure in a worldwide survey

17

Genetic Disorders Among the Palestinians

499

(Lerer et al. 1990; Shoshani et al. 1992). Four mutations were found to be common in Arabs (D F508, G542X, W1282X, and N1303K), accounting for 55% of the CF alleles (Abeliovich et al. 1992).

Phenylketonuria The incidence of classic phenylkonuria (PKU) in Kuwait was 1:6,479 live-births, which is high compared to the general incidence of 1:11,000 (Teebi et al. 1987a). Two out of three cases detected in Kuwait’s PKU screening project were Palestinians or Jordanians. At the genetics clinics in Kuwait, Palestinians and Jordanians families with PKU represented more than 50% of all families identified at that time (Teebi et al. 1987a). The results of newborn screening program for PKU in Gaza showed an overall incidence of 6.35:100,000, while the maximum prevalence of 28.3:100,000 occurred in rural areas (Abu Shahla et al. 2004). In a study from Israel, 36 Palestinian families with various hyperphenylalaninemias were included (Kleinman et al. 1994). Mutations and polymorphisms at the phenylalanine hydroxylase (PAH) locus were studied (Kleinman et al. 1994). Four mutations previously identified in Europe were found among Palestinians, indicating that gene flow from Europe to Palestine could have been early in history. In addition, three new PAH mutations unique to Palestinians were identified (Kleinman et al. 1992a, b, 1993, 1994). A study from Kuwait examining Kuwaiti, Palestinian, and Egyptian patients showed the presence of four common European haplotypes and three unclassified ones (Bender et al. 1994).

Bardet-Biedl Syndrome The prevalence of Bardet-Biedl syndrome was higher among Bedouins in Kuwait (Farag and Teebi 1999). Similarly it is expected to be high in the Bedouin of Negev. Four out of 13 Arab families with BBS patients seen in Kuwait were Palestinians (Farag and Teebi 1988). Reports from Israel indicate a high frequency of BBS with clustering among some Bedouin tribes (Kalbian 1956; Ehrenfeld et al. 1970; Kwitek-Black et al. 1993). In a large Bedouin family, significant linkage was shown with chromosome 3 locus (Sheffield et al. 1994). Linkage was confirmed by homozygosity mapping. In another Bedouin family, BBS locus was found linked to markers that map to 16q21 (Kwitek-Black et al. 1993). The most informative marker was homozygous for the same allele in seven of nine affected individuals. These data indicated locus heterogeneity of BBS among Palestinians. Nonallelic genetic heterogeneity is further documented by finding two more loci causing BBS on chromosomes 11 and (Leppert et al. 1994; Carmi et al. 1995). Phenotypic variability was evident comparing three unrelated Bedouin kindred, which were used for linkage mapping of BBS loci to chromosomes 3, 15, and 16 (Carmi et al. 1995).

500

B. Abu-Libdeh and A.S. Teebi

More than ten genes have been identified so far to cause various types of BBS. Many of the studies conducted involved Palestinians including Bedouin (Chiang et al. 2006; Bin et al. 2009; Zaghloul and Katsanis 2009).

Meckel Syndrome Meckel syndrome is rare malformation syndrome that was found to be highly prevalent in Kuwait, with an incidence of 1:3,500 births in the general population (Teebi et al. 1992). Many of the ascertained cases were Palestinians. A study from Makassed Hospital in Jerusalem showed an incidence of 1:2,000 (Dudin 1994). Similar to a phenotype seen in Kuwait, Meckel syndrome without polydactyly was reported in a Palestinian family (Juabeh et al. 1987).

Lysosomal Disorders Metachromatic leukodystrophy was found to be common among Palestinians. Ten Muslim and Christian families with affected children have been found, three in the Jerusalem region and seven in a small area in lower Galilee (Zlotogora et al. 1994a; Heinisch et al. 1995). While multiple mutations accounted for the high frequency of metachromatic leukodystrophy among Muslim and Christian Palestinians living in a small geographic area (Heinisch et al. 1995), a single origin for the most frequent mutation was found among Muslim and Christian patients (Zlotogora et al. 1994a). This finding indicates that the common mutation may have been introduced into Jerusalem during the Crusades. Krabbe disease was reported among the Druz community in Israel as well as other Arabs (Zlotogora et al. 1985, 1991; Teebi and Teebi 2005). In addition, based on our experience from Palestine and on Palestinians from Kuwait, a wide range of lysosomal disorders was observed some of which were frequently diagnosed. They include various types of mucoploysaccaridosis, mucolipidosis, Nieman – Pick disease, GM1 gangliosidosis, among others. Some of those disorders were studied at molecular level (Bach et al. 1993; Bargal et al. 2006).

Familial Hydrocephalus Familial hydrocephalus of prenatal onset was reported in 8 out of 14 families in which more than one child was diagnosed with this condition in Israel. All the Arab patients had consanguineous parents (Zlotogora et al. 1994b). A large Palestinian family with four affected children was also reported from Kuwait (Teebi and

17

Genetic Disorders Among the Palestinians

501

Naguib 1988). The finding suggests that this entity is relatively frequent in the Palestinian.

Congenital Adrenal Hyperplasia and Male Pseudohermaphroditism Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency has an estimated incidence of at least 1:7,000 live births in the Arabs in Kuwait (Lubani et al. 1990). In this study, Palestinian and Jordanians represented 26.6% of all cases. Inherited defects in the 17 b-hydroxysteroid dehydrogenase type 3 (HSD3), causing male pseudohermaphroditism, are frequent among the population of Gaza. A point mutation in exon 3, codon 80 of the 17 b HSD3 gene, R80Q, was caused by a single base substitution from CGG to CAG in both alleles of 24 individuals from 9 extended families from Gaza, Jerusalem, and Lod-Ramle (Rosler et al. 1996). The frequency of affected males in Gaza is estimated at 1 in 100 to 150 (Rosler 2006).

Genetic Disorders Causing Blindness A study of all schools for the blind in the West Bank and Gaza involving 205 children showed that the main causes of blindness were retinal (52%), optic atrophy (12%), glaucoma (9%), and cataract (7%) (Elder and De Cock 1993). The minimum prevalence of blindness from this study was 0.32:1,000 children. In a recent study (Bandah et al. 2009), the spectrum of retinal diseases caused by NRE3 mutation was studied in Palestinian patients and compared to Israeli patients. A rare cause of blindness is the nonsyndromic microphthalmia or clinical anophthalmia and is frequently diagnosed among Palestinians (Kohn et al. 1988; Teebi and AL-Saleh 1989).

Other Apparently Common Disorders Glanzmann’s thrombasthenia was found to be the second most frequent bleeding disorder in Jordan (Awidi 1983), with a large sector of the population being former Palestinians. The author described 12 patients in 9 families. Coller et al. (1987) found that immunoblot patterns of glycoprotein IIIa could distinguish the defect present in most Iraqi Jewish patients from that in the Palestinian. At the molecular level the mutations in the two populations are different (Newman et al. 1991).

502

B. Abu-Libdeh and A.S. Teebi

Nesidioblastosis was found in a large Bedouin family and a Palestinian Muslim family from Israel (Glaser et al. 1990). In Jordan, this condition is frequently diagnosed among the newborns with hypoglycemia (Mathew et al. 1988). Wilson’s disease (hepatolenticular degeneration) has an estimated incidence of 1:4,000 among Druze and 1:10,000 in Palestinian Arabs, compared to 1:3,000 in Turkish Jews and 1:40,000 in Ashkenazi Jews and Jews from the Maghreb countries (Bonne´-Tamir et al. 1990). In addition to the common disorders mentioned above, several disorders have been found to be very common in large kindred or tribes or restricted to a small geographic region, usually suggesting a founder effect. Examples are families with different types of prelingual, bilateral, severe hearing loss with identifiable mutations (Shahin et al. 2002; Walsh et al. 2002). Other examples of founder effect is the spinal muscular atrophy type 1 (SMA1) in an isolated Palestinian village where 13% of the residents were carriers for SMA1 and 11% were carriers for SMA with respiratory distress (SMARD1) (Basel-Vanagaite et al. 2008).

Patterns of Inborn Errors of Metabolism Detected among Palestinians Inborn errors of metabolism (IEOM), as with other autosomal recessive disorders, are seen with increasing frequency among Palestinians as compared to other populations especially in Western Countries. Different metabolic conditions have been reported among Palestinians. Table 17.2 summarizes the pattern of IEOM diagnosed at Makassed Hospital in Jerusalem between 1/2004 and 5/2009 (Dweikat unpublished data).

New Disorders First Reported Among Palestinians A relatively large number of new disorders, most of which appeared to be autosomal recessive, were reported among Palestinians. Many of these were observed and further characterized elsewhere. Examples of the newly described disorders among Palestinians are limb/ pelvis-hypoplasia/ aplasia syndrome (Al-Awadi et al. 1985; Teebi 1993); microcephaly with normal intelligence (Teebi et al. 1987a, b); Grebelike chondrodysplasia (Teebi et al. 1986a, b); macrosomia, microphthalmia, and cleft lip/palate-lethal (Teebi et al. 1989); trigonobrachycephaly syndrome with bulbous nose and severe mental retardation (Teebi 1991); disordered pigmentation and spastic paraplegia (Abdallat et al. 1980), and hypogonadotropic hypogonadism with mental retardation, obesity, and minor skeletal anomalies (Teebi et al. 1986a, b); congenital dyserthropoietic anemia type 1 associated with chronic recurrent osteomyelitis and Sweet’s syndrome (Majeed et al. 1989) later called Majeed syndrome

17

Genetic Disorders Among the Palestinians Table 17.2 The patterns of Inborn Errors of Metabolism (IEOM) Makassed Hospital in Jerusalem between 1/2004–5/2009 Disease I. Aminoacidopathies Phenylketonuria Alkaptonuria Hereditary Tyrosinemia type 1 MSUD Homocystinuria Nonketotic hyperglycinemia (NKH) Hypermethioninemia Citrin deficiency EPEMA II. Urea cycle disorders Ornithine Transcarbamoylase (OTC) def Citrullinemia Lysinuric protein intolerance (LPI) Hyperornithinemia- hyperammonemia- homocitrullinemia (HHH) syndrome III. Organic acidemias Isovaleric acidemia Biotinidase deficiency 3-methylglutaconic aciduria b-Ketothiolase deficiency 3-hydroxy 3-methylglutaric aciduria (HMG-CoA lyase deficiency) Methylmalonic acidemia (MMA) Propionic acidemia 5-Oxoprolinuria 3-OH-isobutyric aciduria Glutaric aciduria IV. Glycogenosis GSD Type I a GSD Type I b GSD Type III GSD Type VI V. Lysosomal storage disorders GM1 Gangliosidosis Niemann-Pick Disease Krabbe MLD Mucolipidosis type II (I cell disease) Hurler Hunter Sanfilippo Morquio Sandhoff Galactosialidosis VI. Peroxisomal disorders VII. Mitochondrial disorders A. Fatty acids oxidation defects Carnitine Palmoityl Transferase 1 (CPT) deficiency Primary Carnitine Deficiency VLCAD deficiency LCHAD deficiency MCAD deficiency SBCAD deficiency

503 diagnosed at No. of cases 38 5 6 2 6 2 7 1 2 7 7 1 3 2 1 55 14 2 1 4 2 15 11 1 1 4 31 1 3 26 1 39 4 10 5 3 6 3 3 2 1 1 1 8 14 1 1 2 2 5 3 (continued)

504

B. Abu-Libdeh and A.S. Teebi Table 17.2 (continued) Disease B. Mitochondrial respiratory chain disorders Complex I def Complex II def Complex I & IV def Cytochrome c oxidase def Pyruvate DH E3 def E2 (lipoamide DH) def. Complex 1, 3, 4 deficiency - ?mtDNA depletion TOTAL

No. of cases 22 6 1 2 2 7 1 3 214

(Al-Mosawi et al. 2007); diaphragmatic hernia and epidermolysis bullosa (Dudin and Thalji 1991); and Nablus mask like facial syndrome (Teebi 2000; Raas-Rothschild et al. 2009). See the Chapter on New Syndromes Reported First in the Arabs in this book.

Rare Disorders Several extremely rare disorders and unusual associations have been reported. Despite the fact that most of these disorders were reported only once, some of them may not be necessarily rare among Palestinians. In some instances, the association is fortuitous or due to closely linked genes or simply represents a previously unrecognized syndrome. Examples include the infantile osteopetrosis and Hirschsprung’s disease (Dudin and Rambaud-Cousson 1993), autosomal dominant syndactyly type IV/hexadactyly of feet associated with unilateral absence of the tibiae (Rambaud-Cousson et al. 1991), myelomeningocele and cloacal duplication (Telmesani 1994), Menetrier’s disease with early childhood onset and possible autosomal recessive inheritance (Marcus and Verp 1993), Jancar’s syndrome (Zlotogora and Glick 1993), rhizomelic short-limbed dwarfism with abnormal facies (Robinow-like) (Turnpenny and Thwaites 1992), dyssegmental dwarfism (Svejcar 1993), autosomal recessive nephrogenic diabetes insipidus due to deletion in aquaporin2 gene (van Leiburg et al. 1994), familial thyroglossal duct syndrome (Klin et al. 1993), autosomal recessive Robinow’s syndrome (Teebi 1990), autosomal dominant Holt-Oram-like skeletal deformity (Boehme and Shotar 1989), Krause-Kivlin syndrome (Frydman et al. 1991), cerebro-oculo-facio-skeletal syndrome (GershoniBaruch et al. 1991), and Unusual Roberts syndrome (Gershoni-Baruch et al. 1990).

Cancer In a recent study published in the Lancet by Husseini et al. (2009), authors described the patterns of cancers and their crude incidence in the Palestinian

17

Genetic Disorders Among the Palestinians

505

territories. They wrote that in 2005, the reported number of new cancer cases in the occupied Palestinian territory was 1,623 and the crude incidence was 43.1 per 100,000 population – 49.2 per 100,000 in the West Bank and 32.7 per 100,000 in Gaza Strip. Of all cases, 45% were in men and 55% in women. Reported ageadjusted cancer incidence for the occupied Palestinian territory for 1998–2001 was lower than that in Jordan, Lebanon, and in Arabs living in Israel, probably because it was an underestimate as some patients use services outside the territory. In 2005, combined cancer mortality rate was 27.8 per 100,000, which is not much different from that in 2000. Lung cancer, the most commonly diagnosed and most deadly cancer worldwide, is the most common type in Palestinian men, those living in Jordan and Lebanon, and Palestinian Arabs living in Israel (see Table 17.3) [Husseini et al. 2009, with permission]. The estimated incidence is 5.2 per 100,000 men. Lung cancer is the leading cause of death from cancer in men – 7.1 deaths per 100,000 in 2005 and 22.8% of all cancer deaths.

Table 17.3 Age-adjusted cancer incidence and site-specific proportions of all cancers in the occupied Palestinian territory and neighboring countries West Bank Israeli Arabs Israeli Jews Jordanians Lebanese Palestinians Women Year(s) 1998–2001 1996–2001 1996–2001 1996–2001 1998 Age-adjusted incidence 88.5 128.7 272.1 112.2 134.8 (per 100,000 population) Total cancer cases Year 2005 2000 2002 2002 1998 Breast 31.4% 27.7% 31.5% 32.5% 46.7% Colon & rectum 9.2% 9.6% 14.1% 9.0% 11.5% Thyroid 5.5% 7.0% 3.6% 5.4% …. Corpus uteri 4.4% 5.0% 4.1% 2.4% 6.5% Ovary 3.8% 3.2% 2.7% 4.1% 5.9% Cervix uteri 1.0% 2.0% 1.7% 2.2% 2.3% Lung & bronchus 3.0% 3.5% 4.6% 2.3% 4.5% Men Years(s) Age-adjusted incidence (per 100,000 population) Total cancer cases Year Lung Prostate Colon & rectum Non-Hodgkin lymphoma Stomach

1998–2001 108.0

1996–2001 175.7

1996–2001 282.6

1996–2001 115.2

1998 154.2

2005 13.8% 11.3% 9.6% 5.0%

2000 19.0% 8.4% 9.9% 7.7%

2002 9.8% 17.5% 14.1% 5.7%

2002 12.2% 7.5% 9.1% 7.1%

1998 14.1% 14.2% 12.3% 4.2%

4.7%

3.4%

4.3%

4.7%

7.9%

506

B. Abu-Libdeh and A.S. Teebi

Prostate cancer is the second most common type in Palestinian men, followed by colorectal cancer. After lung cancer, the four types of cancer resulting in similar mortality rates in men are prostate (9.5%), nervous system (9.5%), colorectal (9.3%), and liver (9.1%). Breast cancer is the most common type in Palestinian women. The proportion is similar to that in neighboring countries except Lebanon, where breast cancer accounts for nearly half of all cancers in women. This disease causes the highest cancer-related mortality in Palestinian women, 21.1% of all deaths from cancer, and 5.2 deaths per 100,000 women. In theory, some features of Palestinian society, including a high total fertility rate (4.6%), high rate of breast feeding (95.6%) with a mean duration of 10.9 months, young mean age at first birth (20 years), and low alcohol consumption, should be protective against breast cancer. Other features – e.g. obesity and nulliparity – might act against these protective factors. About a third of Palestinian women of reproductive age are single and thus mostly childless. Colorectal cancer is the second most common type in Palestinian women and causes the second highest mortality rate from cancer. The traditional Palestinian Mediterranean diet, characterized by high intake of fiber and carbohydrate and low intake of fat and protein, should provide some protection against colorectal cancer.

General Observations Several other unifactorial and multifactorial disorders have been reported. The following are particularly notable observations: l

l

l

l

l

The incidence of neural tube defects among Palestinians was reported to be high (Dudin 1994). The incidence for spina bifida, encephalocele, and anencephaly were 1.73, 0.24, and 1.96:1,000 births, respectively. This high incidence may be largely attributed to socioeconomic factors, including unbalanced nutrition. Multiple sclerosis (MS) was found to be 2.5 times more frequent among Palestinians than among Kuwaitis (Al-Din et al. 1990a). The association with frequencies of genetic determinants (eye color, HLADR, HLA-DQW, blood group distributions) in Kuwaitis and Palestinians was also different. Among Palestinians, the higher frequency of MS and association with HLA-DR2 and HLADQW1 are similar to Europeans. It is possible that these characteristics are found because of admixture with Europeans (Al-Din et al. 1990a). Familial aggregation of high blood pressure is also seen in some communities (Hurwich et al. 1982). Shoveling of the incisors is probably a polygenic trait, sometimes associated with invagination of affected incisor. Five to six percent of Palestinians/Jordanians have shoveling and 11% of them have invagination (Kharat et al. 1990). The twinning rate among Palestinians was about 12/1,000 gestations with a ratio of 1 monozygotic to 3.9 dizgotic twins (Gedda et al. 1992).

17 l

l

l

l

Genetic Disorders Among the Palestinians

507

A total of 38 individuals in four generations of one Palestinian family were affected with epidermolysis bullosa herpetiformis (Dowling Maera type), a presumed autosomal dominant condition (Hacham-Zadeh et al. 1988). Epidermolysis bullosa dystrophica triggered by sun exposure was also reported (Shubailat et al. 1983). Tay-Sachs disease exists but is rare (Navon et al. 1981). A Palestinian family was reported to have a specific mutation that was originally described in a British patient (Drucker and Novan 1993). Homozygous protein C deficiency resulting in massive venous thrombosis in newborns was reported in Palestinians (Seligsohn et al. 1984). Heterozygotes had partial protein C deficiency but no thrombosis. Other disorders reported in Jordanians and Palestinians include apple peel syndrome (Farag and Teebi 1989; Farag et al. 1993), acrodermatitis enteropathica (Majeed and Barakat 1976), torsion dystonia (Besisso et al. 1987), erythropathogocytic lymphohistiocytosis (Issa et al. 1988), muscular dystrophies (Farag and Teebi 1990b; Mahjneh et al. 1992), Kabuki make up (Niikawa-Kuroki) syndrome (Gillis et al. 1990), X-linked recessive hydrocephalus (Al-Awadi et al. 1984), paruvate kinase deficiency (Karadsheh 1993), Wolman’s disease (Mahdi and Al-Nassar 1991), cyclopia/holoprosencephaly (Bustami and Amr 1986), and others (Yadav and Reavey 1988; Teebi 1994). Besides the conditions mentioned above, we have also seen the following disorders: split hand/split foot, retinitis pigmenosa (AR, AD, XLR), AD Parkinson’s disease, 17,20-desmolase deficiency, Waardenburg’s syndrome, asymmetric crying facies syndrome (Caylor syndrome), asphyxiating June thoracic dystrophy, congenital ichthyosiform erythroderma, and wrinkly skin syndrome.

Comments As progress is made in combating infectious diseases in many developing countries, the contribution to health problems by genetic factors tends to increase. Health-care providers will become more aware of genetic causes and of their impact on human health. Even with the paucity of genetic data, it is evident that there are unique features in the Palestinians. Some factors must be taken into consideration in developing genetics services, including high incidence of consanguinity, large family size, and cultural and religious nuances. In Palestinian territories, there is still much to be done in the field of genetics. In particular, we need: 1. To conduct more population studies to survey genetic diseases. 2. To recognize the field of clinical genetics and establish specialized training programs at medical schools (currently available only in Israel). 3. To expand the currently available laboratory services in the fields of biochemical genetics, molecular genetics, and cytogenetics.

508

B. Abu-Libdeh and A.S. Teebi

4. To provide public awareness and educational programs with emphasis on existing problems. 5. To promote genetic counseling services tailored to the needs of the community and to make preventive measures available including expanding of newborn screening and carrier screening for common diseases. 6. To promote research in genetic disorders prevalent in Palestinians.

References Abdallat A, Davis SM, Farraage N, McDonald WI (1980) Disordered pigmentation, spastic paraparesis and peripheral neuropathy in three siblings: a new neurocutaneous syndrome. J Neurol Neurosurg Psychiatry 43:962–966 Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cuttnig GR (1992) Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts carrier frequency of 1:29 in the Jewish Ashkenazi population. Am J Hum Genet 51:951–956 Abu Shahla AN, Abed Y, Abu Shahla NK (2004) Screening programme for phenylketonuria in the Gaza Strip: evaluation and recommendations. J Trop Pediatr 50(2):101–105 Al-Awadi SA, Teebi AS, Farag TI, Naguib KM, El-Khalifa MY (1985) Profound limb deficiency, thoracic dystrophy, unusual facies, and normal intelligence: a new syndrome. J Med Genet 22:36–38 Al-Awadi SA, Farag TI, Naguib K, Teebi AS, El-Khalifa MY, Yassin S (1984) X-linked hydrocehalus (Bickers-Adam-Edwartds syndrome). J Kwt Med Assoc 18:187–190 Al-Din AS, Khogali M, Poser CM, Al-Nassar KE, Shakir R, Hussaom J, Behbani K, Chadha G (1990a) Epidemiology of multiple sclerosis in Arabs in Kuwait: a comparative study between Kuwaitis and Palestinians. J Neurol Sci 100:137–141 Al-Mosawi ZS, Al Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56(3):960–964 Arnaiz-Villena A, Elaiwa N, Silvera C, Rostom A, Moscoso J, Go´mez-Casado E, Allende L, Varela P, Martı´nez-Laso J (2001) The origin of Palestinians and their genetic relatedness with other Mediterranean populations. Hum Immunol 62:889–900 Awidi AS (1983) Increased incidence of Glanzmann’s thrombasthenia in Jordan as compared with Scandinavia. Scand J Haematol 30:218–222 Ayesh SK, Al-Sharef WA, Nassar SM, Thawabteh NA, Abu-Libdeh BY (2005a) Prenatal diagnosis of beta-thalassemia in the West Bank and Gaza. Saudi Med J 26(11):1771–1776 Ayesh SK, Nassar SM, Al-Sharef WA, Abu-Libdeh BY, Darwish HM (2005b) Genetic screening of familial Mediterranean fever mutations in the Palestinian population. Saudi Med J 26 (5):732–737 Bach G, Moskowitz SM, Tieu PT, Matynia A, Neufeld EF (1993) Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. Am J Hum Genet 53(2):330–338 Bandah D, Merin S, Ashhab M, Banin E, Sharon D (2009) The spectrum of retinal diseases caused by NR2E3 mutations in Israeli and palestinian patients. Arch Ophthalmol 127(3):297–302 Banerjee B, Saha N, Daoud ZF, Khalaf FH, Qudah H (1981) A genetic study of the Jordanians. Hum Hered 31:65–69 Barakat MH, Karnik AM, Majeed HWA, El-Sokbi NI, Fenech FF (1989) Familial Mediterranean fever (recurrent heredity polyserositis) in Arabs. Q J Med 233:837–847 Bargal R, Zeigler M, Abu-libdeh B, Zuri V, Mandel H, Ben Neriah Z, Stewart F, Elcioglu N, Hindi T, Le Merrer M, Bach G, Raas-Rothschild A (2006) When mucolipidosis III meets mucolipidosis II. GNPTA gene mutations in 24 patients. Mol Genet Metab 88(4):359–363

17

Genetic Disorders Among the Palestinians

509

Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, Zlotogora J, Shohat M (2008) Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel. Genet Test 12(1):53–56 Bender C, Buchler A, Schmidt-Mader B, Schlotter M, Teebi AS, Konecki DS, Trefz FK (1994) Haplotype analyses and a new Mspl-polymorphism at the phenylalanine hydroxylase gene in the Arabian population. Eur J Pediatr 153:392 Besisso MS, Neubauer DH, Al-Rashied AA (1987) Torsion dystonia in two Arab siblings. J Kwt Med Assoc 21:214–217 Bin J, Madhavan J, Ferrini W, Mok CA, Billingsley G, Heon E (2009) BBS7 and TTC8 (BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population. Hum Mutat 30(7):E737–E746 Boehme DH, Shotar AO (1989) A complex deformity of appendicular skeleton and shoulder with congenital heart disease in three generations of a Jordanian family. Clin Genet 36:442–450 Bonne´-Tamir B, Frydman M, Agger MS, Bekeer R, Bowcock AM, Hebert JM, Cavalli-Sforza LL, Farrer LA (1990) Wilson’s disease in Israel: a genetic and epidemiological study. Ann Hum Genet 54:155–168 Bram LL, Dickey NH (eds) (1993) Jordan In: Funk, Wagnalls New encyclopedia, vol 15. Funk and Wagnalls, New York, pp 102–109 Bustami FMF, Amr S (1986) Cyclopia: a case study and review. Jordan Med J 21:283–297 Carmi R, Elbedour K, Stone EM, Sheffield VC (1995) Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. Am J Med Genet 59:199–203 Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA, Kim KY, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, Sheffield VC (2006) Homozygosity mapping with SNP arrays identifies TRIM31, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 103(16):6287–6292 Cleve H, Patutschnick W, Nevo S, Wendt GG (1978) Genetic studies of the Gc subtypes. Hum Genet 44:117–122 Cleve H, Koller A, Patutschnick W, Rodewald A, Nabulsi A (1992) Genetic serum protein polymorphisms in Jordanian Arabs: a pilot study of the systems AHSG, BF, FX111B, GC, PI, PLG and TF. Gene Geogr 6:31–40 Coller BS, Seligsohn U, Little PA (1987) Type 1 Glanzmann’s thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein: IIIa immunoblot analysis. Blood 69:1696–1703 Courbage Y, Khlat M (1993) Structure et Accroissement de la population dans le Monde Arabe: Tendances Recentes. In: Confe´rence Arabe sur la population, Amman 4–8 April, 1993, Institut National d’Etudes Demographiques, Paris Darwish HM, El-Khatib FF, Ayesh S (2005) Spectrum of beta-globin gene mutations among thalassemia patients in the West Bank region of Palestine. Hemoglobin 29(2):119–132 Dudin A (1994) Neural tube defects (NTD) among Palestinians living in the Southern part of the West Banks: a hospital based study. Report for Universite´ Catholique de Louvain, Bruxelles Dudin AA, Rambaud-Cousson A (1993) Syndrome of infantile osteopetrosis and Hirschsprung disease in seven children born to four consanguineous unions in two families. Am J Med Genet 47:1083–1085 Dudin AA, Thalji A (1991) Diaphragmatic hernia and epidermolysis bullosa in two sibs. Am J Med Genet 39:498–499 Drucker L, Navon R (1993) Tay-Sachs disease in an Israeli Arab family: Try26 Stop in the alphasubunit of hexoaminidase A. Hum Mut 2:415–417 Ehrenfeld E, Rowe H, Auerbach E (1970) Laurence-Moon-Bardet-Biedl syndrome in Israel. Am J Opthalmol 70:524–532 Elder MJ, De Cock R (1993) Childhood blindness in the West Bank and Gaza Strip: prevalence, aetiology and hereditary factors. Eye 7:580–583

510

B. Abu-Libdeh and A.S. Teebi

Farag TI, Teebi AS (1988) Bardet Biedl and Laurence-Moon syndromes in a mixed Arab population. Clin Genet 33:78–82 Farag TI, Teebi AS (1989) High incidence of Bardet-Biedl syndrome among the Bedouin. Clin Genet 36:463–465 Farag TI, Al-Awadi SA, El-Badramary MH, Aref MA, Kasrawi B, Krishna Murthy DS, El-Khalifa MY, Yadav G, Marafie MJ, Bastaki L, Wahba RA, Mohammed FM, Abul-Hassan S, Redha AA, Redha MA, Al-Aboud H, Al-Hijji S, Al-Digashem D, Al-Hashash N, Al-Jeryan L, Al-Khorafi H, Qurban EA, Al-Sulaiman I (1993) Disease profile of 400 institutionalized mentally retarded patients in Kuwait. Clin Genet 44:329–334 Filon D, Oron V, Krichevski S, Shaag A, Shaag Y, Warren TC, Goldfarb A, Shneor YU, Koren A, Aker M, Abramov A, Rachmilewitz EA, Rund D, Kazazian HH Jr, Oppenheim A (1994) Diversity in b-globin mutations in Israeli ethnic groups reflects recent historic events. Am J Hum Genet 54:836–843 Filon D, Oron V, Shawa R, Elborno E, Najjar K, Tuchinsku T, Rachimilewitz E, Rund D, Oppenheim A (1995) Spectrum of b-thalassemia mutations in the Gaza area. Hum Mutat 5:351–353 Freundlich E, Hino N (1984) Consanguineous marriage among rural Arabs in Israel. Isr J Med Sci 20:1035–1038 Frydman M, Weinstock AL, Cohen HA, Savir H, Varsana I (1991) Autosomal recessive Peter’s anomaly, typical facial appearance, failure to thrive, hydrocephalus, and other anomalies: further delineation of the Krause-Kivlin syndrome. Am J Med Genet 40:34–40 Galacteros F, Girodon E, M’Rad A, Martin J, Goossens M, Jaber L, Cohen LH, Tamary H, Goshen Y, Zaizov R, Wajcman H (1994) HB Taybe (a38 or 39 THR deleted): an a globin defect, silent in the heterozygous state and producing severe haemolytic anemia in the homozygous. C R Acad Sci Paris, Life Sci 317:437–444 Gershoni-Baruch R, Drugan A, Bronshtein M, Zimmer EZ (1990) Robert’s syndrome or X-linked Amelia. Am J Med Genet 37:569–572 Gershoni-Baruch R, Rm L, Lichtig C, Sojov P, Machoul I (1991) Cerebro-oculo-facio-skeletal syndrome: further delineation. Am J Med Genet 41:74–77 Glaser B, Phillip M, Carmi R, Lieberman E, Landau H (1990) Persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis): autosomal recessive inheritance in 7 pedigrees. Am J Med Genet 37:511–515 Hammer MF, Redd AJ, Wood ET, Bonner MR, Jarjanazi KT, Santachiara-Benerecetti S, Oppenheim A, Jobling MA, Jenkins T, Ostrer H, Bonne-Tamir B (2000) Jewish and Middle Eastern non-Jewish populations share a common pool of Y-chromosome biallelic haplotypes. Proc Natl Acad Sci 97(12):6769–6774 Harden D (1962) The Phoenicians. Praeger, New York, p 336 Heinisch U, Zlotogora J, Kafert S, Giselmann V (1995) Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. Am J Hum Genet 56:51–57 Hurwich BJ, Rosner B, Nubani N, Kass EH, Lewitter FI (1982) Familial aggregation of blood pressure in a highly inbred community, Abu Ghosh, Israel. Am J Epidemiol 115:646–656 Husseini A, Abu-Rmeileh NM, Mikki N, Ramahi TM, Ghosh HA, Barghuthi N, Khalili M, Bjertness E, Holmboe-Ottesen G, Jervell J (2009) Cardiovascular diseases, diabetes mellitus, and cancer in the occupied Palestinian territory. Lancet 373(9668):1041–1049. Erratum: Lancet 373(9677):1764 Issa ARA, Teebi AS, Issa MA, Shaabani IS, Ramadan DJ (1988) Metabolic alkalosis in cystic fibrosis: atypical presentation in Kuwait. Ann Trop Paediatr 8:271–272 Jaber L, Merlob P, Bu XD, Rotter JI, Shohat M (1992) Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community. Am J Med Genet 44:1–6 Jaber L, Bailey-Wilson JE, Haj-Yehia M, Hermandez J, Shohat M (1994) Consanguineous matings in an Israeli-Arab community. Arch Pediatr Adolesc Med 148:412–415

17

Genetic Disorders Among the Palestinians

511

Janson S, Jayakoddy A, Abulaban A, Gustavson KH (1990) Severe mental retardation in Jordanian children. A retrospective study. Acta Pediatr Scand 79:1099–1104 Juabeh II, Dudin AA, Thalji A (1987) Meckel-Gruber syndrome in one of non-identical twins: short case report. Acta Genet Med Gemellol 36:571–572 Kalbian V (1956) Laurence-Moon-Bardet-Biedl syndrome in an Arab boy: familial incidence. J Clin Endocrinol 16:1622–1625 Karadsheh NS (1993) Pyruvate kinase (PK) deficiency in Jordan. Haematologica 78:180–183 Katznelson D (1978) Cystic fibrosis in Israel: clinical and genetic aspects. Isr J Med Sci 14:204–207 Katznelson D (1982) Cystic fibrosis in the Middle East. Lancet 1:112 Kleinman S, Bernstein J, Schwartz Eisensmith CR, Woo SLC, Shiloh Y (1992a) A defective splice site at the phenylalanine hydroxylase gene in phenylketonuria and benign hyperphenylalaninemia among Palestinian Arabs. Hum Mutat 1:340–343 Kleinman S, Schwartz G, Akawi Y, Woo SLC, Shiloh Y (1992b) A 22-bp deletion at the phenylalanine hydroxylase gene causing phenylketonuria in an Arab family. Hum Mutat 1:344–346 Kleinman S, Li J, Schwartz G, Eisensmith RC, Woo SLC, Shiloh Y (1993) Inactivation of phenylalanine hydroxylase by a missense mutation, R2705, in a Palestinian kinship with phenylketonuria. Hum Mol Genet 2:605–606 Kleinman S, Avigad S, Vanagaite L, Shmuelevitz A, David M, Eisensmith RC, Brand N, Schwartz G, Rey F, Munnich A, Woo SLC, Shiloh Y (1994) Origins of hyperphenylalaninemia in Israel. Eur J Hum Genet 2:24–34 Klin B, Serour F, Freid K, Efrati Y, Vinograd T (1993) Familial thyroglossal duct cyst. Clin Genet 43:101–103 Kohn G, el Shawwa R, el Ravves E (1988) Isolated “clinical anophtalmia” in an extensively affected Arab kindred. Clin Genet 33(55):321–324 Kwitek-Black AE, Carmi R, Duyk GM, Buetow KH, Elbedour K, Parvari R, Yandava CN, Stone EM, Sheffield VC (1993) Linkage of Bardet-Biedl syndrome to chromosome 16q and evidence for non-allelic genetic heterogeneity. Nat Genet 5:392–396 Leppert M, Baird L, Anderson KL, Otterud B, Lupski JR, Lewis RA (1994) Bardet-Biedl syndrome is linked to DNA markers on chromosome 11q and is genetically heterogenous. Nat Genet 6:108–112 Lerer I, Cohen S, Chemke M, Sanilevich A, Rivlin J, Golan A, Yahav J, Friedman A, Abeliovich D (1990) The frequency of the DF508 mutation on cystic fibrosis chromosomes in Israeli families: correlation to CF haplotypes in Jewish communities and Arabs. Hum Genet 85:416–417 Lewitter FI, Hurwich BJ, Nubani N (1983) Tracing kinship through father’s first name in Abu Ghosh, an Israeli Arab patrilineal society. Hum Biol 55:375–381 Lubani MM, Issa ARA, Bushnaq R, Al-Saleh QA, Dudin KI, Reavey PC, El-Khalifa MY, Manandhar DS, Abdul Al YK, Ismail EA, Teebi AS (1990) Prevalence of congenital adrenal hyperplasia in Kuwait. Eur J Pediatr 149:391–392 Mahdi AH, Al-Nassar M (1991) Wolman’s disease in a Jordanian infant. Ann Trop Paediatr 11:305–308 Mahjneh I, Vannelli G, Bushby K, Marconi GP (1992) A large inbred Palestinian family with two forms of muscular dystrophy. Neuromuscul Disord 2:277–283 Majeed H, Barakat M (1989) Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 148:3636–3641 Majeed HA, Barakat M (1976) Acrodermatitis enteropathica – successful treatment with oral zinc. J Kwt Med Assoc 10:169–179 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, Al-Gharbawy F, Majeed SA, Al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomylitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115:730–734

512

B. Abu-Libdeh and A.S. Teebi

Marcus P, Verp M (1993) Menetrier disease in a child of a consanguineous union. Am J Med Genet 47:1231–1232 Mathew PM, Young JM, Abu-Osba YK, Mulhem BD, Hammoudi S, Hamdan JA, Sadi AR (1988) Persistent neonatal hyperinsulinism. Clin Pediatr 27:148–151 Mattar P (1993) Palestine. In: Bram LL, Dickey NH (eds) Funk and Wagnalls New Encyclopedia, vol 20. Funk and Wagnalls, New York, pp 93–99 Nevo S (1988) Genetic blood markers in Arab Druze of Israel. Am J Phys Anthropol 77: 183–190 Nevo S, Cleve H (1983) Gc subtypes in the Middle East: report on an Arab Moslem population from Israel. Am J Phys Anthropol 60:587–603 Nevo S, Kanaaneh H, Cleve H (1982) A genetic study of alpha-antitrypsin in an Israeli Arab population, with a new allele: Piv-s. Isr J Med Sci 18:891–893 Nevo S, Cleve H, Koller A, Eigel E, Patutschnick W, Kanaaneh H, Joel A (1993) Serum protein polymorphisms in Arab Moslems and Druze in Israel: BF, F13B, AHSG, GC, PLG, PI, and TF. Hum Biol 64:587–603 Newman PJ, Seligsohn U, Lyman S, Coller BS (1991) The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc Natl Acad Sci USA 88:3160–3164 Omari YI (1985) A preliminary study on the fingerprint patterns of Jordanians. Dirasat (Jordan University Publications) 12:53–63 Omari YI (1986a) Distribution of mid-digital hair in Jordanian populations. Broteria Genet 7:133–144 Omari YI (1986b) Taste deficiency of phenylthiouria in Jordanian population. Iraqi J Biol Sci 71:253–265 Omari YI (1991) A dermatoglyphic study of Jordanian populations. Broteria Genet 7:151–160 Omari YI (1992) A dermatoglyphic study of Jordanians: main-line index and transversality. Rev Brasil Genet 15:183–189 Omari YI (1993) A dermatoglyphic study of Jordanian populations. Part II: palmar configurations. Broteria Genet 14:161–166 Raas-Rothschild A, Dijkhuizen T, Sikkema-Raddatz B, Werner M, Dagan J, Abeliovich D, Lerer I (2009) The8q22.1 microdeletion syndrome or Nablus mask-like facial syndrome: report on two patients and review of the literature. Eur J Med Genet 52(2–3):140–144 Rachmilewitz EA, Tamari H, Liff F, Ueda Y, Nagel RL (1985) The interaction of hemoglobin O Arab with Hb S and beta-thalassemia among Israeli Arabs. Hum Genet 70:119–125 Rambaud-Cousson A, Dudin AA, Zuaiter AS, Thalji A (1991) Syndactyly type IV/hexadactyly of feet associated with unilateral absence of the tibia. Am J Med Genet 70:144–145 Ritte U, Neufeld E, Prager EM, Gross M, Hakim I, Khatib A, Bonne´-Tamir B (1993) Mitochondrial DNA affinity of several Jewish communities. Hum Biol 65:359–385 Rosler A (2006) 17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population. Pediatr Endocrinol Rev 3(Suppl 3):455–461 Rosler A, Silverstein S, Abeliovich D (1996) A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females. J Clin Endocrinol Metab 81(5):1827–1831 Rund D, Kornhendler N, Shalev O, Oppenheim A (1990) The origin of sickle cell alleles in Israel. Hum Genet 85:521–524 Saha N, Banerjee B (1986) A study of some blood genetic characteristics of Bedouin and nonBedouin Arabs of Jordan. Hum Hered 35:276–280 Said R, Hamzeh Y, Said S, Tarawneh M, Al-Khateeb M (1992) Spectrum of renal involvement in familial Mediterranean fever. Kidney Int 41:414–419 Shahin H, Walsh T, Sobe T, Lynch E, King MC, Avraham KB, Kanaan M (2002) Genetics of congenital deafness in the Palestinian population: multiple connxin 26 alleles with shared origins in the Middle East. Hum Genet 110(3):284–289

17

Genetic Disorders Among the Palestinians

513

Sheffield VC, Carmi R, Kwitekblack A, Rokhlina T, Nishimura D, Duyk GM, Elbedour K, Sunden SL, Stone EM (1994) Identification of a Bardet-Biedl syndrome locus on chromosomes 3 and evaluation of an efficient approach to homozygosity mapping. Hum Mol Genet 3: 1331–1335 Shoshani T, Augarten A, Gazit E, Bashan N, Yahav Y, Rivlin Y, Tal A, Seret H, Yaar L, Kerem E, Kerem B-S (1992) Association of a nonsense mutation (W 1282 X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet 50:222–228 Seligsohn U, Berger A, Abend M, Rubin L, Attias D, Zivelin A, Rapaport SI (1984) Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Eng J Med 310:559–562 Sirdah M, Bilto YY, el Jabour S, Najjar K (1998) Screening secondary school students in the Gaza strip for beta-thalassaemia trait. Clin Lab Haematol 20(5):279–283 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever: a survey of 470 cases and review of literature. Am J Med Genet 43:120–121 Palestinian Central Bureau of Statistics (2003) The total number of Palestinian population in the world for the end year 2003. Statistical Abstract of Palestine No (5) Palestinian Central Bureau of Statistics (2009) The final census report of 2007 statistics, issued Feb. 2009 Svejcar J (1993) Biochemical abnormalities in connective tissue of osteodyplasty of MelnickNeedles and dyssegmental dwarfism. Clin Genet 23:369–375 Teebi AS (1990) Autosomal recessive Robinow syndrome. Am J Med Genet 35:64–68 Teebi AS (1991) Trigonobrachycephaly, bulbous bifid nose, mascrostomia, micrognathia, acral anomalies, and hypotonia in sibs. Am N Med Genet 38:529–531 Teebi AS (1993) Limb/pelvis/uterus-hypoplasia/aplasia syndrome. Am J Med Genet 30:797 Teebi AS (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 Teebi AS (2000) Nablus mask-like facial syndrome. Am J Med Genet 95:407–408 Teebi AS, AL-Saleh QA (1989) Nonsyndromal microphthalmia. Clin Genet 35(4):311–312 Teebi A, Naguib K (1988) Autosomal recessive nonsyndromal hydrocephalus. Am J Med Genet 31:467–470 Teebi AS, Teebi SA (2005) Genetic diversity among the Arabs. Community Genet 8(1):21–26 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK (1986a) Hypogonadotropic hypogonadism, mental retardation, obesity, and minor skeletal abnormalities: another new autosomal recessive syndrome from the Middle East. Am J Med Genet 24:373–378 Teebi AS, Al-Awadi SA, Opitz JM, Spranger J (1986b) Severe short limb dwarfism resembling Grebe chondrodysplasia. Hum Genet 74:386–390 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK, El-Khalifa MY (1987a) Phenylketonuria in Kuwait and Arab countries. Eur J Pediatr 146:59–60 Teebi AS, Al-Awadi SA, White AG (1987b) Autosomal recessive nonsyndromal microcephaly with normal intelligence. Am J Med Genet 26:355–359 Teebi AS, Al-Saleh QA, Hassoon MM, Farag TI, Al-Awadi SA (1989) Macrosomia, microphthalmia, cleft palate, and early infant death: a new autosomal recessive syndrome. Clin Genet 36:174–177 Teebi AS, Al-Saleh QA, Odeh H (1992) Meckel syndrome and neural tube defects in Kuwait regional hospital. J Med Genet 29:140 Telmesani A (1994) A rare association of myelomeningocele with cloacal duplication malformation. Ann Trop Paediatr 14:253–256 Turnpenny PD, Thwaites RJ (1992) Dwarfism, rhizomelic limb shortness, and abnormal face: new short stature syndrome sharing some manifestations with Robinow syndrome. Am J Med Genet 42:724–727 van Lieburg AF, Verdijk MAJ, Knoers VVAM, van Essen AJ, Proesmans W, Mallman R, Monnens LAH, van Oost BA, van OS CH, Deen PMT (1994) Patients with autosomal

514

B. Abu-Libdeh and A.S. Teebi

nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene. Am J Hum Genet 55:648–652 Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, Lee MK, Kanaan M, King MC, Avraham KB (2002) From flies’ eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Nai Acad Sci USA 99(11):7518–7523 Walsh T, Abu Rayan A, Abu Sa’ed J, Shahin H, Shepshelovich J, Lee MK, Hirschberg K, Tekin M, Salhab W, Avraham KB, King MC, Kanaan M (2006) Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population. Hum Genomics 2(4):203–211 Yadav GC, Reavey PC (1988) Aminoacidopathies: a review of three years experience of investigations in a Kuwaiti hospital. J Inherit Metab Dis 11:277–284 Younis K (2006) Premarital testing for b-thalassemia in Palestine. Thalassemia International Federation (TIF) Magazine 49:23 Zaghloul NA, Katsanis N (2009 Mar) Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest 119(3):428–437 Zlotogora J, Glick B (1993) Jancar syndrome: mental retardation, spasticity, and distal transverse limb defects. Am J Med Genet 47:89–90 Zlotogora J, Regev R, Zeigler M, Iancu TC, Bach G (1985) Krabbe disease: increased incidence in highly inbred community. Am J Med Genet 21:765–770 Zlotogora J, Levy-Lahad E, Legum C, Ianca TC, Zeigler M, Bach G (1991) Krabbe disease in Israel. Isr J Med Sci 31:196–198 Zlotogora J, Furman-Shaharabani Y, Harris A, Barth ML, von Figura K, Gieselmann V (1994a) A single origin for the most frequent mutation causing late infantile metachromatic leukodystrophy. J Med Genet 31:672–674 Zlotogora J, Sagi M, Cohen T (1994b) Familial hydrocephalus of prenatal onset. Am J Med Genet 49:202–204

Chapter 18

Genetic Disorders in Qatar Ahmad S. Teebi and Tawfeg Ben-Omran

Geography and History Qatar occupies a small peninsula that extends into the Persian Gulf from the eastern side of the Arabian Peninsula (Fig. 18.1). Saudi Arabia is to the west and the United Arab Emirates (UAE) to the south. The country, mainly a barren desert, covers an area of 11,437 km2 that roughly stretches across 160 km. Qatar’s history is very eventful, indicating the various phases that led to the ultimate development of the present State. The first trace of human settlements was found in the Qatar Peninsula around 4000 BC. Archeologists from France, Britain and Denmark found some rock carvings and pieces of pottery that indicate signs of human settlements in Qatar. According to some historians, the first inhabitants were the Cannanities, who were experts in navigation and trading skills. The locational importance of Qatar is responsible for the inflow of Arab tribes from the Arabian Peninsula, especially from the Nejd Desert. Its people embraced Islam in the seventh century AD, and later on, Qatar played a significant role in spreading this religion to various parts of the world. Qatar from the very beginning is famous for its expertise in cloth making and weaving. Apart from this, the country also has the best-quality camels and horses. The history of Qatar is also indicative of the fact that Qatar had good relations with the Caliphs of Baghdad. The artifacts of the Abbasids were found in Moab fort in western Qatar. In the beginning of the sixteenth century, Qatar fell under the control of the Portuguese who were successful in establishing their control in many parts of the Arabian Peninsula. The Portuguese also efficiently controlled trade and navigation. Later on, in 1538 AD, the Portuguese were overthrown by the Ottomans. The Ottomans ruled Qatar for four centuries.

A.S. Teebi (*) Weill Cornell Medical College, Qatar Foundation, Doha Education City, Qatar e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_18, # Springer-Verlag Berlin Heidelberg 2010

515

516

A.S. Teebi and T. Ben-Omran

Fig. 18.1 Map of the State of Qatar

Qatar was once controlled by Bani Khaled who also ruled Bahrain, but in 1867 war broke out between the people and their absentee rulers. To keep peace in the Persian Gulf, the British negotiated a settlement and Sheikh Muhammad ibn Thani Al-Thani, head of a leading Qatari family, was installed as the region’s ruler.

18

Genetic Disorders in Qatar

517

In 1893, the Ottoman Turks made incursions into Qatar, but the emir successfully deflected them. In 1916, the emir agreed to allow Qatar to become a British protectorate. In 1971, Qatar agreed to join the other emirates of the Trucial Coast to become part of the UAE. But both Qatar and Bahrain decided against the merger and instead formed independent nations in the same year. In 1998, Qatar became a member of Gulf Cooperation Council (GCC) along with UAE, Saudi Arabia, Oman, Bahrain and Kuwait. Traditionally poor and populated by nomadic peoples, the country’s economy, originally dominated by pearl-diving, was in ruins by the end of the 1930s when cultured-pearl production took off in Japan. Oil was discovered in the 1940s, bringing wealth to the country in the 1950s and 1960s. About 85% of Qatar’s income comes from exports of oil and gas. Its people have one of the highest per capita incomes in the world.

Population of Qatar According to the last census, conducted by the Planning Council in 2004, the total population of Qatar is 744,029. The census shows a 5.3% average annual increase in population between 1997 and 2004. Between 1986 and 1997, the average annual increase was only 3.7%. The rapid increase in population is due to the country’s strong economic performance, fuelling an influx to the country of contracting and services staff as well as expatriate professionals. According to some official estimates, the population was as high as 1,500,000 in 2008. In recent years, the total number of live births was around 15,000. In recent years, the country’s population has been roughly split into 20% native Qatari (largely tribal), 25% other Arabs from Egypt, Syria, Iraq, Lebanon, Yemen, Palestine and Jordan and the rest (50–55%) from non-Arab expatriates. The majority of migrant workers come from South Asia, the Philippines and Iran. The gender breakdown from the 2004 census shows that men represent 66.7% of the total population while women make up only 33.3%. The widening imbalance is due to the large number of male expatriate workers entering the country. Generally, there is rapid population growth with large family size of more than five children per family.

Genetic Services Medical genetic services are relatively new. A small diagnostic cytogenetic laboratory was operational since the late 1980s. In the late 1990s, a clinical genetics and metabolic unit was established within the pediatric department at Hamad Medical Corporation (HMC). As a part of the program, visiting consultants from outside the country were involved. Later on, in 2004, the unit was enlarged to involve permanent consultants with North American and European training. Around this

518

A.S. Teebi and T. Ben-Omran

time, the diagnostic molecular genetic laboratory within HMC became operational, performing a number of the most needed tests. This was commenced with the establishment of an extended state-wide neonatal screening program for metabolic and endocrine disorders (December 2003) in collaboration with the University Children’s Hospital of Heidelberg, Germany. The screening involves more than 30 disorders and includes all live births in the country. In 2009, Qatar’s Medical Genetic Center was established to include all existing clinical and metabolic genetics, counseling, diagnostic laboratories and genetic/genomic research. Additional participation comes from the involvement of Weill Cornell Medical College in Qatar, and the Shafallah Medical Genetics Center involved mainly with people of special needs.

Consanguinity Generally speaking, the national Qatari population is highly endogamous. It is made up of a number of large Bedouin tribes, and some urban people have originated from neighboring countries. Consanguinity rate was found to be 54%, with the majority being between first cousins (Bener and Hussain 2006). The effect of consanguinity is well studied in relation to autosomal recessive disorders, while its effect on common adult diseases was studied recently in Qatar. The study showed an increased prevalence of common adult diseases in the consanguineous group (Bener and Alali 2006; Bener et al. 2007). In an earlier study, the prevalence of first cousin marriage in Qatari population was found to be 47% (Saad and Jauniaux 2002). There was no relationship between recurrent pregnancy losses and consanguinity in this study. A recent study (Bener et al. 2009) revealed that although the consanguinity rate is high in the population of Qatar, it has no effect on the incidence of cancers overall.

Genetic Disorders Reported from Qatar The magnitude of genetic disorders and birth defects is relatively high given the small population size. It is not only the autosomal recessive disorders that are apparently increased because of consanguinity but also the common multifactorial disorders such as diabetes mellitus type 2, obesity, psychosis and the congenital malformations that are seen in excess (Bener and Hussain 2006; Bener et al. 2007).

Chromosomal Disorders Down syndrome incidence was found to be 1:513 live births (Wahab et al. 2006). The most common abnormality was regular trisomy 21 (98.3%). The relatively high

18

Genetic Disorders in Qatar

519

incidence figure was attributed, in part, to the advanced maternal age. The median age was 36 years, and 48.5% of mothers were above 36 years. The existence of some genetic factors predisposing to nondisjunction was not excluded as a contributing factor.

Multifactorial Birth Defects Congenital heart disease was diagnosed in 610 of 49,887 live-born children between 1984 and 1994, making an incidence of 12:1,000 live births (Robida et al. 1997). In the period 1986–1989, 34 case of hydrocephalus were diagnosed prenatally and 31 after delivery (Nogueira 1992). Among them, 17 cases had meningomyelocele and in 12 others malformations outside the nervous system were observed. The incidence of hydrocephalus in this study was 157:100,000 live births and for meningomyelocele the incidence was 41:100,000 live births. A recent analysis of the birth defects registry data revealed that 905 newborns had major birth defects out of 54,314 live births over a 4-year period from 2004 to 2007 giving an incidence of 1.67% (Salameh and Teebi, unpublished). Another study from the main maternity hospital showed that the incidence of neural tube defects including anencephaly, meningomyelocele and congenital hydrocephalus over a 10-year period was 8.7:1,000 births (Kurdi and Teebi, unpublished)

Autosomal Dominant Disorders In the Genetic Clinic, such disorders are observed repeatedly, and the pattern and frequencies are not different from those in other parts of the world. Marfan syndrome, NF1, Tuberous sclerosis, Familial dilated cardiomyopathy, achondroplasia and hypochodroplasia, Treacher Collin syndrome and multiple exostosis syndrome. Craniosynostosis syndromes including Apert syndrome, Crouzon, Pfeiffer, Saethrae Chotzon syndrome and FGFR3-related craniosynostosis (Muenke syndrome) are also diagnosed. Multiple endocrine neoplasia type IIA was reported in a three-generation family (Zirie et al. 2001). Huntington chorea was seen in one family only; however, this was not observed previously by the author (AST) during his long practice in Kuwait, reflecting the extreme rarity of this disorder among the Arabs in this region. Other neurogenetic disorders observed include various types of Charcot-Marie-Tooth syndrome and spinocerebellar ataxias. Other disorders seen include autosomal dominant Robinow syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, Cornelia de Lange’s syndrome, Rubinstein-Taybi syndrome, Beckwith-Wiedemann syndrome and von Hippel-Lindau syndrome.

520

A.S. Teebi and T. Ben-Omran

X-Linked Disorders Among the relatively common disorders is the glucose-6-phosphate dehydrogenase deficiency (G6PD) (Al-Jawadi and Al-Hilali 1998). In Qatar, the frequency is around 5%. However, in Oman and Bahrain the frequency among males is around 27% (White et al. 1986). Other disorders diagnosed include incontinentia pigmenti (El-Benhawi and George 1988) Lenz microphthalmia syndrome, X-linked ichthyosis, hemophilia, color blindness and X-linked hypophosphatemic rickets.

Autosomal Recessive Disorders Similar to other parts of the Arab world, this entity is the most prominent and the frequency of autosomal recessive conditions as a group collectively is apparently increased. It is often not difficult to trace a particular disorder to a common ancestor. Several examples are available including cystic fibrosis (CF), homocystinuria, arterial tortuosity syndrome (ATS), nonsyndromic microphthalmia/ anophthalmia, and Teebi-Shaltout syndrome, among others (Teebi and BenOmran 2008). These disorders are discussed below in detail. In addition to this in relation to consanguinity, there are several examples of families having affected children with more than one autosomal recessive condition in the same person or the same sibship.

Cystic Fibrosis (CF, MIM 219700; CFTR, MIM 602421) The frequency of CF in the Arabs in most parts of Arab world is probably similar to that in western countries but with different clinical presentation and pattern of mutations with many new and rare mutations found. Abdul Wahab et al. (2000) reported on 45 patients with CF diagnosed between 1987 and 1999 in the main hospital in Qatar. Twenty-six of the 32 families ascertained to have CF belonged to the same Bedouin tribe. The parents of 98% of the patients were consanguineous. The patient’s manifestations were mild to moderate. Homozygous I1234V mutation in exon 9 of CFTR gene was identified in all 29 patients belonged to the same tribe illustrating the founder effect in this tribe (Abdul Wahab et al. 2001). A multiparous Qatari lady presented with chronic lung disease was found to have the same homozygous mutation (Wahab 2003). The pattern of microbiological agents responsible for chronic pulmonary infection was studied in 36 patients with mutation from Qatar (Wahab et al. 2004a). The number of cases ascertained with this mutation is close to 75 from Qatar, reflecting a very high incidence of CF in this tribe. There are examples of other mutations seen in the expatriates in Qatar (Wahab et al. 2002, 2004b, c).

18

Genetic Disorders in Qatar

521

Inborn Errors of Metabolism Qatar is the first Arab Country to establish an extended state-wide neonatal screening program. It is performed in collaboration with the University Children’s Hospital of Heidelberg since December 2003, with laboratory situated in Germany. This program had replaced the screening for congenital hypothyroidism (CH) from cord blood that had been in operation since 1996. In less than 3 years, between December 2003 and July 2006, 25,214 neonates born in the State of Qatar were investigated for inborn errors of metabolism and endocrine disorders with the incidence of metabolic disorders (26 disorders) found to be 1:1,327 (in Germany 1:2,517) (Lindner et al. 2007). Among them, aminoacidopathies, fatty acid oxidation defects, organic acidurias and biotinidase deficiency are prevalent. Individual disorders diagnosed and confirmed through the neonatal screening programs as well as those ascertained in the metabolic clinic are included in Table 18.1.

Homocystinuria (CBS, MIM 236200) By clinical evaluation, the incidence of classical homocystinuria (CBS deficiency) was found to be individually higher than 1:3,000; it is the most common metabolic disease in Qatar with the highest incidence in the world (El-Said et al. 2006). Unfortunately, homocystinuria was poorly identified in the screening program before July 2006 when a new tandem mass spectrometric method for neonatal screening of homocystinuria was developed and implemented (Lindner et al. 2007). Sixty-four patients with homocystinuria from 31 nuclear families were ascertained clinically over a period of more than 4 years (2001–2005) (El-Said et al. 2006). Molecular studies performed on all the above showed that all 53 patients from a single tribe (tribe 1) and all 3 patients from another tribe (tribe 2) were homozygous for the mutation p.R336C of CBS gene. There were additionally seven patients resulting from mixed marriages between tribe 1 and tribe 2. Only one patient from tribe 3 was found to have the mutation p.D234N in the CBS gene. A recent study from Qatar showed that increased homocystine concentrations in CBS gene mutation carriers are associated with reduced concentrations of folic acid and vitamin B12 in blood (El-Said et al. 2007). The author recommended routine testing of vitamin status in heterozygous parents and higher doses of dietary vitamins may be warranted. In order to facilitate reliable early diagnosis of this treatable disease, a novel combined metabolic and molecular testing strategy for newborn screening of CBS deficiency in the Qatari population was established. Over a period of two and a half years (July 2006–December 2008), 38,206 newborns born in Qatar were screened. Classical homocystinuria was detected in ten neonates. In addition, 239 were carriers for the common Qatari mutations. This confirms a very high incidence of homocystinuria in Qatar, possibly reaching up to 1:1,800 in native Qataris (Zschocke et al. 2009; Gan-Schreier et al. 2010). However, from our observation, the incidence of homocystinuria was at least 1:1,400 live births.

522

A.S. Teebi and T. Ben-Omran

Table 18.1 Confirmed cases by NBS and disorders ascertained in the metabolic Clinic Disease/syndrome References Arginosuccinate lyase deficiency (ASL) Batten’s disease b-ketothiolase deficiency Biotinidase Carnitine palmitoyltransferase I (CPT I) deficiency Classical homocystinuria Citrullinaemia Ethylmalonic encephalopathy Familial hypertriglyceridaemia GM1 gangliosidosis Glycogen storage disease type I Glycogen storage disease type II Glycogen storage disease type III Glutaric aciduria type I Glutaric aciduria type II Galactosialidosis Gaucher disease Galactosemia HMG-CoA lyase deficiency Hyperinsulinism/hyperammonemia (HI/HA) syndrome Kapoor et al. (2009) Isovaleric acidemia Maple syrup urine disease (MSUD) Medium chain acyl-CoA dehydrogenize deficiency Methylmalonic aciduria 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCC) Mitochondrial diseases Mucopolysaccharidosis type I Mucopolysaccharidosis type II Mucopolysaccharidosis type III Mucopolysaccharidosis type IV Mucopolysaccharidosis type VI Mucolipidosis type II (I cell disease) Niemann-Pick disease type B Metachromatic leukodystrophy Niemann-Pick disease type C Oculocutaneous albinism Phenylketonuria (PKU) Primary carnitine deficiency Propionic aciduria Sandhoff disease Abdul-Wahab et al. (2002) Tetrahydrobiopterin deficiency Tyrosinemia Very long chain acyl-CoA carboxylase deficiency

MIM# 207900 204200 203750 253260 255120 236200 215700 602473 145750 230500 232200 232300 232400 231670 231680 256540 230800 230400 246450 138130 243500 248600 201450 251000 210200 607014 309900 252900 253200 253200 252500 607616 250100 257220 203100 261600 212140 606054 268800 261630 276700 201475

Homocystinuria provides another example of founder effect in Qatar where the bulk of cases with a single mutation present in a single endogamous tribe. It is one of the diseases with carrier status screening included in the National Premarital Screening and Counseling program in Qatar.

18

Genetic Disorders in Qatar

523

Fig. 18.2 Sibling with arterial tortuosity syndrome. Note the similarity in facial features related to looseness of skin

Arterial Tortuosity Syndrome (ATS, MIM 208050) A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries was described in 32 patients in several sibships from a large Qatari tribe with a lot of intermarriages (Abdul Wahab et al. 2003). Subsequently, more patients were identified to have the same disorder from the same tribe in Qatar. Features include variable degree of skin hyperelasticity, hypermobility of small and large joints, characteristic facial appearance, diaphragmatic hernia and tortuous systemic arteries (Fig. 18.2) (Abdul Wahab et al. 2003; Zaidi et al. 2009). Molecular studies of 15 affected individuals from 10 families have identified a p.Ser81Arg encoding mutation in SLC2A10 gene (Faiyaz-Ul-Haque et al. 2008). From a near-by country, two Saudi Arabian unrelated families with similar phenotype have been found to have a novel missense mutation (p.Arg105Cys) and a recurrent mutation (p.Ser81Arg) in the SLC2A10 gene (Faiyaz-Ul-Haque et al. 2009).

Nonsyndromic Microphthalmia/Anophthalmia (MIM 251600, 610092, 6200930) In 2004, we investigated four families ascertained to have nonsyndromic microphthalmia (Fig. 18.3). Patients were recruited from the school of blind. Two of the families with total six affected siblings had homozygous mutation c.599G>C in exon 4 of the CHX10 gene. This mutation produces p.Arg200Pro substitution (Faiyaz-Ul-Haque et al. 2007). The two families belonged to the same Bedouin tribe. Recently, two more families from the same tribe presenting with similarly affected individuals were also found to have the mutation. Carriers were identified and premarital counseling within the same tribe was highly recommended. Two families affected with this disorder had a successful preimplantation genetic diagnosis (PGD).

524

A.S. Teebi and T. Ben-Omran

Fig. 18.3 A new born with nonsyndromic microphthalmia/ anophthalmia ascertained to have CHX10 mutation

Fig. 18.4 A child with TeebiShaltout syndrome (TSS) from Qatar. Note the characteristic facial features with small eyes and mouth

Teebi-Shaltout Syndrome (MIM 272950) To date, three related families with four affected siblings were diagnosed. The families belonged to the same tribe. Another family with two affected children was also ascertained. The origin of this family is from Pakistan. Features included characteristic facies with small mouth opening and deep-set eyes, camptodactyly of fingers, long big toe, and caudal appendage among others (Figs. 18.4–18.6). Families reported here are currently recruited for gene mapping and cloning.

Epidermolysis Bullosa, Junctional Type (MIM226700) To date, five related families with five affected children (two females and three males) were diagnosed. The families belonged to the same Bedouin tribe. Two of the families had homozygous splice mutation c.3609þ1G>A of the LAMA3 gene.

18

Genetic Disorders in Qatar

525

Fig. 18.5 Hands of a child with TSS. Note the camptodactyly

Fig. 18.6 The foot of a child with TSS. Note the long first toe and syndactyly between second and third

Endocrine Disorders According to the neonatal screening program, incidence of endocrine disorders, which include CH and congenital adrenal hyperplasia, was found to be 1:2,801 which is similar to that in Germany (1:2,784) (Lindner et al. 2007). Hemoglobinopathies Thalassemias in particular b-thalassemia (b-thal) are frequently diagnosed in Qatar. In the main pediatric department at HMC in Doha, at least 60 patients with thalassemia major are seen on a regular basis. Adult patients are seen elsewhere by hematologists. The frequency of heterozygotes is estimated to be 2–3%. Recently, Al-Obaidli et al. (2007) studied at molecular level 31 clinically recognized patients with b-thal including three with sickle cell disease and b-thal, and

526

A.S. Teebi and T. Ben-Omran

Fig. 18.7 Three siblings with Peters plus syndrome with overlapping features with Malpuech syndrome including eyes abnormalities, clefting, and caudal appendage

additional six cases referred because of unexplained microcytic anemia. They found 12 different b-thal alleles and 2 undefined alleles which highlights ethnic diversity in the small population of Qatar. Sickle cell disease is also relatively common in Qatar. At least 70 patients are followed up by the pediatric department of HMC. The frequency of sickle cell trait is estimated to be 3%. Sickle cell is amongst the disorders that are included recently in the neonatal screening program, and both sickle cell and thalassemias are included in the National Premarital Screening and Counseling program in Qatar.

Miscellaneous Disorders/Syndromes Many autosomal recessive disorders/syndromes either previously reported from Qatar or diagnosed by our group are included in Table 18.2. This reflects a wide range of disorders seen in Clinical Genetics and Metabolic Clinics. One of those disorders is the Peters plus syndrome overlapping with Malpuech syndrome features including facial clefting and caudal appendage in four siblings of consanguineous parents (Fig. 18.7). The family was confirmed to have Peters plus by finding homozygosity of splice site mutation in intron 6 of the B3GALTL gene (c459þ1G>A)(unpublished). Another disorder is a new disorder with the constellation of lissencephaly, IgG subclass immunodeficiency and easy bruisability with other connective tissue abnormalities, in a male child of first cousin parents (Ehlayel et al. 2009). A presumably new subtype of familial intracracranial calcification is recently reported (El-Said et al. 2010).

Comments The frequency of genetic disorders in Qatar has apparently increased, warranting attention and careful planning, in order to reduce their effects and incidence in

18

Genetic Disorders in Qatar

Table 18.2 Reported or diagnosed disorders/syndromes Disease/syndrome Aicardi-Goutierers Ataxia-telangiectasia

Autosmal recessive isolated ectopia lentis Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome Bartsocas-Papas syndrome Bruck syndrome Cohen syndrome Chondrodysplasia, Grebe type Donnai-Barrow syndrome Ellis-van creveld syndrome Epidermolysis bullosa, dystrophic type Familial hypertrophic synovitis Fanconi anemia Galactosyltransferase-I deficiency (facioskeletal type of Ehlers-Danlos) Gerodermia osteodysplastica Hypergonadotropic hypogonadism, partial alopecia Johanson-Blizzad syndrome Laron syndrome (growth hormone insensitivity syndrome) Leprechaunism Mal de Meleda disease Lethal multiple pterygium syndrome Multiple pterygium syndrome (Eskobar) Myofibrillar myopathy Meckel-Gruber syndrome Autosomal recessive microcephaly Noncompaction cardiomyopathy Peters Plus syndrome Retinitis pigmentosa Rhizomelic chondrodysplasia punctata Seckel syndrome Severe childhood autosomal recessive muscular dystrophy Stuve-Wiedemann syndrome The Carey-Fineman-Ziter syndrome Walker-Warburg syndrome Weaver syndrome Woodhouse-Sakati syndrome Wolcott-Rallison syndrome Xeroderma pigmentosum

Zellweger syndrome

527

References Osundwa and Dawod (1994) Ehlayel et al. (2008) Ahram et al. (2009) Massoud et al. (1998)

Kantarci et al. (2007)

Hammoudeh and Siam (1993) Faiyaz-Ul-Haque et al. (2004)

Hone et al. (1995)

El-Menyar et al. (2004)

El-Menyar et al. (2007)

Salih et al. (1984, 1996)

Fawzi et al. (2000)

Engelmann et al. (2008)

MIM # 225750 208900

225100 276820 263650 259450 216550 200700 222448 225500 226600 208250 227650 130070 604327 278250 241090 243800 262500 246200 248300 253290 265000 601419 249000 608716 300183 261540 608381 227650 210600 253700 608099 601559 254940 236670 277590 241080 226980 278700 278720 278730 278780 214100

528

A.S. Teebi and T. Ben-Omran

future. The pattern of the diseases is somewhat similar to other Arab countries with clustering of autosomal recessive conditions because of the effect of consanguinity, which is high in the population of Qatar. In Qatar, owing to the mixed population, a number of autosomal recessive disorders are found segregating the population in relatively higher frequencies, many of which are traced back to a common origin. There is a golden opportunity to learn classical genetics in Qatar from real-life experiences as well as to find new genes through research of rare and previously unknown disorders in Qatar and other Arab countries.

References Abdul Wahab A, Dawod ST, al Thani G (2000) Cystic fibrosis in a large kindred family in Qatar. Ann Trop Paediatr 20:203–207 Abdul Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M (2001) Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). J Trop Pediatr 47:110–112 Abdul Wahab A, Janahi IA, Eltohami A, Zeid A, Ul Haque NF, Teebi AS (2003) A new type of Ehlers-Danlos syndrome associated with tortuous systemic arteries in a large kindred from Qatar. Acta Paediatr 92:456–462 Abdul Wahab A, Janahi IA, El-Shafie SS (2004) Achromobacter xylosoxidans isolated from the sputum of a patient with cystic fibrosis mutation I1234V with Pseudomonas aeruginosa. Saudi Med J 25:810–811 Abdul-Wahab A, Bessisso MS, Elsaid MF (2002) Sandhoff disease (GM2 Gangliosidoses) in a premature patient with bronchopulmonary dysplasia. Saudi Med J 23:602–605 Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H (2009) A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84:274–278 Al-Jawadi O, Al-Hilali A (1998) Haemoglobin A2 concentration in glucose-6-phosphate-dehydrogenase-deficient patients. Acta Haematol 100:99–100 Al-Obaidli A, Hamodat M, Fawzi Z, Abu-Laban M, Gerard N, Krishnamoorthy R (2007) Molecular basis of thalassemia in Qatar. Hemoglobin 31:121–127 Bener A, Alali KA (2006) Consanguineous marriage in a newly developed country: the Qatari population. J Biosoc Sci 38:239–246 Bener A, Hussain R (2006) Consanguineous unions and child health in the State of Qatar. Paediatr Perinat Epidemiol 20(5):372–378 Bener A, Hussain R, Teebi AS (2007) Consanguineous marriages and their effects on common adult diseases: studies from an endogamous population. Med Princ Pract 16(4):262–267 Bener A, El-Ayoubi HR, Chouchane L, Ali AI, Al-Kubaisi A, Al-Sulaiti H, Teebi AS (2009) Impact of consanguinity on cacer in a highly endogamous population. Asian Pac J Cancer Prev 10:35–40 Ehlayel M, Ben-Omran T, Teebi AS (2009) Lissencephaly, IgG subclass immunodeficiency, and a connective tissue disorder: a new syndrome? Neurol 256:2087–2090 Ehlayel M, de Beaucoudrey L, Fike F, Nahas SA, Feinberg J, Casanova JL, Gatti RA (2008) Simultaneous presentation of 2 rare hereditary immunodeficiencies: IL-12 receptor beta1 deficiency and ataxia-telangiectasia. J Allergy Clin Immunol 122(6):1217–1219 El-Menyar AA, Bener A, Al Suwaidi J (2004) Cardiovascular manifestations of myofibrillar myopathy. Anadolu Kardiyol Derg 4:336–338 El-Benhawi MO, George WM (1988) Incontinentia pigmenti. Cutis 41:259–262, Review

18

Genetic Disorders in Qatar

529

El-Menyar AA, Gendi SM, Numan MT (2007) Noncompaction cardiomyopathy in the State of Qatar. Saudi Med J 28:429–434 El-Said MF, Bener A, Lindner M, Alzyoud M, Shahbek N, Abdelrahman MO, Abdoh G, Bessisso MS, Zschocke J, Hoffmann GF (2007) Are heterocygotes for classical homocystinuria at risk of vitamin B12 and folic acid deficiency? Mol Genet Metab 92:100–103 El-Said MF, Badii R, Bessisso MS, Shahbek N, El-Ali MG, El-Marikhie M, El-Zyoid M, Salem MS, Bener A, Hoffmann GF, Zschocke J (2006) A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat 27:719 El-Said MF, Cow YJ, Livingstone JH, Ben-Omran T (2010) New Subtype of familial intracranial calcification in a mother and two children. Am J Med Genet (in press) Engelmann G, Meyburg J, Shahbek N, Al-Ali M, Hairetis MH, Baker AJ, Rodenburg RJ, Wenning D, Flechtenmacher C, Ellard S, Smeitink JA, Hoffmann GF, Buchanan CR (2008) Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome. J Inherit Metab Dis 31:540–546 Faiyaz-Ul-Haque M, Zaidi SH, Al-Ali M, Al-Mureikhi MS, Kennedy S, Al-Thani G, Tsui LC, Teebi AS (2004) A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. Am J Med Genet A 128A:39–45 Faiyaz-Ul-Haque M, Zaidi SH, Al-Mureikhi MS, Peltekova I, Tsui LC, Teebi AS (2007) Mutations in the CHX10 gene in non-syndromic microphthalmia/anophthalmia patients from Qatar. Clin Genet 72:164–166 Faiyaz-Ul-Haque M, Zaidi SH, Wahab AA, Eltohami A, Al-Mureikhi MS, Al-Thani G, Peltekova VD, Tsui LC, Teebi AS (2008) Identification of a p.Ser81Arg encoding mutation in SLC2A10 gene of arterial tortuosity syndrome patients from 10 Qatari families. Clin Genet 74:189–193 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009) A novel missense and a recurrent mutation in SLC2A10 gene of patients affected with arterial tortuosity syndrome. Atherosclerosis 203:466–471 Fawzi M, Bessisso M, Omar F (2000) Walker-Warburg syndrome: a case report of a Qatari patient. Qatar Med J 9(2):66–67 Gan-Schreier H, Kebbewar M, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Bener A, Al Rifai H, Al Khal AL, Lindner M, Zschocke J, Hoffmann GF (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156(3): 427–432 Hammoudeh M, Siam AR (1993) Familial hypertrophic synovitis. Clin Rheumatol 12:401–404 Hone J, Accili D, Psiachou H, Alghband-Zadeh J, Mitton S, Wertheimer E, Sinclair L, Taylor SI (1995) Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism. Hum Mutat 6:17–22 Kantarci S, Al-Gazali L, Hill RS, Donnai D, Black GC, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, Liu T, MacLaughlin DT, Noonan KM, Russell MK, Walsh CA, Donahoe PK, Pober BR (2007) Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat Genet 39:957–959 Kapoor RR, Flanagan SE, Fulton P, Chakrapani A, Chadefaux B, Ben-Omran T, Banerjee I, Shield JP, Ellard S, Hussain K (2009) Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations. Eur J Endocrinol 161 (5):731–735 Lindner M, Abdoh G, Fang-Hoffmann J, Shabeck N, Al-Sayrafi M, Al-Janahi M, Ho S, Abdelrahman MO, Ben-Omran T, Bener A, Schulze A, Al-Rifai H, Al-Thani G, Hoffmann GF (2007) Implementation of extended neonatal screening and a metabolic unit in the State of Qatar: developing and optimizing strategies in cooperation with the Neonatal Screening Center in Heidelberg. J Inherit Metab Dis 30:522–529

530

A.S. Teebi and T. Ben-Omran

Massoud AA, Ammaari AN, Khan AS, ven Katraman B, Teebi AS (1998) Bartsocas-Papas syndrome in an Arab family with four affected sibs: further characterization. Am J Med Genet 27:16–21 Nogueira GJ (1992) Pre- and neonatal hydrocephalus in the Middle East: experience in Qatar. Childs Nerv Syst 8:40–44 Osundwa VM, Dawod ST (1994) The occurrence of ataxia-telangiectasia and common variable immunodeficiency in siblings: case report. Ann Trop Paediatr 14(1):71–73 Robida A, Folger GM, Hajar HA (1997) Incidence of congenital heart disease in Qatari children. Int J Cardiol 27:19–22 Saad FA, Jauniaux E (2002) Recurrent early pregnancy loss and consanguinity. Reprod Biomed Online 5:167–170 Salih MA, Ekmejian A, Ibrahim M, Omer A (1984) Respiratory insufficiency in a severe autosomal recessive form of muscular dystrophy. Ann Trop Paediatr 4:45–48 Salih MA, Mahdi AH, al-Rikabi AC, al-Bunyan M, Roberds SL, Anderson RD, Campbell KP (1996) Clinical and molecular pathological features of severe childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 38:262–270 Teebi AS, Ben-Omran T (2008) Genetic drift and founder effect: rediscovering genetics from Qatar. Second International Genetic Conference, Al-Ain, UAE. Abstract Wahab AA (2003) Cystic fibrosis mutation I1234V in a Qatari lady. J Trop Pediatr 49:54–55 Wahab AA, Janahi IA, Hebi S, al-Hamed M, Kambouris M (2002) Cystic fibrosis in a child from Syria. Ann Trop Paediatr 22:53–55 Wahab AA, Janahi IA, Marafia MM, El-Shafie S (2004a) Microbiological identification in cystic fibrosis patients with CFTR I1234V mutation. J Trop Pediatr 50:229–233 Wahab AA, Janahi IA, Marafia MM (2004b) Pseudo-Bartter’s syndrome in an Egyptian infant with cystic fibrosis mutation N1303K. J Trop Pediatr 50:242–244 Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M (2004c) Rare CFTR mutation 1525-1G>A in a Pakistani patient. J Trop Pediatr 50:120–122 Wahab AA, Bener A, Teebi AS (2006) The incidence patterns of Down syndrome in Qatar. Clin Genet 69:360–362 White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K (1986) Red cell genetic abnormalities in peninsular Arabs: sickle cell haemoglobin, G6PD deficiency, and alpha and beta thalassemia. J Med Genet 23:245–251 Zaidi SH, Meyer S, Peltekova VD, Lindinger A, Teebi AS, Faiyaz-Ul-Haque M (2009) A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin. Eur J Pediatr 168:867–870 Zirie M, Mohammed I, El-Emadi M, Haider A (2001) Multiple endocrine neoplasia type iia: report of a family with a study of three generations in Qatar. Endocr Pract 7:19–27 Zschocke J, Kebbewar M, Gan-Schreier H, Fischer C, Fang-Hoffmann J, Wilrich J, Abdoh G, Ben-Omran T, Shahbek N, Lindner M, Al Rifai H, Al Khal AL, Hoffmann GF (2009) Molecular neonatal screening for homocystinuria in the Qatari population. Hum Mutat 20

Chapter 19

Genetic Disorders in Saudi Arabia Zuhair N. Al-Hassnan and Nadia Sakati

Introduction The 23rd of September 1932 marks in history the foundation of modern Saudi Arabia, when a royal decree affirmed the unity of the nation and named the country the Kingdom of Saudi Arabia (KSA). Spreading over 2,150,000 km2, KSA occupies almost 80% of the Arabian Peninsula. It is surrounded by the Red Sea on the west and the Arabian Gulf on the east; the coastlines of which stretch more than 2,300 km. Along the Red Sea lies Tihama coastal plain, to the east of which is the chain of Sarawat Mountains that extend beyond the southern and northern borders of Saudi Arabia. In the central part of the country lies the Najd plateau where the capital city, Riyadh, is located. Deserts cover more than half the total area of Saudi Arabia; the largest is the Empty Quarter in the Eastern Province (Saudi Geographical Society). According to the 2007 National Demographic Survey, the population of Saudi Arabia is 24 millions, 73% (17.5 millions) are Saudis of whom 37% are under the age of 15 years. The growth rate of the population is estimated to be 2.3% and the average size of Saudi family is 6.1. The country is divided into 13 regions (Fig. 19.1); of which the most populated are Makkah and Riyadh (Central Department of Statistics & Information). The structure of the Saudi population is largely tribal. Recent decades, however, have seen a change in the demographics of the population influenced by several educational, economic, and social factors. There has been a significant reduction in the illiteracy rate (14.7% in 2004 compared to 28.4% in 1992). Some large tribes have their branches extending to neighboring countries such as Jordan, Iraq, and Yemen, while their origins have remained in Saudi Arabia. Other tribes have

Z.N. Al-Hassnan (*) Associate Prof. of Genetics, College of Medicine, Alfaisal University Consultant, Department of Medical Genetics, MBC-75, King Faisal Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi Arabia e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_19, # Springer-Verlag Berlin Heidelberg 2010

531

532

Z.N. Al-Hassnan and N. Sakati

Fig. 19.1 Map of Saudi Arabia showing the 13 regions Source: Central Department of Statistics & Information

largely immigrated to major cities and Bedouins have moved to small settlements (Hijar). Nevertheless, in spite of this geographic admixture, the consanguinity rate has remained high. In 1995, the overall rate of consanguinity was found to be 57.7%, with 28.4% first-cousin marriages (El-Hazmi et al. 1995a). A recent study revealed very similar results with a prevalence of consanguinity of 56% and firstcousin marriages of 33.6%. There were, however, significant variations in the prevalence of consanguinity between regions as well as between rural and urban settlements (El-Mouzan et al. 2007).

Health Care System and Health Indicators The Health Care System in the Kingdom is divided into three sectors: Ministry of Health (MOH), other governmental health services, and private sector. The financial appropriations for MOH from the government budget is on an average 6%. On the basis of the most recently published MOH Health Statistics Book (2007), there were 387 hospitals across the country; 225 (58%) belongs to MOH, 39 (10%) to other governmental sectors, and 123 (32%) to private. The overall occupancy of hospitals was 53,519 beds; divided into 31,420 (59%) beds in MOH, 10,828 (20%)

19

Genetic Disorders in Saudi Arabia

533

in other governmental sectors, and 11,271 (21%) in private hospitals, which converts into a rate of one bed for 453 people. With respect to the number of physicians, there were 47,919 physicians, giving a rate of one physician for 476 people, 21.6% of them were Saudis, whereas 44.1% of the 51,188 nurses in the MOH hospitals were Saudis (MOH Health Statistics Book 2007). The other health indicators in 2007 were as follows: the crude birth rate/1,000 people was 24.5; the stillbirth rate was 16.3/1,000 live birth; and the infants mortality rate was 17.4/1,000 Saudi live birth. There were 337,177 deliveries in the MOH and other governmental hospitals (MOH Health Statistics Book 2007). Concerning the heath care provided to patients with genetic disorders in Saudi Arabia, King Faisal Specialist Hospital and Research Center (KFSH&RC) represents the leading comprehensive genetic service in the country. The clinical care provided covers diagnostic, therapeutic, and preventive interventions with the presence of: molecular, biochemical and cytogenetics laboratories, advanced treatment modalities including stem cell transplantation, organ transplantation, and enzyme replacement therapy, and the availability of preventive interventions via prenatal diagnosis, preimplantation genetic diagnosis, and carrier screening, in addition to well-established genetic counseling services. Though less comprehensive, genetic services are also provided in other hospitals: MOH tertiary centers, National Guard and Military medical services. On the other hand, the Medical Genetic Fellowship and the Genetic Counseling Training Programs at KFSH&RC have kept the momentum for continuing highly specialized local training for Saudi physicians and genetic counselors.

Genetic Disorders in Saudi Arabia Over the past decade, there has been a remarkable upsurge of interest to study genetic disorders in Saudi Arabia. This is evident by the number of relevant publications and the contributions to the entries in Online Mendelian Inheritance in Man (OMIM) database, which have increased noticeably. As an example, searching PubMed for “Saudi” and “gene” reveals only ten publications for the year 1990 while there were 73 in 2008. In OMIM, the number of entries for the word “Saudi” was 160 (accessed, 28 March 2009) describing 115 genetic disorders; of note, 107 (93%) were autosomal recessive. Clinical observations and anecdotal data note a clear geographic distribution of many autosomal recessive genetic disorders mirroring the tribal distribution across the country. Several disorders have high prevalence in certain tribes and their founder mutations represent the majority of mutant alleles. Examples are propionic acidemia and very long chain acyl-CoA dehydrogenase deficiency (VLCAD). Others, however, have very evident geographic distribution such as sickle-cell anemia and b-thalassemia. In the following sections, we present short synopses of genetic disorders we have observed in our clinical practice or have been published and focus on seven groups of inherited diseases of: (1) metabolism; (2) hematology; (3) neurology;

534

Z.N. Al-Hassnan and N. Sakati

(4) congenital malformations; (5) endocrinology; (6) ophthalmology; and (7) rheumatology. A separate section on novel syndromes described in the Saudi population follows.

Inherited Metabolic Diseases Inherited metabolic disorders (IMD) are amongst the most common genetic disorders in Saudi Arabia. The introduction of metabolic screening using tandem mass spectrometry (MS/MS) (Rashed et al. 1995b; Rashed et al. 1997) in the presence of clinical expertise at KFSH&RC for more than two decades has provided a great opportunity to study IMD. In 1999, the incidence of IMD that can be detected by MS/MS was found to be 1:1,381 after screening 27,624 blood spots (Rashed et al. 1999b). However, a more recent data from the Saudi National Newborn Screening (NBS) Program indicate that the collective incidence of the 16 disorders that are screened for is much higher reaching one in almost 850 newborns (Al-Odaib, personal communication). Of those 16 diseases, methylmalonic acidemia (MMA), maple syrup urine disease (MSUD), and propionic acidmeia (PA) are commonly detected metabolic disorders. Examining the neurometabolic diseases in general, however, revealed that the most frequently diagnosed disorders among 473 conditions were lysosomal storage diseases (LSDs), followed by organic acid disorders, and aminoacidopathies (Ozand et al. 1992a). The high incidence of IMD has provided an opportunity for reviewing the clinical profiles of these disorders from various aspects, including unusual findings in PA (Ozand et al. 1994a), emergency presentation of MSUD, PA, and MMA (Henriquez et al. 1994), the high frequency of infections in PA (Al Essa et al. 1998f), in addition to the brain imaging features in Canavan disease (Brismar et al. 1990a), MSUD (Brismar et al. 1990b), PA & MMA (Brismar and Ozand 1994), glutaric acidemia type I (GAI) (Brismar and Ozand 1995), and 3-methylglutaconic aciduria (Al-Essa et al. 1999a). Research for developing new analytical methods for various metabolites has also flourished. Examples include MMA (Al-Dirbashi et al. 2005), glyceric aciduria (Rashed et al. 2002), tyrosinemia type I (Rashed et al. 2005; Al-Dirbashi et al. 2006), cystinuria (Al-Dirbashi et al. 2007), and peroxisomal disorders (Al-Dirbashi et al. 2008). LSDs comprise a prevalent group of IMD. In 125 referred cases with LSD, mucopolysaccharidosis (MPS) type IVA (Morquio disease), Niemann–Pick disease type B, Sandhoff disease, and neuronal ceroid lipofuscinosis (NCL) were frequently encountered as compared to other storage diseases (Ozand et al. 1990a). Also, Maroteaux-Lamy syndrome (MPS type VI) is a common MPS in Saudi Arabia. Sly disease (MPS type VII), which was reported in a case (Stangenberg et al. 1992), has been diagnosed in several infants with nonimmune hydrops fetalis. Niemann–Pick disease is one of the most common LSD in Saudi Arabia; the disease manifests

19

Genetic Disorders in Saudi Arabia

535

with severe phenotype involving the nervous system, and two mutations (H421Y and K576N) account for approximately 85% of the alleles (Simonaro et al. 2002). A third novel mutation (W533R) was also reported (Hellani et al. 2004). Gaucher disease, both types I and III, has been diagnosed in several patients, and causative mutations have been identified (Kaya et al. 2008a). The other relatively common LSD is Canavan disease which was reported in 12 Saudi infants almost two decades ago (Ozand et al. 1990b) and several mutations have been identified (Kaya et al. 2008b). Other reported LSDs are GM1 gangliosidosis type 2 (Gascon et al. 1992a), galactosialidosis (Ozand and Gascon 1992b), sialidosis type 1 (Gascon et al. 1992b), the AB variant of GM2 gangliosidosis (Schepers et al. 1996), and Wolman disease (Al Essa et al. 1998c). Organic acidurias (OA) are a common group of IMD with an estimated frequency of 1/740 births (Rashed et al. 1994). In addition to MMA and PA, data from NBS indicate that 3-methylcrotonyl-CoA carboxylase deficiency, GAI, and 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency are also common in Saudi Arabia. The prevalent mutations in the latter disorder have been reported (Mitchell et al. 1998; Al-Sayed et al. 2006). In addition, biotinidase deficiency has been diagnosed frequently (Joshi et al. 1999) and mutations have been reported (Pomponio et al. 2000). Other less-encountered OAs are 3-ketothiolase deficiency (Ozand et al. 1994b), malonic aciduria (Ozand et al. 1994c), 4-hydroxybutyric aciduria, (Rahbeeni et al. 1994), 3-methylglutaconic aciduria (al Aqeel et al. 1994), pyroglutamic aciduria (Al-Jishi et al. 1999), glutaric aciduria type II (al-Essa et al. 2000b), D-glyceric and L-glyceric acidurias (Rashed et al. 2002), and L-2-hydroxyglutaric aciduria (Sass et al. 2008). Aminoacidopathies, in particular, homocystinuria (HCU) (Al-Essa et al. 1998e), MSUD, and phenylketonuria (PKU) are frequent. A large series of 45 patients with HCU with a focus on ophthalmic complications was reviewed (Harrison et al. 1998). The NBS data indicate that the incidence of MSUD is one of the highest worldwide. Biopterin-dependent PKU due to deficiency of 6-pyruvoyl tetrahydropterin synthase, particularly prevalent in one tribe, is not a rare variant in comparison to classic PKU (al Aqeel et al. 1991). Although it has not been included in the NBS program, tyrosinemia type I has been diagnosed in several cases (Al-Dirbashi et al. 2006). Other amino acid disorders that have been reported in Saudis are: tyrosinemia type II (Tallab 1996; Al-Essa et al. 1998a), nonketotic hyperglycinemia (Haider et al. 1996); alkaptonuria (Al Essa et al. 1998b), methylenetetrahydrofolate reductase (MTHFR) deficiency (Al-Essa et al. 1999c), cystinuria (Al-Dirbashi et al. 2007), and hyperornithinemia–hyperammonemia–homocitrullinuria (HHH) syndrome (Al-Hassnan et al. 2008). On the other hand, two urea cycle detects (UCD) are included in the NBS program: argininosuccinic aciduria (ASA) and citrullinemia (Cit). ASA is relatively more common than other UCD in Saudi Arabia (Rashed et al. 1999a), with a common mutation (Q354X) in 50% of tested cases (Al-Sayed et al. 2005). The other UCD have also been diagnosed but less frequently with arginase deficiency, reported in a single case (Grody et al. 1992), being rarely encountered.

536

Z.N. Al-Hassnan and N. Sakati

Glycogen storage diseases (GSD), notably type I and III, are also commonly diagnosed in Saudi patients. Moreover, rare GSD variants have been described including phosphorylase b kinase deficiency (Sanjad et al. 1993), phosphofrucokinase deficiency (Al-Hassnan et al. 2007a), and Fanconi–Bickel syndrome (Taha et al. 2008). Fructose-1,6-bisphosphatase deficiency is another condition of hypoglycemia that is specifically prevalent in one tribe; the disorder mutations have been recently reported (Faiyaz-Ul-Haque et al. 2009b). Clinical observation indicates that a large group of patients have been clinically suspected to have mitochondrial disorders. Yet, in spite of extensive workup, a specific molecular defect is not reached in the majority of patients suggesting that mitochondrial disorders in Saudi Arabia are mostly due to autosomal recessive nuclear gene defects yet to be elucidated. Reports of such disorders are thus scarce. In children with stroke, mitochondrial disorders were the underlying risk factor in 4 (3.8%) of 104 children, nevertheless, the specific molecular defect was not identified (Salih et al. 2006). A novel mtDNA mutation in a patient with MELAS (Abu-Amero et al. 2006c) and a homozygous R19H substitution in COX6B1 gene in two brothers with cytochrome c oxidase deficiency (Massa et al. 2008) have been reported. Certain defects of fatty acid oxidation disorders (FAOD) and peroxisomal disorders are especially frequent. VLCAD is probably the most common FAOD in Saudi Arabia. In addition, medium-chain acyl-CoA dehydrogenase deficiency (MCAD) was once thought to be rare in Arabs; however, recent data suggest that its incidence is close to what has been observed in Caucasians approaching one in 18,000. One mutation (T121I) was identified in 72% of the cases (Al-Hassnan et al. 2006). In addition, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Rashed et al. 1995a), carnitine palmityl transferase I deficiency (Al-Aqeel et al. 2001), carnitine transporter defect (Rahbeeni et al. 2002), and carnitine acylcarnitine translocase deficiency (Al Aqeel et al. 2003) have been reported in Saudis. With respect to peroxisomal disorders, the clinical phenotype of both Zellweger syndrome (al-Essa et al. 1999b), and X-linked adrenoleukodystrophy (Al-Essa et al. 2000a) have been described in Saudi patients. The molecular defects in the peroxisomal biogenesis disorders seem to be heterogeneous with several PEX genes implicated including PEX5, PEX13, and PEX26. Hyperpipecolic acidemia (Al-Essa et al. 1999d) and rhizomelic chondrodysplasia punctata type II (Barr et al. 1993) were also described. A novel biotin-responsive basal ganglia disease was described by Ozand et al. (1998) in ten patients who had an onset of subacute encephalopathy that progressed to severe cogwheel rigidity, dystonia, and quadriparesis. On brain MRI, patients displayed central bilateral necrosis in the head of the caudate, with complete or partial involvement of the putamen. The patients responded dramatically to high dose of biotin (Ozand et al. 1998). Using linkage analysis, causative mutations in SLC19A3 gene were identified (Zeng et al. 2005). The list of reported IMD includes as well bile acid synthesis defect (HSD3B7 gene defect) (Clayton et al. 1987), hyperinsulinism and hyperammonemia syndrome (al-Shamsan et al. 1998), isolated sulfite oxidase deficiency (Seidahmed et al. 2005), and cerebrotendinous xanthomatosis (Price Evans et al. 2007).

19

Genetic Disorders in Saudi Arabia

537

Blood Disorders The sickle-cell hemoglobin (Hb S) was first reported in Saudi Arabia in 1963 (Lehmann et al. 1963). Years later, a study has characterized sickle cell–b0 thalassemia (S–b0 thal) in Eastern Saudi Arabia (Pembrey et al. 1980). Then Hb S, a- and b-thalassemia, glucose-6-phosphate dehydrogenase deficiency (G6PD), and other enzymopathies were shown to occur at a variable prevalence in different regions of the country (el-Hazmi 1987a) The comprehensive national survey of the distribution of the Hb S and thalassemia genes on more than 30,000 blood samples showed that the Hb S, a- and b-thalassemia gene frequency ranges were: 0.005–0.145, 0.01–0.40, and 0.01–0.15, respectively, in various areas of Saudi Arabia. The highest frequency (0.149) of Hb S was found in the Eastern Province and the lowest (0.001) was in the Central Region (el-Hazmi and Warsy 1996, 1999). Studies have shown extensive polymorphism of the b-globin gene existing at a variable frequency in different regions of the country (el-Hazmi 1986a). Individuals from the southwest of the Arabian peninsula have the same b S-chromosome haplotype previously found in west African, Jamaican, and African Americans, whereas those from the eastern oases of Saudi Arabia and from the west and the east coast of India showed a different haplotype not found in Africa (Kulozik et al. 1986). Patients from the Eastern Province who have sickle-cell anemia (SCA) have high circulating levels of fetal hemoglobin (HbF) and, as a consequence, have a mild form of the disease. A cytosine-to-thymine substitution at the cap site of the G-g-globin gene of the HbF chromosome was found in nearly 100% of patients with sickle-cell disease or trait while it was present in 22% of normal Saudis (Miller et al. 1987). Homozygosity for haplotype 31 (Saudi Arabian) confers high HbF levels and hence milder phenotype (Morgan et al. 1996). Patients from the Eastern Province generally had a mild clinical presentation, while in the South West and North West Provinces majority of the patients suffered from a severe disease (el-Hazmi 1992a). The polymorphism in the b-globin gene cluster was shown to be significantly related to the expression of the b S-gene and clinical severity of SCA (el-Hazmi et al. 1992c). On the other hand, studying the Xmn I polymorphic site revealed that 10% of g-genes in normal individuals were linked to the 7.0-kb fragment while in the SCA patients and Hb S heterozygotes the frequency of the polymorphic site was 0.932 and 0.625, respectively (el-Hazmi 1989). The first report on the types of mutations in Saudi b-thalassemia patients revealed that the most commonly encountered mutations were IVS1-110, IVS2-1, codon 39, IVS1-5, and IVSI 30 end (–25) (el-Hazmi et al. 1995b). The spectrum of mutations found in the Western Region is significantly different from that previously reported in the Eastern Region (Hasounah et al. 1995). In the latter, ten mutations were detected in 91% of the subjects with four novel alleles. IVS21G > A, IVS1-5G > A, and codon 39 mutations were found to be the most frequent (Al-Ali et al. 2005a). a-Thalassemia exists at a high prevalence in several regions of Saudi Arabia. On 504 cord blood samples from Qatif area, the prevalence of a-thalassemia was

538

Z.N. Al-Hassnan and N. Sakati

39.99% (Quadri et al. 2000). The deletion type of a-thalassemia from the Eastern and Northwestern Regions of the country was studied. The arrangements alpha/ alpha alpha and a/a were common. A rightward deletion was detected in a majority of the cases. Leftward deletions, both homozygous and heterozygous, were also identified. Triple a-gene arrangements alpha alpha alpha anti 3.7/ were observed at a low frequency in both regions (el-Hazmi 1987b). The nondeletional a-thalassemia allele, a (T-Saudi), which is due to a single-base mutation (AATAAA–AATAAG) in the polyadenylation signal of the a-2 gene, is responsible for the clinical phenotype of Hb H disease in some Saudi individuals with five a-genes (a-T Saudi alpha/(alpha alpha alpha)T Saudi) (Pressley et al. 1980; Thein et al. 1988). Moreover, reported a-thalassemia mutations in Saudi patients have included three a-genes on one chromosome (alpha alpha alpha anti3.7) and two on the other (el-Hazmi and Warsy 1992b), and homozygosity of a3.7(a3.7/a3.7) (Katol et al. 2006). Similarly, G6PD deficiency is a frequently identified hematological disorder in Saudi Arabia. In 31 different areas, screening 24,407 Saudis for G6PD deficiency detected a frequency of 0.0905 and 0.041 in males and females, respectively (Warsy and El-Hazmi 2001). G6PDA-Mediterranean (G-6-PD-B+) is the major variant producing the severe deficiency state in our population. The frequency of the variants, however, shows significant differences among the regions with the highest being in areas which are endemic to malaria and have high frequencies of SCA and thalassemia, namely, the Eastern and the Southern Regions (el-Hazmi et al. 1986b; el-Hazmi and Warsy 1990). Of note, screening 40 G6PD-deficient females in the Eastern Region identified 34 (84%) homozygous cases for the Mediterranean mutation (Al-Ali et al. 2002). Several hemoglobin variants have been identified and published. In 1980, a report described the first finding of Hb O Arab in Saudi Arabia (El-Hazmi and Lehmann 1980). Hb Setif, initially described in an Algerian family, was detected in Saudi individuals (Al-Awamy et al. 1985). A new Hb variant in the heterozygous state, Hb Al-Hammadi Riyadh (codon 75 (GAC ! GTC); a75(EF4)Asp ! Val (a2)) corresponding to an A to T transversion on the second exon of the a2-globin gene was described in a boy from Riyadh (Burnichon et al. 2006). Hb Jeddah (a68 (E17)Asn ! His (a1)), which is a previously unrecognized a chain variant, was reported in combination with Hb S in three families from Saudi Arabia, Yemen, and United Arab Emirates (Markley et al. 2008). In addition to the extensively studied hemoglobinpathies, other inherited blood disorders have also been identified and reported. In a study on 1,691 Saudi individuals, the overall frequency of partial glutathione reductase (GR) deficiency was 24.5 and 20.3% in males and females, respectively (Warsy and el-Hazmi 1999). GR deficiency was encountered in combination with SCA, G6PD deficiency, and thalassemia (el-Hazmi and Warsy 1985). Molecular analysis on three Saudi brothers with early childhood thrombocytopenia was suggestive of an X-linked disorder distinct from the classical Wiskott–Aldrich syndrome phenotype (Knox-Macaulay et al. 1993). Selective intestinal malabsorption of vitamin B12 causing juvenile megaloblastic anemia was reported in two Saudi sisters (Al Essa

19

Genetic Disorders in Saudi Arabia

539

et al. 1998d), and causative mutations were identified (Tanner et al. 2004). In a family consisting of four brothers with thrombocytosis, segregation analysis excludes THPO gene which suggests the existence of a new locus whereby the disease is transmitted as a recessive, possibly X-linked trait (Stuhrmann et al. 2001). Two families with “factor X (FX)-Riyadh” were described with a novel missense mutation (Q51K) of FX gene. Affected members of both families exhibit prolongation in prothrombin time with normal partial thromboplastin time and low assay levels of FX (Al-Hilali et al. 2007). Other reported hematological disorders in Saudi families have been: hereditary pyropoikilocytosis (Mallouh et al. 1984); congenital afibrinogenemia (Elseed and Karrar 1984); congenital dyserythropoietic anemia type I (al-Fawaz and al-Mashhadani 1995); protein C deficiency (Abu-Amero et al. 2003a); hereditary hemorrhagic telangiectasia (El-Harith et al. 2006); thiamineresponsive megaloblastic anemia in a girl who was homozygous for a mutation in the thiamine transporter gene SLC19A2 (Alzahrani et al. 2006b); and combined factor V and factor VIII deficiency which was recently reported in a family who segregated a mutation in the MCFD2 gene (Zhang et al. 2008).

Neurological Disorders Numerous publications have addressed the genetics of inherited neurological disorders in Saudi Arabia. Spinal muscular atrophy (SMA) appears to be a common neuromuscular disease in the Saudi population; the carrier frequency was estimated to be 1in 20 in a pilot study (Al Jumah et al. 2007). The deletion rate of the SMN1 gene in Saudi SMA patients was found to be similar to what has been reported in other ethnic groups; homozygous deletions of exons 7 and 8 of the SMN1 gene were found in 94 and 87%, respectively (Al-Jumah et al. 2003). Previous work showed that the incidence of NAIP gene deletion is higher in the more severe SMA cases and the dual deletions of the SMN and NAIP genes are more common in Saudi SMA type I patients compared to patients of other ethnic groups (Al Rajeh et al. 1998). The molecular profile in Duchenne and Becker muscular dystrophies (DMD/BMD) were reported too. In 41 Saudi patients with DMD/BMD, the intragenic dystrophin gene deletions were found to occur with the same frequency compared to other ethnic groups (Al-Jumah et al. 2002). Severe childhood autosomal recessive muscular dystrophy (SCARMD), which appears to be more common than DMD in Saudi Arabia, was described in 14 patients. Muscles were dystrophinpositive while adhalin, the dystorphin-associated glycoprotein, was deficient (Salih et al. 1996a). Various other neuromuscular diseases have also been reported. Congenital muscular dystrophy (CMD) with diffuse periventricular white-matter abnormalities was reported in 11 children with a homogeneous clinical syndrome characterized by weakness of all muscle groups, normal nerve conduction velocity, and dystrophic changes on muscle biopsy (Cook et al. 1992). Two siblings with CMD were found to have a deleted laminin a2-chain as a result of a splice site mutation in the

540

Z.N. Al-Hassnan and N. Sakati

LAMA2 gene. These patients appeared mildly affected compared to others who completely lack this protein (Allamand et al. 1997). A Saudi kindred with four affected individuals with a recessive hereditary motor and sensory neuropathy (HMSN) was described. The genetic study confirmed linkage to a previously identified locus on chromosome 11q23 and refined the location of the gene to a 3.3-cM region (Salih et al. 2000). Charcot–Marie–Tooth disease type 4B1 was diagnosed in a patient who was found to have two different homozygous mutations in the MTMR2 gene; an in-frame deletion and an E276X mutation (Bolino et al. 2000). Three patients with fast-channel congenital myasthenia syndrome were described. Homozygous mutation (P250Q) in the CHRND gene was identified (Shen et al. 2002). Hyaline body myopathy was reported in a kindred with 11 affected members who had the disease inherited in an autosomal dominant pattern (Bohlega et al. 2003b). Through linkage analysis and candidate gene approach, sequencing MYH7 revealed an H1904L substitution (Bohlega et al. 2004). In children with congenital muscle weakness and childhood-onset fatal dilated cardiomyopathy, a homozygous titin deletion in exons encoding the C-terminal M-line region was identified. This represents the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle (Carmignac et al. 2007). Mutations in the acetylcholinesterase collagen-like tail subunit gene (COLQ) causing congenital myasthenic syndrome were recently reported in Saudi patients (Mihaylova et al. 2008). Neurodegenerative disorders are amongst the most common reasons for referrals to Genetics and Neurology services in tertiary hospitals in the Kingdom. The impact of high consanguinity is again observed; three notable examples are illustrative. An autosomal recessive juvenile Huntington disease-like neurodegenerative disorder was reported in five siblings (Al-Tahan et al. 1999). The disease manifests at approximately 3–4 years and is characterized by both pyramidal and extrapyramidal abnormalities, including chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain MRI findings include progressive frontal cortical atrophy and bilateral caudate atrophy. Huntington CAG trinucleotide-repeat analysis was normal. The inheritance pattern and localization to 4p15.3 were consistent with the identification of a novel, autosomal recessive, neurodegenerative Huntington-like disorder (Kambouris et al. 2000a). Pelizaeus– Merzbacher disease is a hypomyelinating leukoencephaloathy disorder that is inherited in X-linked fashion. However, an autosomal recessive form, Pelizaeus– Merzbacher-like disease (PMLD), has been recently described in a Saudi family who was found to segregate a frameshift mutation (P131fs144X) in GJA12 gene (Bugiani et al. 2006). The third example is SAP-B deficiency (SAPBD) which is the metachromatic leukodystrophy (MLD) variant, caused by mutated PSAP gene, in which arylsulfatase-A (ASA) is normal. Out of 16 patients with MLD who were evaluated in one center, seven patients from three families were diagnosed to have ASA-deficient MLD, while nine children from four unrelated Saudi families were found to have SAPBD. PSAP analysis found that the four families segregate the same homozygous mutation (C241S) which was previously reported in an Arab patient suggesting that SAPBD is likely to be more

19

Genetic Disorders in Saudi Arabia

541

common than classic MLD in the Saudi population (Al-Hassnan et al. 2009). Likewise, and to the contrary to what has been observed in other populations, mutated CLN6 is likely to be a common cause of NCL in comparison to CLN1 and CLN2. Another rare NCL variant due to mutated MFSD8 (CLN7) gene has been reported recently (Aldahmesh et al. 2009b). The genetics of mental retardation has not been well studied in the Saudi population yet. Few publications, however, provided introductory views on this aspect. Screening 305 Saudi patients with mental retardation/developmental delay/ clinical suspicion of fragile X syndrome by cytogenetic methods detected 24 males (7.86%) and two females (0.65%) who were found to express fragile X site; a frequency that is similar to other reports of fragile X syndrome in preselected patients (Iqbal et al. 2000). Rett syndrome was also described in five Saudi girls (al-Jarallah et al. 1996). In one family, three siblings were reported to have mental retardation, calcification of the choroid plexus, and increased CSF protein (Singh et al. 1993). A pedigree with multiple affected individuals with microcephaly and seizures was reported to have a novel nonsense mutation in ASPM gene (Shen et al. 2005). A consanguineous family with four affected children presented with generalized tonic–clonic epilepsy, ataxia, and mental retardation. MRI and muscle biopsy of one patient revealed, respectively, posterior white matter hyperintensities and vacuolization of the sarcotubular system. The defective gene was localized by homozygosity mapping to a 19 Mb interval in 16q21–q23 (Gribaa et al. 2007). Other novel and unusual neurogenetic disorders have been reported too. The selective deficiency of b-dystroglycan with muscular dystrophy, a borderline elevation of serum creatine kinase level, early-onset proximal symmetrical muscle weakness and wasting without calf hypertrophy was described as a likely novel form of muscular dystrophy (Salih et al. 1996b). Juvenile primary lateral sclerosis was reported in three affected members of a Saudi family who were homozygous for a 2-bp deletion (1867delCT) in ALS2 gene (Yang et al. 2001). In a family that had an autosomal recessive form of spinocerebellar ataxia with axonal neuropathy (SCAN1), the presenting symptom was disturbance of gait in the teen years with signs of peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus, and normal intelligence. Linkage analysis mapped the mutant gene to 14q31–q32. TDP1 was identified as one of the candidate genes in the region and a homozygous mutation (H493R) was detected (Takashima et al. 2002). In three affected individuals from a family displaying pure novel autosomal recessive hereditary spastic paraplegia and sensorineural deafness, the paraplegic trait was linked to a 1.8-Mb region of chromosome 13q14. The deafness did not link to this region and did not cosegregate with the paraplegic trait (Hodgkinson et al. 2002). In three families with chorea-acanthocytosis, three different homozygous mutations in VPS13A were identified (Bohlega et al. 2003a). Ataxia telangiectasia-like disorder (ATLD) was diagnosed in ten patients from three unrelated families. They presented with an early-onset slowly progressive ataxia plus ocular apraxia with an absence of tumor development, telangiectasia, raised a-fetoprotein or reduced immunoglobulin levels. All patients were homozygous for a novel missense mutation (W210C) in the MRE11 gene (Fernet et al. 2005). The carrier

542

Z.N. Al-Hassnan and N. Sakati

frequency of this particular mutation was found to be 0.5% in a cohort of 428 Saudis (Alsbeih et al. 2008). In two affected members of a large consanguineous family with early-onset parkinsonism, a homozygous T313M substitution in PINK1 gene was identified. Both patients had onset at age 34 and 30 years, respectively, without cognitive impairment or major axial symptoms (Chishti et al. 2006). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) was reported in a family who was found to have a mutation in Notch 3 (Bohlega et al. 2007).

Malformation Syndromes Alleleic homogeneity has not always been the rule. Explained by the diverse tribal components of the Saudi population, locus heterogeneity was, rather, found in many autosomal recessive diseases. Two exemplifying disorders are Bardet–Biedl syndrome (BBS) and Joubert syndrome. In BBS, which is a common disorder, at least five loci have been linked to Saudi pedigrees and mutations have been identified: a splicing mutation in the BBS4 gene in one family (Katsanis et al. 2002); a 4-bp deletion in the BBS7 gene in nine families (Badano et al. 2003); a 6-bp in-frame deletion in the BBS8 gene (TTC8) in two families (Ansley et al. 2003); a missense mutation in the BBS3 gene (ARL6) in another family (Fan et al. 2004), and a nonsense mutation in the BBS5 gene in two affected siblings (Li et al. 2004). With respect to Joubert syndrome, three independent mutations in the AHI1 gene in three families (Ferland et al. 2004), and a mutation in the CC2D2A gene in two others (Gorden et al. 2008) were identified. Similarly, the molecular basis of Meckel–Gruber syndrome, which is a common multiple malformations syndrome in Saudi Arabia, is yet to be identified; screening known causative genes in some families have been negative. Though less frequently, Walker–Warburg syndrome has also been diagnosed in several families, and in two affected siblings, a homozygous 63-kb intragenic deletion in the LARGE gene was recently discovered (van Reeuwijk et al. 2007). Cockayne syndrome has been diagnosed in several cases too and was reported in three sisters with varying clinical presentation (Mahmoud et al. 2002). In addition, other conditions with malformations have been encountered and described. Almost two decades before, osteodysplastic variant of primordial dwarfism was reported in an infant (Shebib et al. 1991). Severe microcephaly, lymphedema, and attention deficit disorder were described in a sister and brother from a nonconsanguineous family. An X-linked dominant inheritance could not be excluded (Kozma et al. 1996). In a family with first-cousin parents and three affected children with lissencephaly, a splice acceptor site mutation in the RELN gene was found (Hong et al. 2000). Recently, a nonsense mutation (E220X) in the PCNT2 gene was identified in two patients with Seckel syndrome (Griffith et al. 2008). Reports of rare dysmorphic syndromes in Saudi patients have also described: Johanson–Blizzard syndrome in three affected family members (Mardini et al.

19

Genetic Disorders in Saudi Arabia

543

1978); Borjeson–Forssman–Lehmann syndrome in a sibship (Robinson et al. 1983); Donnai–Barrow syndrome in a male infant (Gripp et al. 1997), Sotos syndrome in 14 children (al Rashed et al. 1999); Alstrom syndrome in four families who had their mutations identified (Aldahmesh et al. 2009a).

Endocrine Disorders Congenital adrenal hyperplasia (CAH) and congenital hypothyroidism are the most commonly detected disorders in the NBS program. The clinical findings and biochemical defects in CAH have been illustrated. Over a 10-year period, 78 Saudi children were diagnosed with CAH in a university hospital; 20 (25.6%) of them had 11b-hydroxylase deficiency (Al-Jurayyan 1995). In another retrospective review of 120 patients with ambiguous genitalia, CAH was the underlying cause in 41 of 63 patients with ambiguity because of endocrine causes; the most common of which was 21-hyroxylase deficiency. 3b-Hydroxylase deficiency was the cause in two patients (Al-Mutair et al. 2004). CAH due to 3b-hydroxysteroid dehydrogenase type II deficiency was also reported in four children (Bin-Abbas et al. 2004a). Among eight patients with congenital lipoid adrenal hyperplasia from six unrelated families, seven were found to be homozygous for an R182H mutation in the steroidogenic acute regulatory protein (STAR) (Chen et al. 2005). Clinical and molecular studies have extended to various endocrine disorders. Persistent hyperinsulinaemic hypoglycemia of infancy (PHHI) is relatively common in Saudi Arabia (al-Rabeeah et al. 1995; Bin-Abbas et al. 2003) with an estimated incidence of 1 in 2,675 live births (Mathew et al. 1988). Using homozygosity mapping, the locus of PHHI was detected in five consanguineous families (Thomas et al. 1995a) and, in 14 affected children, two homozygous point mutations were found in the SUR gene (Thomas et al. 1995b; Dunne et al. 1997). In two families with isolated growth hormone (GH) deficiency, splicing mutations were identified in the GH1 gene (Cogan et al. 1993; Phillips and Cogan 1994). Mutations in the GH receptor (GHR) gene were also identified in four individuals with Laron syndrome (Wojcik et al. 1998). Three unrelated kindreds were diagnosed to have pseudohypoaldosteronism type I. A 2-bp deletion at codon 68 resulting in a frameshift was identified in the a subunit of the SCNN1A gene (Chang et al. 1996). Idiopathic hypogonadotropic hypogonadism was described in a large family with six affected members (Bo-Abbas et al. 2003). Linkage analysis localized the gene to 19p13.3 (Acierno et al. 2003) and an L148S substitution was identified in the GPR54 gene (Seminara et al. 2003). Three siblings were reported to have a specific thyroid phenotype associated with a reduction in type II iodothyronine deiodinase activity. The patients had abnormal thyroid function tests with high TSH, total T4, free T4, and total triiodothyronine metabolite, whereas total and free T3 were low. Affected individuals were found to be homozygous for an R540Q mutation in the SECISBP2 gene (Dumitrescu et al. 2005).

544

Z.N. Al-Hassnan and N. Sakati

Further, published work on Saudi patients with inherited endocrine disorders have included: the syndrome of alacrima–achalasia–addisonianism (triple-A syndrome) in an 8-year-old girl (Lanes et al. 1980); X-linked hypophosphataemic rickets in a family with 13 affected members with identified locus on Xp22.3–p21.3 (Thakker et al. 1992); hereditary 1,25-dihydroxyvitamin D3-resistant rickets in two children who had novel point mutations (G46D and I268T respectively) in the vitamin D receptor (VDR) gene (Lin et al. 1996; Malloy et al. 2004); Wolfram syndrome in a 10-year-old child who was homozygous for a 7-bp repeat insertion at nucleotide 1610 of the WFS1 gene (Inoue et al. 1998); GH, prolactin, and thyrotropin deficiency with a novel recessive mutation (P239S) in the Pit-1 gene (Pernasetti et al. 1998); hypothalamic hypopituitarism with the syndrome of septooptic dysplasia in ten children (Bin-Abbas et al. 2004b); anterior hypopituitarism with mutated PIT1/POU1F1 gene (Taha et al. 2005); recurrent goiters in two siblings, one of whom had metastatic follicular thyroid carcinoma, with a homozygous splicing mutation in thyroglobulin gene (Alzahrani et al. 2006a); adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum in 46, XY patient who had homozygous mutation (V359A) in the CYP11A1 gene (al Kandari et al. 2006); multiple endocrine neoplasia type 1 (MEN 1) syndrome with a splicing mutation (Alzahrani et al. 2008); primary cortisol resistance in three siblings who were homozygous for a G679S mutation in the glucocorticoid receptor-a (GR-a) gene (Raef et al. 2008).

Rheumatological and Musculoskeletal Disorders The first series of Saudi patients with familial arthropathy with a triad of camptodactyly, arthropathy, and coxa vara (CAC syndrome) were reported in three children (Bahabri et al. 1994). Other cases were later described (Suwairi et al. 1997; Bahabri et al. 1998). The gene locus was mapped to chromosome 1q25–31 (Bahabri et al. 1998) and, in seven children from four unrelated families diagnosed with camptodactyly–arthropathy–coxa vara–pericarditis (CACP), five novel mutations in the PRG4 gene were uncovered (Alazami et al. 2006). In addition, diverse rheumatological/skeletal disorders have been reported. Progressive pseudorheumatoid arthropathy was diagnosed in two families who were found to have homozygosity for a 1-bp deletion at nucleotide 246 of the WISP3 gene (Hurvitz et al. 1999). In two large affected consanguineous families of Saudi and Lebanese origin consistent with autosomal recessive Weill–Marchesani syndrome, a genome-wide search mapped the disease gene to 19p13.3–p13.2 (Faivre et al. 2002). Three of 12 affected siblings were homozygous for a splicing mutation in the ADAMTS10 gene (Dagoneau et al. 2004). The clinical findings in a patient with Wolcott–Rallison syndrome were reported (Al-Gazali et al. 1995) and further cases have also been described (Abdelrahman et al. 2000; Bin-Abbas et al. 2001, 2002). The phenotype of infantile systemic hyalinosis in 19 patients were reviewed; 13 (68%) were

19

Genetic Disorders in Saudi Arabia

545

products of first-cousin marriages and five families had more than one affected child (Al-Mayouf et al. 2005). Almost three decades ago, osteopetrosis was reported in children of three Saudi families who were observed to have striking facial similarities and cerebral calcifications (Ohlsson et al. 1980). Other Saudi cases were later reported (Ohlsson et al. 1986; Al Rajeh et al. 1988), and the long-term clinical, biochemical, and radiological features of 35 children with carbonic anhydrase II (CA II) deficiency syndrome were reviewed (Awad et al. 2002). A splice junction mutation at the exon 2–intron 2 boundary of the CA II gene was previously shown to be the unique mutation in patients of Arab descent. The malignant osteopetrosis variant is also prevalent in Saudi Arabia (Solh et al. 1995). On the hand, we have observed a frequent occurrence of various forms of lethal skeletal dysplasias. The most notable examples have been short rib-polydactyly syndromes, and severe osteogenensis imperfecta, the molecular basis of both conditions is yet to be elucidated in our population. Reported skeletal and rheumatological disorders in Saudi patients have covered: tibial aplasia with ectrodactyly syndrome in four siblings (Mufti and Wood 1987); Rowbinow syndrome (Nazer et al. 1990); hyperostosis with hyperphosphatemia in two sisters born to consanguineous parents (Narchi 1997); cartilage hair hypoplasia with identified mutation in RMRP (Ridanp€a€a et al. 2002); spondyloepiphyseal dysplasia and bilateral femoral fractures with homozygosity for a 4-bp deletion (1563delGAAA) in the EIF2AK3 gene (Brickwood et al. 2003); familial Mediterranean fever with identified common mutations (Al-Alami et al. 2003); Meier– Gorlin in a girl who was found to have GH deficiency (Faqeih et al. 2008); and Grebe-type chondrodysplasia in three affected children from a consanguineous family who had a novel mutation (C429R) in the GDF5 gene (Faiyaz-Ul-Haque et al. 2008).

Ophthalmological Disorders Several novel loci and mutations have been identified in Saudi families with inherited eye disorders. Autosomal recessive congenital fibrosis of extraocular muscles (CFEOM) was diagnosed in 18 members of three consanguineous families. By genetic linkage analysis, the disorder was not linked to the classic CFEOM chromosome 12 locus, but to 11q13.1 (Engle et al. 1997). The same disease-associated haplotype was found in two of the three families suggesting founder effect (Wang et al. 1998). An R72V substitution was identified in the ARIX gene in two consanguineous families with CFEOM2, (Nakano et al. 2001). In two other consanguineous families with horizontal gaze palsy and progressive scoliosis, homozygosity for two mutations (3325þ1G and S705P) in the ROBO3 gene were identified (Jen et al. 2004). Later, several affected individuals from consanguineous families with novel homozygous mutations were reported (Bosley et al. 2005; Abu-Amero et al. 2009). A novel ROBO3 mutation was also reported in a girl with synergistic convergence (Khan et al. 2008). Sequence analysis of the CYP1B1 gene in families with primary

546

Z.N. Al-Hassnan and N. Sakati

congenital glaucoma revealed several mutations with G61E, R469W, and D374N being the most common Saudi variants. However, affected individuals from five families had no CYP1B1 mutations (Bejjani et al. 1998, 2000). Twelve affected patients with recessive cornea plana were homozygous for one of two mutations in the KERA gene; a novel deletion (1634delC) or a previously reported nonsense mutation (R313X). An additional KERA mutation (R279X) has been reported previously in one Saudi family (Khan et al. 2006b). In three affected siblings with a phenotype resembling blepharophimosis–ptosis–telecanthus–epicanthus inversus, linkage analysis excluded FOXL2 as the underlying gene (Khan et al. 2006a). Congenital total white cataract with microcornea was diagnosed in three affected siblings who were homozygous for a novel nonsense mutation (R54C) in the CRYAA gene (Khan et al. 2007). Moreover, the molecular lesions of several retinal disorders have been described. By linkage analysis, a novel locus on 14q24 for Leber congenital amaurosis was identified in a consanguineous family and the locus was designated LCA3 (Stockton et al. 1998). Four consanguineous kindreds were diagnosed with fundus albipunctatus; in one family, a homozygous R150Q alteration was found in RLBP1, the gene associated previously with both recessive retinitis pigmentosa (RP) and retinitis punctata albescens (Katsanis et al. 2001). Autosomal recessive RP without glaucoma was described in an individual who was homozygous for an R368H mutation in the CYP1B1 gene (Vincent et al. 2002). Novel missense mutation was detected in two brothers who had Norrie disease (Khan et al. 2004). Recently, autosomal recessive congenital hereditary endothelial dystrophy was reported in nine members of a family who were homozygous for a novel mutation (T271M) in the SLC4A11 gene (Shah et al. 2008). Clinical reports on inherited ophthalmological disorders in Saudi patients have also included Stargardt disease in one consanguineous family (Allikmets et al. 1997) and brittle cornea syndrome in nine Saudi families who also had blue sclerae, joint laxity, and skin hyperelasticity (Al-Hussain et al. 2004).

Other Inherited Disorders The genetic basis of mendelian cardiovascular diseases in Saudi Arabia is just starting to be unraveled. Cardiomyopathies, arryhthmogenic disorders, and congenital heart diseases, have been observed to affect multiple cases in consanguineous families. Dilated cardiomyopathy, for example, was diagnosed in 55 children from 41 families; in 19 (46%) families, parents were first cousins suggesting an autosomal recessive inheritance (Seliem et al. 2000). Similarly, the long QT syndrome (LQTS), which is classically inherited as autosomal dominant in the absence of deafness, was described in two consanguineous Saudi families who segregated a novel homozygous splicing mutation in the KCNQ1 gene. This novel mutation is very likely to be a founder mutation (Bhuiyan et al. 2008). Mendelian cardiovascular diseases have also been encountered. Twelve patients from eight different

19

Genetic Disorders in Saudi Arabia

547

families were initially reported as a novel syndrome (Al Fadley et al. 2000) which was later found to be arterial tortuosity syndrome (ATS). Two mutations, a novel (R105C) and a recurrent (S81R), were recently described in SLC2A10 gene in seven patients of two unrelated families with ATS (Faiyaz-Ul-Haque et al. 2009a). Expectedly, genetic causes of known cardiovascular diseases extend beyond known loci. The rare cardiomyopathy disorder, Naxos disease, was diagnosed in two Saudi patients whose disease was not linked to the previously identified plakoglobin gene (Stuhrmann et al. 2004). Likewise, various inherited skin disorders have also been diagnosed in Saudi families. The genetic causes of junctional epidermolysis bullosa (EB) were elucidated in seven families form several Middle Eastern countries including Saudi Arabia. Mutations in genes encoding one of the three polypeptides of laminin-5: LAMB3; LAMA3; and LAMC2, were identified. In a 15-month-old Saudi girl with non-Herlitz type junctional EB, homozygosity for a Q1368X mutation in the LAMA3 gene was found (Nakano et al. 2002). Autosomal recessive EB simplex has been reported too (Abanmi et al. 1994). Progressive hair loss was observed in a consanguineous family in which four siblings are affected (Al Aboud et al. 2002); a homozygous truncating mutation in the P2RY5 gene was found (Pasternack et al. 2008). Dyschromatosis universalis hereditaria (DUH) was diagnosed in a consanguineous family with four affected siblings. Genome-wide scan identified a new locus for dyschromatosis on chromosome 12q21–q23 which revealed the first locus for autosomal recessive DUH (Stuhrmann et al. 2008). Unusual forms of connective tissue disorders are not uncommon too. Congenital cutis laxa, in particular, appears to be frequently diagnosed in Saudi Arabia. The disorder was diagnosed in two sisters who also had severe intrauterine growth retardation and congenital dislocation of the hip (Reisner et al. 1971). Seven more cases were later described (Sakati et al. 1983; Allanson et al. 1986). Reports of familial skin disorders have also included: wrinkly skin syndrome in two sibs (Karrar et al. 1983); porokeratosis punctata palmaris et plantaris in seven members of a family (Lestringant and Berge 1989); ichthyosis congenita, harlequin fetus type in two affected siblings (Prasad et al. 1994); congenital insensitivity to pain in five members of one family (Karkashan et al. 2002); Kindler syndrome (hereditary acrokeratotic poikiloderma) in one kindred (al aboud et al. 2002); Netherton syndrome in four siblings (Saif and Al-Khenaizan 2007); and congenital atrichia in a family who was found to have a homozygous insertion (c.2661dupG) in the human hairless gene (HR) (Betz et al. 2007). Informative work on the genetics of gastroenterological disorders in Saudi Arabia has been published with notable examples. Cystic fibrosis (CF) had been thought to be very rare in Arabs; however, the disease was documented in 13 Saudi children two decades ago (Nazer et al. 1989) and later in 70 patients from 46 families (Banjar et al. 1999). Eight novel mutations have been identified with the 1548delG being the most prevalent (Banjar et al. 1999; Kambouris et al. 2000b). Screening six mutations, though, would account for 70% of Saudi CFTR alleles (El-Harith et al. 1998). In Saudi patients with congenital chloride diarrhea (CLD), a major founder effect was observed: 94% of the CLD-associated chromosomes

548

Z.N. Al-Hassnan and N. Sakati

carried a nonsense mutation (G187X) in the SLC26A3 gene (Ho¨glund et al. 1998). In Wilson disease, causative mutations have been studied and variants in exons 21 and 19 of the ATP7B gene appear to be unique for Saudis (Majumdar et al. 2000, 2003; Al Jumah et al. 2004). The first report of arthrogryposis, renal tubular dysfunction, and cholestasis (ARC) syndrome form Saudi Arabia was described in a consanguineopus family with several affected infants (Abdullah et al. 2000). Linkage analysis on this family and other similarly affected patients identified the defective gene, VPS33B (Gissen et al. 2004). In a1-antitrypsin deficiency, the frequency of the two most common deficiency alleles, protease inhibitor (PI)*S and PI*Z, was estimated in Saudi individuals (de Serres et al. 2006) as was the frequency of the two major alleles: C282Y and H63D in hereditary hemochromatosis gene (Alsmadi et al. 2006). A clinical report described Crigler–Najjar syndrome in concurrence with Robinow syndrome in two siblings of first-cousin Saudi parents (Nazer et al. 1990). Studies on the genetics of immunodeficiency disorders in Saudi patients have been very enlightening. A multisystem disorder with partial albinism, immunodeficiency, and progressive demyelination was described in eight Saudi kindreds (Harfi et al. 1992). This disorder, referred originally as PAID syndrome, was later confirmed to be Griscelli syndrome caused by mutated RAB27A gene (de Saint Basile 2007). Noteworthy, novel genes have been discovered to cause various forms of immunodeficiency in Saudi patients: CD40 gene in autosomal recessive immunodeficiency with hyper-IgM (Ferrari et al. 2001); IL12B gene in interleukin-12 deficiency (Picard et al. 2002); IRAK4 gene and recurrent pyogenic bacterial infections (Picard et al. 2003); IFNGR2 gene and severe mycobacterial disease (Vogt et al. 2005); and NOLA3 gene in autosomal recessive dyskeratosis congenita (Walne et al. 2007). Molecular studies have also revealed: a novel intronic mutation in ADA gene in four patients from three families who had adenosine deaminase deficiency (Arredondo-Vega et al. 2002); a novel splicing mutation in the WAS gene in two affected brothers with Wiskott–Aldrich syndrome (Abu-Amero et al. 2004b); and a novel SAP gene mutation in a case with X-linked lymphoproliferative disease associated with hypogammaglobulinemia and GH deficiency (Alangari et al. 2006). Children in the Kingdom probably have a higher incidence of polycystic kidney disease, familial juvenile nephronophthisis, congenital urological anomalies, and familial nephrotic syndrome (Mattoo 1998). The genetics of renal diseases, however, is still in its infancy and published work has covered a few disorders: distal renal tubular acidosis and presumably normal hearing in a 13-year-old male with a deletion of 1 bp in codon 376 of the ATP6N1B gene (Smith et al. 2000); Schimke immuno-osseous dysplasia in a patient with SMARCAL1 mutation (Taha et al. 2004); familial hypomagnesemia with hypercalciuria and nephrocalcinosis in two sisters (Al-Elq 2008). In families with nephrogenic diabetes insipidus (NDI), several novel mutations have been identified in both AQP2 (G100R and G180S mutations) and AVPR2 (G122N and contiguous deletion mutations) genes (Carroll et al. 2006).

19

Genetic Disorders in Saudi Arabia

549

A range of other genetic disorders have been observed and reported. Papillon– Lefe`vre syndrome was reported in five unrelated Saudi families with two cathepsin C gene mutations: a novel G300D substitution and a common R272P one (Zhang et al. 2001). Lipoid proteinosis was described in 31 affected individuals from six unrelated consanguineous families. Linkage analysis mapped the disorder to 1q21, and six different homozygous mutations were detected in the ECM1 gene (Hamada et al. 2002). Recently, a homozygous missense mutation (G66C) in fibroblast growth factor 3 (FGF3) was identified in 21 affected individuals from a large extended consanguineous family, phenotypically characterized by autosomal recessive syndromic congenital sensorineural deafness, microtia, and microdontia (Alsmadi et al. 2009).

Novel Syndromes Not unexpectedly, the high incidence of consanguineous marriages in Saudi Arabia has been the reason behind the frequent occurrences of rare and novel autosomal recessive disorders; only a few have been reported in literature though. Here, we briefly review the novel syndromes that have been described in Saudi patients (listed according to date of publication): l

l

l

l

Woodhouse and Sakati (1983) first reported seven individuals from two consanguineous families with a combination of hypogonadism, partial alopecia, diabetes mellitus (DM), mental retardation, and deafness. This autosomal recessive multisystemic disorder was later described in 12 Saudi families (Al-Semari and Bohlega 2007), one of them had been previously reported and three affected members had since developed a neurologic extrapyramidal syndrome with choreoathetoid movements and dystonia. A founder mutation consisting of a single base-pair deletion in a novel gene, C2orf37, was recently identified (Alazami et al. 2008). A report described a child with pancytopenia and several dysmorphic features which have never collectively been described in any of the bone marrow aplasia syndromes (Sackey et al. 1985). Sanjad–Sakati syndrome, an autosomal recessive disorder with congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure, was reported for the first time more than two decades ago (Sanjad et al. 1988, 1991). Linkage analysis in three consanguineous families identified a candidate region on chromosome 1q42–43 (Kelly et al. 2000), and mutated TBCE gene was later found to be the cause of the syndrome (Parvari et al. 2002). A 12-bp deletion was identified in all the 17 Saudi pedigrees studied. An autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive faces was described in a number of

550

l

l

l

l

l

Z.N. Al-Hassnan and N. Sakati

consanguineous families (Al-Mayouf et al. 2000; Al Aqeel et al. 2000). Two family-specific homoallelic MMP2 mutations, R101H and Y244X, were identified (Martignetti et al. 2001). Boyadjiev et al. (2003) described a dysmorphic syndrome in five males and one female in an inbred Saudi family. The craniofacial features included wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. By a genome-wide scan, linkage to chromosome 14q13–q21 was found. Using positional cloning approach, an F382L missense mutation in the SEC23A gene was demonstrated (Boyadjiev et al. 2006). A distinct autosomal recessive syndrome was described in a consanguineous Saudi family in which two of four sibs had the constellation of minor facial anomalies, proportionate intrauterine growth retardation, neonatal nonimmune DM, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys (Taha et al. 2003). Mutations in the GLIS3 gene were later identified in this original family as well as in a second Saudi family (Sene´e et al. 2006). A syndrome with horizontal gaze abnormalities in association with deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder was described and designated as Bosley–Salih–Alorainy syndrome. Homozygous I75–I76insG truncating mutation in HOXA1 was identified (Tischfield et al. 2005). The spectrum of the phenotype was defined in several other families (Bosley et al. 2007, 2008). Al-Hassnan and Teebi (2007b) reported two sisters, born to consanguineous parents, who had a syndromic form of humeroradial synostosis. Both children had a distinctive facial appearance with a high, broad forehead, high frontal hairline, sparse scalp hair, hypertelorism, epicanthus inversus, depressed nasal bridge, and exotropia, as well as low-set, posteriorly rotated, and malformed ears, and rhizomelic limb shortening. Both girls had a very large anterior fontanel, cranium bifidum occultum, and plagiocephaly. Faqeih et al. (2007) reported four siblings born to first-cousin parents with the constellation of distal renal tubular acidosis, small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features (prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule) as a possibly new autosomal recessive syndrome.

Polymorphisms and Common Diseases in Saudi Arabia Several studies have focused on identifying associations between various polymorphisms and common diseases in the Saudi population. Research has concentrated

19

Genetic Disorders in Saudi Arabia

551

on coronary artery disease (CAD), cancer, DM, and to a lesser extent on other conditions.

Coronary Artery Diseases (CADs) Studies have shown no association between CAD and the following polymorphisms: the infrequent band of 3.2-kb of the apolipoprotein A-I/C-III (Johansen et al. 1991); the insertion/deletion sites in the polymorphic region of intron 16 of the angiotensin I-converting enzyme (ACE) gene (Dzimiri et al. 2000); lipoprotein lipase (LPL) polymorphisms (LPL-HindIII and LPL-PvuII) (Abu-Amero et al. 2003b); the W64R polymorphism of the b3-adrenoceptor (b3-AR) gene (Abu-Amero et al. 2005); LPL gene PvuII polymorphism (Cagatay et al. 2007); and the 677C>T and 1298A>C variants of the MTHFR gene (Abu-Amero et al. 2003c). However, another study suggests that the MTHFR C677T variant mildly influences CAD in Saudi individuals (Al-Ali et al. 2005b). On the other hand, CAD was found to be associated with: a variant allele (a C to G substitution in the 30 UTR) of apoprotein-CIII (Hussain et al. 1999); the PlA2 allele resulting from a genetic polymorphism in the glycoprotein IIIa gene (Abu-Amero et al. 2004a); and the null-genotypes of GSTT1 and GSTM1 (AbuAmero et al. 2006a). The E-selectin p.S128R (g.561A>C) polymorphism was associated with angiographic CAD in univariate analysis, but lost its association in multivariate analysis (Abu-Amero et al. 2006b).

Cancer Polymorphisms in five genes (CYP1A1, GSTT1, GSTP1, GSTM1, and NQO1) were characterized in patients with diffuse large B-cell lymphoma (DLBCL). The CYP1A1*2C, GSTT1 null, and GSTP1 TT genotypes demonstrated significant association with DLBCL. None of the other alleles tested proved to be significant indicators (Al-Dayel et al. 2008). Two MTHFR polymorphisms (C677T and A1298C) were found to be possibly associated with susceptibility to develop DLBCL (Siraj et al. 2007). In addition to reported mutations in BRCA1 and BRCA2 in Saudi patients (El-Harith et al. 2002), the frequency of the valine allele at codon 655 of the HER-2 protooncogene, which is associated with increased breast cancer risk, was studied in Saudi women (Ameyaw et al. 2002). The CYP1A1 C4887A genotypes CA, AA and variant allele A were demonstrated to have significant differences and greater risk of developing papillary thyroid cancer in Saudi patients compared to wild type genotype CC. Also, in thyroid cancer GSTT1 null showed higher risk while GSTM1 null showed protective effect (Siraj et al. 2008a). In eight DNA repair genes, RAD52 2259 and RAD52 GLN221GLU were found to be associated with papillary thyroid cancer too (Siraj et al. 2008b).

552

Z.N. Al-Hassnan and N. Sakati

Diabetes Mellitus (DM) A positive association of the E23K variant of KCNJ11 with DM type 2 was found in Saudi individuals (Alsmadi et al. 2008a). To the contrary to what has been found in other populations, there was weak or no association with the rs7903146 and rs12255372 variants of TCF7L2 (Alsmadi et al. 2008b). In a series of 55 Saudi women with abnormal glucose tolerance test during pregnancy, the distribution of HLA antigen frequencies did not differ from a reference group of healthy individuals (Stangenberg et al. 1990). In patients with DM type 2, the risk of acquiring CAD increases significantly in the presence of the 128R mutant allele of the E-selectin gene (Abu-Amero et al. 2007).

Other Diseases Association studies with dyslipidemia was negative for a variant allele (a C to G substitution in the 30 UTR) of apoprotein-CIII (Hussain et al. 1999) but positive for the cholesteryl ester transfer protein TaqI-detectable B polymorphism (Al-Daghri et al. 2003). One study showed significantly higher frequency of Asp-9 residue, but not the Ala-73 residue, of Cw6 and Cw7 alleles of the HLA-C gene in Saudi patients with psoriasis vulgaris (Abanmi et al. 2005). The frequency of various HLA loci with vitiligo suggested that HLA-B7, Bw6, Cw6, Cw7, and DRB4*010101 could be associated with the disease (Abanmi et al. 2006). Several polymorphisms within the promoter region of the human interleukin-10 gene were significantly different in vitiligo patients compared to healthy subjects suggesting an association (Abanmi et al. 2008).

Polymorphisms in the Saudi Population The frequency and distributions of a variety of polymorphisms have been examined and published. In the following section, a summary of these publications is provided: l

Three decades ago, an analysis was performed for EsD, GPT, AcP, ADA, AK, 6-PGD, PGM, C3, Tf, Hp, Gc, Pi, Bf, Hb, and ABO-blood groups, Rh-factor, level of the third component of complement, and immunoglobulins in Saudi Arabia (Goedde et al. 1979). The distribution of eight blood phenotypes (ABO, Rh, MNSs Lutheran, Kell, Duffy, Kidd, and Lewis) was also determined (Abdelaal et al. 1999). The ABO phenotype distribution was similar to African Americans; as was the distribution of the rhesus phenotypes to Caucasians but the MNSs pattern was largely distinct. Heterozygous Kell phenotype, Kk, was much more frequent in Saudis than in either Caucasians, or African Americans.

19

l

l

l

l

l

l

l

Genetic Disorders in Saudi Arabia

553

The Kidd system null allele, JKab was not seen in the studied group. However, increased frequencies of null alleles of the Duff (Fyab) and Lewis (Le(ab)) systems were observed (Abdelaal et al. 1999). In a total of 292 randomly selected subjects belonging to two indigenous Arab and two immigrant tribes from the Western Region, genetic variants of six blood groups, four serum proteins, and five red cell enzyme systems were tested. The distribution of the polymorphic systems was different between indigenous and immigrant tribes, and there was a considerable degree of admixture from the surrounding countries, in particular Africa (Saha et al. 1980). The distribution of human Gm-globulin and Inv-allotypes in Saudi Arabia was also published (Hirth et al. 1979). A study on cord blood samples in Riyadh revealed that the A g T chain or HbF Sardinia was present in 28% with a gene frequency of 0.160. The frequency of two G g-globin genes was 0.0061 and 0.0122, respectively, which is comparable with other ethnic or racial groups (Niazi et al. 1991). The prevalence of a-1-antitrypsin phenotypes was analyzed. The prevalences of PiMM, MS, MZ, SZ, and ZZ of a-1-antitrypsin (a1AT) were 0.8676, 0.0931, 0.0245, 0.0098, and 0.0049, respectively. The gene frequencies of the a1AT variants, PiM, PiS, and PiZ, were 0.9265, 0.0515, and 0.022, respectively (Warsy et al. 1991). Distribution of group-specific component/vitamin-D-binding protein subtypes in Saudi Arabia did not differ significantly from what was found in other population samples from the Middle East (Degheishem et al. 1991). The prevalence of human platelet alloantigens (HPA)-1 polymorphism was found to be similar to that in Caucasians. On the other hand, HPA-4 polymorphism in Saudi individuals was greater than in Caucasians, and more similar to that of Japanese (al-Sheikh et al. 2000). The human neutrophil antigen system-one was found to be highly polymorphic and was similar in its distribution to the Hispanic and Native Americans but different from the Caucasians (Al-Sheikh et al. 2002). Factor V G1691A (FV-Leiden) and prothrombin G20210A single nucleotide polymorphisms were investigated in 149 Saudi healthy subjects. The prevalence of the two variants was 0.0101 and 0.000, respectively. The frequency of the FVLeiden G/A and A/A genotypes were 2.0 and 0.0%, respectively (Almawi et al. 2005). From five different regions of Saudi Arabia, 432 anonymous neonatal blood samples were screened for the lactase persistence/nonpersistence variant C/ T-13910 of the MCM6 gene. One variant, T/G-13915, residing 5 bp upstream of the C/T-13910 variant, was present in 76.9% of the neonatal samples (Imtiaz et al. 2007). This variant as a compound allele, T/G(–13915) within the –13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C (–3712), were found in Saudi individuals. It was suggested that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption (Enattah et al. 2008). The structure of the mtDNA in Saudi Arabia was elucidated recently (Abu-Amero et al. 2008). The results showed that the Arabian Peninsula has

554

Z.N. Al-Hassnan and N. Sakati

received substantial gene flow from Africa (20%), detected by the presence of L, M1, and U6 lineages, and that an 18% of the Arabian Peninsula lineages have a clear eastern provenance, mainly represented by U lineages; but also by Indian M lineages and rare M links with Central Asia, Indonesia and even Australia. However, the bulk (62%) of the Arabian lineages has a Northern source.

References Abanmi A, Joshi RK, Atukorala DN, Pedersen NB, Khamis OA (1994) Autosomal recessive epidermolysis bullosa simplex. A case report. Br J Dermatol 130(1):115–117 Abanmi A, Al Harthic F, Al Agla R, Khan HA, Tariq M (2005) Study of alanine-73 and aspartate-9 of HLA-C locus in Saudi psoriasis patients, using sequence-specific primers (PCR-SSP). J Biochem Mol Biol 38(3):350–353 Abanmi A, Al Harthi F, Al Baqami R, Al Assaf S, Zouman A, Arfin M, Tariq M (2006) Association of HLA loci alleles and antigens in Saudi patients with vitiligo. Arch Dermatol Res 298(7):347–352 Abanmi A, Al Harthi F, Zouman A, Kudwah A, Jamal MA, Arfin M, Tariq M (2008) Association of interleukin-10 gene promoter polymorphisms in Saudi patients with vitiligo. Dis Markers 24 (1):51–57 Abdelaal MA, Anyaegbu CC, al Sobhi EM, al Baz NM, Hodan K (1999) Blood group phenotype distribution in Saudi Arabs. Afr J Med Med Sci 28(3–4):133–135 Abdelrahman S, Bin-Abbas B, Al-Ashwal A (2000) Wolcott–Rallison syndrome in a Saudi infant. Curr Pediatr Res 4:51–52 Abdullah MA, Al-Hasnan Z, Okamoto E, Abomelha AM (2000) Arthrogryposis, renal dysfunction and cholestasis syndrome. Saudi Med J 21(3):297–299 Abu-Amero KK, Al-Hamed MH, Al-Batniji FS (2003a) Homozygous protein C deficiency with purpura fulminans: report of a new case and a description of a novel mutation. Blood Coagul Fibrinolysis 14(3):303–306 Abu-Amero KK, Wyngaard CA, Al-Boudari OM, Kambouris M, Dzimiri N (2003b) Lack of association of lipoprotein lipase gene polymorphisms with coronary artery disease in the Saudi Arab population. Arch Pathol Lab Med 127(5):597–600 Abu-Amero KK, Wyngaard CA, Dzimiri N (2003c) Prevalence and role of methylenetetrahydrofolate reductase 677 C!T and 1298 A!C polymorphisms in coronary artery disease in Arabs. Arch Pathol Lab Med 127(10):1349–1352 Abu-Amero KK, Wyngaard CA, Dzimiri N (2004a) Association of the platelet glycoprotein receptor IIIa (PlA1/PlA1) genotype with coronary artery disease in Arabs. Blood Coagul Fibrinolysis 15(1):77–79 Abu-Amero KK, Owaidah TM, Al Jefri A, Al-Ghonaium A, Fawaz IM, Al-Hamed MH (2004b) A novel splice site mutation in the WAS gene causes Wiskott–Aldrich syndrome in two siblings of a Saudi family. Blood Coagul Fibrinolysis 15(7):599–603 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2005) Beta 3 adrenergic receptor Trp64Arg polymorphism and manifestation of coronary artery disease in Arabs. Hum Biol 77 (6):795–802 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2006a) T null and M null genotypes of the glutathione S-transferase gene are risk factor for CAD independent of smoking. BMC Med Genet 7:38 Abu-Amero KK, Al-Boudari OM, Mohamed GH, Dzimiri N (2006b) E-selectin S128R polymorphism and severe coronary artery disease in Arabs. BMC Med Genet 7:52 Abu-Amero KK, Ozand PT, Al-Dhalaan H (2006c) Novel mitochondrial DNA transversion mutation in transfer ribonucleic acid for leucine 2 (CUN) in a patient with the clinical features of MELAS. J Child Neurol 21(11):971–972

19

Genetic Disorders in Saudi Arabia

555

Abu-Amero KK, Al-Mohanna F, Al-Boudari OM, Mohamed GH, Dzimiri N (2007) The interactive role of type 2 diabetes mellitus and E-selectin S128R mutation on susceptibility to coronary heart disease. BMC Med Genet 8:35 Abu-Amero KK, Larruga JM, Cabrera VM, Gonza´lez AM (2008) Mitochondrial DNA structure in the Arabian Peninsula. BMC Evol Biol 8:45 Abu-Amero KK, Dhalaan HA, Zayed ZA, Hellani A, Bosley TM (2009) Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations. J Neurol Sci 276(1–2):22–26 Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Crowley WF Jr, Seminara SB (2003) A locus for autosomal recessive idiopathic hypogonadotropic hypogonadism on chromosome 19p13.3. J Clin Endocrinol Metab 88(6):2947–2950 Al Aboud K, Al Hawsawi K, Al Aboud D, Al Githami A (2002) Kindler syndrome in a Saudi kindred. Clin Exp Derm 27:673–676 Al-Alami JR, Tayeh MK, Najib DA, Abu-Rubaiha ZA, Majeed HA, Al-Khateeb MS, El-Shanti HI (2003) Familial Mediterranean fever mutation frequencies and carrier rates among a mixed Arabic population. Saudi Med J 24(10):1055–1059 Al-Ali AK, Al-Mustafa ZH, Al-Madan M, Qaw F, Al-Ateeq S (2002) Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in the Eastern Province of Saudi Arabia. Clin Chem Lab Med 40(8):814–816 Al-Ali AK, Al-Ateeq S, Imamwerdi BW, Al-Sowayan S, Al-Madan M, Al-Muhanna F, Bashaweri L, Qaw F (2005a) Molecular bases of beta-thalassemia in the Eastern Province of Saudi Arabia. J Biomed Biotechnol 2005(4):322–325 Al-Ali AK, Al-Muhana FA, Larbi EB, Abdulmohsen MF, Al-Sultan AI, Al-Maden MS, Al-Ateeq SA (2005b) Frequency of methylenetetrahydrofolate reductase C677T polymorphism in patients with cardiovascular disease in Eastern Saudi Arabia. Saudi Med J 26 (12):1886–1888 Alangari A, Abobaker A, Kanegane H, Miyawaki T (2006) X-linked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency. Eur J Pediatr 165 (3):165–167 al Aqeel A, Ozand PT, Gascon G, Nester M, al Nasser M, Brismar J, Blau N, Hughes H, Subramanyan SB, Reynolds CT (1991) Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. Neurology 41(5):730–737 al Aqeel A, Rashed M, Ozand PT, Brismar J, Gascon GG, al Odaib A, Dabbagh O (1994) 3-Methylglutaconic aciduria: ten new cases with a possible new phenotype. Brain Dev 16:23–32 Al Aqeel A, Al Sewairi W, Edress B, Gorlin RJ, Desnick RJ, Martignetti JA (2000) Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family. Am J Med Genet 93(1):11–18 Al-Aqeel AI, Rashed MS, Ruiter JP, Al-Husseini HF, Al-Amoudi MS, Wanders RJ (2001) Carnitine palmityl transferase I deficiency. Saudi Med J 22(11):1025–1029 Al Aqeel AI, Rashid MS, Ruiter JP, Ijlst L, Wanders RJ (2003) A novel molecular defect of the carnitine acylcarnitine translocase gene in a Saudi patient. Clin Genet 64(2):163–165 Al-Awamy B, Niazi GA, Wilson JB, Huisman TH (1985) Hb Setif or alpha 2 94(G1)Asp–Tyr beta 2 observed in a Saudi Arabian family. Hemoglobin 9(1):87–90 Alazami AM, Al-Mayouf SM, Wyngaard CA, Meyer B (2006) Novel PRG4 mutations underlie CACP in Saudi families. Hum Mutat 27(2):213 Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, Bavi P, Kaya N, Colak D, Khalak H, Baltus A, Peterlin B, Danda S, Bhatia KP, Schneider SA, Sakati N, Walsh CA, Al-Mohanna F, Meyer B, Alkuraya FS (2008) Mutations in c2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet 83(6):684–691 Al-Daghri NM, Al-Attas O, Patel A, Belyaev ND, Bartlett WA, Jones AF, Kumar S, Bain SC (2003) Association between the cholesteryl ester transfer protein TaqI-detectable B polymorphism and low high-density lipoprotein cholesterol concentration in Saudis. Clin Sci 105 (4):467–472

556

Z.N. Al-Hassnan and N. Sakati

Aldahmesh MA, Abu-Safieh L, Khan AO, Al-Hassnan ZN, Shaheen R, Rajab M, Monies D, Meyer BF, Alkuraya FS (2009a) Allelic heterogeneity in inbred populations: the Saudi experience with Alstro¨m syndrome as an illustrative example. Am J Med Genet A 149A (4):662–665 Aldahmesh MA, Al-Hassnan ZN, Aldosari M, Alkuraya FS (2009b) Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emerging. Neurogenetics 10(4):307–311 Al-Dayel F, Al-Rasheed M, Ibrahim M, Bu R, Bavi P, Abubaker J, Al-Jomah N, Mohamed GH, Moorji A, Uddin S, Siraj AK, Al-Kuraya K (2008) Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population. Leuk Lymphoma 49(1):122–129 Al-Dirbashi OY, Jacob M, Al-Hassnan Z, El-Badaoui F, Rashed MS (2005) Diagnosis of methylmalonic acidemia from dried blood spots by HPLC and intramolecular-excimer fluorescence derivatization. Clin Chem 51(1):235–237 Al-Dirbashi OY, Jacob M, Al-Ahaidib LY, Al-Qahtani K, Rahbeeni Z, Al-Owain M, Rashed MS (2006) Quantification of succinylacetone in urine of hepatorenal tyrosinemia patients by HPLC with fluorescence detection. Clin Chim Acta 365(1–2):243–248 Al-Dirbashi OY, Abu-Amero KK, Alswaid AF, Hoffmann GF, Al-Qahtani K, Rashed MS (2007) LC-MS/MS determination of dibasic amino acids for the diagnosis of cystinuria. Application in a family affected by a novel splice-acceptor site mutation in the SLC7A9 gene. J Inherit Metab Dis 30(4):611 Al-Dirbashi OY, Santa T, Rashed MS, Al-Hassnan Z, Shimozawa N, Chedrawi A, Jacob M, Al-Mokhadab M (2008) Rapid UPLC-MS/MS method for routine analysis of plasma pristanic, phytanic, and very long chain fatty acid markers of peroxisomal disorders. J Lipid Res 49 (8):1855–1862 Al-Elq AH (2008) Familial hypomagnesemia with hypercalciuria and nephrocalcinosis in 2 sisters. Saudi Med J 29(3):447–451 Al-Essa M, Rashed M, Ozand PT (1998a) Tyrosinemia type II: report of the first four cases in Saudi Arabia. Ann Saudi Med 18(5):466–468 Al Essa M, Al-Shamsan L, Rashed MS, Ozand PT (1998a) Alkaptonuria: case report and review of the literature. Ann Saudi Med 18(5):442–444 Al Essa M, Nounou R, Sakati N, Le Quesne G, Joshi S, Archibald A, Ozand PT (1998b) Wolman’s disease: the King Faisal Specialist Hospital and Research Centre experience. Ann Saudi Med 18(2):120–124 Al Essa M, Sakati NA, Dabbagh O, Joshi S, Al Jishi EA, Rashed MS, Powe JE, Ozand PT (1998c) Inborn error of vitamin B12 metabolism: a treatable cause of childhood dementia/paralysis. J Child Neurol 13(5):239–243 Al Essa M, Rashed M, Ozand PT (1998d) Saudi experience with classic homocystinuria. Ann Saudi Med 18(3):230–233 Al Essa M, Rahbeeni Z, Jumaah S, Joshi S, Al Jishi E, Rashed MS, Al Amoudi M, Ozand PT (1998e) Infectious complications of propionic acidemia in Saudi Arabia. Clin Genet 54(1):90–94 Al-Essa M, Bakheet S, Al-Shamsan L, Patay Z, Powe J, Ozand PT (1999a) 18Fluoro2-deoxyglucose (18FDG) PET scan of the brain in type IV 3-methylglutaconic aciduria: clinical and MRI correlations. Brain Dev 21(1):24–29 Al-Essa M, Dhaunsi GS, Rashed M, Ozand PT, Rahbeeni Z (1999b) Zellweger syndrome in Saudi Arabia and its distinct features. Clin Pediatr 38(2):77–86 Al-Essa MA, Al Amir A, Rashed M, Al Jishi E, Abutaleb A, Mobaireek K, Shin YS, Ozand PT (1999c) Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency. Brain Dev 21(5):345–349 Al-Essa MA, Chaves-Carballo E, Ozand PT (1999d) Hyperpipecolic acidemia: clinical, biochemical, and radiologic observations. Pediatr Neurol 21(5):826–829 Al-Essa MA, Sakati NA, Bakheet SM, Patay ZJ, Dabbagh O, Chaves-Carbello E, Ozand PT (2000a) X-linked adrenoleukodystrophy. The Saudi experience. Saudi Med J 21(1):61–71

19

Genetic Disorders in Saudi Arabia

557

Al-Essa MA, Rashed MS, Bakheet SM, Patay ZJ, Ozand PT (2000b) Glutaric aciduria type II: observations in seven patients with neonatal- and late-onset disease. J Perinatol 20(2):120–128 Al Fadley F, Al Manea W, Nykanen DG, Al Fadley A, Bulbul Z, Al Halees Z (2000) Severe tortuosity and stenosis of the systemic, pulmonary and coronary vessels in 12 patients with similar phenotypic features: a new syndrome? Cardiol Young 10(6):582–589 al-Fawaz IM, al-Mashhadani SA (1995) Congenital dyserythropoietic anaemia type I. Report of two siblings from Saudi Arabia. Acta Haematol 93(1):50–53 al-Gazali LI, Makia S, Azzam A, Hall CM (1995) Wolcott–Rallison syndrome. Clin Dysmorphol 4 (3):227–233 Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Rashed MS (2006) Identification of the Prevalent MCAD Mutation in the Saudi Population. In: The 6th Meeting of the International Society for Neonatal Screening, 16–19 September 2006, Awaji, Japan Al-Hassnan ZN, Al Budhaim M, Al-Owain M, Lach B, Al-Dhalaan H (2007a) Muscle phosphofructokinase deficiency with neonatal seizures and nonprogressive course. J Child Neurol 22 (1):106–108 Al-Hassnan ZN, Teebi AS (2007b) Craniofacial anomalies, humero-radial synostosis, rhizomelic limb shortness: previously unrecognized autosomal recessive syndrome. Am J Med Genet 143A:521–527 Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK (2008) Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci 264 (1–2):187–194 Al-Hassnan ZN, Al Dhalaan H, Patay Z, Faqeih E, Al-Owain M, Al-Duraihem A, FaiyazUl-Haque M (2009) Sphingolipid activator protein-B deficiency: Report of 9 patients and review of literature. J Child Neurol 24(12):1513–9 Al-Hilali A, Wulff K, Abdel-Razeq H, Saud KA, Al-Gaili F, Herrmann FH (2007) Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly. Thromb Haemost 97(4):542–545 Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B (2004) Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet 124A:28–34 al-Jarallah AA, Salih MA, al Nasser MN, al Zamil FA, al Gethmi J (1996) Rett syndrome in Saudi Arabia: report of six patients. Ann Trop Paediatr 16(4):347–352 Al-Jishi E, Meyer BF, Rashed MS, Al-Essa M, Al-Hamed MH, Sakati N, Sanjad S, Ozand PT, Kambouris M (1999) Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet 55(6):444–449 Al-Jumah M, Majumdar R, Al-Rajeh S, Chaves-Carballo E, Salih MM, Awada A, Al-Shahwan S, Al-Uthaim S (2002) Deletion mutations in the dystrophin gene of Saudi patients with Duchenne and Becker muscular dystrophy. Saudi Med J 23(12):1478–1482 Al-Jumah M, Majumdar R, Al-Rajeh S, Awada A, Chaves-Carbello E, Salih M, Al-Shahwan S, Al-Subiey K, Al-Uthaim S (2003) Molecular analysis of the spinal muscular atrophy and neuronal apoptosis inhibitory protein genes in Saudi patients with spinal muscular atrophy. Saudi Med J 24(10):1052–1054 Al Jumah M, Majumdar R, Al Rajeh S, Awada A, Al Zaben A, Al Traif I, Al Jumah AR, Rehana Z (2004) A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudispecific mutations. Eur J Neurol 11(2):121–124 Al Jumah M, Majumdar R, Rehana Z, Al Rajeh S, Eyaid W (2007) A pilot study of spinal muscular atrophy screening in Saudi Arabia. J Pediatr Neurol 5(3):221–224 al-Jurayyan NA (1995) Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta Paediatr 84(6):651–654 al Kandari H, Katsumata N, Alexander S, Rasoul MA (2006) Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46, XY patient with adrenal insufficiency,

558

Z.N. Al-Hassnan and N. Sakati

complete sex reversal, and agenesis of corpus callosum. J Clin Endocrinol Metab 91 (8):2821–2826 Allamand V, Sunada Y, Salih MA, Straub V, Ozo CO, Al-Turaiki MH, Akbar M, Kolo T, Colognato H, Zhang X, Sorokin LM, Yurchenco PD, Tryggvason K, Campbell KP (1997) Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain. Hum Mol Genet 6(5):747–752 Allanson J, Austin W, Hecht F (1986) Congenital cutis laxa with retardation of growth and motor development: a recessive disorder of connective tissue with male lethality. Clin Genet 29 (2):133–136 Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, Gerrard B, Baird L, Stauffer D, Peiffer A, Rattner A, Smallwood P, Li Y, Anderson KL, Lewis RA, Nathans J, Leppert M, Dean M, Lupski JR (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15(3):236–246 Almawi WY, Keleshian SH, Borgi L, Fawaz NA, Abboud N, Mtiraoui N, Mahjoub T (2005) Varied prevalence of factor V G1691A (Leiden) and prothrombin G20210A single nucleotide polymorphisms among Arabs. J Thromb Thrombolysis 20(3):163–168 Al-Mayouf SM, Majeed M, Hugosson C, Bahabri S (2000) New form of idiopathic osteolysis: nodulosis, arthropathy and osteolysis (NAO) syndrome. Am J Med Genet 93(1):5–10 Al-Mayouf SM, AlMehaidib A, Bahabri S, Shabib S, Sakati N, Teebi AS (2005) Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs. Clin Exp Rheumatol 23 (5):717–720 Al-Mutair A, Iqbal MA, Sakati N, Ashwal A (2004) Cytogenetics and etiology of ambiguous genitalia in 120 pediatric patients. Ann Saudi Med 24(5):368–372 al-Rabeeah A, al-Ashwal A, al-Herbish A, al-Jurayyan N, Sakati N, Abobakr A (1995) Persistent hyperinsulinemic hypoglycemia of infancy: experience with 28 cases. J Pediatr Surg 30 (8):1119–1121 Al Rajeh S, el Mouzan MI, Ahlberg A, Ozaksoy D (1988) The syndrome of osteopetrosis, renal acidosis and cerebral calcification in two sisters. Neuropediatrics 19(3):162–165 Al Rajeh S, Majumdar R, Awada A, Adeyokunnu A, Al Jumah M, Al Bunyan M, Snellen A (1998) Molecular analysis of the SMN and NAIP genes in Saudi spinal muscular atrophy patients. J Neurol Sci 158(1):43–46 al Rashed AA, al-Jarallah AA, Salih MA, Kolawole T, al-Jarallah J (1999) Sotos syndrome (cerebral gigantism): a clinical and radiological study of 14 cases from Saudi Arabia. Ann Trop Paediatr 19(2):197–203 Al-Sayed M, Alahmed S, Alsmadi O, Khalil H, Rashed MS, Imtiaz F, Meyer BF (2005) Identification of a common novel mutation in Saudi patients with argininosuccinic aciduria. J Inherit Metab Dis 28(6):877–883 Al-Sayed M, Imtiaz F, Alsmadi OA, Rashed MS, Meyer BF (2006) Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population. BMC Med Genet 7:86 Alsbeih G, Al-Hadyan K, Al-Harbi N (2008) Assessment of carriers’ frequency of a novel MRE11 mutation responsible for the rare ataxia telangiectasia-like disorder. Genet Test 12 (3):387–389 Al-Semari A, Bohlega S (2007) Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1. Am J Med Genet 143A:149–160 al-Shamsan L, al-Essa M, al-Mutair A, al-Ashwal A, Sakati N, Ozand PT (1998) Hyperinsulinism and hyperammonaemia. J Inherit Metab Dis 21(6):671–673 al-Sheikh I, Rahi A, al-Khalifa M (2000) Genotyping human platelet alloantigens (HPA 1–5) in Saudis from Eastern Province, Saudi Arabia. East Mediterr Health J 6(1):168–175 Al-Sheikh IH, Al-Khalifa MA, Rahi AS (2002) Frequency of neutrophil alloantigens by polymerase chain reaction. Saudi Med J 23(5):548–551

19

Genetic Disorders in Saudi Arabia

559

Alsmadi OA, Al-Kayal F, Al-Hamed M, Meyer BF (2006) Frequency of common HFE variants in the Saudi population: a high throughput molecular beacon-based study. BMC Med Genet 7:43 Alsmadi O, Al-Rubeaan K, Wakil SM, Imtiaz F, Mohamed G, Al-Saud H, Al-Saud NA, Aldaghri N, Mohammad S, Meyer BF (2008a) Genetic study of Saudi diabetes (GSSD): significant association of the KCNJ11 E23K polymorphism with type 2 diabetes. Diabetes Metab Res Rev 24(2):137–140 Alsmadi O, Al-Rubeaan K, Mohamed G, Alkayal F, Al-Saud H, Al-Saud NA, Al-Daghri N, Mohammad S, Meyer BF (2008b) Weak or no association of TCF7L2 variants with type 2 diabetes risk in an Arab population. BMC Med Genet 9:72 Alsmadi O, Meyer BF, Alkuraya F, Wakil S, Alkayal F, Al-Saud H, Ramzan K, Al-Sayed M (2009) Syndromic congenital sensorineural deafness, microtia and microdontia resulting from a novel homoallelic mutation in fibroblast growth factor 3 (FGF3). Eur J Hum Genet 17(1):14–21 Al-Tahan AY, Divakaran MP, Kambouris M, Bohlega S, Salih M, Ogunniyi A, Al-Ghanmi H (1999) A novel autosomal recessive ‘Huntington’s disease-like’ neurodegenerative disorder in a Saudi family. Saudi Med J 20:85–89 Alzahrani AS, Baitei EY, Zou M, Shi Y (2006a) Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene. J Clin Endocrinol Metab 91(3):740–746 Alzahrani AS, Baitei E, Zou M, Shi Y (2006b) Thiamine transporter mutation: an example of monogenic diabetes mellitus. Eur J Endocrinol 155(6):787–792 Alzahrani AS, Al-Khaldi N, Shi Y, Al-Rijjal RA, Zou M, Baitei EY, Amin T (2008) Diagnosis by serendipity: Cushing syndrome attributable to cortisol-producing adrenal adenoma as the initial manifestation of multiple endocrine neoplasia type 1 due to a rare splicing site MEN1 gene mutation. Endocr Pract 14(5):595–602 Ameyaw MM, Tayeb M, Thornton N, Folayan G, Tariq M, Mobarek A, Evans DA, Ofori-Adjei D, McLead HL (2002) Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer. J Hum Genet 47(4):172–175 Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425(6958):628–633 Arredondo-Vega FX, Santisteban I, Richard E, Bali P, Koleilat M, Loubser M, Al-Ghonaium A, Al-Helali M, Hershfield MS (2002) Adenosine deaminase deficiency with mosaicism for a “second-site suppressor” of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. Blood 99(3):1005–1013 Awad M, Al-Ashwal AA, Sakati N, Al-Abbad AA, Bin-Abbas BS (2002) Long-term follow up of carbonic anhydrase II deficiency syndrome. Saudi Med J 23(1):25–29 Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N (2003) Identification of a novel Bardet–Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72(3):650–658 Bahabri S, Sakati N, Hugosson C, Hainau B, Al-Balla SR, Al-Mazyed A, Al-Dalaan A (1994) Syndrome of camptodactyly, arthropathy and coxa vara (CAC syndrome). Ann Saudi Med 14 (6):479–482 Bahabri SA, Suwairi WM, Laxer RM, Polinkovsky A, Dalaan AA, Warman ML (1998) The camptodactyly–arthropathy–coxa vara–pericarditis syndrome: clinical features and genetic mapping to human chromosome 1. Arthritis Rheum 41(4):730–735 Banjar H, Kambouris M, Meyer BF, al-Mehaidib A, Mogarri I (1999) Geographic distribution of cystic fibrosis transmembrane regulator gene mutations in Saudi Arabia. Ann Trop Paediatr 19 (1):69–73 Barr DG, Kirk JM, al Howasi M, Wanders RJ, Schutgens RB (1993) Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency. Arch Dis Child 68(3):415–417

560

Z.N. Al-Hassnan and N. Sakati

Bejjani BA, Lewis RA, Tomey KF, Anderson KL, Dueker DK, Jabak M, Astle WF, Otterud B, Leppert M, Lupski JR (1998) Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 62 (2):325–333 Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, Astle WF, Lupski JR (2000) Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 9(3):367–374 Betz RC, Indelman M, Pforr J, Schreiner F, Bauer R, Bergman R, Lentze MJ, No¨then MM, Cichon S, Sprecher E (2007) Identification of mutations in the human hairless gene in two new families with congenital atrichia. Arch Dermatol Res 299(3):157–161 Bhuiyan ZA, Momenah TS, Amin AS, Al-Khadra AS, Alders M, Wilde AA, Mannens MM (2008) An intronic mutation leading to incomplete skipping of exon-2 in KCNQ1 rescues hearing in Jervell and Lange–Nielsen syndrome. Prog Biophys Mol Biol 98(2–3):319–327 Bin-Abbas B, Shabib S, Hainau B, Al-Ashwal A (2001) Wolcott–Rallison syndrome: clinical, radiological and histological findings in a Saudi child. Ann Saudi Med 21(1–2):73–74 Bin-Abbas B, Al-Mulhim A, Al-Ashwal A (2002) Wolcott–Rallison syndrome in two siblings with isolated central hypothyroidism. Am J Med Genet 111(2):187–190 Bin-Abbas BS, Al-Mulhim AN, Sakati NA, Al-Ashwal AA (2003) Persistent hyperinsulinemic hypoglycemia of infancy in 38 children. Saudi Med J 24(8):890–894 Bin-Abbas BS, Sakati NA, Al-Ashwal AA (2004a) Congenital adrenal hyperplasia due to 3 betahydroxysteroid dehydrogenase type II deficiency in 4 Saudi children. Long term follow up. Saudi Med J 25(9):1293–1295 Bin-Abbas BS, Al-Ashwal AA, Al-Alwan IA, Al-Qahtani MH, Al-Mutair AN, Sakati NA (2004b) The syndrome of septo-optic dysplasia in Saudi children. Saudi Med J 25(11):1675–1678 Bo-Abbas Y, Acierno JS Jr, Shagoury JK, Crowley WF Jr, Seminara SB (2003) Autosomal recessive idiopathic hypogonadotropic hypogonadism: genetic analysis excludes mutations in the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes. J Clin Endocrinol Metab 88(6):2730–2737 Bohlega S, Al-Jishi A, Dobson-Stone C, Rampoldi L, Saha P, Murad H, Kareem A, Roberts G, Monaco AP (2003a) Chorea-acanthocytosis: clinical and genetic findings in three families from the Arabian Peninsula. Mov Disord 18(4):403–407 Bohlega S, Lach B, Meyer BF, Al Said Y, Kambouris M, Al Homsi M, Cupler EJ (2003b) Autosomal dominant hyaline body myopathy: clinical variability and pathologic findings. Neurology 61(11):1519–1523 Bohlega S, Abu-Amero SN, Wakil SM, Carroll P, Al-Amr R, Lach B, Al-Sayed Y, Cupler EJ, Meyer BF (2004) Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy. Neurology 62(9):1518–1521 Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW, Farah S, Abu-Amero KK (2007) CADASIL in Arabs: clinical and genetic findings. BMC Med Genet 8:67 Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, Christodoulou K, Hausmanowa-Petrusewicz I, Mandich P, Schenone A, Gambardella A, Bono F, Quattrone A, Devoto M, Monaco AP (2000) Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet 25(1):17–19 Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, Abu-Amero KK, MacDonald DB, al Zayed Z, al Dhalaan H, Kansu T, Stigsby B, Baloh RW (2005) Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology 64(7):1196–1203 Bosley TM, Salih MA, Alorainy IA, Oystreck DT, Nester M, Abu-Amero KK, Tischfield MA, Engle EC (2007) Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology 69(12):1245–1253 Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP (2008) The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet 146A:1235–1240

19

Genetic Disorders in Saudi Arabia

561

Boyadjiev SA, Justice CM, Eyaid W, McKusick VA, Lachman RS, Chowdry AB, Jabak M, Zwaan J, Wilson AF, Jabs EW (2003) A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13–q21. Hum Genet 113(1):1–9 Boyadjiev SA, Fromme JC, Ben J, Chong SS, Nauta C, Hur DJ, Zhang G, Hamamoto S, Schekman R, Ravazzola M, Orci L, Eyaid W (2006) Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking. Nat Genet 38(10):1192–1197 Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn T, Wilson DI, Hanley NA (2003) Wolcott–Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40(9):685–689 Brismar J, Brismar G, Gascon G, Ozand P (1990a) Canavan disease: CT and MR imaging of the brain. Am J Neuroradiol 11(4):805–810 Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P (1990b) Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. Am J Neuroradiol 11(6):1219–1228 Brismar J, Ozand PT (1994) CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. Am J Neuroradiol 15(8):1459–1473 Brismar J, Ozand PT (1995) CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients. Am J Neuroradiol 16(4):675–683 Bugiani M, Al Shahwan S, Lamantea E, Bizzi A, Bakhsh E, Moroni I, Balestrini MR, Uziel G, Zeviani M (2006) GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 67(2):273–279 Burnichon N, Lacan P, Becchi M, Zanella-Cleon I, Aubry M, Mowafy M, Couprie N, Francina A (2006) A new alpha chain hemoglobin variant: Hb Al-Hammadi Riyadh (alpha75(EF4) Asp!Val (alpha2)). Hemoglobin 30(2):155–164 Cagatay P, Susleyici-Duman B, Ciftci C (2007) Lipoprotein lipase gene PvuII polymorphism serum lipids and risk for coronary artery disease: meta-analysis. Dis Markers 23(3):161–166 Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A (2007) C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 61(4):340–351 Carroll P, Al-Mojalli H, Al-Abbad A, Al-Hassoun I, Al-Hamed M, Al-Amr R, Butt AI, Meyer BF (2006) Novel mutations underlying nephrogenic diabetes insipidus in Arab families. Genet Med 8(7):443–447 Chang SS, Grunder S, Hanukoglu A, Ro¨sler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP (1996) Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet 12(3):248–253 Chen X, Baker BY, Abduljabbar MA, Miller WL (2005) A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings. J Clin Endocrinol Metab 90(2):835–840 Chishti MA, Bohlega S, Ahmed M, Loualich A, Carroll P, Sato C, St George-Hyslop P, Westaway D, Rogaeva E (2006) T313M PINK1 mutation in an extended highly consanguineous Saudi family with early-onset Parkinson disease. Arch Neurol 63(10):1483–1485 Clayton PT, Leonard JV, Lawson AM, Setchell KD, Andersson S, Egestad B, Sjo¨vall J (1987) Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta, 7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest 79(4):1031–1038 Cogan JD, Phillips JA 3rd, Sakati N, Frisch H, Schober E, Milner RD (1993) Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency. J Clin Endocrinol Metab 76 (5):1224–1228 Cook JD, Gascon GG, Haider A, Coates R, Stigsby B, Ozand PT, Banna M (1992) Congenital muscular dystrophy with abnormal radiographic myelin pattern. J Child Neurol 7(Suppl):S51–S63 Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Me´garbane´ A, Alswaid A, Dollfus H, Alembik Y, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) ADAMTS10 mutations in autosomal recessive Weill–Marchesani syndrome. Am J Hum Genet 75(5):801–806

562

Z.N. Al-Hassnan and N. Sakati

Degheishem SM, Sedrani SH, Van Baelen H, Bouillon R, Duhaiman AS (1991) Distribution of group-specific component/vitamin-D-binding protein subtypes in Saudi Arabia. Hum Hered 41 (1):53–56 de Saint Basile G (2007) Inherited hemophagocytic syndromes. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases: a molecular and genetic approach, 2nd edn. Oxford University Press, New York, pp 578–588 de Serres FJ, Blanco I, Ferna´ndez-Bustillo E (2006) Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of alpha1-antitrypsin deficiency in Asia. Eur Respir J 28 (6):1091–1099 Dumitrescu AM, Liao XH, Abdullah MS, Lado-Abeal J, Majed FA, Moeller LC, Boran G, Schomburg L, Weiss RE, Refetoff S (2005) Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 37(11):1247–1252 Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley-Green A, Lu S, Clement JP 4th, Lindley KJ, Seino S, Aguilar-Bryan L (1997) Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 336 (10):703–706 Dzimiri N, Basco C, Moorji A, Meyer BF (2000) Angiotensin-converting enzyme polymorphism and the risk of coronary heart disease in the Saudi male population. Arch Pathol Lab Med 124 (4):531–534 El-Harith EH, Stuhrmann M, Dork T, Eskandarani HA, Schmidtke J (1998) PCR-based analysis of cystic fibrosis mutations specific for Saudi patients. Saudi Med J 19:148–152 El-Harith el-HA, Abdel-Hadi MS, Steinmann D, Dork T (2002) BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia. Saudi Med J 23(6):700–704 El-Harith el-HA, K€uhnau W, Schmidtke J, Gadzicki D, Ahmed M, Krawczak M, Stuhrmann M (2006) Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality. Eur J Med Genet 49 (4):323–330 El-Hazmi MA, Lehmann H (1980) Human haemoglobins and haemoglobinopathies in Arabia: Hb O Arab in Saudi Arabia. Acta Haematol 63(5):268–273 el-Hazmi MA, Warsy AS (1985) Glutathione reductase deficiency in association with sickle cell and thalassaemia genes in Saudi populations. Hum Hered 35(5):326–332 el-Hazmi MA (1986a) Beta-globin gene polymorphism in the Saudi Arab population. Hum Genet 73(1):31–34 el-Hazmi MA, Al-Swailem AR, Al-Faleh FZ, Warsy AS (1986b) Frequency of glucose6-phosphate dehydrogenase, pyruvate kinase and hexokinase deficiency in the Saudi population. Hum Hered 36(1):45–49 el-Hazmi MA (1987a) Haemoglobinopathies, thalassaemias and enzymopathies in Saudi Arabia: the present status. Acta Haematol 78(2–3):130–134 el-Hazmi MA (1987b) Alpha-thalassemia in Saudi Arabia: deletion pattern. Hum Genet 76 (2):196–198 el-Hazmi MA (1989) Xmn I polymorphism in the gamma-globin gene region among Saudis. Hum Hered 39(1):12–19 el-Hazmi MA, Warsy AS (1990) Frequency of glucose-6-phosphate dehydrogenase variants and deficiency in Arabia. Gene Geogr 4(1):15–19 el-Hazmi MA (1992a) Heterogeneity and variation of clinical and haematological expression of haemoglobin S in Saudi Arabs. Acta Haematol 88(2–3):67–71 el-Hazmi MA, Warsy AS (1992b) Triple alpha-genes (alpha alpha alpha anti3.7) in a patient with sickle cell anaemia. Hum Hered 42(6):360–366 el-Hazmi MA, Bahakim HM, Warsy AS (1992c) DNA polymorphism in the beta-globin gene cluster in Saudi Arabs: relation to severity of sickle cell anaemia. Acta Haematol 88 (2–3):61–66 el-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem AM, Sulaimani R, al-Meshari AA (1995a) Consanguinity among the Saudi Arabian population. J Med Genet 32:623–626

19

Genetic Disorders in Saudi Arabia

563

el-Hazmi MA, al-Swailem AR, Warsy AS (1995b) Molecular defects in beta-thalassaemias in the population of Saudi Arabia. Hum Hered 45(5):278–285 el-Hazmi MA, Warsy AS (1996) Frequency of sickle cell gene in Arabia. Gene Geogr 10(2): 87–91 el-Hazmi MA, Warsy AS (1999) Appraisal of sickle-cell and thalassaemia genes in Saudi Arabia. East Mediterr Health J 5(6):1147–1153 El-Mouzan MI, Al-Salloum AA, Al-Herbish AS, Qurachi MM, Al-Omar AA (2007) Regional variations in the prevalence of consanguinity in Saudi Arabia. Saudi Med J 28(12):1881–1884 Elseed FA, Karrar ZA (1984) Congenital afibrinogenaemia in a Saudi family: a case report and family study. Acta Haematol 71(6):388–392 Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82(1):57–72 Engle EC, Wang SM, Zwaan JT, Mullaney PB, Jabak MH, Beggs AH (1997) Linkage and homozygosity mapping of a variant of congenital fibrosis of the extraocular muscles to chromosome 11q13.1. Am J Hum Genet 61(Suppl):A30 (abstract) Faivre L, Me´garbane´ A, Alswaid A, Zylberberg L, Aldohayan N, Campos-Xavier B, Bacq D, LegeaiMallet L, Bonaventure J, Munnich A, Cormier-Daire V (2002) Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3–p13.2. Hum Genet 110(4):366–370 Faiyaz-Ul-Haque M, Faqeih EA, Al-Zaidan H, Al-Shammary A, Zaidi SH (2008) Grebe-type chondrodysplasia: a novel missense mutation in a conserved cysteine of the growth differentiation factor 5. J Bone Miner Metab 26(6):648–652 Faiyaz-Ul-Haque M, Zaidi SH, Al-Sanna N, Alswaid A, Momenah T, Kaya N, Al-Dayel F, Bouhoaigah I, Saliem M, Tsui LC, Teebi AS (2009a) A novel missense and a recurrent mutation in SLC2A10 gene of patients affected with arterial tortuosity syndrome. Atherosclerosis 203(2):466–471 Faiyaz-Ul-Haque M, Al-Owain M, Al-Dayel F, Al-Hassnan Z, Al-Zaidan H, Rahbeeni Z, Al-Sayed M, Balobaid A, Cluntun A, Toulimat M, Abalkhail H, Peltekova I, Zaidi SH (2009b) Novel FBP1 gene mutations in Arab patients with fructose-1, 6-bisphosphatase deficiency. Eur J Pediatr 168(12):1467–71 Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet–Biedl syndrome. Nat Genet 36 (9):989–993 Faqeih E, Al-Akash SI, Sakati N, Teebi PA (2007) Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: a possible new autosomal recessive syndrome. Am J Med Genet A 143A(17):1951–1957 Faqeih E, Sakati N, Teebi AS (2008) Meier–Gorlin (ear–patella–short stature) syndrome: growth hormone deficiency and previously unrecognized findings. Am J Med Genet 137A:339–341 Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA (2004) Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36 (9):1008–1013 Fernet M, Gribaa M, Salih MA, Seidahmed MZ, Hall J, Koenig M (2005) Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. Hum Mol Genet 14(2):307–318 Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A (2001) Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A 98(22):12614–12619

564

Z.N. Al-Hassnan and N. Sakati

Gascon GG, Ozand PT, Erwin RE (1992a) GM1 gangliosidosis type 2 in two siblings. J Child Neurol 7(Suppl):S41–S50 Gascon GG, Youssef NG, Subramanyam SB, Ozand PT (1992b) Coincident neuraminidase and aspartoacylase deficiency associated with chromosome 9Q paracentric inversion in a Saudi family. J Child Neurol 7(Suppl):S73–S78 Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, McKiernan PJ, Klomp LW, Morris AA, Wraith JE, McClean P, Lynch SA, Thompson RJ, Lo B, Quarrell OW, Di Rocco M, Trembath RC, Mandel H, Wali S, Karet FE, Knisely AS, Houwen RH, Kelly DA, Maher ER (2004) Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome. Nat Genet 36(4):400–404 Goedde HW, Benkmann HG, Agarwal DP, Hirth L, Bienzle U, Dietrich M, Hoppe HH, Orlowski J, Kohne E, Kleihauer E (1979) Genetic studies in Saudi Arabia: red cell enzyme, haemoglobin and serum protein polymorphisms. Am J Phys Anthropol 50(2):271–277 Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, Mans DA, Hikida A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter CM, Bammler TK, Farin FM, Dorschner M, Topc¸u M, Zackai EH, Rosenthal P, Owens KN, Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, Chance PF, Roepman R, Moens CB, Glass IA, Doherty D (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83(5):559–571 Gribaa M, Salih M, Anheim M, Lagier-Tourenne C, H’mida D, Drouot N, Mohamed A, Elmalik S, Kabiraj M, Al-Rayess M, Almubarak M, Be´tard C, Goebel H, Koenig M (2007) A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21–q23. Brain 130(Pt 7):1921–1928 Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, Al Sanna N, Saggar A, Hamel B, Earnshaw WC, Jeggo PA, Jackson AP, O’Driscoll M (2008) Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nat Genet 40 (2):232–236 Gripp KW, Donnai D, Clericuzio CL, McDonald-McGinn DM, Guttenberg M, Zackai EH (1997) Diaphragmatic hernia–exomphalos–hypertelorism syndrome: a new case and further evidence of autosomal recessive inheritance. Am J Med Genet 68(4):441–444 Grody WW, Klein D, Dodson AE, Kern RM, Wissmann PB, Goodman BK, Bassand P, Marescau B, Kang SS, Leonard JV et al (1992) Molecular genetic study of human arginase deficiency. Am J Hum Genet 50(6):1281–1290 Haider N, Salih MA, Al-Rasheed S, Al-Mofada S, Krahn PM, Kabiraj M (1996) Nonketotic hyperglycinemia: a life-threatening disorder in Saudi Newborns. Ann Saudi Med 16 (4):400–404 Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, Edelstein I, South AP, Bleck O, Wessagowit V, Mallipeddi R, Orchard GE, Wan H, Dopping-Hepenstal PJ, Mellerio JE, Whittock NV, Munro CS, van Steensel MA, Steijlen PM, Ni J, Zhang L, Hashimoto T, Eady RA, McGrath JA (2002) Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet 11(7):833–840 Harfi HA, Brismar J, Hainau B, Sabbah R (1992) Partial albinism, immunodeficiency, and progressive white matter disease: a new primary immunodeficiency. Allergy Proc 13 (6):321–328 Harrison DA, Mullaney PB, Mesfer SA, Awad AH, Dhindsa H (1998) Management of ophthalmic complications of homocystinuria. Ophthalmology 105(10):1886–1890 Hasounah FH, Sejeny SA, Omer JA, Old JM, Oliver RW (1995) Spectrum of beta-thalassaemia mutations in the population of Saudi Arabia. Hum Hered 45(4):231–234 Hellani A, Schuchman EH, Al-Odaib A, Al Aqueel A, Jaroudi K, Ozand P, Coskun S (2004) Preimplantation genetic diagnosis for Niemann–Pick disease type B. Prenat Diagn 24 (12):943–948

19

Genetic Disorders in Saudi Arabia

565

Henriquez H, el Din A, Ozand PT, Subramanyam SB, al Gain SI (1994) Emergency presentations of patients with methylmalonic acidemia, propionic acidemia and branched chain amino acidemia (MSUD). Brain Dev 16(Suppl):86–93 Hirth L, Benkmann HG, Goedde HW (1979) The distribution of human Gm-globulin and Inv-allotypes in populations of Egypt, Saudi-Arabia, Afghanistan and Ecuador. Z Morphol Anthropol 70(2):174–180 Hodgkinson CA, Bohlega S, Abu-Amero SN, Cupler E, Kambouris M, Meyer BF, Bharucha VA (2002) A novel form of autosomal recessive pure hereditary spastic paraplegia maps to chromosome 13q14. Neurology 59(12):1905–1909 Ho¨glund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U, Al Sanie A, Al-Ghanim M, Holmberg C, de la Chapelle A, Kere J (1998) Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 63(3):760–768 Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 26(1):93–96 Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML (1999) Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23(1):94–98 Hussain SS, Buraiki J, Dzimiri N, Butt AI, Vencer L, Basco MC, Khan B (1999) Polymorphism in apoprotein-CIII gene and coronary heart disease. Ann Saudi Med 19(3):201–205 Iqbal MA, Sakati N, Nester M, Ozand P (2000) Cytogenetic diagnosis of fragile X syndrome: study of 305 suspected cases in Saudi Arabia. Ann Saudi Med 20(3–4):214–217 Imtiaz F, Savilahti E, Sarnesto A, Trabzuni D, Al-Kahtani K, Kagevi I, Rashed MS, Meyer BF, J€arvel€a I (2007) The T/G 13915 variant upstream of the lactase gene (LCT) is the founder allele of lactase persistence in an urban Saudi population. J Med Genet 44(10):e89 Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA (1998) A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 20(2):143–148 Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, R€ ub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC (2004) Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 304(5676):1509–1513 Johansen K, Dunn B, Tan JC, Kwaasi AA, Skotnicki A, Skotnicki M (1991) Coronary artery disease and apolipoprotein A-I/C-III gene polymorphism: a study of Saudi Arabians. Clin Genet 39(1):1–5 Joshi S, al-Essa MA, Archibald A, Ozand PT (1999) Biotinidase deficiency: a treatable genetic disorder in the Saudi population. East Mediterr Health J 5(6):1213–1217 Kambouris M, Bohlega S, Al-Tahan A, Meyer BF (2000a) Localization of the gene for a novel autosomal recessive neurodegenerative Huntington-like disorder to 4p15.3. Am J Hum Genet 66(2):445–452 Kambouris M, Banjar H, Moggari I, Nazer H, Al-Hamed M, Meyer BF (2000b) Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations. Eur J Pediatr 159 (5):303–309 Karkashan EM, Joharji HS, Al-Harbi NN (2002) Congenital insensitivity to pain in four related Saudi families. Pediatr Dermatol 19:333–335 Karrar ZA, Elidrissy AT, Al Arabi K, Adam KA (1983) The wrinkly skin syndrome: a report of two siblings from Saudi Arabia. Clin Genet 23(4):308–310

566

Z.N. Al-Hassnan and N. Sakati

Katol J, Takao M, Ideguchi H, Sawada H, Kawashima H, Ono J (2006) Genetic screening for alpha-thalassemia deletional determinants by GapPCR method. Rinsho Byori 54(11): 1095–1100 Katsanis N, Shroyer NF, Lewis RA, Cavender JC, Al-Rajhi AA, Jabak M, Lupski JR (2001) Fundus albipunctatus and retinitis punctata albescens in a pedigree with an R150Q mutation in RLBP1. Clin Genet 59(6):424–429 Katsanis N, Eichers ER, Ansley SJ, Lewis RA, Kayserili H, Hoskins BE, Scambler PJ, Beales PL, Lupski JR (2002) BBS4 is a minor contributor to Bardet–Biedl syndrome and may also participate in triallelic inheritance. Am J Hum Genet 71(1):22–29 Kaya N, Al-Zahrani F, Al-Odaib A, Rahbeeni Z, Al-Hassnan Z, Al-Sharif F, Ozand P, Al-Sayed M (2008a) Identification of Gaucher disease mutations found in Saudi Arabia. Blood Cells Mol Dis 41(2):200–201 Kaya N, Imtiaz F, Colak D, Al-Sayed M, Al-Odaib A, Al-Zahrani F, Al-Mubarak BR, Al-Owain M, Al-Dhalaan H, Chedrawi A, Al-Hassnan Z, Coskun S, Sakati N, Ozand P, Meyer BF (2008b) Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease. Genet Med 10(9):675–684 Kelly TE, Blanton S, Saif R, Sanjad SA, Sakati NA (2000) Confirmation of the assignment of the Sanjad–Sakati (congenital hypoparathyroidism) syndrome (OMIM 241410) locus to chromosome 1q42–43. J Med Genet 37(1):63–64 Khan AO, Shamsi FA, Al-Saif A, Kambouris M (2004) A novel missense Norrie disease mutation associated with a severe ocular phenotype. J Pediatr Ophthalmol Strabismus 41(6):361–363 Khan AO, Alam SK, Aldahmesh M, Rajab M, Meyer B (2006a) Familial blepharophimosis-like syndrome with esotropia, uveal coloboma, and short stature. Ophthalmic Genet 27(3):79–82 Khan AO, Aldahmesh M, Meyer B (2006b) Recessive cornea plana in the Kingdom of Saudi Arabia. Ophthalmology 113(10):1773–1778 Khan AO, Aldahmesh MA, Meyer B (2007) Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C). Am J Ophthalmol 144(6):949–952 Khan AO, Oystreck DT, Al-Tassan N, Al-Sharif L, Bosley TM (2008) Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu). Ophthalmology 115(12):2262–2265 Knox-Macaulay HH, Bashawri L, Davies KE (1993) X linked recessive thrombocytopenia. J Med Genet 30(11):968–969 Kozma C, Scribanu N, Gersh E (1996) The microcephaly–lymphoedema syndrome: report of an additional family. Clin Dysmorphol 5(1):49–54 Kulozik AE, Wainscoat JS, Serjeant GR, Kar BC, Al-Awamy B, Essan GJ, Falusi AG, Haque SK, Hilali AM, Kate S et al (1986) Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am J Hum Genet 39(2):239–244 Lanes R, Plotnick LP, Bynum TE, Lee PA, Casella JF, Fox CE, Kowarski AA, Migeon CJ (1980) Glucocorticoid and partial mineralocorticoid deficiency associated with achalasia. J Clin Endocrinol Metab 50(2):268–270 Lehmann H, Maranjian G, Mourant AE (1963) Distribution of sickel cell haemoglobin in Saudi Arabia. Nature 198:492–493 Lestringant GG, Berge T (1989) Porokeratosis punctata palmaris et plantaris. A new entity? Arch Dermatol 125(6):816–819 Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117(4):541–552 Lin NU, Malloy PJ, Sakati N, al-Ashwal A, Feldman D (1996) A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol Metab 81(7):2564–2569

19

Genetic Disorders in Saudi Arabia

567

Mahmoud AA, Yousef GM, Al-Hifzi I, Diamandis EP (2002) Cockayne syndrome in three sisters with varying clinical presentation. Am J Med Genet 111(1):81–85 Majumdar R, Al Jumah M, Al Rajeh S, Fraser M, Al Zaben A, Awada A, Al Traif I, Paterson M (2000) A novel deletion mutation within the carboxyl terminus of the copper-transporting ATPase gene causes Wilson disease. J Neurol Sci 179(S1–2):140–143 Majumdar R, Al Jumah M, Fraser M (2003) 4193delC, a common mutation causing Wilson’s disease in Saudi Arabia: rapid molecular screening of patients and carriers. Mol Pathol 56(5):302–304 Mardini MK, Ghandour M, Sakati NA, Nyhan WL (1978) Johanson–Blizzard syndrome in a large inbred kindred with three involved members. Clin Genet 14(5):247–250 Mallouh A, Sa’di AR, Ahmad MS, Salamah M (1984) Hereditary pyropoikilocytosis: report of two cases from Saudi Arabia. Am J Med Genet 18(3):413–417 Malloy PJ, Xu R, Peng L, Peleg S, Al-Ashwal A, Feldman D (2004) Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function. Endocrinology 145(11):5106–5114 Markley KM, Elkhalifa M, Maini A, Hoyer JD (2008) Hb Jeddah (alpha68(E17)Asn!His (alpha1)): a newly recognized alpha chain variant, seen in combination with Hb S (beta6 (A3)Glu!Val), and found in three separate families of middle eastern origin. Hemoglobin 32 (3):297–302 Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ (2001) Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28(3):261–265 Massa V, Fernandez-Vizarra E, Alshahwan S, Bakhsh E, Goffrini P, Ferrero I, Mereghetti P, D’Adamo P, Gasparini P, Zeviani M (2008) Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet 82(6):1281–1289 Mathew PM, Young JM, Abu-Osba YK, Mulhern BD, Hammoudi S, Hamdan JA, Sa’di AR (1988) Persistent neonatal hyperinsulinism. Clin Pediatr 27(3):148–151 Mattoo TK (1998) Genetically transmitted renal diseases in children: a Saudi perspective. Saudi J Kidney Dis Transpl 9(2):105–109 Mihaylova V, M€uller JS, Vilchez JJ, Salih MA, Kabiraj MM, D’Amico A, Bertini E, Wo¨lfle J, Schreiner F, Kurlemann G, Rasic VM, Siskova D, Colomer J, Herczegfalvi A, Fabriciova K, Weschke B, Scola R, Hoellen F, Schara U, Abicht A, Lochm€ uller H (2008) Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndrome. Brain 131 (Pt 3):747–759 Miller BA, Olivieri N, Salameh M, Ahmed M, Antognetti G, Huisman TH, Nathan DG, Orkin SH (1987) Molecular analysis of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia. N Engl J Med 316(5):244–250 Mitchell GA, Ozand PT, Robert MF, Ashmarina L, Roberts J, Gibson KM, Wanders RJ, Wang S, Chevalier I, Plo¨chl E, Miziorko H (1998) HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q. Am J Hum Genet 62(2):295–300 Morgan JC, Scott DF, Lanclos KD (1996) Two mutations in the locus control region hypersensitivity site-2 (50 HS-2) of haplotype 19 beta s chromosomes alter binding of trans-acting factors. Am J Hematol 51(1):12–18 Mufti MH, Wood SK (1987) Ectrodactyly in sisters and half sisters. J Med Genet 24(4):220–224 Nakano A, Lestringant GG, Paperna T, Bergman R, Gershoni R, Frossard P, Kanaan M, Meneguzzi G, Richard G, Pfendner E, Uitto J, Pulkkinen L, Sprecher E (2002) Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol 46(4):510–516 Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC (2001) Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2. Nat Genet 29(3):315–320

568

Z.N. Al-Hassnan and N. Sakati

Narchi H (1997) Hyperostosis with hyperphosphatemia: evidence of familial occurrence and association with tumoral calcinosis. Pediatrics 99(5):745–748 Nazer H, Riff E, Sakati N, Mathew R, Majeed-Saidan MA, Harfi H (1989) Cystic fibrosis in Saudi Arabia. Eur J Pediatr 148(4):330–332 Nazer H, Gunasekaran TS, Sakati NA, Nyhan WL (1990) Concurrence of Robinow syndrome and Crigler–Najar syndrome in two offspring of first cousins. Am J Med Genet 37(4):516–518 Niazi GA, Yaish HM, Kutlar F, Huisman TH (1991) Heterogeneity of gamma-globin chain synthesis in Saudi newborns. Int J Hematol 54(5):377–383 Ohlsson A, Stark G, Sakati N (1980) Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. Dev Med Child Neurol 22:72–84 Ohlsson A, Cumming WA, Paul A, Sly WS (1986) Carbonic anhydrase II deficiency syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediatrics 77:371–381 Ozand PT, Gascon G, al Aqeel A, Roberts G, Dhalla M, Subramanyam SB (1990a) Prevalence of different types of lysosomal storage diseases in Saudi Arabia. J Inherit Metab Dis 13 (6):849–861 Ozand PT, Gascon GG, Dhalla M (1990b) Aspartoacylase deficiency and Canavan disease in Saudi Arabia. Am J Med Genet 35(2):266–268 Ozand PT, Devol EB, Gascon GG (1992a) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Ozand PT, Gascon GG (1992b) Heterogeneity of carboxypeptidase activity in infantile-onset galactosialidosis. J Child Neurol 7(Suppl):S31–S40 Ozand PT, Rashed M, Gascon GG, Youssef NG, Harfi H, Rahbeeni Z, al Garawi S, al Aqeel A (1994a) Unusual presentations of propionic acidemia. Brain Dev 16(Suppl):46–57 Ozand PT, Rashed M, Gascon GG, al Odaib A, Shums A, Nester M, Brismar J (1994b) 3-Ketothiolase deficiency: a review and four new patients with neurologic symptoms. Brain Dev 16(Suppl):38–45 Ozand PT, Nyhan WL, al Aqeel A, Christodoulou J (1994c) Malonic aciduria. Brain Dev 16(1):7–11 Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, Al Watban J, Al-Kawi MZ, Dabbagh O (1998) Biotin-responsive basal ganglia disease: a novel entity. Brain 121 (Pt 7):1267–1279 Parvari R, Hershkovitz E, Grossman N, Gorodischer R, Loeys B, Zecic A, Mortier G, Gregory S, Sharony R, Kambouris M, Sakati N, Meyer BF, Al Aqeel AI, Al Humaidan AK, Al Zanhrani F, Al Swaid A, Al Othman J, Diaz GA, Weiner R, Khan KT, Gordon R, Gelb BD, HRD/ Autosomal Recessive Kenny–Caffey Syndrome Consortium (2002) Mutation of TBCE causes hypoparathyroidism–retardation–dysmorphism and autosomal recessive Kenny–Caffey syndrome. Nat Genet 32(3):448–452 Pasternack SM, von K€ ugelgen I, Aboud KA, Lee YA, R€ uschendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, N€ urnberg P, No¨then MM, Betz RC (2008) G proteincoupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 40(3):329–334 Pembrey ME, Perrine RP, Wood WG, Weatherall DJ (1980) Sickle beta 0 thalassemia in Eastern Saudi Arabia. Am J Hum Genet 32(1):26–41 Pernasetti F, Milner RD, al Ashwal AA, de Zegher F, Chavez VM, Muller M, Martial JA (1998) Pro239Ser: a novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J Clin Endocrinol Metab 83(6):2079–2083 Phillips JA 3rd, Cogan JD (1994) Genetic basis of endocrine disease. 6. Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab 78(1):11–16 Picard C, Fieschi C, Altare F, Al-Jumaah S, Al-Hajjar S, Feinberg J, Dupuis S, Soudais C, Al-Mohsen IZ, Ge´nin E, Lammas D, Kumararatne DS, Leclerc T, Rafii A, Frayha H, Murugasu B, Wah LB, Sinniah R, Loubser M, Okamoto E, Al-Ghonaium A, Tufenkeji H, Abel L, Casanova JL (2002) Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am J Hum Genet 70(2):336–348

19

Genetic Disorders in Saudi Arabia

569

Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299 (5615):2076–2079 Pomponio RJ, Ozand PT, Al Essa M, Wolf B (2000) Novel mutations in children with profound biotinidase deficiency from Saudi Arabia. J Inherit Metab Dis 23(2):185–187 Prasad RS, Pejaver RK, Hassan A, al Dusari S, Wooldridge MA (1994) Management and followup of harlequin siblings. Br J Dermatol 130(5):650–653 Pressley L, Higgs DR, Clegg JB, Perrine RP, Pembrey ME, Weatherall DJ (1980) A new genetic basis for hemoglobin-H disease. N Engl J Med 303(24):1383–1388 Price Evans DA, Salah KA, Mobrad MA, Mitchell WD, Olin M, Eggertsen G (2007) Cerebrotendinous xanthomatosis in a Saudi Arabian family-genotyping and long-term follow-up. Saudi Med J 28(7):1113–1118 Quadri MI, Islam SI, Nasserullah Z (2000) The effect of alpha-thalassemia on cord blood red cell indices and interaction with sickle cell gene. Ann Saudi Med 20(5–6):367–370 Raef H, Baitei EY, Zou M, Shi Y (2008) Genotype–phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism. Eur J Endocrinol 158(4):577–582 Rahbeeni Z, Ozand PT, Rashed M, Gascon GG, al Nasser M, al Odaib A, Amoudi M, Nester M, al Garawi S, Brismar J (1994) 4-Hydroxybutyric aciduria. Brain Dev 16(Suppl):64–71 Rahbeeni Z, Vaz FM, Al-Hussein K, Bucknall MP, Ruiter J, Wanders RJ, Rashed MS (2002) Identification of two novel mutations in OCTN2 from two Saudi patients with systemic carnitine deficiency. J Inherit Metab Dis 25(5):363–369 Rashed M, Ozand PT, al Aqeel A, Gascon GG (1994) Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev 16(Suppl):1–6 Rashed MS, Ozand PT, Bennett MJ, Barnard JJ, Govindaraju DR, Rinaldo P (1995a) Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 41(8(Pt 1)):1109–1114 Rashed MS, Ozand PT, Bucknall MP, Little D (1995b) Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatr Res 38(3):324–331 Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT (1997) Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles. Clin Chem 43(7):1129–1141 Rashed MS, Rahbeeni Z, Ozand PT (1999a) Screening blood spots for argininosuccinase deficiency by electrospray tandem mass spectrometry. Southeast Asian J Trop Med Public Health 30(Suppl 2):170–173 Rashed MS, Rahbeeni Z, Ozand PT (1999b) Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol 23(2):183–193 Rashed MS, Aboul-Enein HY, AlAmoudi M, Jakob M, Al-Ahaideb LY, Abbad A, Shabib S, Al-Jishi E (2002) Chiral liquid chromatography tandem mass spectrometry in the determination of the configuration of glyceric acid in urine of patients with D-glyceric and L-glyceric acidurias. Biomed Chromatogr 16(3):191–198 Rashed MS, Al-Ahaidib LY, Al-Dirbashi OY, Al Amoudi M, Al-Sayed MM, Rahbeeni Z, Al-Hassnan Z, Al-Dbaas A, Al-Owain M, Ni Luanaigh M (2005) Tandem mass spectrometric assay of succinylacetone in urine for the diagnosis of hepatorenal tyrosinemia. Anal Biochem 339(2):310–317 Reisner SH, Seelenfreund M, Ben-Bassat M (1971) Cutis laxa associated with severe intrauterine growth retardation and congenital dislocation of the hip. Acta Paediatr Scand 60(3):357–360 Ridanp€a€a M, Sistonen P, Rockas S, Rimoin DL, M€akitie O, Kaitila I (2002) Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A!G mutation of the untranslated RMRP. Eur J Hum Genet 10(7):439–447

570

Z.N. Al-Hassnan and N. Sakati

Robinson LK, Jones KL, Culler F, Nyhan WL, Sakati N, Jones KL (1983) The Bo¨rjeson–Forssman–Lehmann syndrome. Am J Med Genet 15(3):457–468 Sackey K, Sakati N, Aur RJ, Shebib S, Sabbah RS, Rifai S (1985) Multiple dysmorphic features and pancytopenia: a new syndrome? Clin Genet 27(6):606–610 Sass JO, Jobard F, Topc¸u M, Mahfoud A, Werle´ E, Cure S, Al-Sannaa N, Alshahwan SA, Bataillard M, Cimbalistiene L, Grolik C, Kemmerich V, Omran H, Sztriha L, Tabache M, Fischer J (2008) L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis (Epub ahead of print) Saha N, Bayoumi RA, El Sheikh FS, Samuel AP, El Fadil I, El Houri IS, Sebai ZA, Sabaa HM (1980) Some blood genetic markers of selected tribes in Western Saudi Arabia. Am J Phys Anthropol 52(4):595–600 Saif GB, Al-Khenaizan S (2007) Netherton syndrome: successful use of topical tacrolimus and pimecrolimus in four siblings. Int J Dermatol 46(3):290–294 Sakati NO, Nyhan WL, Shear CS, Kattan H, Akhtar M, Bay C, Jones KL, Schackner L (1983) Syndrome of cutis laxa, ligamentous laxity, and delayed development. Pediatrics 72:850–856 Salih MA, Mahdi AH, al-Rikabi AC, al-Bunyan M, Roberds SL, Anderson RD, Campbell KP (1996a) Clinical and molecular pathological features of severe childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 38(3):262–270 Salih MA, Sunada Y, Al-Nasser M, Ozo CO, Al-Turaiki MH, Akbar M, Campbell KP (1996b) Muscular dystrophy associated with beta-dystroglycan deficiency. Ann Neurol 40 (6):925–928 Salih MA, Maisonobe T, Kabiraj M, al Rayess M, al-Turaiki MH, Akbar M, Tahan A, Urtizberea JA, Grid D, Hamadouche T, Guilbot A, Brice A, Leguern E (2000) Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity. Neuromuscul Disord 10(1):10–15 Salih MA, Abdel-Gader AG, Zahraa JN, Al-Rayess MM, Alorainy IA, Hassan HH, Ruitenbeek W, Zeviani M (2006) Stroke due to mitochondrial disorders in Saudi children. Saudi Med J 27 (Suppl 1):S81–S90 Sanjad S, Sakati N, Abu-Osba Y (1988) Congenital hypoparathyroidism with dysmorphic features: a new syndrome. Pediatr Res 23:271A (abstract) Sanjad SA, Sakati NA, Abu-Osba YK, Kaddoura R, Milner RD (1991) A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features. Arch Dis Child 66(2):193–196 Sanjad SA, Kaddoura RE, Nazer HM, Akhtar M, Sakati NA (1993) Fanconi’s syndrome with hepatorenal glycogenosis associated with phosphorylase b kinase deficiency. Am J Dis Child 147(9):957–959 Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K (1996) Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet 59(5):1048–1056 Seidahmed MZ, Alyamani EA, Rashed MS, Saadallah AA, Abdelbasit OB, Shaheed MM, Rasheed A, Hamid FA, Sabry MA (2005) Total truncation of the molybdopterin/dimerization domains of SUOX protein in an Arab family with isolated sulfite oxidase deficiency. Am J Med Genet A 136(2):205–209 Seliem MA, Mansara KB, Palileo M, Ye X, Zhang Z, Benson DW (2000) Evidence for autosomal recessive inheritance of infantile dilated cardiomyopathy: studies from the Eastern Province of Saudi Arabia. Pediatr Res 48(6):770–775 Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349(17):1614–1627 Sene´e V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougne`res P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a

19

Genetic Disorders in Saudi Arabia

571

rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38 (6):682–687 Shah SS, Al-Rajhi A, Brandt JD, Mannis MJ, Roos B, Sheffield VC, Syed NA, Stone EM, Fingert JH (2008) Mutation in the SLC4A11 gene associated with autosomal recessive congenital hereditary endothelial dystrophy in a large Saudi family. Ophthalmic Genet 29 (1):41–45 Shebib S, Hugosson C, Sakati N, Nyhan WL (1991) Osteodysplastic variant of primordial dwarfism. Am J Med Genet 40(2):146–150 Shen XM, Ohno K, Fukudome T, Tsujino A, Brengman JM, De Vivo DC, Packer RJ, Engel AG (2002) Congenital myasthenic syndrome caused by low-expressor fast-channel AChR delta subunit mutation. Neurology 59(12):1881–1888 Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA (2005) ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet 42 (9):725–729 Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH (2002) The demographics and distribution of type B Niemann–Pick disease: novel mutations lead to new genotype/phenotype correlations. Am J Hum Genet 71(6):1413–1419 Singh B, Jamil A, al-Shahwan SA, Sharif H, al-Deeb SM, Biary N (1993) Choroido-cerebral calcification syndrome with retardation. Neurology 43(11):2387–2389 Siraj AK, Ibrahim M, Al-Rasheed M, Bu R, Bavi P, Jehan Z, Abubaker J, Murad W, Al-Dayel F, Ezzat A, El-Solh H, Uddin S, Al-Kuraya K (2007) Genetic polymorphisms of methylenetetrahydrofolate reductase and promoter methylation of MGMT and FHIT genes in diffuse large B cell lymphoma risk in Middle East. Ann Hematol 86(12):887–895 Siraj AK, Ibrahim M, Al-Rasheed M, Abubaker J, Bu R, Siddiqui SU, Al-Dayel F, Al-Sanea O, Al-Nuaim A, Uddin S, Al-Kuraya K (2008a) Polymorphisms of selected xenobiotic genes contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. BMC Med Genet 9:61 Siraj AK, Al-Rasheed M, Ibrahim M, Siddiqui K, Al-Dayel F, Al-Sanea O, Uddin S, Al-Kuraya K (2008b) RAD52 polymorphisms contribute to the development of papillary thyroid cancer susceptibility in Middle Eastern population. J Endocrinol Invest 31(10):893–899 Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE (2000) Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet 26(1):71–75 Solh H, Da Cunha AM, Giri N, Padmos A, Spence D, Clink H, Ernst P, Sakati N (1995) Bone marrow transplantation for infantile malignant osteopetrosis. J Pediatr Hematol Oncol 17 (4):350–355 Stangenberg M, Agarwal N, Rahman F, Sheth K, al Sedeiry S, De Vol E (1990) Frequency of HLA genes and islet cell antibodies (ICA) and result of postpartum oral glucose tolerance tests (OGTT) in Saudi Arabian women with abnormal OGTT during pregnancy. Diabetes Res 14 (1):9–13 Stangenberg M, Lingman G, Roberts G, Ozand P (1992) Mucopolysaccharidosis VII as cause of fetal hydrops in early pregnancy. Am J Med Genet 44(2):142–144 Stockton DW, Lewis RA, Abboud EB, Al-Rajhi A, Jabak M, Anderson KL, Lupski JR (1998) A novel locus for Leber congenital amaurosis on chromosome 14q24. Hum Genet 103(3):328–333 Stuhrmann M, Bashawri L, Ahmed MA, Al-Awamy BH, K€ uhnau W, Schmidtke J, El-Harith EA (2001) Familial thrombocytosis as a recessive, possibly X-linked trait in an Arab family. Br J Haematol 112(3):616–620 Stuhrmann M, Bukhari IA, El-Harith el-HA (2004) Naxos disease in an Arab family is not caused by the Pk2157del2 mutation. Evidence for exclusion of the plakoglobin gene. Saudi Med J 25 (10):1449–1452 Stuhrmann M, Hennies HC, Bukhari IA, Brakensiek K, N€ urnberg G, Becker C, Huebener J, Miranda MC, Frye-Boukhriss H, Knothe S, Schmidtke J, El-Harith EH (2008) Dyschromatosis

572

Z.N. Al-Hassnan and N. Sakati

universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 73(6):566–572 Suwairi WM, Bahabri SA, Laxer RM, Polinkovsky A, Warman ML (1997) Autosomal recessive camptodactyly–arthropathy–coxa vara–pericarditis syndrome: clinical features and genetic mapping to chromosome 1q25–31. Am J Hum Genet 61(Suppl):A48 (abstract) Taha D, Barbar M, Kanaan H, Williamson Balfe J (2003) Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am J Med Genet 122A:269–273 Taha D, Boerkoel CF, Balfe JW, Khalifah M, Sloan EA, Barbar M, Haider A, Kanaan H (2004) Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia. Am J Med Genet A 131(2):194–199 Taha D, Mullis PE, Iba´n˜ez L, de Zegher F (2005) Absent or delayed adrenarche in Pit-1/POU1F1 deficiency. Horm Res 64(4):175–179 Taha D, Al-Harbi N, Al-Sabban E (2008) Hyperglycemia and hypoinsulinemia in patients with Fanconi–Bickel syndrome. J Pediatr Endocrinol Metab 21(6):581–586 Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR (2002) Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 32(2):267–272 Tallab TM (1996) Richner–Hanhart syndrome: importance of early diagnosis and early intervention. J Am Acad Dermatol 35(5 Pt 2):857–859 Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Gr€asbeck R, de la Chapelle A (2004) Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East. Hum Mutat 23(4):327–333 Thakker RV, Farmery MR, Sakati NA, Milner RD (1992) Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family. Clin Endocrinol 37(4):338–343 Thein SL, Wallace RB, Pressley L, Clegg JB, Weatherall DJ, Higgs DR (1988) The polyadenylation site mutation in the alpha-globin gene cluster. Blood 71(2):313–319 Thomas PM, Cote GJ, Hallman DM, Mathew PM (1995a) Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 56(2):416–421 Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J (1995b) Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268(5209):426–429 Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan WM, Andrews C, Erickson RP, Engle EC (2005) Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet 37 (10):1035–1037 van Reeuwijk J, Grewal PK, Salih MA, de Bernabe´ Beltra´n-Valero D, McLaughlan JM, Michielse CB, Herrmann R, Hewitt JE, Steinbrecher A, Seidahmed MZ, Shaheed MM, Abomelha A, Brunner HG, van Bokhoven H, Voit T (2007) Intragenic deletion in the LARGE gene causes Walker–Warburg syndrome. Hum Genet 121(6):685–690 Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D, He´on E (2002) Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 70(2):448–460 Vogt G, Chapgier A, Yang K, Chuzhanova N, Feinberg J, Fieschi C, Boisson-Dupuis S, Alcais A, Filipe-Santos O, Bustamante J, de Beaucoudrey L, Al-Mohsen I, Al-Hajjar S, Al-Ghonaium A, Adimi P, Mirsaeidi M, Khalilzadeh S, Rosenzweig S, de la Calle Martin O, Bauer TR, Puck JM, Ochs HD, Furthner D, Engelhorn C, Belohradsky B, Mansouri D, Holland SM, Schreiber RD, Abel L, Cooper DN, Soudais C, Casanova JL (2005) Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 37(7):692–700

19

Genetic Disorders in Saudi Arabia

573

Walne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, Al-Qurashi FH, Aljurf M, Dokal I (2007) Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet 16 (13):1619–1629 Wang SM, Zwaan J, Mullaney PB, Jabak MH, Al-Awad A, Beggs AH, Engle EC (1998) Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13. Am J Hum Genet 63(2):517–525 Warsy AS, El-Hazmi MA, Sedrani SH, Kinhal M (1991) Alpha-1-antitrypsin phenotypes in Saudi Arabia: a study in the central province. Ann Saudi Med 11(2):159–162 Warsy AS, el-Hazmi MA (1999) Glutathione reductase deficiency in Saudi Arabia. East Mediterr Health J 5(6):1208–1212 Warsy AS, El-Hazmi MA (2001) G6PD deficiency, distribution and variants in Saudi Arabia: an overview. Ann Saudi Med 21(3–4):174–177 Wojcik J, Berg MA, Esposito N, Geffner ME, Sakati N, Reiter EO, Dower S, Francke U, Postel-Vinay MC, Finidori J (1998) Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J Clin Endocrinol Metab 83(12):4481–4489 Woodhouse NJ, Sakati NA (1983) A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities. J Med Genet 20(3):216–219 Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T (2001) The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet 29 (2):160–165 Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF (2005) Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 77(1):16–26 Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, Hart PS, Gorry MC, Marks JJ, Hart TC (2001) Evidence of a founder effect for four cathepsin C gene mutations in Papillon–Lefe`vre syndrome patients. J Med Genet 38(2):96–101 Zhang B, Spreafico M, Zheng C, Yang A, Platzer P, Callaghan MU, Avci Z, Ozbek N, Mahlangu J, Haw T, Kaufman RJ, Marchant K, Tuddenham EG, Seligsohn U, Peyvandi F, Ginsburg D (2008) Genotype–phenotype correlation in combined deficiency of factor V and factor VIII. Blood 111(12):5592–5600

URLs OMIM http://www.ncbi.nlm.nih.gov/OMIM PubMed http://www.ncbi.nlm.nih.gov/OMIM The Saudi Central Department of Statistics & Information http://www.cdsi.gov.sa The Saudi Ministry of Heath Health statistics book for the year of 2007. http://www.moh.gov.sa/ statistics/stats2007/2007.html Saudi Geographical Society http://www.saudigs.org

Chapter 20

Genetic Disorders in Sudan Mustafa A.M. Salih

The Country and Population Sudan is Africa’s largest country in surface area (2,505,805 km2). It constitutes more than 8% of the African continent and 1.7% of the world’s total land (Fig. 20.1). It has boundaries with nine countries and extends on its eastern side to the Red Sea, which separates it from Saudi Arabia. The main part of the Nile Valley lies within its boundaries. Connections between the two sides of the Red Sea have been intimate from the dawn of history. Trade routes that passed via the Nile valley were established in ancient times between Arabia and the ports of Abyssinia (current names: Eritrea and Ethiopia), Sudan, and Egypt (MacMichael 1967). Immigration and settlements followed. Following the conquest of Egypt by the Arabs in the eighth century (AD), small groups drifted to Sudan for varied reasons (Hassan 1965b). However, the fall of Dongola (the capital of the Christian kingdom of Nubia), into Muslim hands, by the middle of the fourteenth century opened the door for large successive waves of immigrating Arab nomads who proceeded further to the richer plains of the country. However, western Sudan was affected by settlements of Libyans (Temehu) coming from the western Oasis about 2750 BC and was also influenced by migratory waves from North Africa starting around the fourteenth century (MacMichael 1967). Natural sources of Sudan have made it the focal point for trans-African migrations by humans (Wickens 1970). Sudan’s ethic composition is diverse. The 1955–1956-population census listed 56 separate ethnic groups, further subdivided into 597 subgroups. Of the 115 spoken languages, Arabic is spoken by the majority and forms, as well, the lingua

M.A.M. Salih Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia e-mail: [email protected], [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_20, # Springer-Verlag Berlin Heidelberg 2010

575

576

M.A.M. Salih

Fig. 20.1 Map of the Sudan showing geographic locations mentioned

franca of others (Beshir 1980). Generally, the ethnic composition of the Sudanese population can be described as Hamitic in the east, African Nilotes and NiloHamitics in the south, and a mixture of Arab descent in the north, middle, and west. This is reflected in the physical features of the population, which shows a great deal of heterogeneity depending on the degree of Arabic admixture with the aboriginal inhabitants of the land. Among the latter major groups are the Nilotes in the south and the Nuba and Fur in the west of Sudan (Fig. 20.2). While the Fur embraced Islam, the Nuba and Nilotes maintained their cultural identity and were mainly pagans, although many have recently become either Muslims or Christians.

Consanguinity Consanguinity is common in most ethnic groups. However, the Nuba are usually exogamous; marriage within the clan is forbidden (Bayoumi and Saha 1987). Field studies that addressed consanguinity among four tribes living in western Sudan found no incidence of consanguineous marriages among the indigenous Nubian (Nuba) people living within the Nuba Mountains. A high inbreeding

20

Genetic Disorders in Sudan

577

Fig. 20.2 Location of Sudanese tribes and tribal groups where some genetic studies were performed

coefficient (respectively, 0.04167 and 0.036) was recorded among the Baggara tribal group (Arab ancestry) and the Hawazma tribe (part of the Baggara group living adjacent to the Nuba). However, the Fur (aboriginals in Jabal Marra Plateau) had also a high inbreeding coefficient, 0.04450.

Population Genetics The Y chromosome has proved to be crucial in human evolutionary studies (Hammer and Zegura 1996). Binary polymorphisms associated with the nonrecombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of the human species that has persisted to the present. An international study (Underhill et al. 2000), in collaboration with the Institute of Endemic Diseases, University of Khartoum, explored the haplotype frequencies of 1,062 globally representative individuals. The study showed that the Sudanese and the Ethiopians are distinct from the other Africans and appear to be more associated with populations from the Mediterranean region. This may reflect either repeated genetic contact between Arabia and East Africa during the last 5,000–6,000 years or a Middle Eastern origin with acquisition of African alleles while migrating southwest with agricultural expansion (Cavalli-Sforza et al. 1994). In a comparative population study, Bayoumi et al. 2006 investigated the frequencies of the *I and *D alleles of the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, and Arab nationals of the United Arab Emirates (UAE)

578

M.A.M. Salih

and Oman. The ACE gene in humans contains an insertion–deletion polymorphism in its intron 16 and has been widely investigated in different populations owing to its involvement with the rennin–angiotensin system. The allele frequencies of the *I and *D were found to be 0.36 and 0.64, respectively in the 121 Sudanese subjects. A preponderance of the *D allele was observed among the Arab and African populations studied (Sudanese, 0.64; Somalis, 0.73; Emiratis, 0.61; and Omanis, 0.71. The study (Bayoumi et al. 2006) suggested that the lack of significant difference between the groups was probably due to the mixing of gene pools, attributed to the close proximity of UAE and Oman. Another suspected factor was the significant interaction between Omanis and East Africans through trade routes.

Genetic Disorders in Sudan Studies of individual genetic disorders in Sudan were overshadowed by interest in the other major causes of morbidity and mortality, such as endemic diseases, including malaria, schistosomiasis, and leishmaniasis and other health problems related to nutrition. In 1965, a doctoral thesis, “Congenital Diseases in Sudanese Children,” (Hassan 1965a) documented many early reports of genetic disorders in Sudan. In recent years, attention has been directed to red cell genetics and autosomal recessive disorders in general.

Genetic Susceptibility to Infectious Diseases Epidemiological and animal model studies have shown that many apparently nonhereditary diseases, including infectious diseases, develop predominantly in genetically predisposed individuals (Somech et al. 2003).

Malaria Malaria is one of the major causes of death by infectious diseases worldwide and is endemic in more than 90 countries (Greenwood and Mutabingwa 2002). Over the past 50 years, substantial evidence has accumulated to indicate that genetic variants influence response to malaria in humans regarding onset, progression, severity, and ultimate outcome (Fortin et al. 2002). Interaction Between Red Blood Cell Abnormalities and Malaria In areas with high endemicity, innate resistance to falciparum malaria infection appears to have arisen in human populations due to a strong selective pressure (Luzzatto 1979). Inherited defects in the red cell genes had probably evolved as a

20

Genetic Disorders in Sudan

579

result of this selection and there is considerable evidence for the role played by HbS, G6PD deficiency (G6PD), and thalassemia genes in protecting against falciparum malaria. In this respect, the heterozygote individual is at an advantage over homozygotes for either the normal or the abnormal genes (Gilles et al. 1967; Playfair 1982). In Sudan, Saha and El Sheikh (1987) found a good correlation between the frequencies of HbS and G6PD alleles in eight tribes, suggesting a common ecogenic or selective force for the mutation at the Hb and G6PD loci. This was in agreement with an observed positive association of G6PD with sickle cell and thalassemia genes in the western part of Saudi Arabia (Samuel et al. 1986). In a study in the Sennar region of central Sudan, where Plasmodium falciparum is hyperendemic, erythrocyte traits (HbS and G6PD) were detected in 20% of subjects resistant to falciparum malaria and in only 5% of patients (Bayoumi et al. 1986). The frequency of HbAS heterozygotes was significantly higher among resistant subjects (15%) than among malaria patients (3%) and 3–15 times higher than that (1–5%) of the general population of central Sudan. Bayoumi (1987) suggested that the selective advantage of HbAS individuals is due to the modulation of the immune response in these individuals to P. falciparum malaria. In an endemic area of unstable transmission (a village 20 km south of Gadarif, Fig. 20.1), lymphocytes isolated from healthy individuals with HbAS during the malaria season have been shown to have higher responses to affinity-purified soluble P. falciparum antigens (SPAg) and to purified protein derivative of tuberculin (PPD) compared to lymphocytes isolated from HbAA individuals (Bayoumi et al. 1990; Abu-Zeid et al. 1991). The difference between the two groups was more marked in children than in adults (Abu-Zeid et al. 1991). The lymphoproliferative responses to SPAg of peripheral blood mononuclear cells (PBMC) obtained before and during the malaria season showed two distinct seasonal changes in relation to the Hb phenotype (Theander et al. 1990; Abu-Zeid et al. 1992a). During the malaria season, the lymphoproliferative responses to SPAg were suppressed in HbAA subjects (children and adults) but enhanced in HbAS individuals. No distinct seasonal change in the response to PPD was found in relation to the Hb phenotype. These enhanced responses were explained by better priming of the immune system in carriers of the sickle cell gene. It was suggested that sickling may induce modified expression of parasite antigens, analogous to the recently described modified expression of parasite-induced neoantigens by thalassemia (Luzzi et al. 1991). In a subsequent investigation (Abu-Zeid et al. 1992b), individuals with sickle cell trait who had clinical malaria were found to have lower plasma soluble interleukin-2 (IL-2) receptors and parasite counts compared to normal subjects.

Segregation and Genetic Linkage Analyses An international collaborative study, involving the Department of Biochemistry, Faculty of Medicine, University of Khartoum, and the Malaria Administration of the Sudan Ministry of Health, revealed interesting findings (Roper et al. 1996).

580

M.A.M. Salih

The study was conducted in Daraweesh village in Gadarif state in eastern Sudan, approximately 50 km from the Ethiopian boarder. Malaria transmission is markedly seasonal with cases peaking in October and November in frequently severe outbreaks. A study (Roper et al. 1996) which used nested polymerase chain reaction (PCR) to assay for low level P. falciparum infections that were below the threshold of detection of blood film examination, revealed that many individuals were infected but healthy for most of the year. Longitudinal data, collected from the same village over 11 years, showed distinctly variable level of disease susceptibility (Creasey et al. 2004). Thirty-two percent of the village inhabitants never reported malaria symptoms or required malaria treatment, while others experienced up to eight clinical episodes during the 11 years of observation. It is noteworthy that the people of Daraweesh are descendents of a Fulani group who originated from Burkina Faso and settled in Sudan about a century ago. Of note is that a polymorphism present in the interleukin4 (IL-4) gene showed high frequency in the Fulani of West Africa, and has been associated with elevated antibody levels against malaria antigens (Luoni et al. 2001). In a recent study (Nasr et al. 2007), the FC g receptor IIa (CD32) polymorphism and antibody responses to asexual blood-stage antigens of P. falciparum were explored in 256 Sudanese individuals. These consisted of 115 patients with severe malaria, 85 with mild malaria and 56 malaria-free controls. The study revealed that the Fcg RIIa-R/R131 genotype is associated with the development of severe malaria, while the H/H131 genotype is more likely to be associated with mild malaria. Another finding was that the natural acquisition of immunity against clinical malaria appeared to be more associated with IgG1 and IgG3 antibodies, highlighting their roles in parasite-neutralizing immune mechanisms.

Schistosomiasis Schistosomiasis is the second most important disease worldwide after malaria with an estimated 200 million infected people (Campino et al. 2006; Gryseels et al. 2006). In Sudan, the disease is highly endemic in the Gezira Province which lies between the Blue Nile and the White Nile (in Arabic the word Gezira means Island). Located in this province is the Gezira Scheme, which is the largest single farm in the world under the same irrigation and administration system. The prevalence of Bilharziasis is very high with 68–90% of the population infected by Schistosoma mansoni (Omer et al. 1979; Saeed et al. 2006). Most people living in S. mansoni endemic areas are asymptomatic. However, a few develop periportal fibrosis (PPF) of the liver which is part of the healing process that follows the acute granulomatous reaction around schistosome eggs trapped in hepatic small vessels (Gryseel et al. 2006). Lethal disease due to the hepatic fibrosis occurs in 2–10% of subjects infected by S. mansoni in endemic regions such as the Sudan (Dessein et al. 1999). A series of studies involving researchers from the University of Gezira, University of Khartoum and Al Zaiem Al Azhari University, in collaboration with

20

Genetic Disorders in Sudan

581

international research centers, focused on the susceptibility to PPF in human S. mansoni infections. These were mainly conducted in Al Taweel, a small village of the Managil area at the southwestern extension of the Gezira Scheme, 300 km south of Khartoum. The study subjects were migrants who settled in the village in the late 1970s, and came from the same region of western Sudan, where Schistosomiasis is not endemic. The population of the village consisted of two tribes: the Tama-Messeria tribe (67%) and Rawashda tribe (33%), who are closely related ethnic groups (Mohamed-Ali et al. 1999). Using ultrasonography at the field, early, moderate and advanced PPF were observed in 58%, 9% and 3%, respectively of Al Taweel village population (Mohamed-Ali et al. 1999). Severe disease (moderate and advanced fibrosis) with portal hypertension affected 6%, occurred mostly in adult men, and was clustered in a few pedigrees. These observations suggested that infection intensity and duration, gender-related factors, and hereditary factors are important in the development of PPF. Combining segregation and linkage analysis, a major locus predisposing subjects infected with S. mansoni to severe hepatic fibrosis was mapped to chromosome 6q22-q23 (Dessein et al. 1991). The locus is closely linked to the IFN – gR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-g. This result was subsequently replicated in an Egyptian population (Blanton et al. 2005). Dessein et al. (1999) also demonstrated that levels of infection and hepatic disease owing to S. mansoni are under distinct genetic control. Interferon-g (IFN-g) is a key regulator of the development and function of the immune system and plays a major role in immune defense against infections by various human pathogens. In a study by the same core group of investigators (Henri et al. 2002a), INF-g was found to play a key role in the protection of S. mansoniinfected patients against PPF, whereas tumor necrosis factor-a (TNF-a) may aggravate the disease. They also uncovered three new single nucleotide polymorphisms in the IFN-g genes (Henri et al. 2002b). In a following study (Chevilland et al. 2003), they screened putative polymorphic sites within the IFN-g gene in the populations of two villages, Al Taweela and Umzukra. They found that IFN-g þ 2,109 A/G polymorphism is associated with a higher risk for developing PPF, whereas the IFN-g þ 3,810 G/A polymorphism is associated with less PPF. Eosinophil cationic protein (ECP) is not only a secretary protein of eosinophil granulocytes that efficiently kills the larval stage of S. mansoni but also affects fibroblast function. The prevalence of the ECP gene polymorphism 434 (G > C) was investigated in 297 individuals from an S. mansoni endemic area in Uganda and compared to that of 78 subjects from a nonendemic area in Sudan, as well as a Swedish population (n ¼ 209) (Eriksson et al. 2007). In the Uganda population, there was a significant association between genotypes and prevalence of infection (P ¼ 0.03). The study (Eriksson et al. 2007) suggested that ECP may be important as a component of the immune response against S. mansoni and in the development of PPF. It also suggested genetic selection towards the ECP 434 CC genotype in populations living in S. mansoni endemic areas.

582

M.A.M. Salih

Leishmaniasis Visceral leishmaniasis (VL), which is caused by the protozoa of the Leishmania donovani complex and transmitted by sand flies, is an endemic disease in Sudan and many other tropical countries (Elshafie et al. 2006). Human infections may be asymptomatic (sub-clinical) or may cause a severe visceral disease which is called kala-azar (KA). Post-KA dermal leishmaniasis (PKDL) afflicts patients who have recovered from VL and who are otherwise well. Several studies, that were conducted by the Institute of Endemic Diseases and the Department of Parasitology and Microbiology, Faculty of Medicine, University of Khartoum (in collaboration with international institutes), showed marked differences in the incidence of VL between adjacent villages inhabited by different ethnic groups (Ibrahim et al. 1999). Also, when members of these different populations share the same immediate environment and exposure, certain ethnic groups show a higher risk of developing VL. In one study (Ibrahim et al. 1999), vulnerability to VL was observed in two ethnic groups, namely the Nilotic Baria and Nuba similar to the Nilotic Nuer in the Upper Nile Province in southern Sudan. Other studies (Mohamed et al. 2004) also documented high vulnerability in the Nilosaharan speaking Masalit population who migrated from western Sudan in the early-mid 1980 and settled along the Rahad River in the center of the endemic area in eastern Sudan. Members of the Aringa ethnic group, who migrated from the western Sudan/Chad area and settled in eastern Sudan as agricultural laborers in the 1940s, were also found to have high susceptibility to VL (Bucheton et al. 2003a,b). Utilizing candidate-gene studies in these vulnerable communities, immune system genes have been explored and significant genetic influences were detected. PKDL, which is induced by L. donovani, was found to be influenced by a polymorphism in the IFN-receptor, and polymorphisms in the genes that encode IL-4 (Mohamed et al. 2003; Salih et al. 2007). Natural resistance-associated macrophage protein-1 (NRAMP1), which has initially been implicated in mouse innate susceptibility studies, has been shown to contribute to an increased risk for VL (Bucheton et al. 2003b; Blackwell et al. 2004; Mohamed et al. 2004; El-Safi et al. 2006). Moreover, the findings of the first published genome-wide scan that analyzes susceptibility to human leishmaniasis (Bucheton et al. 2003a) identified a major locus that controls the susceptibility to L. donovani on chromosome 22q12. A second genome-wide scan was undertaken in two villages occupied by the Masalit ethnic group in eastern Sudan, who were also related to the Aringa group (Miller et al. 2007). The cohort included 69 families with 173 affected relatives. Results of the analysis provided evidence for two major susceptibility loci in this ethnic group at 1p22 and 6q27 that were Y chromosome lineage and villagespecific. Contrary to the findings in the related Aringa group (Bucheton et al. 2003a), neither village had evidence for a VL susceptibility gene on 22q12. These findings pointed towards strong lineage-specific genes due to founder effect and consanguinity in these recently immigrant populations.

20

Genetic Disorders in Sudan

583

Red Cell Genetic Disorders Sickle Cell Disease Sixteen years after the report of Sickle Cell Disease (SCD) from the United States (Herrick, 1910), Archibald (1926) described the first case in Sudan. Since Sudan has been, and is still, affected by mass population movements both within and from outside its borders (El Tay et al. 1988), a comparison with other African countries regarding the prevalence of sickle cell trait may be pertinent. The prevalence was reported to be between 25% and 29% in Nigeria (Molineaux et al. 1979; Adekile et al. 1992), 23.8% in the Lake Victoria region in Kenya (Ojwang et al. 1987), and 14% in Zaire (Nagel and Fleming 1992). In Sudan (Fig. 20.2.) foci of high prevalence were reported from its western and southern regions. A rate of 11.2–30% was detected among the Baggara tribal group that includes Hawazma and Messeria (Vella 1964; Lauder and Ibrahim 1970), and one of up to 18% was found in southern Nilotes and Nilo-Hamitic tribes (Foy et al. 1954). Among tribes that immigrated, from West Africa and settled around the southern part of the Blue Nile, a prevalence of 16% was reported compared to 0–5% among the indigenous population (Ahmed and Baker 1986). The aboriginal tribes of Beja and Nuba (Fig. 20.2) characteristically have zero frequency of hemoglobin S (HbS), whereas studies on aboriginal northern Nilotes (Dinka, Nuer, and Shilluk) have shown variable low frequencies of the sickle cell gene, ranging from 0 to 4% (Foy et al. 1954; Roberts and Lehmann 1955; El Hassan et al. 1968; Omer et al. 1972; Bayoumi and Saha 1987; Saha and El Sheikh 1987). However, the tribal groups residing along the northern part of the Nile (Nubians including Danagla, Shaigia, and Gaalyeen; Fig. 20.2) also have a very low frequency (0.5–1.1%). It is noteworthy that the Nuba Mountains where the Nuba tribes live have been reported to be endemic for malarial infection (Saha and El Sheikh 1987), whereas the Shaigia and Gaalyeen, who are of Arab descent, live in a nonendemic area (Omer 1978). The pattern of clinical manifestations of SCD in Sudan has also been studied. Hassan (1960) described three cases in three families who belonged to the Masalit tribe of western Sudan. Subsequent publications documented the severity of phenotypic expression (Hassan 1965a, 1970). In a group of 25 affected children, a mortality of 20% was recorded and serious complications were noted in others. These included osteomyelitis, hemiplegia, avascular necrosis of the femoral head, and severe anemia leading to congestive heart failure. Bayoumi et al. (1988a) reported on the clinical, hematological and biochemical features of 50 Sudanese patients with SCD. Twenty one patients were children <2 years, 19 were 3–10 year old; and the remaining ten were older. Of 23 patients with complete family data, 21 had sickle cell anemia (SCA) (homozygous HbSS), two had sickle-cell/b+ thalassemia (S-b+ thal) but none had sickle cell/b O thalassaemia (S-b0 thal). The majority of patients (84%) were from the Baggara tribe in western Sudan. The study concluded that the observed pattern of SCD in Sudanese children was comparable to the severe type described for Africans. Infarctive

584

M.A.M. Salih

lesions of the long bones were seen in 20% and another 8% had Salmonella osteomyelitis. Leg ulcers, priapism, enuresis and cholelithiasis were not observed in this cohort. In a later study, ten (11.2%) of 87 children (3 months–16 years) with homozygous SCD, who were prospectively screened by ultrasound, were found to have gallstones (Ibrahim 1991). The prevalence of gallstones was found to increase with age and the youngest child who developed this complication was aged 6 years. It is noteworthy that in a more recent study on clinical indicators of severity of SCA in children in Khartoum (Osman 2003), 59.4% of 69 children with severe SCA had more than four episodes of vaso-occlusive crises per year. Proteinuria and hematuria were detected in 37.7%, 8.7% had history of stroke, 7.2% had more than four times blood transfusion per year and 5.8% were diagnosed as having osteonecrosis. Acute chest syndrome, recurrent priapism and bilateral proliferative retinopathy occurred in 1.4%. The iron status of Sudanese children (aged <16 years) was studied in 100 patients with SCD (Mustafa 1988). Of these, bone marrow staining for iron was done in 82 (82%). The diagnosis of SCA and iron deficiency was as high 86% in this study. Mohamed (1993) studied the clinical and biochemical features of 90 patients homozygous for the abnormal gene (HbSS). The study confirmed the severe course of the disease in Sudan, similar to what has been reported from other African countries (Kaine 1982; Kasili and Bwibo 1982) and in contrast to the mild form, which is compatible with life, reported from eastern Saudi Arabia (El-Hazmi et al. 1987; El Mouzan et al. 1990) and other Arabian Gulf States (White et al. 1986; Awaad and Bayoumi 1993). Vaso-occlusive crises followed by fever (probably due to infections) were the main problems among these 90 patients, in agreement with previous reports from Sudan (Bayoumi et al. 1988a). They were the presenting symptom in 50% and initially manifested as dactylitis in 25% (Mohamed et al. 1992a). Most of the patients (96%) were children (<15 years) and 43 of them (47%) were below 5 years of age. At the time of examination, 18% were found to have dactylitis (hand–foot syndrome), all of whom were below 15 years of age. Liver enlargement was found in 60% while an enlarged spleen was only detected in five patients. Neurological abnormalities were reported in four: three had hemiplegia and one had hemiparesis. Hemoglobin F median was 0.9% (range: 0.5–8.9%) and did not seem to influence the clinical presentation since it was maintained at levels lower than the reported effective concentration (Noguchi et al. 1988). In two papers that examined the erythrocyte membrane (EM) proteins of a subset of these patients, band 3 protein (one of the EM integral proteins) was found to be reduced in one group (Mohamed and Ronquist 1991). Another subset of patients showed increased glyceraldehydes-3-phosphate dehydrogenase (GAPDH). Those who had markedly increased GAPDH showed significantly lower Hb concentrations and significantly higher lactate dehydrogenase in serum than those who had normal GAPDH (Mohamed et al. 1992c). The authors drew attention to the potential usefulness of the measurement of membrane GAPDH as an indicator for the severity of the hemolytic process in SCD patients. A third report, on the same cohort, examined the immunological profile of 43 patients (HbSS) and compared it

20

Genetic Disorders in Sudan

585

to that of 24 heterozygous (HbAS) subjects and 24 controls (HbAA). No evidence was found for altered complement or immunoglobulin levels in SCD patients that would account for their increased susceptibility to infections (Mohamed et al. 1992b). In a preliminary study (Mohamed et al. 1993a) to investigate the in vivo complement and neutrophil leucocyte activation in SCD, another eight patients had their plasma myeloperoxidase (a marker for neutrophil activation), lysozyme (a macrophage marker), and C3d (a marker for the in vivo activation of complement) assayed and compared to a group of 12 heterozygous AS subjects and eight controls. The results indicated clear in vivo activation of complement and neutrophils leucocyte activation in SCD. Another study from this cohort (Mohamed et al. 1993b) evaluated the usefulness of serum 5 necleotidase (50 NT) for detecting the presence of liver involvement in SCD. Fifty-nine patients (HbSS), 17 heterozygotes (HbAS), and 22 controls (HbAA) had their 50 NT assayed and compared with other markers of hepatobiliary damage – that is, bilirubin, aspartate aminotransferase (ASAT), gammaglutamyltransferase (gGT), and alkaline phosphatase. Serum 50 NT (which was significantly higher in patients compared to heterozygotes and controls) showed a direct correlation to corresponding serum values of bilirubin, ASAT, and gGT but did not correlate with serum AP. The authors concluded from the study that the liver involvement in patients with SCD is a mixture of hepatocyte damage and biliary tree involvement. The effect of SCD on physical growth and school performance was studied in 94 Sudanese children with HbSS and compared to 60 control children (HbAA) (Omer 1994). Children with SCD were found to have significantly lower anthropometric values than the control group regarding the weight, height and head circumference within all age groups (P < 0.05). They also had comparatively lower school performance and 78% lost a year or more at school. These findings were related to the repeated episodes of illnesses, frequency of hospital admissions, and the frequency of blood transfusions. To determine the prevalence of falciparum malaria and bacterial infections among hospitalized children with SCD in Khartoum, 107 children (aged 0–5 years with homozygous sickle cell gene (SS) and 90 aged-matched controls were studied (Shummo 1996). Anemia, jaundice and hand–foot syndrome were the commonest modes of presentation of SCD at the time of diagnosis. The main complications were vaso-occlusive crises and intercurrent infections. The types of infections included osteomyelitis (20%), pneumonia (15%), urinary tract infections (15%), and septicemia (8.3%). The predominant causative pathogens were Salmonella (33.3%), Escherichia coli (28.6%) and Streptococcus pneumoniae (19%). Organisms were isolated from only two patients in the control group; both were E. coli. Malaria was diagnosed in 17 patients (16%) with SCD, eight (47.1%) of whom had high density parasitaemia. In the control group, 30 (33%) patients had malaria, of whom 18 (60%) revealed high density parasitaemia. The immunoglobulins and complement profiles of 60 Sudanese children with SCD (HbSS) were studied while they were stable and when in crises (Hasseb El Rasoul 1998). These were compared to the profiles of 20 children with normal adult hemoglobin (HbAA), who served as control. There were no statistically significant

586

M.A.M. Salih

differences between the levels of immunoglobulins (IgG, IgA and IgM), or complements C3 and C4 among the group of children with SCD, both in crises and during stable condition, as compared to the control group. The majority of patients presented at 6 months of age. The commonest presenting complaint was hand and foot syndrome, while the commonest presenting sign was pallor. The prevalence of hepatitis B surface antigen (HBsAg) was estimated in 207 children (16 years) who had SCD and was compared to a control group of 70 children with HbAA (Abuzeid 2004). There was no significant difference in the prevalence of HBs antigenemia between the two groups (3.9% and 4.3%, respectively). Repeated hospital admission was a risk factor for hepatitis B virus (HBV) infection (P < 0.007). Other risk factors, including blood transfusion, tribal marks, traditional treatment, surgery and circumcision were not associated with HBV infection. In a hospital-based study, the psychosocial impact of SCD was studied in 244 children and their families (Abd Elhafeez 2004). Painful crises were found to be the main cause for frequent hospitalizations. School problems were encountered among both children with SCD and their siblings. The main detected psychological dysfunctions were emotional (23.7%) and peer problems (34.8%). Conduct problems were found to be statistically significant when adjusted to age (P < 0.05). The majority (69.3%) of children with SCD had IQ scores less than 90. Anxiety and depression were detected in 59.8% and 39.3% of caretakers, respectively. The disease was found to be a financial burden for families, and many problems had emerged because of the child’s illness. These included weakness of children relationships with siblings in 44 (21.5%) families, restriction of activity in 123 children; whereas seven children left school because of their illness. Restriction of social life on account of child’s illness was also encountered in many families. A more recent study (Mohamed et al. 2006) on the distribution of the S gene among various ethnic and linguistic groups in the Sudan, confirmed previous observations. Analysis of a hospital-based sample of 189 SCA patients who reported to Khartoum Teaching Hospital and 118 controls with other complaints found that 73% of all SCA cases originated from western Sudan (Kordofan and Darfur). Analysis of the haplotypes associated with the S gene indicated that the most abundant were, respectively, the Cameroon, Benin, Bantu and Senegal haplotypes. The study highlighted the fact that Sudan has been the focal point for transAfrican migrations by man through the open plateau of the Sahel (Wickens 1970), and also pointed to the relatively young age of the S gene in this country. Hemoglobin S/O Arab (Hb S/O-Arab) is a rare compound heterozygous hemoglobinopathy characterized by the presence of two variant b-globin chains: b6 GluVal (HbS) and b121 Glu–Lys (HbO–Arab) (Nagel et al. 1999). It is considered to be a severe sickling hemoglobinopathy with clinical and laboratory manifestations similar to those of homozygous SCA (Zimmerman et al. 1999). This severity was first highlighted, worldwide, in two Sudanese siblings of Arab ancestry (Ibrahim and Mustafa 1967). Case 1 was a 27-year-old male who had fever, joint pains, was wasted and anemic. His 15-year-old sister also had fever, was wasted, anemic and mildly jaundiced. Onset of symptoms of the disease began early in life, in both

20

Genetic Disorders in Sudan

587

patients. The most prominent clinical features in the two cases were joint pains and bony lesions involving humeri, ribs, skull, hands, femur, and radius. Of particular prominence was the marked affliction of the head of the humerus. While the spleen was not palpable in either case, both had marked decrease of plasma albumin along with considerable increase in g-globulin (reflecting hepatic involvement). The older patient developed severe left loin pain which was associated with microscopic hematuria. Hemoglobin electrophoresis showed Hb S þ O in both patients, whereas HbF constituted 5.5% of the total hemoglobin in case 1 and 4.5% in case 2. The father had Hb A þ S while the mother had Hb A þ O.

Thalassemia Thalassemia was first identified in Sudan in 1961 when Vella and Hassan described a case of thalassemia major in a 12-month-old girl in a Sudanese family of Arab origin (Vella and Hassan 1961). Another case in a 3-year-old girl from central Sudan was reported later (Hassan and Ziada 1965). Her family has no relation to the people of Mediterranean origin or any foreign ancestry. A third child was later described together with another two cases of sickle cell thalassemia (Hassan 1970). No population studies have been conducted in Sudan to estimate the frequency of thalassemia trait.

Other Hemoglobinopathies The unstable Hb Khartoum with a Pro –> Arg replacement at position b 124 was first identified during screening for hemoglobinopathies in Khartoum (Vella and Verzin 1963) and later reported in other populations (Hendy et al. 1999). Bayoumi et al. (1999) highlighted that the presence of Hb Khartoum/g thalassemia is a cause of neonatal jaundice. A Sudanese mother was homozygous for two putative g thalassemia point mutations, whereas the father had normal g genes. Two of their three sons, who were compound heterozygous for Hb Khartoum/ g thalassemia, presented at birth with severe neonatal jaundice requiring exchange blood transfusions. The third male child, who did not carry the Hb Khartoum anomaly but was heterozygous for g thalassemia, did not develop neonatal jaundice.

Glucose-6-Phosphate Dehydrogenase Deficiency Several variants of the enzyme exist. The “normal” one is designated G6PD B and represents the most common type of enzyme in all the population groups that have been studied. A mutant enzyme (known as G6PD A+) with normal activity is prevalent among individuals of African descent (Beutler 1991). The most common deficiency variants are the Mediterranean type and A-type of G6PD. The latter

588

M.A.M. Salih

variant is very common in West Africa and its incidence in the United States among Black males is approximately 11% (Heller et al. 1979). The frequencies of G6PD deficiencies among Sudanese tribes are summarized in Table 20.1. An increased frequency of G6PD (17.4%) was detected in the Baggara tribal group (including Hawazma and Messeria), the Fur (14.9%), and the Nuba (23.8%), who inhabit the part of the Nuba Mountains adjacent to the land of the Hawazma subgroup of Baggara (Bayoumi et al. 1985; Bayoumi and Saha 1987). The high frequency in the Baggara (Arab origin) was explained by an influx of the G6PDdeficient gene (G6PD) through admixture with West African populations since this tribal group still maintains intimate contact with people of Chad and northern Nigeria (Bayoumi and Saha 1987). Admixture with the Baggara group has been suggested to explain the observed high frequency in the Fur and Nuba tribes, who represent the indigenous population (Bayoumi et al. 1985; Saha and El Sheikh 1987). In favor of this, the tribes who remained out of reach of the West African influence have either no or low frequencies of G6PD deficiency. These include the Beja living in the Red Sea hills (Hamitic) and Shaigia (Arab descent) living along the curve of the Nile in whom no deficiency was detected (El Hassan et al. 1968; Omer et al. 1972; Saha and El Sheikh 1987). However, a group of northern Nilotes living in Khartoum Province (originally from the swampy tributaries of the White Nile) were found to have a low frequency (1.1–1.2%) of G6PD deficiency. The frequency was also low (2.0%) in a sample of 297 Nubian males who live in Khartoum Province, and no incidence of G6PD was detected in a small number of males from the Fur and Messeria tribes (Saha et al. 1983; Saha and El Sheikh 1987). In Khartoum, blood samples tested for G6PD showed deficient enzyme activity in 8.1% of adults and 7.3% of newborn children (Vella and Ibrahim 1962). However, only seven children were admitted over 2 years (1967–1969) to Khartoum Teaching Hospital with acute hemolytic anemia due to G6PD deficiency (Hassan 1971). They were all males and their age varied between 7 months and 9 years (57% aged <1 year). Family history of acute hemolytic anemia was verified in three families, including a history of neonatal hyperbilirubinemia in one family and two affected males in another. Hemoglobin electrophoresis revealed HbA in all patients except in one, who proved to have an associated SCD. Symptoms started in the majority of patients within 2 days of eating broad beans (fava beans), whereas in two cases pallor was initiated by medications such as aspirin or a sulfa preparation. Similarly, of 1,144 babies born in Khartoum Teaching Hospital during one year (1972–1973), 52 had neonatal hyperbilirubinemia but G6PD deficiency could not be demonstrated in any of them (Omer 1977). A similar obvious lack of the clinical syndromes associated with oxidative hemolysis, despite a high frequency of G6PD deficiency, was reported in peninsular Arab populations of the UAE, Yemen, and Oman (Kamel et al. 1980; White et al. 1986). The frequencies in these populations were found to be 8.7%, 6.2%, and 32.8%, respectively. This phenotype–genotype discrepancy was accounted for by the lack of fava beans or fresh legumes in their diet. However, fava beans are included in at least one family meal in Khartoum and most urban areas of Sudan as well as in Egypt. Hence, factors other than the aforementioned seem to be operating in the Sudanese.

Table 20.1 Frequency of glucose-6-dehydrogenase deficiency among studied Sudanese tribes Study Tribes Hawazma Baggara Messeria Beja Fur Gaalyeen Northern nilotes El-Hassan et al. (1968) – – – 0 – – – Bayoumi et al. (1985) – 17.4 – – 14.9 – – Bayoumi and Saha (1987) 13 – – – – – – Saha and El Sheikh (1987) 13 – 10.6 – 11.3 1.2 1.2 –, Not included in the study a Geographic location shown in Fig. 20.2 Nubaa – – 23.8 –

Nubiansa – – – 2.0

Danagala – – – 5.8

Shaigia – – – 0

20 Genetic Disorders in Sudan 589

590

M.A.M. Salih

Disorders of Hemostasis The pattern of bleeding disorders was described in 120 Sudanese children (0–16 years of age; mean ¼ 1.7 0.7 years) (Mohamed 2004). The majority of patients belonged to the Shaigia (21.7%), Gaalyeen (20.8%) and Baggara (18.3%) tribes. Bleeding was caused by hemophilia A in the majority of patients (43.4%), 25 (20.8%) had von Willebrand disease, and 11 (9.2%) patients had hemophilia B. Seven (5.8%) patients had idiopathic thrombocytopenic purpura, six (5%) aplastic anemia, four (3.3%) hemorrhagic disease of the newborn, and another four (3.3%) thrombasthenia. Two patients were affected with factor VII deficiency and only one patient was assumed to have factor XIII deficiency. Five patients died before reaching definite diagnoses. It is noteworthy that one of the causes of thrombasthenia (Glanzmann thrombasthenia), which is inherited as autosomal recessive, has been reported in a Sudanese boy by Bashawri et al. (2005).

Inherited Metabolic Disorders Amino Acid Disorders Phenylketonuria was reported in two Sudanese siblings in 1964 (Hassan 1964). Until then, only one case had been reported previously from the Middle East (Salam 1963), and reports in African children were entirely lacking. The parents who belonged to the Gaalyeen tribe of Arab descent were cousins. Other reports on defective amino acid metabolism (Hassan 1965a; Hassan and Rabie 1981) included cases of albinism, alkaptonuria (in two siblings), and a family wherein a 3-year-old boy with cystinuria presented with urinary stones and sequelae of obstructive uropathy. His mother and one sister also excreted cystine in urine. The first report on Hartnup’s disease among Arabs (Hassan and Rabie 1981) was in a family where three brothers were affected. In a collaborative study between the Department of Pediatrics at the University of Khartoum and University of Padua of Italy (Mutwakel 2005), a pilot neonatal screening program was undertaken for inborn errors of metabolism using tandem mass spectrometry (Saadallah and Rashed 2007). Samples from 282 newborns were screened and found to be negative for aminoacidemias and organic acidemias. One newborn was diagnosed to have multiple-acyl-CoA dehydrogenase deficiency (MADD). This affected baby was a male and a product of a first degree cousin consanguineous marriage. Birth weight was 2,500 g and he has been quite well when his blood sample was taken on the first day of life. However, he died at 5 days of age of fever, reluctance to breastfeed, convulsions and loss of consciousness. A diagnosis of septicemia, not responding to antibiotics, was made at the hospital where he has been admitted. Family history revealed that his maternal aunt, who is also married to a first degree cousin, had all of her three offspring dying during the early neonatal period with similar presentation, and that she chose not to conceive again.

20

Genetic Disorders in Sudan

591

Carbohydrate Disorders Report on aberrant carbohydrate metabolism included two unrelated patients with galactosemia (diagnosed by urine chromatography), one of whom had consanguineous parents and two siblings who died soon after birth (Hassan 1965a). There is also a report (Hassan 1965a) on a case of glycogenesis type 1 (Von Gierke’s disease) and another on a family where three boys had hereditary fructosuria (Karrar et al. 1984).

Mucopolysaccharidosis Three cases of Hurler’s syndrome were described (Hassan 1965a, 1966). These were diagnosed on clinical and radiological grounds. However, the first case report on Morquio’s disease came in 1953 (Hassan 1953), and was followed by the report of seven cases in three Sudanese families (Townsend-Coles 1954). Another four cases were described by Hassan in 1965, who commented on the relatively high proportion of cases from Sudan compared to 78 cases reported, until then, in the world literature (Hassan 1965a). Of 11 patients described in a later series (Hassan 1966), 10 belonged to three consanguineous families.

Metabolic Bone Disease The most commonly described category of metabolic bone disease was the hypophosphatemic rickets which was considered by Hassan (1977) to be the most common type of rickets in the Sudan. In a series of seven patients (three males and four females, aged between 2½ and 11 years), three (two males and one female) belonged to one family whose parents were first cousins (Hassan 1966). Rickets was documented radiologically in all cases, whereas the biochemical profile was characterized by low serum phosphate, high alkaline phosphatase, and normal serum calcium. Renal excretion of phosphate was reported to be increased in these patients. However, other family members were not investigated for the presence of hypophosphatemia. In Sudan and other Arab countries, the existence of consanguineous marriages and manifestation of a disease in both sexes may favor autosomal recessive inheritance in some cases. In a later publication, Hassan (1977) described a Sudanese family with five children presenting with alopecia and rickets. Four of these died of intercurrent infections at about the age of 2 years. The index case was a 14-month-old girl who had been presented with hair loss, muscle weakness, and features of rickets since the age of 8 months. Biochemical investigations revealed low serum calcium and phosphate but remarkably high alkaline phosphate. It is interesting to note that this entity later became known as vitamin D-dependent rickets type II, and about 50%

592

M.A.M. Salih

of affected kindreds were reported to have alopecia (Brooks et al. 1978; Rosen et al. 1979; Nyhan and Sakati 1987). Reports on Fanconi’s syndrome included a 10-year old boy who presented with inability to walk for 2 years and had features of rickets (Hassan 1977) and a 9-month-old boy presented initially with glycosuria and was found later to have rickets (Omer and El Sheikh 1977). Although both cases were documented radiologically and biochemically, no further investigations were done to elucidate whether the syndrome was primary or secondary (for example, due to cystinosis).

Skeletal Dysplasias Reported patients included three cases of achondroplasia and another three with osteogenesis imperfecta (Hassan 1965a, 1966). The ages of the latter patients were 14 months, 3 years, and 5 years. The 3-year-old boy was the first and the only child of a cousin marriage and had normal sclerae (MIM No. 166220 in McKusick (1994)). The other two had blue sclerae (MIM No. 166200). However, osteopetrosis was reported in a 7-year-old girl who presented with dental caries and osteomyelitis of the right mandible (Hassan 1965a, 1966). In a prospective study by Doumi et al. (1994) of fractures in 231 children received at Khartoum North Teaching Hospital (KNTH), pathological fractures accounted for 2.2%. These were due to bone cysts and osteogenesis imperfecta.

Endocrine Disorders Studies dealing with thyroid diseases in the Sudan focused on the endemic goiter caused by iodine deficiency, which is a significant health problem both in highlands and lowlands of the country (Kambal 1968, 1969; Eltom et al. 1984, 1985). A prevalence of 57–85% was found among the population of the land-locked mountainous area of Jabal Marra (Kambal 1969; Eltom et al. 1984). In a study to determine whether factor other than iodine deficiency were involved in the causation of endemic goiter in this region, Bayoumi et al. (1988b) studied two tribes (Fur and Baggara) living in the Jabal Marra area. The study focused on the inheritance of endemic goiter and its association with phenylthiocarbamide (PTC) taste response and with blood-genetic markers. The overall frequency of goiter (all grades) was found to be 74%, and it was similar in both the Fur and Baggara tribes. Studies in 60 nuclear families showed a significantly higher incidence of endemic goiter among the offspring of affected parents than among the offspring of normal parents. This suggested the involvement of a hereditary factor which increases the liability of the offspring to the disease, which is similar to a previous observation from Greece (Malmos et al. 1966). The proportion of PTC nontasters was found to be 13% among the goiterous subjects compared to 17.5% among nongoiterous subjects.

20

Genetic Disorders in Sudan

593

However, the association of goiter with PTC, as well as six blood-genetic markers, was not statistically significant. The contribution of genetic defects in thyroid hormonogenesis (MIM No. 274400) in the etiology of goiter in nonendemic areas of Sudan was highlighted by Mukhtar (1974), who found abnormal secretions of iodiproteins to account for a group of cases. Subsequently, Pendred’s syndrome (MIM No. 274600) was described in a family (Salih and Hashem 1978). Two members (a boy and a girl aged 14 and 11 years, respectively) had goiter, sensorineural deafness, evidence of mild hypothyroidism, and positive perchlorate discharge test. The parents were double first cousins and a history of similar illness was revealed in a 30-year-old paternal cousin. Other studies included a report on DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness – MIM No. 222300) in two families (Salih and Tuvemo 1991). The patients (three males and one female) first manifested with diabetes mellitus (at 3–8 years), followed by deafness and visual failure. The disease ended fatally in one patient (aged 20 years). In the other three, diabetes insipidus was confirmed using a water deprivation test for 8 h. They also had severe bilateral hydronephrosis, dilated ureters, and distended bladder without vesicoureteral reflux. Consanguinity was a feature, as it was in several of the familial cases reported from North African and Middle East communities (Nagi 1979; Dliga et al. 1985; Najjar et al. 1985). The authors highlighted the need in such communities to examine children with diabetes mellitus for the presence of a palpable bladder and/ or optic atrophy. In a study (Osman 1996) to ascertain thyroid disorders in 80 children (<16 years), who were followed at a specialized outpatient clinic in Khartoum, juvenile hypothyroidism was the commonest thyroid disorder (31.3%) followed by congenital hypothyroidism (27.5%). Dyshormonogenesis was the least common (5%). Lethargy (95.5%) and constipation (63.6%) were the most common presenting symptoms in children with congenital hypothyroidism, while poor school performance (32%) was a common complaint among those with juvenile hypothyroidism. Of the group with congenital hypothyroidism, 27.7% had severe mental retardation. Most of these patients were diagnosed after the age of 4 months. Appropriate therapy was reported to be quite effective in reverting the course facial features and improving the delayed bone age in children with hypothyroidism. True hermaphroditism (TH) is the rarest variant of intersex malformations and is characterized by the combined presence of both ovarian and testicular tissue (Krstic et al. 2000). Most patients present themselves because they have ambiguous genitalia and/or gynecomastia. Gindeel (2005) reported a Sudanese patient with TH who presented, at the age of 13 years, with recurrent abdominal pain. He has been reared as a male. Clinical examination revealed bilateral gynecomastia, ambiguous genitalia with severe hypospadias, left-sided undescended testes, and left irreducible congenial mass. Karyotyping showed a normal male pattern of 46 XY. Normal assays showed normal levels of prolactin, follicle stimulating hormone and testosterone, with slightly raised luteinizing hormone reacting

594

M.A.M. Salih

15.8 U/L (normal 9). Histological examination of the mass (after resection) revealed it to be consisting of the left ovary, tube and uterus. The ovary contained the corpus luteum and several Graffian follicles.

Disorder of the Digestive System Published observations on inherited disorders of the digestive system included a Sudanese family who had two children affected with cystic fibrosis (Hassan 1965a, 1966). The parents were first cousins who lost three children in early infancy with diarrhea and vomiting. Both patients presented with repeated attacks of bronchopneumonia and diarrhea. Investigations revealed excess fat in the stools, greatly reduced tryptic activity of duodenal juice and raised sweat sodium (121 and 127 mEq/L; N ¼ 10–90). In the similar hot climate of Saudi Arabia, cystic fibrosis was identified later by Abdalla and associates (Abdalla et al. 1986). The distribution of adult lactase phenotypes and lactose malabsorption in 563 subjects who belonged to various Sudanese ethnic groups was investigated by Bayoumi et al. (1981). A field version of the hydrogen breath test for disaccharide absorption was used (Howell et al. 1981). The frequency of the “hypolactasia allele” ranged between 60% and 87% in the major regional groups. The authors considered their finding supportive of the contention that in the Old World only a few populations outside central and northern Europe have lactase persistence gene frequencies over 50% (Flatz and Rotthauwe 1977). There was a high prevalence of lactose malabsorption in the residential agricultural societies of the Nile valley (64%) and in the aboriginal African groups of central Sudan (76%). Neither group relies heavily on dairying. However, a lower frequency (38%) of lactose malabsorption was detected in nomadic pasturalists residing in the arid areas east and west of the Nile Valley. Another study (Bayoumi et al. 1982) explored lactose tolerance (using breath hydrogen determination) in 585 Sudanese adolescents and adults. Of these, 303 belonged to the Beja tribal group and 282 were Nilotes (mainly Dinka). Milk consumption is substantial in both populations but only in the Beja, true milk dependence existed. The proportion of lactose malabsorbers was 16.8% in the Beja and 74.5% in the Nilotes. In humans, expression of lactose enzyme in adulthood or lactose persistence (LP) is a polymorphic trait, the frequency of which has been shown to be moderately well correlated with the cultural habit of drinking fresh milk (Holden and Mace 1997). LP or non-persistence into adult life has been attributed in Europeans to a single nucleotide polymorphism C/T-13910 in an enhancer 13.9 kb upstream of the lactase (LCT) gene (Enattah et al. 2002). A collaborative study (Ingram et al. 2007), including Sudanese volunteers, showed no association of the LP trait in Sudanese and the T-13910 variant (which characterizes European populations). This study included one of the pastoralist Beja groups, the Beni Amir and some of their urban and non-pastoralist neighbors, namely Dounglawi (Nubians) and Shaigi

20

Genetic Disorders in Sudan

595

(Shaigia). Samples were also collected, in this study, from a cohort of 99 Jaalu (Gaalyeen), a Sudanese group of Arab ancestry with previously reported intermediate LP frequency (Bayoumi et al. 1981). In another genotype–phenotype LP association study (Tishkoff et al. 2007) in 470 Tanzanians, Kenyans and Sudanese, the T-13910 allele was absent in all of the African populations tested including the Nilo-Saharan (Nilotes) and Afro-Asiatic (Beja) from Sudan. Instead, the C-13907 and G-13915 alleles were at 5% frequency in the Afro-Asiatic (Beja) populations (21% and 12%, respectively). The Authors (Tishkoff et al. 2007) suggested that G-13907 and G-13915 might form probable candidate LCT regulatory mutations. Enattah et al. (2008) assessed the genotype of LP in populations that use camel milk from Saudi Arabia and other neighboring countries of the Middle East, and compared them to other populations. They identified two mutations underlying LP among Saudis (C-3712 and G-13915) and confirmed the absence of the European allele T-13910. Sequencing of individuals from two tribes of Arab descent from Northern Sudan revealed the presence of the G-13915 allele (17%) among the Mahas and G-13907 allele (5%) among Gaali (Gaalyeen). Further analysis of the Saudi samples combined with 143 global samples, from 12 worldwide populations revealed that the European T-13910 LP and the Arab C-3712 and G-13915 LP variants have emerged from different allelic backgrounds. These were postulated to have been driven to high frequencies in different populations because of different histories of animal domestication and dairy culture.

Neurogenetic Disorders The contribution of genetic disorders as a causative for childhood neurological handicaps seems to have evolved over time. A study in 1983 (Hussein 1983) involving 220 Sudanese children identified 100 (45.5%) with neuroskeletal handicap and 40 (18.2%) with mental deficiency. Bad obstetric care, mismanaged labors, neglected neonatal and postnatal conditions were blamed as being causative in the majority of cerebral palsy cases, while lack of vaccination, together with unnecessary intramuscular injections were the two main significant factors in the development of poliomyelitis. Apart from the few patients in whom the etiology of mental deficiency could not be identified, obstetric, neonatal and postnatal problems were thought to be the major factors. Meningitis and measles were the main infections leading to deafness. However, hereditary deafness was found to be quite frequent and in the majority of blind children the cause was congenital. A study (Yahia 2001) conducted more than a decade later (from December 1997 to December 1998) included 115 children in six institutes caring for mentally handicapped children in Khartoum State. The most common underlying cause was Down’s syndrome (n ¼ 32 (27.8%)), of whom two-thirds of cases occurred above maternal age of 30 years. Infectious causes were reported in 14 (12.2%) cases, of which meningitis was the leading cause (n ¼ 11 (9.6%)). It is noteworthy

596

M.A.M. Salih

that Sudan lies within the meningitis belt (Salih 1990). In this cohort, increasing maternal age was significantly associated with increasing frequency of mentally retarded children (P < 0.01). In a study (Ahmed 2000) conducted on 199 deaf institutionalized children (61.3% had severe and 38.7% profound deafness), positive family history of deafness was reported in 74.2%, and the majority of them had similarly affected sibling. Parental consanguinity was reported on 88.3% of deaf children with positive family history. History of adverse perinatal factors was found in 6.5% of the total, whereas severe neonatal jaundice, which needed exchange transfusion, was reported in 2%. Meningitis caused deafness in 15% of the affected children, and 66.6% of these acquired their infection at an age <2 years.

Birth Defects Birth defects were ascertained in a prospective hospital-based longitudinal study involving 4,152 newborns who were examined at birth at Khartoum Teaching Hospital and Soba University Hospital (Ali 1999). A total of 99 congenital malformations (CMs) were documented in 75 newborns giving an incidence of 18/1,000 births. Genitourinary system anomalies were the most prevalent (n ¼ 20, 4.8/1,000 births) and neural tube defects (NTDs) were detected in ten newborns (2.4/1,000 births). Congenital malformations were most prevalent in the offspring of mothers aged 36–40 years and 24.7% were above 35 years. Nearly two-third of the parents were consanguineous and the incidence of CMs was statistically significant among newborns of grand multi-parous mothers (P < 0.03). The etiology was unknown for more than half (57.8%) of CMs. The case fatality rate was 14.7%, the main causes of death being cardiac and central nervous system anomalies.

NTDs NTDs comprised four cases of meningocele among 101 children with hydrocephalus, ascertained during the period from 1971 to 1974 (Aziz 1983). In a retrospective study of 43 patients with NTDs (Nugud et al. 2003), 83.7% were from Arab tribes and 16.3% had African ancestry. There was no significant difference in male to female ratio, maternal diabetes was reported in 9% of cases and sib recurrence rate was 7.0%. The pattern of defect showed 90.8% cystica (88.4% myelomeningocele and 11.6% meningocele), 4.6% spina bifida occulta, 4.6% encephalocele and no anencephaly. Associated anomalies included 34.9% club foot, 23.3% hydrocephalus, 2.3% facial clefts, and 2.3% polycystic kidneys. A prospective case–control study (Elsheikh 2004), which included 18,378 deliveries at Omdurman Maternity Hospital found the incidence of NTDs to be

20

Genetic Disorders in Sudan

597

3.48/1,000, constituting 59.4% of all congenital malformations at birth. The male to female ratio was 1:5. Myelomeningocele was the most common (60%) followed by anencephaly (38%), encephalocele (10%) and one case of iniencephaly. Most of the cases were either stillbirth or died in the early neonatal period. Other congenital anomalies were found in 20% of cases. The majority (63.5%) of mothers of affected babies and their controls (64.0%) belonged to tribes from western Sudan who migrated recently to Omdurman. About 60% of mothers were < 25 years of age, and there was a significant association between young maternal age (< 25 years) and the occurrence of NTDs (relative risk 2.3, P < 0.0001). Most of the mothers had a significant history of previous stillbirth delivery. No mothers from the case or control groups had used folic acid pre-conceptionally.

Neuromuscular Disorders Inherited neuromuscular disorders included by Hassan (1965a) consisted of a case with Duchenne muscular dystrophy (MD), a case of Werdnig–Hoffman disease, and four cases of Charcot–Marie–Tooth disease. History of similar illness was obtained in two cases. A male of 9 years, who was a product of consanguineous marriage, had a maternal cousin similarly affected with Charcot–Marie–Tooth disease. Similarly, a 10-month-old boy (a product of consanguineous marriage) with Werdnig–Hoffman disease had an affected sister who died at 1 year of age. In 1977, investigations started on an “unusual” severe autosomal recessive MD that affected 15 members (seven males and eight females) of a kindred consisting of 176 individuals in eight generations (Salih 1980, 1982, 1985; Salih et al. 1983). Clinically the disease resembled Duchenne MD, but it had its unique differences; attention was drawn in later publications to its similarity to other cases reported from North Africa and Arabia (Salih et al. 1983; Salih 1985). This phenotype of MD became known as severe childhood autosomal recessive MD (MIM No. 253700). In 1994, the sarcoglycan complex was discovered among the dystrophin-associated proteins which link the cytoskeleton of muscle fibers, through dystrophin, to the extracellular matrix proteins (Jeanpierre et al. 1996; Ozawa et al. 1998). The sarcoglycan complex consists of four primary proteins (a, b, g, and d) which are encoded, respectively, by a-, b-, g-, d-sarcoglycan genes. Mutation of any one of the sarcoglycan genes leads to SCARMD. A follow-up study (Salih et al. 2007) of the Sudanese kindred identified a b-sarcoglycan deletion in a 9-year and 4 months-old male belonging to the ninth generation Salih et al. The parents were heterozygous for the mutation (see Chap. 6). An international collaborative research identified C-terminal titin deletions as causative for a novel early-onset myopathy with fatal cardiomyopathy, currently referred to as “Salih myopathy” (Fukuzawa et al. 2008, Peringo et al. 2010) (see below and the Chap. 6).

598

M.A.M. Salih

Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders caused by genetic defects that affect transmission at the neuromuscular junction. As of the year 2009, ten genes, including the muscle specific kinase (MUSK), are known to cause CMS if mutated (Muller et al. 2007). Across the world, the second family with CMS caused by a novel MUSK mutation was reported in five affected siblings from a consanguineous Sudanese family (Mihaylova et al. 2009). The father and the maternal grandmother are first-degree cousins.

Parkinson’s Disease Parkinson’s Disease (PD), the second most prevalent neurodegenerative disorder, results from the selective loss of dopaminergic neurons in the nigrostriatal pathway of the brain. The disease is mostly sporadic; fewer than 10% of PD cases are familial (McInerney-Leo et al. 2005). Nevertheless, a recent review observed that the majority of studies in Arab populations related to the role of genes in the etiology of PD in North African Arabs (Benamer et al. 2008). Familial forms have been shown to be related to several genes. Mutations in three of these, namely parkin (PARK2), PTEW-induced putative kinase 1 (PINK1) and DJ-1 gene are responsible for the autosomal recessive forms PARK2 (Kitada et al. 1998), PARK 6 (Valente et al. 2004) and PARK7 (Bonifati et al. 2003), respectively. The phenotype of these recessive forms is characterized by an early age of onset of the clinical signs (early onset PD, EOPD), a good response to Levodopa therapy, and a slow disease progression. The largest kindred with EOPD associated with PINK1 mutation was reported from Sudan (Leutenegger et al. 2006). The kindred originated from north Sudan and the sibships are currently living in Khartoum. Eight individuals (six females and two males) in two generations were affected. Onset was early (age 9–17 years) and the phenotype varied from dopa-responsive dystonia (Segawa disease) – like to that of typical EOPD. Three affected individuals (all females) died at 20–25 years of age. The disease was caused by a novel mutation, p.A217D, located in the highly conserved adenosine triphosphate orientation site of the PINK 1 kinase domain. Another family, living in a village in central Sudan and belonging to Kawahla tribe (who originated from the Central Region of Saudi Arabia) was also found to have another PINK1 gene mutation (Cazeneuve et al. 2009). Among 12 siblings born from second degree cousins, three individuals (one female and two males) presented with EOPD. The patients were aged 15, 27 and 35 years, respectively. Symptoms started at 11–21 years and all of them showed a good response to levodopa therapy. However, the eldest patient revealed significant levodopa-induced dyskinesia following 8 years of treatment. The three patients were homozygous for a novel deletion of PINK1 exons 4–8. The study recommended that PINK1 gene analysis, including search for large re-arrangement, should be considered in recessively inherited EOPD, particularly in those patients of Arab descent.

20

Genetic Disorders in Sudan

599

Hereditary Ataxia Ataxia with oculomotor apraxia type 2 (AOA2, MIM No. 606002) belongs to the autosomal recessive cerebellar ataxias. The phenotype consists of progressive cerebellar ataxia, starting between 12 and 20 years of age, in association with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated serum a-foetoprotein level. The disease is caused by mutations in the senataxin (SETX) gene. Two Sudanese siblings (living in Saudi Arabia) and one isolated case (from the Northern Province of Sudan) were among the 90 established cases reported by Anheim et al. (2009). This collaborative study included cases from 15 countries worldwide and identified 26 SETX mutations.

Cutaneous and Neurocutaneous Disorders Hidayatalla (1970) described a 30-year-old woman who had neurofibromatosis complicated by two rare features of the disease – namely, a giant plexiform neurofibroma of the trigeminal nerve and neurofibrosarcomatous growth in the left popliteal fossa. Karrar and Mabrouk (1991) described the first Sudanese case of a rare variant of autosomal recessive cutis laxa (MIM No. 219200). He was a 5.5-year-old boy who presented with redundant skin, growth and development retardation, facial dysmorphism, hyperextensible joints, dislocation of the hips, and a large umbilical hernia. Clustering of similar cases was noted in Saudi Arabia (Karrar et al. 1985). Epidermolysis bullosa (EB) is a group of inherited diseases characterized by easy blistering of the skin and mucous membranes after minor physical trauma. The disease has been classified into three major groups based on the level of cleavage within the skin, as seen by electron microscopy. In EB simplex, blister formation appears within the basal cell larger of the epidermis, whereas junctional EB is caused by blister formation within the basement membrane. In dystrophic EB, the tissue separation occurs beneath the basement membrane. In 1985 (Salih et al. 1985b), a new type of EB simplex was described in 13 members of an inbred Sudanese family (see below). More recently, Nakano et al. (2002) described a consanguineous family originating from Sudan with generalized atrophic benign EB (one of the subtypes of the junctional EB). The proband presented with milia over the face, and immune fluorescence studies on frozen skin sections showed lack of staining for type XVII collagen. The child was homozygous for the R1226X mutation in the CoLI7A1 gene.

Cancer Genetics A cohort of 20 breast cancer patients from the Sudan were tested for germ line and somatic mutation in their BRCA2 exon 11, as well as the main conserved area of the

600

M.A.M. Salih

p53 tumor suppressor gene (Masri et al. 2002). Both regions seemed to play a limited role in the pathogenesis of breast cancer in those patients. The fact that no somatic mutations were detected in p53 was particularly surprising since the expected rate for mutations in breast cancer is 30–50%. Bilharzia-associated bladder cancer (BAC) is a major health problem in Sudan, as well as other countries where urinary schistosomiasis is endemic. While chemicals, including cigarette smoke and occupational exposures, cause transitional cell carcinoma (TCC) of the bladder in industrialized countries, a similarly strong association with urinary bilharziasis exists in Africa and the Middle East (Badawi et al. 1995). In a study (Fadl-Elmula et al. 2002) to characterize chromosomal imbalances in benign and malignant post-bilharzial lesions, DNAs from 20 archival paraffin-embedded post-bilharzial bladder lesions (six benign and 14 malignant) obtained from Sudanese patients (12 males and 8 females) with a history of bilharziasis were investigated for chromosomal imbalances using comparative genomic hybridization (CGH). To confirm the CGH results, subsequent FISH analysis with pericentromeric probes was performed on paraffin sections of the same cases. The study concluded that the cytogenetic profiles of chemical and bilharzias-induced carcinomas are largely similar since most of the detected imbalances have been repeatedly reported in non-bilharzial bladder carcinomas. However, loss of 9p seemed to be more ubiquitous in BAC than in bladder cancer in industrialized countries.

New Syndromes A new variant of EB (Salih et al. 1985b) was reported among 13 members (eight males and five females) of a highly inbred, large Sudanese family extending over nine generations with several double-cousin marriages. On ultrastructural grounds the skin disease appeared to be a simplex type, which is known to be inherited as a dominant trait. However, in this family it was inherited in an autosomal recessive manner and was associated with a high mortality (MIM No. 226670). Ten of the thirteen affected individuals (seven boys and three girls) died at or before 20 months of age. This entity later became known as EB simplex lethalis (Fine et al. 1991). Another new hereditary defect of tryptophan metabolism was described in a consanguineous Sudanese family that extended over six generations (Salih et al. 1985a; Winter and Baraister 1991). The disorder, which was inherited as autosomal recessive (MIM No. 260650), manifested as a pellagra-like skin rash within 8 weeks after birth, with signs of cerebellar ataxia and developmental retardation. Cataracts developed early and none of the ten affected children had survived beyond 32 months. Biochemically, the condition was characterized by an apparent impairment of the ability to synthesize quinolinic acid and nicotinamide nucleotides from tryptophan, which might be due to abnormally high activity of the enzyme picolinate carboxylase.

20

Genetic Disorders in Sudan

601

A novel form of early-onset myopathy that evolves into MD and childhood-onset fatal dilated cardiomyopathy was described in two Sudanese siblings (Salih et al. 1998; Subahi 2001). These cases, together with three Moroccan siblings had M-line titin homozygous truncations and formed the first reported congenital and purely recessive titinopathy (Carmignac et al. 2007). The disease is currently referred to as “Salih myopathy” (Fukuzawa et al. 2008, Pernigo et al. 2010) (see Chap. 6).

Cytogenetic Abnormalities The first report on Down’s syndrome (Hassan 1956) came 3 years before the association of this disorder with a chromosomal abnormality and was demonstrated by Lejeune et al. (1959). The report dealt with seven cases (seen exclusively in two small cities, Port Sudan and Kosti) including a twin pair discordant for the syndrome (Hassan, 1958). Hassan (1962) described another series of 30 cases seen in Khartoum. Another 15 cases were added to these (Hassan 1965a) and published collectively in his thesis “Congenital Diseases in Sudanese Children.” He stated that the disease was uncommon in Sudan and gave an approximate incidence of one in 18,000. In this series of 45 cases, the maternal age at the time of delivery was >35 years in 66%. In the other, 57% of the parents were consanguineous. The clinical features were generally similar to those described in Caucasians. However, reported eye abnormalities included blepharitis in four (8.8%) patients, entropion trichiasis in three (6.6%) corneal opacity in two (4.4%), and strabismus in one (2.2%) but no Brushfield spots were seen in any of the patients. It is noteworthy that Brushfield spots are seen most often in blue eyes (Nyhan and Sakati 1987). Other associated congenital anomalies in these 45 patients included ventricular septal defect (VSD) in nine (20%) children and the occurrence of tetralogy of Fallot (TOF), hypospadias, and imperforate anus each in one patient. The frequency rate of thyroid disease and other associated conditions were studied in 96 children (aged <16 years) with Down’s syndrome (Babiker 2004). The male to female ratio was 1.34:1. Thyroid disturbances were detected in 38 (39.6%), 20 (20.8%) had definite hypothyroidism, 17 (17.7%) had evidence of thyroid dysfunction and sub-clinical hypothyroidism, and one (1%) had hyperthyroidism. Two neonates had congenital hypothyroidism, no significant sex association was found, and there was poor correlation between clinical symptoms and biochemical thyroid dysfunction. Other associated conditions in children with Down’s syndrome and thyroid diseases were congenital heart disease, diabetes mellitus, alopecia, cataract and genitourinary tract anomalies. In a descriptive cross-sectional and health units institute-based study (El Tayeb 2004), 96 children with Down’s syndrome were screened for congenital heart diseases (CHD) using two-dimensional echocardiography. Thirty-six (37.5%) were found to have CHD, mainly in the age group 3–12 months. The male to female ratio was 1:1.14 and 42 (43.8%) of their mothers were aged between 35 and 45 years. Of the affected children 17 (47.2%) had VSD, eight (22.2%)

602

M.A.M. Salih

atrioventricular canal defect, four (11.1%) atrial septal defect, two (5.8%) TOF, one (2.8%) patent ductus arteriosus and four (11.1%) had combined defects. The findings of the first human cytogenetic project in Sudan entitled “Cytogenetic and Fish Analyses in Sudanese Patients with Dysmorphic Features, Ambiguous Genitalia, and Infertility” were reported by Ellaithi et al. (2006b). To characterize the genetic alterations in patients with dysmorphic features, ambiguous genitalia and/or infertility, chromosomal G-bonding and fluorescent in situ hybridization (FISH) analysis were performed on 44 Sudanese patients. The study group included 29 females, 14 males, and one patient with unassigned sex. The patients age ranged between 17 days and 39 years (mean ¼ 18 years). Of the 44 patients, 20 had ambiguous genitalia, eight dysmorphic features, 11 had puberty and/or fertility complaints, and five were healthy individuals (parents of three patients with dysmorphic features). Cystogenetic analysis of the 20 patients who had ambiguous genitalia (13 females and 6 males, and 1 case with unassigned sex) showed that eight had karyotypes different from their assigned sex and the other cases showed karyotypes consistent with Edward syndrome (47, XX, +18 (case 7), and a case of with 45, Xdel (X) (p11) (case 11). Using FISH for Case 11 with 45, Xdel (X) (p11) revealed a very small piece from the Y chromosome translocated to the q-arm of the del (X). PCR confirmed translocation of the SRY (sex-determining region Y) gene to the active X chromosome (Ellaithi et al. 2006a). It is noteworthy that SRY (sexdetermining region, Y) is the gene responsible for gonadal differentiation in the male and is essential for the development of male genitalia. Regarding the eight patients with dysmorphic features, five showed karyotypes consistent with Down’s syndrome, one of whom showed Robertsonian translocation using both ordinary G-bonding and FISH. On the other hand, all cases of infertility had normal karyotypes except for two cases of Turner syndrome and one who showed a male karyotype although he was raised as a female. In the latter case, ultrasound showed a mass in the position of the prostate. The study emphasized the importance of cytogenetic and FISH analyses in the diagnosis and management of genetic diseases in Sudan. The first case of Cornelia de Lange syndrome (Brachmann de lange syndrome, MIM No. 122470) from Sudan was described in a 7-month-old female infant (Ellaithi et al. 2007). Apart from the characteristic dysmorphic features, the patient had additional clinical findings not previously reported including crowded ribs and tied tongue. The karyotype revealed no evidence of chromosomal imbalances or gross rearrangements. Acknowledgments I am grateful to Professor Ahmed Mohamed El Hassan, the late Professor Mahmoud Mohamed Hassan, and Professor Riad A. Bayoumi, who cordially provided me with reprints of their work and with constructive discussions. Thanks are also extended to Professor Muntasir E. Ibrahim and Professor Imad Fadl-Elmoula for providing lists of their publications. The collaborative neurogenetic research projects wouldn’t have attained success without the cordial help of Professor Maowia M. Mukhtar, the Institute of Endemic Diseases, University of Khartoum. The dedicated help of Dr. Muddathir Hamad Abd Elgadir is gratefully acknowledged. Special thanks are due to Prof. Zein A. Karrar, former Dean, Graduate College, University of Khartoum (U of K) and Prof. Salah Ahmed Ibrahim, Convenor and Chairman, Department of Pediatrics and

20

Genetic Disorders in Sudan

603

Child Health, Faculty of Medicine, U of K who faithfully edited the first and second editions of the Book of Abstracts, Clinical MD in Pediatrics and Child Health (1976–2004) which highlighted a wealth of genuine and original scientific research. Thanks are also due to Vir Salvador (medical illustration) and for Loida M. Sese and Rowena Fajardo for secretarial assistance.

References Abd Elhafeez AA (2004) Psychosocial impact of sickle cell anemia on affected children and their families. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Abdalla MA, Katugampola M, Za K (1986) Cystic fibrosis in Saudi Arabia: a case report. Saudi Med J 7:189–191 Abuzeid SO (2004) Hepatitis B surface antigen among children with sickle cell disease in some Khartoum hospitals. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Abu-Zeid YA, Abdulhadi NH, Hviid L, Theander TG, Saeed BO, Jepsen S, Jensen JB, Bayoumi RA (1991) Lymphoproliferative responses to Plasmodium falciparum antigens in children with and without sickle cell trait. Scand J Immunol 34:237–242 Abu-Zeid YA, Abdulhadi NH, Theander TG, Hviid L, Saeed BO, Japsen S, Jensen JB, Bayoumi RA (1992a) Seasonal changes in cell-mediated immune responses to soluble Plasmodium falciparum in children with haemoglobin AA and haemoglobin AS. Trans R Soc Trop Med Hyg 86:20–22 Abu-Zeid YA, Theander TG, Abdulhadi NH, Hviid L, Saeed BO, Japsen S, Jensen JB, Bayoumi RA (1992b) Modulation of the cellular immune responses during Plasmodium falciparum infections in sickle cellular trait individuals. Clin Exp Immunol 88:112–118 Adekile AD, Kitundu MN, Gu L-H, Landos KD, Adeodu OO, Huisman THJ (1992) Haplotypes in SS patients from Nigeria; characterization of one atypical Bshaplotype no. 19 [Benin] associated with elevated Hb F and high Ggamma levels. Ann Hematol 65:41–45 Ahmed AA (2000) Risk factors to deafness in institutionalized children. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Ahmed HA, Baker EA (1986) Sickling in the Sudan; results of surveys in Blue Nile Province. East Afr Med J 6:395–399 Ali IF (1999) Pattern of clinically detectable congenital malformations among Sudanese children at birth. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Schol L, et al (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/ phenotype correlation study of a cohort of 90 patients. Brain 132:2688–2698 Archibald RG (1926) A case of sickle cell anaemia in the Sudan. Trans R Soc Trop Med Hyg 19:389–393 Awaad MO, Bayoumi RAL (1993) Sickle cell disease in adult Bedouins of Al-Ain District, United Arab Emirates. Emirates Med J 11:21–24 Aziz IA (1983) Hydrocephalus in Sudan. J R Coll Surg 28:151–153 Babiker GMZ (2004) Frequency rate of thyroid disease and other associated conditions in children with Down’s syndrome in Khartoum state. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Badawi AF, Mostafa MH, Probert A, O’Connor PJ (1995) Role of schistosomiasis in human bladder cancer: evidence of association, aetiological factors, and basic mechanisms of carcinogenesis. Eur J Cancer Prev 4:45–59 Bashawri L, Qatary A, Fawaz N, Al-Attas RA, Ahmed M (2005) Glanzmaan’s thrombosthenia. Bahrain Med Bull 27:123–128

604

M.A.M. Salih

Bayoumi RA (1987) The sickle-cell trait modifies the intensity and specificity of the immune response against P. falciparum malaria and leads to acquired protective immunity. Med Hypotheses 22:287–298 Bayoumi RA, Abu-Zeid YA, Abdul Sadig A, Awad Elkarim O (1988a) Sickle cell disease in Sudan. Trans R Soc Trop Med Hyg 82:164–168 Bayoumi RA, Abu-Zeid YA, Abdulhadi NH, Theander TG, Hviid L, Ghalib HW, Nugud AHD, Jepsen JB (1990) Cell-mediated immune response to P. falciparum purified soluble antigens in sickle cell trait subjects. Immunol Lett 25:243–250 Bayoumi RA, Bashir AH, Abdulhadi NH (1986) Resistance to falciparum malaria among adults in central Sudan. Am J Trop Med Hyg 35:45–55 Bayoumi RA, Dawodu A, Qureshi MM, Al-Khider A, Fitzgerald P, Riou J, Fisher CA, Fitches A, Old JM (1999) The association of Hb Khartoum [beta 124 (H2) Pro –> Arg] with gamma +thalassemia is responsible for hemolytic disease in the newborn of a Sudanese family. Hemoglobin 23:33–45 Bayoumi RA, Flatz SD, Kuhnau W, Flatz G (1982) Beja and Nilotes: nomadic pastoralist groups in the Sudan with opposite distributions of the adult lactase phenotypes. Am J Phys Anthropol 58:173–178 Bayoumi RA, Saha N (1987) Some blood genetic markers of the Nuba and Hawazma tribes of western Sudan. Am J Phys Anthropol 43:103–112 Bayoumi RA, Simsek M, Yahya TM, Bendict S, Al-Hinai A, Al-Barwani H, Hassan MO (2006) Insertion–deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, Emiratis, and Omanis. Hum Biol 78:103–108 Bayoumi RA, Taha TSM, Saha N (1985) A study of some genetic characteristics of the Fur and Baggara tribes of the Sudan. Am J Phys Anthropol 65:363–370 Bayoumi RA, Taha TSM, Saha N (1988b) Study of possible genetic predisposition to endemic goitre among the Fur and Baggara tribes of the Sudan. Hum Hered 38:8–11 Bayoumi RAL, Saha N, Salih AS, Bakkar AE, Flatz G (1981) Distribution of the lactase phenotypes in the population of the democratic republic of the Sudan. Hum Genet 57:279–281 Benamer HT, de Silva R, Siddiqui KA, Grosset DG (2008) Parkinson’s disease in Arabs: a systematic review. Mov Disord 23:1205–1210 Beshir MO (1980) Ethnicity, regionalism and national cohesion in the Sudan. Sudan Notes Rec 61:1–14 Beutler E (1991) Glucose-6-phosphate dehydrogenase deficiency. In: Williams WJ, Beutler E, Erslev AS, Lichtman MA (eds) Haematology. McGraw-Hill, New York, pp 591–606 Blackwell JM, Mohamed HS, Ibrahim ME (2004) Genetics and visceral leishmaniasis in the Sudan. Trends Parasitol 20:268–274 Blanton RE, Salam EA, Ehsan A, King CH, Goddand KA (2005) Schistosoma hepatic fibrosis and the interferon gamma receptor: a linkage analysis using single-nucleotide polymorphic markers. Eur J Hum Genet 13:660–668 Bonifati V, Rizzu P, van Baren M, Schaap O, Breedveld G, Krieger E, Dekker M, Squitieri F, Ibanez P, Joosse M, van Dongen J, Vanacore N, van Swieten J, Brice A, Meco G, van Duijin C, Oostra B, Heutink P (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299:256–259 Brooks MH, Bell NH, Love L, Stern PH, Orfei E, Queener SF, Hamstra AJ, DeLuca HF (1978) Vitamin-D-dependent rickets type II: resistance of target organs to 1,25 dihydroxyvitamin D. New Eng J Med 298:996–999 Bucheton B, Adel L, Kheir MM, Mirgani A, El-Safi SH, Chevillard C, Dessein A (2003a) Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region. Genes Immun 4:104–109 Bucheton N, Abel L, El-Safi S, Kheir MM, Pavek S, Lemainque A, Dessein AJ (2003b) A major susceptibility locus on chromosome 22q12 plays a critical role in the control of kala-azar. Am J Hum Genet 73:1052–1060 Campino S, Kwiatkowski D, Dessein A (2006) Mendelian and complex genetics of susceptibility and resistance to parasitic infections. Semin Immunol 18:411–422

20

Genetic Disorders in Sudan

605

Carmignac V, Salih MAM, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturq F et al (2007) C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 61:340–351 Cavalla-Sforza LL, Menozzi P, Piazza A (1994) The history and geography of human genes. Princeton University Press, Princeton, NJ Cazeneuve C, San C, Ibrahim SA, Mukhtar MM, Kheir MM, Leguern E, Brice A, Salih MA (2009) A new complex homozygous large rearrangement of the PINK 1 gene in a Sudanese family with early onset Parkinson’s disease. Neurogenetics 10:265–270 Chevilland C, Mackoko CE, Elwali NMA, Bream JH, Kouriba B, Argiro L, Rahoud S, Mergani A, Henri S, Gaudart J, Mohamed-Ali Q, Dessein AJ (2003) IFN-g polymorphisms (IFN-g + 2109 and IFN-g + 3810) are associated with severe hepatic fibrosis in human hepatic schistosomiasis (Schistosoma mansoni). J Immunol 171:5596–5601 Creasey A, Giha H, Hamad AA, El Hassan IM, Theander TG, Arnot DE (2004) Eleven years of malaria surveillance in a Sudanese village highlighted unexpected variation in individual disease susceptibility and outbreak severity. Parasitology 129:263–271 Dessein AJ, Hillaire D, Elwali NMA, Marquet S, Mohamed-Ali Q, Henri S, Abdelhameed AA, Saeed OK, Magzoub MMA, Abel L (1991) Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-g receptor gene. Am J Hum Genet 68:709–721 Dessein AJ, Marquet S, Henri S, El Wali NE, Hillaire D, Rodrigues V, Prata A, Ali QM, Gharib B, de Reggi M, Magzoub MM, Saeed OK, Abdelhameed AA, Abel L (1999) Infection and disease in human Schistosomiasis mansoni are under strict major gene control. Microbes Infect 1:561–567 Dliga Y, Chaabouni H, Largueche D, Bennaceur Z, Ferchiou A (1985) Le syndrome de Wolfram. A propos d’un cas tunisien. Ann Pediatr (Paris) 32:889–892 Doumi BA, Ahmed ME, Hassan R, El Nour SH, Kashan A (1994) Fractures in childhood in Khartoum. East Afr Med J 71:354–357 El Hassan AM, Godber MJ, Kopec AC, Mourant AE, Tills D, Lehmann H (1968) The hereditary blood factors of the Bija of the Sudan. Man 3:272–283 El Mouzan MI, Al Awamy BH, Al Torki MT (1990) Clinical features of sickle cell disease in eastern Saudi Arab children. Am J Pediatr Hematol Oncol 12:51–55 El Tay O, Saghayroun AAR, Mills R (1988) Population of Sudan: implications of current trends. In: Saghayroun AA, Farah A-AA, Ahmed SA, Kheir A-AHM (eds) Population and development in the Sudan: the quest for a national policy. JPA, Chapel Hill, pp 1–11 El Tayeb NS (2004) Incidence and patterns of congenital heart disease in Sudanese children with Down’s syndrome. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum El-Hazmi MAF, Jabbar FA, Al-Faleh FZ, Al-Swailem AR, Warsy AS (1987) The haematological, biochemical and clinical presentation of haemoglobin S in Saudi Arabia – (i) haematological and clinical expression. Trop Geogr Med 39:157–162 Ellaithi M, Gisselsson D, Nilsson T, Abd El-Fatah S, Ali T, Elagib A, Ibrahim ME, Fadl-Elmula I (2006a) A del (X) (p11) carrying SRY sequences in an infant with ambiguous genitalia. BMC Pediatr 6:11 Ellaithi M, Gisselsson D, Nilsson T, Elagib A, Fadl-Elmula I (2006b) Overview on the first human cytogenetic research in Sudan. Sudan J Med Sci 1:25–33 Ellaithi M, Gisselsson D, Nilsson T, Elagib A, Fadl-Elmula I, Abdelgadir M (2007) A case of Cornelia de Lange syndrome from Sudan. BMC Pediatr 7:6 Elshafie AI, Elghazali G, Ronnelid J, Venge P (2006) Cystatin C as a marker of immune complexassociated renal impairment in a Sudanese population with visceral leishmaniasis. Am J Trop Med Hyg 75:864–868 Elsheikh GEA (2004) Neural tube defects: pattern and incidence in Omdurman maternity hospital, Sudan. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Eltom M, El Mahdi EMA, Salih MAM, Mukhtar E, Omer MIA (1985) A new focus of endemic goitre in the Sudan. Trop Geogr Med 37:15–21

606

M.A.M. Salih

Eltom M, Hofvander Y, Torelm I, Fellstrom B (1984) Endemic goitre in the Darfur region (Sudan): epidemiology and aetiology. Acta Med Scand 215:467–475 Enattah NS, Jensen TGK, Nielsen M, Lewinski R, Kuokkaaen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF et al (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82:57–72 Enattah NS, Sahi T, Savilahti E, Terivilliger JD, Peltonen L, Jarvela I (2002) Identification of a variant associated with adult-type hypolactasia. Nat Genet 30:233–237 Eriksson J, Reimert CM, Kabatereine NB, Kazibwe F, Ireri E, Kadzo H, Eltahir HB, Mohamed AO, Vennervald BJ, Venge P (2007) The 434 (G>C) polymorphism within the coding sequence of Eosinophil Cationic Protein (ECP) correlates with the natural course of Schistosoma mansoni infection. Int J Parasitol 37:1359–1366 El-Safi S, Kheir MM, Bucheton B, Argiro L, Abel L, Dereure J, Dedet JP, Dessein A (2006) Genes and environment in susceptibility to visceral leishmaniasis. C R Biol 329:863–870 Fadl-Elmula I, Kytola S, El Leithy M, Abdel-Hameed M, Mandahl N, Elagib A, Ibrahim M, Larsson C, Heim S (2002) Chromosomal aberrations in benign and malignant Bilharziaassociated bladder lesions analyzed by comparative genomic hybridization. BMC Cancer 2:5 Fine Jo-D, Bauer EA, Briggman RA, Carter DM, Eady RAJ, Esterly NB, Holbrook KA, Hurwitz S, Johnson L, Lin A, Pearson R, Sybert VP (1991) Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. J Am Acad Dermatol 24:119–135 Flatz G, Rotthauwe HW (1977) Lactose nutrition and natural selection. Lancet 2:76–77 Fortin A, Stevenson MM, Gros P (2002) Susceptibility to malaria as a complex tract: big pressure from a tiny creature. Hum Mol Genet 11:2469–2478 Foy H, Kondi A, Timms GL, Brass W, Bushra F (1954) The variability of sickle cell rates in the tribes of Kenya and southern Sudan. Br Med J 1:294–297 Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiri A, Udd B, Gautel M (2008) Interactions with titin myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies. J Cell Sci 121:1841–1851 Gilles HM, Fletcher KA, Hendrickse RG, Linder R, Reddy S, Allan N (1967) Gluocse-6-phosphate dehydrogenase deficiency, sickling, and malaria in African children in southwestern Nigeria. Lancet 1:138–140 Gindeel A (2005) A case of true hermaphroditism presenting at the age of thirteen. Sudan J Paediatr 7:161–166 Greenwood B, Mutabingwa T (2002) Malaria in 2002. Nature 415:670–672 Gryseels B, Palman K, Clerinx J, Kestens L (2006) Human schistosomiasis. Lancet 368:1106–1118 Hammer MF, Zegura SL (1996) The role of the Y chromosome in human evolutionary studies. Evol Anthropol 5:116–134 Hassan MM (1953) Chondro-osteodysplasia. Sudan Med J 1:23 Hassan MM (1956) Mongolism in the Sudan. Sudan Med J 1:50 Hassan MM (1958) Mongolism in a twin. Br Med J 5063:162 Hassan MM (1960) Sickle cell disease in Sudanese children. Gaz Egypt Paediatr Assoc 8:570–583 Hassan MM (1962) Mongolism in the Sudanese children. J Trop Pediatr 8:48–50 Hassan MM (1964) Phenylketonuria in a Sudanese family. J Pediatr (St Louis) 64:282–284 Hassan MM (1965a) Congenital diseases in Sudanese children. M.D. thesis, University of Khartoum, Khartoum Hassan MM (1966) Congenital retardation of growth in Sudanese children. Sudan Med J 4:174–180 Hassan MM (1970) Haemoglobinopathies in Sudanese children. Sudan Med J 8:160–167 Hassan MM (1971) Glucose-6-phosphate dehydrogenase deficiency in the Sudan. J Trop Med Hyg 74:187–188 Hassan MM (1977) Glucose-6-phosphate dehydrogenase deficiency in the Sudan. Sudan Med J 1:49–58

20

Genetic Disorders in Sudan

607

Hassan MM, Rabie F (1981) Inborn errors of metabolism of amino acids in Sudanese children. King Abdulaziz Med J 1:38–54 Hassan MM, Ziada MAR (1965) Thalassaemia major in the Sudan. Br Med J 1:295 Hassan YF (1965b) The Umayyad genealogy of the Funj. Sudan Notes Rec 46:27–32 Hasseb El, Rasoul SA (1998) Immunological and complement profile in Sudanese children with sickle cell disease. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Heller P, Best WR, Nelson RB, Becktel J (1979) Clinical implications of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency in hospitalized black male patients. N Engl J Med 300:1001 Hendy JG, Garofalo K, Bowden DK (1999) Hb Khartoum [beta 124 (H2) Pro ! Arg] in a Vietnamese female. Hemoglobin 23:291–293 Henri S, Chevillard C, Mergani A, Paris P, Gaudart J, Camilla C, Dessein H, Montero F, Elwali NE, Saeed OK, Magzoub M, Dessein AJ (2002a) Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease. J Immunol 169:929–936 Henri S, Stefani S, PArzy D, Eboumbou C, Dessein A, Chevillard C (2002b) Description of three new polymorphisms in the intronic and 30 UTR regions of the human interferon gamma gene. Genes Immun 3:1–4 Herrick JB (1910) Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anaemia. Arch Intern Med 6:517–521 Hidayatalla A (1970) Neurofibrosarcdoma and plexiform neuroma in a case of generalised neurofibromatosis. Sudan Med J 8:178–181 Holden C, Mace R (1997) Phylogenetic analysis of the evolution of lactose digestion in adults. Hum Biol 69:605–628 Howell JN, Schockenhoff T, Flatz G (1981) Population screening for the human adult lactase phenotypes with a multiple breath version of the breath hydrogen test. Hum Genet 57: 276–278 Hussein AA (1983) The mentally and neuroskeletal handicapped children as a medical and social problem in Sudan. M.P.C.H. (Clinical M.D., Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Ibrahim BA (1991) Study of the gallstones in sickle cell anaemia in Sudanese children. M.P.C.H. (Clinical M.D., Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Ibrahim ME, Lambson B, Yousef AO, Defalla NS, Alnaiem DA, Ismail A, Yousef H, Ghalib HW, Khalil AG, Kadaro A, Barker DC, El Hassan AM (1999) Kala-Azar in a high transmission focus: an ethnic and geographic dimension. Am J Trop Med Hyg 61:941–944 Ibrahim SA, Mustafa D (1967) Sickle-cell hemoglobin O disease in a Sudanese family. Br Med J 3:715–717 Ingram CJE, Elamin MF, Mulcare CA, Weale ME, Tarekegn A, Raga TO, Bekele E, Elamin FM, Thomas MG, Bradman N et al (2007) A novel polymorphism associated with lactose tolerance in Africa: multiple causes for lactose persistence? Hum Genet 120:779–788 Jeanpierre M, Carrie A, Picollo F, Leturcq F, Azibi K, De Toma C, Beldjord C, Merlini L, Voil T, Romero N et al (1996) From adhalinopathies to alpha-sarcoglyconopathies: an overview. Neuromuscul Disord 6:463–465 Kaine WN (1982) Sickle cell anaemia in children in eastern Nigeria. A detailed analysis of 210 cases. East Afr Med J 59:742–749 Kambal A (1968) Endemic goitre in the Sudan. Sudan Med J 6:74 Kambal A (1969) Endemic goitre in Dar-Fur province. M.Sc. Dissertation, University of Khartoum, Khartoum Kamel K, Chandy R, Mousa H, Yunis D (1980) Blood groups and types, haemoglobin variants, and G-6-PD deficiency among Abu Dhabians in the United Arab Emirates. Am J Phys Anthropol 52:481–484 Karrar O, Omer MIA, Ilahi M (1984) Fructosuria in a Sudanese family. Sudan J Paediatr 3:37–40

608

M.A.M. Salih

Karrar ZA, Al-Arabi KM, Adam KA, Elidrissy AT (1985) Cutis laxa, intrauterine growth retardation and bilateral dislocation of the hips: a report of four patients. Saudi Med J 6:561–565 Karrar ZA, Mabrouk AA (1991) Cutis laxa, growth retardation and hip dislocation in a Sudanese child. Ann Trop Paediatr 11:367–370 Kasili EG, Bwibo NO (1982) Hematological observations in Kenyan children with sickle cell anemia in the first decade of life. Am J Pediatr Hematol Oncol 4:182–186 Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutations in the Parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392:605–608 Krstic ZD, Smoljanic Z, Vukanic D, Varinac D, Janjic G (2000) True hermaproditism: 10 years’ experience. Pediatr Surg Int 16:580–583 Lauder IR, Ibrahim SA (1970) Sickling in south-west Kordofan. Sudan Med J 8:206–214 Lejeune J, Gauthier M, Turpin R (1959) Les chromosomes humains en culture de tissus. Acad Sci 248:602 Leutenegger A, Salih M, Ibanez P, Mukhtar M, Lesage S, Arabi A, Lohmann E, Durr A, Ahmed A, Brice A (2006) Juvenile-onset Parkinsonism as a result of the first mutation in the adenosine triphosphate orientation domain on PINK1. Arch Neurol 63:1257–1261 Luoni G, Verra F, Arca B, Sirima BS, Troye-Blomberg M, Coluzzi M, Kwiatkowiski D, Modiano D (2001) Antimalanial antibody levels and IL4 polymorphism in the Fulani of West Africa. Genes Immun 2:411–414 Luzzatto L (1979) Genetics of red cells and susceptibility to malaria. Blood 54:961–976 Luzzi GA, Merry AH, Newbold CI, Marsh K, Pasvol G, Weatherall DJ (1991) Surface antigen expression on Plasmodium falciparum-infected erythrocytes is modified in alpha and betathalassemia. J Exp Med 173:785–791 MacMichael HA (1967) A history of the Arabs in the Sudan. Frank Cass, London Malmos B, Koutras DA, Kostamis P, Kralios AC, Rigopoulos G, Zerefos N (1966) Endemic goitre in Greece: epidemiology and genetic studies. J Clin Endocrinol Metab 26:688–695 Masri MA, Abdel Seed NM, Fahal AH, Romano M, Barelle F, Hassan AM E, Ibrahim ME (2002) Minor role for BRCA2 (exon 11) and p53 (exon 5-9) among Sudanese breast cancer patients. Breast Cancer Res Treat 71:145–147 McInerney-Leo A, Hadley DW, Gwinn-Hardy K, Hardy J (2005) Genetic testing in Parkinson’s disease. Mov Disord 20:1–10 McKusick VA (1994) Mendelian inheritance in man, a catalog of human genes and genetic disorders, 11th edn. The John Hopkins University Press, Baltimore Mihaylova V, Salih MAM, Mukhtar MM, Abuzeid HA, El-Sadig SM, von der Hagen M, Huebner A, Nurnberg G, Abicht A, Muller JS, Lochmuller H, Guergueltcheva V (2009) Refinement of the clinical phenotype in MUSK-related congenital myasthenic syndromes. Neurology 73:1926–1928 Miller EN, Fadl M, Mohamed HS, Elzein A, Jamieson SE, Cordell HJ, Peacock CS, Fakiola M, Raju M, Khalil EA, et al (2007) Y chromosome lineage-and-village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan. PLoS Genet 3 (5): e71 doi: 10.1371/journal.pgen.0030071 Mohamed AO (1993) Sickle cell disease in the Sudan: clinical and biochemical aspects. Acta Univ Uppsaliensis 391:1–47 Mohamed AO, Attala B, Bashir FM, Ahmed FE, El Hassan AM, Ibnauf G, Jiang W, CavalliSforza LL, Karrar ZA, Ibrahim ME (2006) Relationship of the sickle cell gene to the ethnic and geographic groups populating the Sudan. Community Genet 9:113–120 Mohamed AO, Bayoumi RA, Hofvander Y, Omer MI, Ronquist G (1992a) Sickle cell disease in the Sudan: clinical findings, haematological and serum variables. Ann Trop Paediatr 12:131–136 Mohamed AO, Hashim MS, Nilsson UR, Venge P (1993a) Increase in vivo activation of neutrophils and complement in sickle cell disease. Am J Trop Med Hyg 49(6):799–803

20

Genetic Disorders in Sudan

609

Mohamed AO, Jansen A, Ronquist G (1993b) Increased activity of 50 nucleotidase in serum of patients with sickle cell anaemia. Scand J Clin Lab Invest 53(7):701–704 Mohamed AO, Nilsson UR, Omer MIA, Ronquist G (1992b) Lack of evidence for altered complement and immunoglobulin levels in patients with sickle cell anaemia. Scand J Clin Lab Invest 52:313–316 Mohamed AO, Ronquist G (1991) Reduction in band 3 protein of red cells in sickle cell anaemia. Uppsala J Med Sci 96:23–33 Mohamed AO, Ronquist G, Bayoumi RA (1992c) Increased membrane activity of glyceraldehydes 3-phosphate dehydrogenase in erythrocytes of patients with homozygous sickle cell anaemia. Clin Chim Acta 209:189–195 Mohamed HS, Ibrahim ME, Miller EN, Peacock CS, Khalid EA, Cordell HJ, Howson JM, El Hassan AM, Bereir RE, Blackwell JM (2003) Genetic susceptibility to visceral leishmaniasis in The Sudan: linkage and association with IL4 and IFNGRI. Genes Immun 4:351–355 Mohamed HS, Ibrahim ME, Miller EN, White JK, Cordell HJ, Howson JMM, Peacock CS, Khalil EAG, el Hassan AM, Blackwell JM (2004) SLC11A1 (formerly NRAMP1) and susceptibility to visceral leishmaniasis in The Sudan. Eur J Hum Genet 12:66–74 Mohamed IN (2004) Pattern of bleeding disorders in children in Khartoum. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Mohamed-Ali Q, Elwali NE, Abdelhameed AA, Mergani A, Rahoud S, Elagib KE, Saeed OK, Abel L, Magzoub MM, Dessein AJ (1999) Susceptibility to periportal (Symmers) fibrosis in human Schistosoma mansoni infections: evidence that intensity and duration of infection, gender, and inherited factors are critical in disease progression. J Infect Dis 180:1298–1306 Molineaux L, Fleming AF, Cornille-Brogger R, Kagan I (1979) Abnormal hemoglobins in the Sudan savanna of Nigeria: malaria immunoglobulins and anti-malarial antibodies in sickle cell disease. Ann Trop Med Parasitol 73:301–310 Mukhtar E (1974) Congenital dyshormogenesis as a possible aetiological factor in the development of some cases of goitre in the Sudan. Sudan Med J 1:16 Muller JS, Mihaylova V, Abicht A, Lochmuller H (2007) Congenital myasthenic syndromes: spotlight on genetic defects of neuromuscular transmission. Exp Rev Mol Med 9:1–20 Mustafa MI (1988) Iron deficiency in Sudanese children with sickle cell anaemia: a hospital based study. M.P.C.H. (Clinical M.D., Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Mutwakel M (2005) Neonatal screening for inborn errors of metabolism, a new experience with tandem mass spectrometry. Sudan J Paediatr 7:107–125 Nagel RL, Fleming AF (1992) Genetic epidemiology of the Bs gene. Bailierres Clin Haematol 5:331–365 Nagel RL, Krishnamoorthy R, Fattoum S, Elian J, Genard N, Romero J, Fabry ME (1999) The erythrocyte effect of haemoglobin OARAB. Br J Haematol 107:516–521 Nagi NA (1979) Diabetes insipidus, diabetes mellitus, optic atrophy and deafness: a clinical and genetic study. Postgrad Med J 55:377–380 Najjar SS, Saikaly MG, Zaytoun GM, Abdelnoor A (1985) Association of diabetes insipidus, diabetes mellitus, optic atrophy and deafness. The Wolfram or DIDMOAD syndrome. Arch Dis Child 60:823–828 Nakano A, Lestringant GG, Paperna T, Bergman R, Gershoni R, Frossard P, Kanaan M, Meneguzzi G, Richard G, Pfender E, Uitto J, Pulkkinen L, Sprecher E (2002) Junctional Epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol 46:510–516 Nasr A, Iriemenam NC, Troye-Blomberg M, Giha HA, Balogun HA, Osman OF, Montgomery SM (2007) Fc gamma receptor IIa (CD 32) polymorphism and antibody responses to asexual blood-stage antigens of falciparum malaria in Sudanese patients. Scan J Immunol 66:87–96 Noguchi CT, Rodgers GP, Serjeant G, Schechter AN (1988) Levels of fetal haemoglobin necessary for treatment of sickle cell disease. N Engl J Med 2:96–99 Nugud A, Arbab M, Osman TM (2003) Pattern of neural tube fusion defects in Sudan. Saudi Med J 24:554

610

M.A.M. Salih

Nyhan WL, Sakati NA (1987) Diagnostic recognition of genetic disease. Lea and Febiger, PA Ojwang PJ, Ogada T, Beris P (1987) Haplotypes and b-globin gene analyses in sickle cell anaemia patients from Kenya. Br J Haematol 65:211–215 Omer A, Ali M, Omer AHS, Mustafa MD, Satir AA, Samuel AP (1972) Incidence of G6PD deficiency and abnormal haemoglobins in the indigenous and immigrant tribes of the Sudan. Trop Geogr Med 24:401–405 Omer AH, Hamilton PJ, Marshall TF, Draper CC (1979) Infection with Schistosoma mansoni in the Gezira area of the Sudan. J Trop Med Hyg 79:151–157 Omer AHS (1978) Species prevalence of malaria in northern and southern Sudan and control by mass chemoprophylaxis. Am J Trop Med Hyg 27:858–863 Omer IM (1994) A study of physical growth and school performance in sickle cell anaemia in Sudanese children. Clinical M.D. (Paediatrics and Child health) thesis, University if Khartoum, Khartoum Omer MIA (1977) Neonatal problems in Khartoum. Sudan J Paediatr 1(2):1–9 Omer MIA, El Sheikh OK (1977) Fanconi syndrome: a case report. Sudan J Paediatr 1:36–43 Osman NSE (2003) Clinical indicators of severity of sickle cell anaemia in children in Khartoum. Dissertation, Clinical M.D. (Paediatrics and Child Health), University of Khartoum Osman SA (1996) Thyroid disorders in children presenting to Khartoum hospitals. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Ozawa E, Noguchi S, Mizuno Y, Hagiwara Y, Yoshida M (1998) From dystropphinopathy to sarcoglycanopathy: evolution of a concept of muscular dystrophy. Muscle Nerve 21:421–438 Pernigo S, Fukuzawa A, Bertz M, Holt M, Reif M, Steiner RA, Gautel M (2010) Structural insight into M-band assembly and mechanics from the titin-obscurin-like-1 complex. Proc Natl Acad Sci USA 107:2908–2913 Playfair JHL (1982) Immunity to malaria. Br Med Bull 38:153–159 Roberts DF, Lehmann H (1955) A search for normal haemoglobins in some southern Sudanese people. Br Med J 1:519–521 Roper C, Elhassan IM, Hviid L, Giha H, Richardson W, Babiker H, Satti GMH, Theander TG, Arnot DE (1996) Detection of very low level Plasmodium falciparum infections using the nested polymerase chain reaction and re-assessment of the epidemiology of unstable malaria in Sudan. Am J Trop Med Hyg 54:325–331 Rosen JF, Fleischmann AR, Finberg L, Hamstra A, De Luca HF (1979) Rickets with alopecia: an inborn error of vitamin D metabolism. J Pediatr 94:729 Saadallah AA, Rashed MS (2007) Newborn screening: experience in the Middle East and North Africa. J Inherit Metab Dis 30:482–489 Saeed OK, Elwali NMA, Dessein AJ, Adeel AA, Magzoub MMA, El Samani KE, Yousif YM, Qurashi MA (2006) Schistosoma mansoni associated morbidity in Gezira: determined by clinical and ultrasound examination. SJPH 1:27–30 Saha N, El Sheikh FS (1987) Some blood genetic characteristics of several Sudanese tribes. Am J Phys Anthropol 73:397–406 Saha N, Samuel APW, Omer A, Hoffbrand AV (1983) The inter and intra-tribal distribution of red cell G6PDphenotypes in Sudan. Hum Hered 33:39–43 Salam M (1963) Phenylketonuria in a child form the Middle East. Am J Dis Child 105:102 Salih MA, Al Rayess M, Cutshall S, Urtizberea JA, Al-Turaiki MH, Ozo CO, Straub V, Akbar M, Abid M, Andeejani A et al (1998) A novel form of familial congenital muscular dystrophy in two adolescents. Neuropediatrics 29:289–293 Salih MAM (1980) Unusual muscular dystrophy in an extended Sudanese kindred. M.P.C.H. (Clinical M.D., Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Salih MAM (1982) Unusual muscular dystrophy in an extended Sudanese kindred. M.D. thesis, University of Khartoum, Khartoum Salih MAM (1990) Childhood Acute Bacterial Meningitis in the Sudan: An epidemiological, clinical and laboratory study. Scand J Infect Dis (Suppl 66):1–103

20

Genetic Disorders in Sudan

611

Salih MAM (1985) Childhood muscular dystrophy: an African review. Ann Trop Pediatr 5:167–173 Salih MAM, Urtizberea JA, Leturq F, Mukhtar M, Anderson L, Bushby K (2007) Molecular characterization and clinical update on open of the earliest described families with severe childhood autosomal recessive muscular dystrophy (SCARMD). Neuromuscul Disord 9:113–120 [Abstract] Salih MAM, Bender DA, McCreanor GM (1985a) Lethal familial pellagra-like skin lesion associated with neurologic and developmental impairment and the development of cataracts. Pediatrics 76:787–793 Salih MAM, Hashem N (1978) Pendrred’s syndrome in a Sudanese family. Sudan J Paediatr 2:25–34 Salih MA, Ibrahim ME, Blackwell JM, Khalil MEN, EA ElHassan AM, Musa AM, Mohamed HS (2007) IFNG ang IFNGR1 gene polymorphisms and susceptibility to post-kala-azar dermal leishmaniasis in Sudan. Genes Immun 8:75–78 Salih MAM, Lake BD, El Haq MA, Atherton DJ (1985b) Lethal epidermolytic epidermolysis bullosa: a new autosomal recessive type of epidermolysis bullosa. Br J Dermatol 113:135–143 Salih MAM, Omer MIA, Bayoumi RA, Karrar O, Johnson M (1983) Severe autosomal recessive muscular dystrophy in an extended Sudanese kindred. Dev Med Child Neurol 25:43–52 Salih MAM, Tuvemo T (1991) Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD syndrome). Acta Paediatr Scand 80:567–572 Samuel APW, Saha N, Acquaye JK, Omer A, Ganeshaguru K, Hassounh E (1986) Association of red cell glucose-6-phosphate dehydrogenase with haemoglobinopathies. Hum Hered 36:107–112 Shummo HAM (1996) Malaria and bacterial infections in children with sickle cell anaemia. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum Somech R, Amariglio N, Spirer Z, Rechavi G (2003) Genetic predisposition to infectious pathogens: a review of less familiar variants. Pediatr Infect Dis J 5:457–461 Subahi SA (2001) Distinguishing cardiac features of a novel form of congenital muscular dystrophy (Salih cmd). Pediatr Cardiol 22:297–301 Theander TG, Hviid L, Abu-Zeid YA (1990) Reduced cellular immune reactivity in health individuals during the malaria transmission season. Immunol Lett 25:237–242 Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M et al (2007) Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39:31–40 Townsend-Coles WF (1954) A report of seven cases of chondro-osteo-dystrophy (Morquio’s disease). Arch Dis Child 29:7 Underhill PA, Shen P, Lin AA, Jin L, Passarino G, Yang WH, Kauffman E, Bonne-Tamir B, Bertranpetit J, Francalacci P et al (2000) Y chromosome sequence variation and the history of human populations. Nat Genet 26:358–361 Valente E, Abou-Sleiman P, Caputo V, Muqit M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A, Healy D, Albanese A, Nussbaum R, Gonzales-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W, Latchman D, Harvey R, Dallapicolla B, Auburger G, Wood N (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160 Vella F (1964) Sickling in the Western Sudan. Sudan Med J 1:16–17 Vella F, Hassan MM (1961) Thalasaemia major in a Sudanese Arab family. J Trop Med Hyg 64:199–201 Vella F, Ibrahim SA (1962) Erythrocyte glucose-6-phosphate dehydrogenase deficiency in Khartoum. Sudan Med J 1:136–137 Vella F, Verzin JA (1963) Fast foetal haemoglobin in Khartoum. East Afr Med J 40:9–10 Vella I, Vella F, Hassan MM (1961) Thalassaemia major in a Sudanese Arab family. J Trop Med Hyg 64:199–201

612

M.A.M. Salih

White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K (1986) Red cell genetic abnormalities in Peninsular Arabs: sickle haemoglobin, G6PD deficiency, and b and b thalassaemia. J Med Genet 23:245–251 Wickens GE (1970) A brief note on the early history of Jebel Marra and the recently discovered Tora city of Kebeleh. Sudan Notes Rec 51:147–151 Winter RM, Baraister M (1991) Multiple congenital anomalies: a diagnostic compendum. Chapman and Hall Medical, London, p 545 Yahia SMS (2001) The pattern of mental retardation in institutionalized children in Khartoum State. Clinical M.D. (Paediatrics and Child Health) thesis, University of Khartoum, Khartoum Zimmerman SA, O’Branski EE, Rosse WF, Ware RE (1999) Hemoglobin S/OARAB: thirteen new cases and review of the literature. Am J Hematol 60:279–284

Chapter 21

Genetic Disorders in Tunisia Elham Hassen and Lotfi Chouchane

The Tunisian contribution to medicine and genetics was continuum through the various civilizations. In Carthage, on the famous hill Byrsa stood the monumental temple of Eshmun, God of Medicine and Health and a leading figure of the Punic pantheon. Bottles and prophylactic Carthaginian masks, medical devices and surgical and Roman remains, of the “Antonin” Baths at Carthage, attest to this day the large share which was then granted the necessary conservation of bodily health and the spirit. The recent history of medicine in Tunisia is marked by the great achievement of Charles Nicolle, director of the Pasteur Institute of Tunis from 1903 to his death in 1936, who received the Nobel Prize in 1928 for his demonstration of the louse as the vector for typhus. “Modern” Tunisia is one of the countries of the Arab world that developed genetic services, early. Genetic disorders are common in Tunisia. Some conditions have been known for a long time to be familial, including hemoglobinopathies and neuromuscular disorders. The high incidence of genetic diseases is favored by the high rate of consanguineous marriages. Large and consanguineous families contributed to the description of a number of new autosomal recessive conditions and to identify the causing genes. Homozygotes for the same mutation are frequent even in the case of rare diseases in these highly endogamous families. Investigations conducted on genetic diseases in Tunisians are numerous, including those assessing the implications of genetic diseases on the healthcare system. Several molecular studies allowed for the identification of the genes underlying genetic defects. The first use of homozygosity mapping by studying three Tunisian consanguineous families has led to the localization of Friedreich

L. Chouchane (*) Professor of Genetic Medicine and Immunology, Genetic Medicine Department, Weill Cornell Medical College, Qatar e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_21, # Springer-Verlag Berlin Heidelberg 2010

613

614

E. Hassen and L. Chouchane

ataxia phenotype with selective vitamin E deficiency to chromosome 8q (Ben Hamida et al. 1993). Genetic counseling and prenatal diagnosis are well established, but more efforts are needed to strengthen genetic medicine in Tunisia.

The Geography and Ethnography of Tunisia Tunisia is a Muslim Arab country located on the North-African Mediterranean coast. It is bordered by Algeria to the west, Libya to the southeast and the Mediterranean Sea along its northern and eastern sides (Fig. 21.1.). With, a surface of 162.155 km2, Tunisia is the smallest country of the North African countries. In 2009, Tunisia’s population was estimated to be just over 10.3 millions, 64% are between 15 and 59 years old and only 26.2% are under 14. Sixty-five percent of the Tunisian population is urban and approximately 76% of Tunisians live in littoral areas. The current population growth rate is about 1%, seems to be the lowest rate among Arab countries. On an average, two children are born for every woman in Tunisia. This relative low rate is the consequences of several social, legislative and economic factors. Since 1964 the legal age of marriage was fixed at 17 for women and 20 for men and conversely to all other Arab countries polygamy was prohibited in Tunisia. Then since 1966, Tunisia adopted family planning measures in order to reduce fertility and slow population growth. Moreover, the Tunisian legislation authorized both contraception and, since 1973, abortions for families that already have four or more children. Recently, the age of first pregnancy has risen to 28 years. The official religion in Tunisia is Islam however minorities of Christians (1%) and Jews (< 1%) are found as well. Literary Arabic is the official language, but Tunisians speak a Tunisian dialect and a small population of Berbers (1%) speaks another dialect called “Shelha.” Among Tunisians French is commonly spoken and English is the second foreign language. Due to its long coastline and its geographical location, Tunisia is at the crossroads of Europe, the Middle East and Africa. This strategical location allows meeting, crossing and interaction of the different Mediterranean civilizations along several centuries. Since about 8,000 years ago native Berbers have been the major population group in all the North African regions. After the Berbers and until the last century several invading and colonizing episodes have built Tunisia’s history. In the tenth century BC coming from what is now Lebanon the Phoenicians established the Tunisian land. Until the second and the third century BC, the Phoenicians were amongst the greatest traders and the most prosperous of the Mediterranean pond. Then, throughout three important wars Romans conquered Tunisia, which was completely, Latinized and Christianized. When the Roman Empire fell, several European tribes including the Spanish Vandals invaded Tunisia.

21

Genetic Disorders in Tunisia

Fig. 21.1 Map of modern Tunisia

615

616

E. Hassen and L. Chouchane

After the Vandals conquest the Byzantines came from Constantinople (now Istanbul) and took Tunisia as a province. In the seventh century bringing Islam with them the Arabs arrived from the east and ruled Tunisia until the sixteenth century. In the sixteenth century, Tunisia was brought under the rule of the Ottoman Empire. In 1881, France imposed its protectorate and colonization until 1956 when Tunisia gained independence and the Republic of Tunisia was born.

Genetic Services Genetic services in Tunisia do not cover all parts of the country. The three main centers dedicated to genetic counseling are located on the three major cities of Tunisia: Tunis, Sousse and Sfax. The mandatory premarital medical investigation, implemented in 1964, included only communicable diseases. In 1986, it was extended to cover genetic counseling. Premarital genetic counseling is mandatory for all couples with a history of genetic conditions. Cytogenetic and molecular diagnoses are performed both at the postnatal and prenatal stage. Ultrasound fetal scanning is routinely performed for pregnant women. Chorionic villous sampling and amniocentesis procedures are commonly performed. All sophisticated cytogenetic and DNA analyses are available in the Tunisian laboratories.

Consanguinity The Tunisian population shows a high level of endogamy, but isolates are rare. Consanguineous marriages are prevalent. Despite women’s emancipation and their active role in the Tunisian society, social and economic factors still play significant roles in favoring consanguineous marriages among the new generations. Consanguinity rates studied in North Tunisia, including Tunis, and evaluated for two thirds of the population for marriages contracted between the years 1983 and 1985 (Riou et al. 1989) revealed a rate of 32%, with 23% for the first-cousin marriages. Mean coefficient of inbreeding is 8.76 103 in the North-West regions and 21.34 103 in the central regions (Chalbi and Zakaria 1998). More recently, Kerkeni et al. (2007) showed the consanguinity prevalence of 24.81% in 1,016 students (offspring of second cousins or closer). This rate is lower than rates reported in most Arab countries, 54% in the state of Qatar (Bener and Hussain 2006); 52% in Saudi Arabia (Al-Abdulkareem and Ballal 1998); 50.5% in the United Arab Emirates (Al-Gazali et al. 1997); 25.6% in Jordan (Hamamy et al. 2005); and 25% in Lebanon (Khlat 1988). As a consequence of this elevated rates neonatal, postneonatal, and children mortality were more frequent in the offspring of consanguineous than in nonconsanguineous spouses.

21

Genetic Disorders in Tunisia

617

Genetic and Congenital Disorders Red Cell Genetic Disorders b-Thalassemia (OMIM 141900) In Tunisia, the average prevalence of b-thalassemia carriers was estimated at 2.21% (Fattoum 2006). Several studies aimed to determine the mutational spectrum causing b-thalassemia (Chibani et al. 1988; Fattoum et al. 1991; Chouk et al. 2004). They showed that stop codon 39 (C>T) and IVS-I-110 (G>A) mutations are the most common b-thalassemia defects in Tunisia (about 36 and 14%, respectively). The codon 39 allele could have been introduced in Tunisia during the Roman occupation and the IVS-I-110 mutation might have been introduced by the Turkish and Phoenician influence (Chouk et al. 2004). Other less frequent mutations were detected: IVS-I-2 (T>G), codon 6 (–A), IVS-I-6 (T>C), codon 44 (–C), IVS-II-745 (C>G), codon 30 (G>C), 30 (T>G), IVS-I-5 (G>A), codon 5 (–CT), IVS-I-1 (G>A), IVS-II-848 (C>A), IVS-I-2 (T>C), codons 25/26 (þT), codon 8 (–AA), IVS-I-1 (G>T), codon 37 (G>A), and IVS-II-849 (A>C). When the mutation frequencies from the different Tunisian regions were compared the distribution of b-thalassemia alleles differs significantly within each area, Northern Tunisia displays the greatest heterogeneity (Haj Khelil et al. 2004).

a-Thalassemia (OMIM 141800) Compared to the other haemoglobinopathies, a-thalassemia research studies was limited in Tunisia. Hemoglobin screening on newborns has shown a frequency of a-thalassemia trait of 5.48% (Fattoum 2006). Through a screening study conducted on 304 cord blood samples, Zorai et al. (2002) found that the -alpha3.7 deletion was the most common defect (4.5% allele frequency) followed by a polyadenylation (poly A) signal mutation (1.8%), the five nucleotide deletion and the -alpha4.2 deletion (both 0.9%), and no alpha0-thalassemia alleles were found.

Sickle Cell Disease (OMIM 603903) Average frequency of sickle cell disease carriers in Tunisia is 1.89% (Fattoum 2006). The severity pattern of the disease ranges from moderate to severe. This pattern is similar to that of the African type. Ninety-five percent of patients with sickle disease were homozygous for the Benin haplotype (Fattoum et al. 1991).

618

E. Hassen and L. Chouchane

Glucose-6-Phosphate Dehydrogenase (OMIM 305900) Blibech et al. (1989) performed a screening study for glucose-6-phosphate dehydrogenase (G6PD) deficiency on male students originating from several towns in Tunisia. In this study the incidence of the G6PD deficiency was of 1.84%. Blibech et al. (1989) study also showed a marked predominance of the Bþ type (96.2%) compared with the A þ type (1.96%). In a recent study, Daoud et al. (2008) aimed at identifying G6PD mutations in 41 deficient unrelated Tunisian subjects. The most prevalent variant was the G6PD African variant A, which account for 63.63% as allelic frequency. This variant was responsible for severe phenotype leading to haemolytic anemia due to ingestion of fava beans. The presence of this variant in Tunisian population is not surprising since Tunisia is in majority consisting of Africans coming from neighboring regions. The second most prevalent variant is the Mediterranean variant, which was found with an allelic frequency of 11.36%. The third variant detected was the G6PD Aure`s mutation. This mutation was described originally in Algeria (Nafa et al. 1993) and then with less frequency in Saudi Arabia (Niazi et al. 1996) and UAE (Bayoumi et al. 1996). SSCP analysis of mild deficient males, revealed the presence of the association of 1311 CT/93 TC, a newly described silent mutation in the exon 12 associated with the polymorphism in the intron 11 93 TC and tow single intronic base deletion (the first is IVS V 17 (-C) and the second is IVS VIII 43 (-G)) (Daoud et al. 2008). Fanconi Anemia (OMIM 227650) Fanconi anemia (FA) is a rare autosomal recessive and heterogeneous disease with at least eight complementation groups (A–H). In Tunisia a relatively high incidence of FA is observed: 1.4/million/year (Bouchlaka et al. 2003). In order to identify to which complementation group Tunisian patients belong, Bouchlaka et al. (2003), analyzed gene mutations in 39 unrelated families from different regions in Tunisia. Thirty-four families were assigned to the FAA group (94%), whereas one family was probably not linked to FANCA gene or to any known FA gene. For the patients who are assigned to the FAA group, Bouchlaka et al. (2003), identified two homozygous deletions 1693delT and 1751–1754del, which occurred in exon 17 and exon 19, respectively, and two transitions 513G > A in exon 5 and A > G at position 166 (IVS24 + 166A > G) of intron 24. Two new polymorphisms IVS24 – 5G/A, and IVS24–6C/G were also identified in intron 24.

Chromosomal Disorders Down Syndrome (OMIM 190685) To reduce Down syndrome incidence a screening strategy has been established in Tunisia. In a recent retrospective study of a 4-year period, Chelli et al. (2008) found a total prevalence of the Down syndrome of 0.98%. Sixty percent of the cases were

21

Genetic Disorders in Tunisia

619

diagnosed at a prenatal stage and the median gestational age at diagnosis was 21 weeks. In Tunisia legal and religious authorities permit pregnancy termination. After, medical approval parents have the possibility to choose to terminate pregnancy. In Tunisia more than 90% accept termination of pregnancy. (Chaabouni et al. 2001; Chelli et al. 2008).

Turner Syndrome A retrospective analysis of 89 cases of the Turner Syndrome observed during a 6-year period, was performed (Kammoun et al. 2008). Karyotyping was achieved when stature retardation or dysmorphic features or reproduction anomalies were observed. Mosaicism was found in 47%, homogeneous karyotype 45,X was found in 32% and structural anomalies were found in 21%. In the same study a relationship between chromosome anomalies and the clinical expression of Turner Syndrome was established. Total deletion of one chromosome X or imbalanced gene dosage due to structural X anomalies was correlated with short stature and primary amenorrhea. Cases of infertility, recurrent miscarriages and secondary amenorrhea were associated with a mosaic karyotype pattern (45,X/46,XX or 45,X/46,XX/47, XXX ...), with a slight mosaicism in most cases.

Klinefelter’s Syndrome Klinefelter syndrome, also known as the 47, XXY syndrome, is a syndrome where males have an extra X chromosome in most of their cells. A retrospective study was carried out on infertile Tunisian men to determine the prevalence of sex chromosome abnormalities (Abdelmoula et al. 2004). Cytogenetic analysis were performed and among 14 chromosomal abnormalities found, nine were compatible with Klinefelter’s syndrome. Six Klinefelter’s patients showed a nonmosaic 47, XXY and three showed a 47, XXY/46, XY mosaic.

Neuromuscular and Neurodegenerative Disorders Muscular Dystrophies Muscular dystrophies (MDs) constitute a clinically and genetically heterogeneous group of inherited autosomal recessive myopathies. Among Tunisians mutations in the fukutin-related protein gene (FKRP) gene were associated with structural and neurological abnormalities in a subset of patients with a severe congenital form classified as MDC1C (OMIM 606612) (Louhichi et al. 2004). Two homozygous missense FKRP mutations associated with MDC1C and mental retardation were reported in a series of six unrelated Tunisian families (A455D) and in an Algerian patient (V405L) (Louhichi et al. 2004). Moreover, among the Tunisian families a

620

E. Hassen and L. Chouchane

microsatellite close to the FKRP gene was identified, allowing authors to confirm the founder origin of the Tunisian A455D mutation. Mutations in the LAMA2 gene may provoke a primary deficiency in the laminin a2 chain (merosin) resulting in another MD, the MDC1A type (OMIM 607855). Louhichi et al. (2006), identified among two Tunisian consanguineous families with severe MDC1A two homozygous mutations (c.8007del T and c.8244 þ 1G > A) in the LAMA2 gene. An autosomal form of Duchenne-like dystrophy was first described in large Tunisian families (Ben Hamida et al. 1983), affecting both males and females. Later on, this genetic disorder was assigned to chromosome 13q12 (Ben Othmane et al. 1992) and further classified under limb girdle MD type 2 C (OMIM 253700). Mutations in SGCG gene are associated with LMGD2C. A del521T homozygous mutation in exon 6 of the SGCG gene was widely distributed in Tunisian patients (Kefi et al. 2003). Using identified mutations in LAMA2 and SGCG genes among Tunisian families with MDC1A and LGMD2C respectively, Siala et al. (2008) carried out for the first time a molecular prenatal diagnosis and a postnatal follow up. This study included consanguineous families, two affected with MDC1A and one affected with LGMD phenotype. The prenatal diagnosis was successful; however, the postnatal follow up showed a phenotypic intrafamilial variability in two patients with MDC1A form sharing the same mutation in LAMA2 gene.

Spinal Muscular Atrophy (OMIM 253300) Spinal muscular atrophy (SMA) refers to another group of autosomal recessive neuromuscular disorders, which is estimated to be a common disease in Tunisia (Chaabouni-Bouhamed 2008). Spinal muscular atrophy type I (SMA I) is caused by mutation or deletion in the telomeric copy of the SMN gene, known as SMN1. Mrad et al. (2006) examined the deletion of SMN1 and NAIP genes in 60 Tunisian families with the four types of SMA. They showed that exons 7 and 8 of the SMN1 gene were homozygously deleted in 95 and 88%, respectively, while exon 5 of the NAIP gene was homozygously deleted in 58% (77% in ASM I, 27.7% ASM II and 50% in ASM III), with higher deletion prevalence in the more severe SMA cases.

Congenital Myasthenic Syndrome Associated with Acetylcholine Receptor Deficiency (OMIM 608931) Twenty-three families with an early onset form of congenital myasthenic syndrome (CMS) from North African origins (Tunisia, Algeria, Morocco and Libya) were screened for the epsilon1293insG mutation (Richard et al. 2008). The epsilon1293insG mutation was identified in 14 families. Among the later, nine were from Algeria, three from Tunisia, one from Morocco and one from Libya. All these 14 families were consanguineous and included 27 patients who were homozygous

21

Genetic Disorders in Tunisia

621

for the epsilon1293insG mutation. Epsilon1293insG was previously detected in patients originating from the Maghreb including Mauritania, Morocco, Algeria, Tunisia and Libya. Moreover, this mutation has never been reported in the homozygous state in CMS patients of nonMediterranean origin. Thus, in the Richard et al. (2008) study authors suggested that epsilon1293insG is derived from an ancient single founder event in the North African population. The age of the founder event was estimated at approximately 700 years.

Parkinson Disease (OMIM 168600) Parkinson disease (PD) is a complex multifactorial neurodegenerative disease with substantial evidence for genetic risk factors. In the familial cases mutation in at least one of the following genes has been implicated in the PD development: LRRK2 (Leucine-Rich Repeat Kinase 2), PARK2, PARK7, PINK1 (PTENInduced Putative Kinase 1), or SNCA (Synuclein, Alpha). Through a prospective study Gouider-Khouja et al. (2000) described the clinical and genetic characteristics of 88 affected subjects belonging to 21 Tunisian families. A clinically similar feature between familial and sporadic PD cases, apart from younger age at onset, was observed. Moreover, in Tunisia familial PD is genetically heterogenous with an autosomal recessive and autosomal dominant form. The most frequent mutation associated with PD is the Lrrk2 p.G2019S. This mutation was present in 42% of Tunisian families and 2% of US families (Warren et al. 2008). In a recent study Nishioka et al. (2010) compared clinical features of patients with familial PD of unknown etiology and those carrying LRRK2 or PINK1 pathogenic mutations in a Tunisian population with high prevalence of Lrrk2 p.G2019S (32%) and PINK1 (18%) mutation carriers. Clinical data analysis showed that despite similar ages, ages at onset and disease duration, Tunisian patients harboring Lrrk2 p.G2019S have a more severe motor phenotype, a higher rate of dyskinesia and use of dopamine agonists, and less postural tremor than mutation-negative patients. LRRK2 mutation carriers appear to have the most severe clinical phenotype while PINK1 carriers have a longer disease course and the lowest incidence of tremor as initial symptom. LRRK2 and PINK1 carriers have an increased prevalence of resting tremor and dyskinesia compared to those not genetically defined.

Alzheimer Disease (OMIM 104300) In Tunisia, Alzheimer Disease (AD) affects nearly 25,000 people. AD is an irreversible, progressive brain disease. Both, the two AD types, early onset and late-onset forms, have genetic links. Early onset type is a rare form of AD mainly composed of familial cases. Most cases of AD are of the late-onset form. One predisposing genetic risk factor does appear to increase the risk of developing AD, the apolipoprotein E (APOE) gene found on chromosome 19. Smach et al. (2008) conducted a

622

E. Hassen and L. Chouchane

case-control study on 93 AD patients from the central region of Tunisia to study whether genetic polymorphism in ApoE gene is a risk factor for AD Tunisians patients. The ApoE epsilon4 allele increased the risk for AD; odds ratios for heterozygous and homozygous subjects were 3.29 and 9.47, respectively. The same observation was found for French, Italian and Iranian AD patients (Raygani et al. 2005; Piscopo et al. 2006).

Genetic Endocrine Disorders Congenital Adrenal Hyperplasia (OMIM 201910) Approximately 95% of cases of congenital adrenal hyperplasia (CAH) are due to defects in the steroid 21-hydroxylase (CYP21) gene. The mutational spectrum in the Tunisian CAH population was established by Kharrat et al. (2004). The CYP21 gene was analyzed in 51 unrelated patients; at least 31 of them were from consanguineous families. In this study, mutations were detected in over 94% of the chromosomes. The most frequent defect in CYP21 gene was found with a prevalence of 35.3% to be the Q318X mutation in exon 8, followed by large deletions (19.6%), a splice site mutation in intron 2 (17.6%) and I172N mutation in exon 4 (10.8%). Furthermore, novel mutations were detected including R483W, W19X, 2669insC and one small conversion of DNA sequence from exon 5 to exon 8. Investigators also showed a good genotype/phenotype correlation in the case of most mutations. A fifth small 13-bp deletion in exon 1 was found in the CYP21 gene of a Tunisian CAH patient (Kharrat et al. 2005). The patient was homozygous for the deletion that causes a stop codon at amino acid 47 resulting in a nonfunctional enzyme.

Autoimmune Thyroid Diseases Autoimmune thyroid diseases (AITDs), such as Graves’ hyperthyroidism (GD) and Hashimoto’s thyroiditis (HT), are common multifactorial disorders. Some pathogenetic genes are probably shared between these diseases and nonendocrine autoimmune diseases, whereas others are disease specific. Tunisian population studies show that major histocompatibility complex alleles and CTLA4 confer risk for AITDs (Ayadi et al. 2004). A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders including 39 patients affected with GD or HT and 68 related controls, who, belonged to a large consanguinous family composed of more than 200 members. Linkage analysis was performed and a positive Lod score was found for D2S171 marker suggesting the presence of a major AITD susceptibility gene on chromosome 2p21 (Maalej et al. 2001).

21

Genetic Disorders in Tunisia

623

Cystic Fibrosis (OMIM 219700) In Tunisia Cystic Fibrosis (CF) does not seem to be rare. To identify genetic variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, Messaoud et al. (2005) conducted a molecular epidemiological study on 390 cystic fibrosis children belonging to 383 families. In this study 70% of the CF patients were seen carrying CFTR gene’s variations. Seventeen different mutations were identified in the different exons, among them four were newly and exclusively described in the Tunisian population (T665S, 2766del8, F1166C and L1043R). The most frequent mutation was the F508del (50.74%) mutation followed by G542X (7.96%), W1282X (6.66%), N1303K (5.92%), 2766del8 (4.25%), 711 þ 1G > T (4.23%), E1104X (1.85%) and ten rare mutations G85E, D1270N, R74W, R1066C, Y122X, T665S, I148T, V201M, F1166C, L1043R. More recently, among 68 unrelated CF patients, Fredj et al. (2009) detected three novel mutations: I1203V (1.47%), 1811+5A > G (0.74%) and 4268 þ 2T > G (1.47%).

Metabolic and Nutritional Diseases Phenylketonuria (OMIM 261600) Although phenylketonuria (PKU) is a frequent inherited metabolic disorder, epidemiologic and molecular data are lacking in Tunisia. In Tunisia the birth prevalence of PKU would be of 1:9,000 (Chaabouni-Bouhamed 2008). In a recent study conducted on 805 mentally handicapped patients aged between 6 and 46 years, phenylalanine was analyzed using the fluorimetric method. Eleven patients (1.32%) were diagnosed as having PKU (Khemir et al. 2009), this frequency is close to the frequency of 1.6% observed in Kuwaiti mentally handicapped institutions (Teebi et al. 1987).

Insulin-Dependent Diabetes Mellitus (OMIM 222100) Insulin-dependent diabetes mellitus (IDDM) or diabetes type 1 results from an autoimmune selective and irreversible destruction of b-cells of Langerhans. It is one of the most frequent chronic diseases in children, in Tunisia the IDDM incidence is of 6.76–6.95/100,000 (Ben Khalifa et al. 1997). While the etiology is still unclear genetic and environmental factors are suspected. Molecular analysis of HLA-DR subtypes of 18 Tunisian multiplex families with diabetic children showed that two DR subtypes, DR4-DQw8 and DR-Dw25, were significantly more common in the diabetic patients (Jenhani et al. 1990). More recently, Stayoussef et al. (2009) reported an association between HLA-DRB1 and DQB1 alleles and haplotypes in 50 Tunisian patients and identified two susceptibility haplotypes (DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302).

624

E. Hassen and L. Chouchane

Noninsulin-Dependent Diabetes Mellitus (OMIM 125853) Noninsulin-Dependent Diabetes Mellitus (NIDDM) or type 2 diabetes is a major public health problem in Tunisia. Hypertension and obesity were found in respectively 71.3 and 37.6% of diabetic patients (Ben Abdelaziz et al. 2006). Diabetic neuropathy was the most frequent degenerative complication (41.1%) followed by diabetic retinopathy (18.3%). Arfa et al. (2007) reported that familial aggregation of NIDDM was prominent, and among studied subjects, 70% reported at least one relative with diabetes and 34% had at least one parent with diabetes. The calpain-10 (CAPN10) was suggested to be a putative NIDDM susceptibility gene (Horikawa et al. 2000). Kifagi et al. (2008) analyzed the frequency distribution of four CAPN10 polymorphisms (UCSNP-43, UCSNP-19, UCSNP-110 and UCSNP-63) in 222 Tunisian patients. The A allele of UCSNP-43 showed an association with NIDDM and a novel combination of haplotypes (121/221) defined by three polymorphisms (UCNSP-43, -19 and -63) was identified to be associated with an increased risk of NIDDM. Several other associations were described with HSP702 (Zouari Bouassida et al. 2004), glucose transporter 1 (GLUT1) (Makni et al. 2008), methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzyme (ACE) gene polymorphisms (Mehri et al. 2009).

Inflammatory Disorders Familial Mediterranean Fever Gene (OMIM 608107) Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease caused by mutations in MEFV gene. To identify the frequency and distribution of MEFV mutations among Tunisians, Chaabouni et al. (2007) screened eight known MEFV gene mutations in 139 unrelated Tunisian patients. Allele frequencies were for mutations M680l, M694V, E148Q, M694l, V726A, A744S, R761H, l692del and of 32, 27, 18, 13, 5, 3, 1 and 1%, respectively. M680l is the most common mutation, while V726A, the commonest mutation among other Arabs, (Majeed et al. 2005), is, rare in the Tunisian population. Moreover, Belmahi et al. (2006) described the frequencies of the MEFV mutation spectrum among North African Arab patients (85 Algerians, 87 Moroccans, and 37 Tunisians). They found that the M694I mutation is specific to the Arab population from Maghreb and suggested that the M694V mutation arrived at the Maghreb region with migrations from the Middle East.

Systemic Lupus Erythematosus (OMIM 152700) Several association studies have been conducted on Tunisians to identify Systemic Lupus Erythematosus (SLE) susceptibility gene polymorphisms. The

21

Genetic Disorders in Tunisia

625

deoxyribonuclease I (DNASE1) gene seems to contribute in the genetic susceptibility of SLE among Japanese and Spanish patients. Through case-control studies, Chakraborty et al. (2003) first studied the occurrence of the A/T transversion polymorphism in exon 2 at position 172 of the DNASE1 gene, and then Belguith-Maalej et al. (2010) assessed known SNPs genotyping. In both the studies no associations were found with DNASE1 gene polymorphisms. Ayed et al. (2004) assessed the MHC class II (DRB1, DQA1, DQB1) and C4 null allele frequencies in 62 SLE Tunisian patients and 100 controls. In this report, HLA-DRB1*0301, DRB1*1501, C4AQO, HLA-DQA1*0102, DQA1*0501, HLA-DQB1*0201, DQB1*0602 and the C4A null alleles were increased in the SLE patients, while the frequencies of HLA-DRB1*04 and DQB1*03 were decreased. These observations were also noticed in other ethnic groups, suggesting shared susceptibility factors to SLE across ethnic groups.

Dermatological Disorders Xeroderma Pigmentosum (XP) This disease is rare worldwide, but in Tunisia where consanguineous marriage and endogamy are frequent the disease prevalence was estimated to be of 1/10,000 cases per inhabitants (Zghal et al. 2006). XP has eight known complementation groups (XP-A to XP-G and XP-V), seven of which are caused by mutations in genes encoding components of the nucleotide excision repair (NER) pathway. Nishigori et al. (1993) studied the XPA (OMIM 278700) gene alterations in seven Tunisian XPA patients and found that 86% of them had a nonsense mutation in codon 228. To identify the spectrum of XPC (OMIM 278720) gene mutations, Ben Rekaya et al. (2009) examined 20 patients and their family members. All studied patients presented a homozygous deletion of two bases TG, V548AfsX572 XPC mutation that leads to a frame-shift mutation and a premature termination of the encoded protein. Like described previously, in North African (Mahindra et al. 2008), Italian, Turkish (Gozukara et al. 2001) and Ashkenazi–Jewish Israeli patients (Slor et al. 2000) all studied patients correspond to a severe clinical form of XP-C. Furthermore, previous studies of XP-C showed that Moroccan and Algerian (Khan et al. 2006) patients had the V548AfsX572 XPC mutation. Haplotype analysis showed that all available patients from unrelated families shared the same haplotype, suggesting a possible founder effect of the V548A fsX572 XPC mutation.

Dystrophic Epidermolysis Bullosa (RDEB OMIM 226600; DDEB OMIM 131750) Dystrophic Epidermolysis bullosa (DEB) is a clinically and genetically heterogeneous group of dermatological diseases. DEB is a disorder caused by defects in

626

E. Hassen and L. Chouchane

the type VII collagen gene (COL7A1) which encode a fibrous protein that is the main component of the anchoring filaments. Both autosomal dominant (DDEB) and recessive (RDEB) forms were described. Using microsatellite markers, Ouragini et al. (2008) investigated COL7A1 genotyping on 23 Tunisian epidermolysis bullosa consanguineous families. These families were affected by different EB forms: 19 were diagnosed to present the dystrophic form, two the simplex form, one the junctional EB, and one an unclassified form of EB. Haplotype and homozygosity analysis suggest that all families classified clinically as having DEB and the patient who presented himself with an unclassified form of EB are likely linked to the COL7A1 gene, and showed evidence for exclusion for the simplex and junctional cases. Mutational heterogeneity among Tunisian DEB families was also reported and the genetic results correlated with the clinical examination in 94.7% of all studied DEB families. More recently a large DEB multiplex consanguineous family originating from the North of Tunisia was studied (Ouragini et al. 2009). The family included eight affected individuals, three of whom died with a generalized bullous eruption. Screening for the deleterious mutation (c.7178delT) showed that a member with the generalized form was homozygous.

Deafness Nonsyndromic Deafness (OMIM 220290) Nonsyndromic congenital deafness is common in Tunisia, especially in some villages where the prevalence ranges from 2% to 8%. To evaluate the effect of inbred unions on deafness, a study was conducted on 5,020 individuals (160 were deaf) from the northern region of Tunisia (Ben Arab et al. 2004). The highest level of inbreeding was observed in the rural districts. Autosomal recessive genes are responsible for about 80% of the cases of hereditary nonsyndromic deafness. DFNB1 loci is the most important locus for nonsyndromic autosomal recessive deafness, it was originally assigned to chromosome 13q11 by linkage analysis in two large consanguineous Tunisian families with prelingual, profound deafness (Guilford et al. 1994a, b). The 35delG mutation in the GJB2 (connexion 26) gene, which was the first DFNB1 identified mutation, is the single most frequent allele for nonsyndromic recessive deafness in Tunisia and in the world (Ben Arab et al. 2000; Denoyelle et al. 1997). The DFNB2 locus was mapped by a genome search to 11q13.5 in a highly consanguineous family also from Tunisia segregating nonsyndromic, profound deafness (Guilford et al. 1994a). Recently, Tlili et al. (2007) reported the mapping of a novel locus, DFNB63, to chromosome 11q13.3–q13.4 in a large consanguineous Tunisian family.

21

Genetic Disorders in Tunisia

627

Usher Syndrome Type IIA (OMIM 276901) Usher syndrome (USH) is clinically and genetically heterogeneous, and it is categorized into three clinical subtypes. Mutations in USH2 genes can also manifest as atypical USH, as nonsyndromic recessive HI, or as nonsyndromic recessive RP. Ben Rebeh et al. (2008) assessed to localize the USH responsible gene in a consanguineous family originating from the Tunisian center. This consanguineous Tunisian family exhibited no evidence of linkage to any known USH locus. However, Ben Rebeh et al. (2008) suggest that a novel gene implicated in USH2 is likely to reside on 15q.

X-Linked Mental Retardations (OMIM 300419) Among 492 unrelated Tunisian patients suffering from mental retardation (MR) of nonchromosomal origin, familial MR was present in 30% of the cases and consanguinity was prevalent in 59% (Chaabouni-Bouhamed 2008). A new locus was identified in a large Tunisian family with nonspecific X-linked MR, and then the gene was identified as ARX (Bienvenu et al. 2002; Jemaa et al. 1999). To date mutations in the PAK3 gene have been found in four different families of X-linked MR. Rejeb et al. (2008) reported the first PAK3 gene splice mutation identified in a Tunisian family with X-linked MR.

Hereditary Multiple Exostoses Type I (OMIM 133700) Sfar et al. (2009a) investigated the screening of the EXT1 gene mutations among two Tunisian families originating from the middle coast of Tunisia. For each family one distinct mutation was reported, the first in exon 2 was previously described (c.1019G > T) and the second is a novel frame-shift deletion of adenine in exon 1 (c.529_531delA). This newly identified mutation was associated with a wide intrafamilial clinical variability of HME disease ranging from the severe form to subclinical signs.

Predisposition to Cancer Bladder Cancer (OMIM 109800) Bladder cancer is not an inherited disease. Nevertheless, polymorphisms in genes involved in DNA repair or in the detoxification of xenobiotics may play an important role in disease susceptibility. In Tunisia, bladder cancer is the most

628

E. Hassen and L. Chouchane

prevalent cancer of the urogenital tract and the second most frequent cancer affecting men after lung cancer (10.7/100,000 men) (Hsairi et al. 2002). Several case-control studies have been conducted on Tunisians to identify susceptibility genes. Tunisian smokers carrying the GSTM1 null allele are at an approximately 2.2-fold high risk of bladder cancer (Ouerhani et al. 2006). Furthermore, individuals carrying at least one copy of the methionine synthase (MS) variant allele A2756G and heterozygous for MTHFR A1298C polymorphism displayed a 2.33 and 1.8 times increased risk of developing bladder cancer, respectively (Ouerhani et al. 2007). The study of the combined effect of tobacco, MS and MTHFR genotypes in bladder cancer development, has suggested that the inheritance of MTR 2756*G allele (AG or GG genotype) and wild-genotype for MTHFR (MTHFR 677CC) was associated with an increased risk of bladder cancer in both smokers and nonsmoker patients (Ouerhani et al. 2009). However, polymorphisms of the p53 (codon 72) (Mabrouk et al. 2003), the GSTT1 (Ouerhani et al. 2006) and the CYP2D6 (Ouerhani et al. 2008) genes did not appear to influence bladder cancer susceptibility.

Prostate Cancer (OMIM 176807) Prostate cancer (PCa) is the most frequent cancer among men in several industrialized countries. In Tunisia PCa is the fourth more frequent cancer with an incidence rate of 6.1/100,000 men. Like the majority of the cancers, PCa is a multifactorial disorder implying complex interactions among environmental, genetic, and dietary factors. Sfar et al. (2009b, 2006, 2007) assessed the implication of several angiogenic gene polymorphisms effects (individual and combined effects) on PCa susceptibility and progression and demonstrated that angiogenic gene polymorphisms increased markedly the risk of prostate cancer onset and aggressiveness. Indeed, a significant increased risk was associated with the VEGF-634 (GC þ CC) combined genotype and the VEGF-634C allele was associated with high histological grade. However, the VEGF-1154A/-634G haplotype was negatively associated with PCa risk and high tumor grade (Sfar et al. 2006) and no association was observed between the N700S TSP1 polymorphism and PCa risk or severity. Moreover, subjects carrying one copy of the MMP9-1562T allele exhibited a threefold higher risk of developing PCa. Regarding prognostic value, a significant association was found between the occurrence of the MMP9 T allele and the high-grade tumor and the advanced disease (Sfar et al. 2007). Combined effect analysis of the angiogenic gene polymorphisms (VEGF-1154G/A; VEGF-634G/C; MMP9-1562C/T) showed a significant gene-dosage effect for the increasing numbers of potential high-risk genotypes. Compared to referent group (low-risk genotypes), individuals with one (OR ¼ 2.79), two (OR ¼ 4.57) and three highrisk genotypes (OR ¼ 7.11) had increasingly elevated risks of prostate cancer (Sfar et al. 2009b). Cross-classified analysis revealed potential higher order gene– gene interactions between VEGF and TSP1 polymorphisms in increasing the risk of developing an aggressive phenotype disease. Patients carrying three high-risk genotypes showed a 20-fold increased risk of high-grade tumor (Sfar et al. 2009b).

21

Genetic Disorders in Tunisia

629

Breast Cancer (OMIM 114480) In Tunisia like in the countries worldwide, breast cancer is the most frequent cancer among women. Several epidemiological studies about breast cancer have been carried out in Tunisia especially in the national institute of cancer of Salah-Azaiz (ISA). In order to update clinical and epidemiological profile of breast cancer Maalej et al. (2008) census of all new cases of breast cancer were diagnosed in Tunisia during the year 2004. During this period 1,437 new cases of invasive breast cancer were diagnosed. Most of the patients were women, with 1,408 women versus 29 men. The patients mean age was of 51 years and the highest incidence of breast cancer was between 40 and 54 years old. Compared to previous epidemiologic studies (Maalej et al. 1999), an increase in the incidence rate from the age of 40 years which continues until the age of 55 years was observed. Clinical feature revealed that the most frequent tumor stage were T2 in 46.9% cases, then T4 in 24.7% cases (T1 in 12.2% cases, T3 in 11.2% cases). Invasive ductal carcinoma was the most frequent (86.6%) with SBR II grade representing 54.5%. In Western countries, incidence of breast cancer and mortality are higher than in Mediterranean countries. Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive and patients were 10 years younger at diagnosis (Chalabi et al. 2008). Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. This study strongly suggests the need to identify specific clinical and genetic features of patients from South Mediterranean countries. In hereditary breast carcinoma, mutations in highly penetrant genes such as BRCA1 or BRCA2 confer a high risk for developing breast carcinoma, though this risk accounts only for about 5–10% of all breast carcinoma cases. As most cases of breast cancer are not inherited (90–95%), it is suggested that the effect of low penetrance cancer susceptibility genes modulated by environmental exposure and lifestyle factors are likely to account for most of the sporadic breast carcinoma cases. In Tunisia, both high and low penetrant genes were studied. Recently, Troudi et al. (2007) published the spectrum of BRCA1 and BRCA2 mutations from 36 Tunisian index cases. Six deleterious mutations were identified four in BRCA1 and two in BRCA2. Among the six distinct mutations identified in this study, only one (c.211dupA) in BRCA1 (exon 5) had not been described previously. Moreover, Troudi et al. (2008) suggested that when breast/ovarian cancer cases are diagnosed in a Tunisian family the molecular analysis should be directed to sequencing the BRCA1 gene and exon 11 region of the BRCA2 gene. Moreover, when a male breast cancer is observed among relatives, the molecular analysis should be directed to sequencing the BRCA2 gene. Uhrhammer et al. (2008) observed a BRCA1 deleterious mutation (c.798–799delTT) in two Algerian families and in two families from Tunisia. These last observations, suggest a North African founder allele, and may be a common genetic profile that would be used as a novel criterion for analysis in the Northern African population. As sporadic cases of breast cancer are frequent in Tunisia, several case-control reports have identified genetic association with cancer risk and/ or aggressiveness (Baccar Harrath et al. 2006; Kharrat et al. 2007; Snoussi et al. 2005). For instance;

630

E. Hassen and L. Chouchane

Khedhaier et al. (2003, 2008) studies assessed the implication of Xenobiotic Metabolizing Enzyme gene polymorphisms (GSTT1, GSTM1, CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) in sporadic breast cancer cases. Khedhaier et al. (2003) showed that the gene deletion of GSTs may predict the early onset of breast carcinoma, the clinical response to chemotherapy and the recurrence-free survival for patients with lymph node-negative breast carcinoma. Moreover, the mEH (C/C) mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk, the CYP2D6 (G/G) wild type was associated with breast carcinoma risk only in postmenopausal patients, and significant differences in overall disease survival with the mEH gene polymorphisms (Khedhaier et al. 2008).

Nasopharyngeal Carcinoma (OMIM 161550) In Tunisia, the incidence of nasopharyngeal carcinoma (NPC) is about 3.5 per 100,000 inhabitants. There are some epidemiological and clinical differences between Asian and North African NPCs. The main difference relates to their age distribution, which is unimodal in China, with one single incidence peak seen at the age of around 50 years old, but bimodal in the Mediterranean area, with a main peak around 50 years (80% of patients) associated with a secondary peak in the range of 10–25 years (20% of patients) (Lombardi et al. 1982). As the incidence is restricted to some ethnic groups or certain geographical regions of the world, numerous etiological environmental factors associated to lifestyle and genetic factors might be responsible for this cancer. In recent years, great progress has been made in genetic research of familial and sporadic NPC cases. In Tunisia published studies were mainly conducted on sporadic cases of NPC. Serological analyses observed positive associations between NPC and HLA class I alleles. Numerous studies based on genetic analysis have indicated that specific human leukocyte antigen (HLA) haplotypes and genes within the HLA complex are associated with NPC (Hassen et al. 2010). Among Tunisians, direct sequencing of the HLA class I genes showed positive associations for HLA-B-18, -B51 and -B57 with NPC risk and allowed the identification a rare haplotype (HLA-B*1402/Cw*0802) in Tunisian patients with NPC (Li et al. 2007). Moreover, Makni et al. (2010) observed positive association for DRB1*03, DRB1*13 and DQB1*02 alleles with NPC. Moreover, nonHLA gene polymorphisms located on chromosome six, nearby or within the HLA class I loci was found to be associated with NPC. Indeed, a panel of positive associations has been described including TAP-1 gene (Hassen et al. 2007), MHC class I chain-related A (MICA) gene belonging to the nonclassical HLA family (Douik et al. 2009) and heat shock protein (HSP) gene located in 6p21.2–p23 (Jalbout et al. 2003). Furthermore, the association between age and NPC onset was demonstrated for several genes, such as HLA-class I, TAP-1, IL-18 promoter, IL-10 and IFN-g genes polymorphisms (Li et al. 2007; Farhat et al. 2008a, b; Hassen et al. 2007).

21

Genetic Disorders in Tunisia

631

Colorectal Cancer (OMIM 114500) In Tunisia, Colorectal cancer (CRC) represents the first digestive cancer with an incidence of 7.4 new cases per 100,000 inhabitants per year. CRC is a multifactorial disease that involves environmental and genetic factors. CRC cases can present sporadic or more rarely hereditary form. Genetic studies on Tunisian cases of CRC are weak. The Bougatef et al. (2009) study conducted on Tunisian sporadic cases showed significant association between the I1307K, E1317Q and D1822V variants of the Adenomatous polyposis coli gene (APC) and CRC risk. Hereditary nonpolyposis CRC (HNPCC; OMIM 120435) is the most frequent cause of inherited CRC. It is caused by constitutional mutations in the DNA mismatch repair (MMR) genes. In a family with six patients diagnosed with a colorectal or an endometrial cancer at an early age, MMR gene analysis revealed the presence of a large deletion in MLH1 removing exon 6. This germline MLH1 rearrangement was associated to a severe phenotype (Aissi-Ben Moussa et al. 2009).

Conclusion After listing the above-described genetic disorders among Tunisians, it is clear that these diseases constitute a major national health problem. Some disorders occur in high frequencies causing suffering or handicaps leading most of the time to premature death. To limit the damages caused by genetic disorder in Tunisia, a better knowledge on the local risk factors are required. In fact, more data on the epidemiological and biological feature of each disease will allow the implementation of efficient prevention strategies. Epidemiological studies will permit to select a target population at high risk of disease incidence and genetic defects census will be useful for genetic counseling. In Tunisia, although insufficient, published reports on genetic disorders are markedly increasing. Seventy-two percent of the reports were published between 1997 and 2009. Some of these studies reported very useful data on specific mutational spectrum of some monogenic diseases in Tunisia. In Tunisia, there are national centers and laboratories that offer genetic counseling services. Unfortunately, this genetic service is only localized in the greatest urban region of Tunisia and needs to be expanded to cover a larger part of the Tunisian territory.

References Abdelmoula NB, Amouri A, Portnoi MF, Saad A, Boudawara T, Mhiri MN, Bahloul A, Rebai T (2004) Cytogenetics and fluorescence in situ hybridization assessment of sex-chromosome mosaicism in Klinefelter’s syndrome. Ann Genet 47:163–175 Aissi-Ben Moussa S, Moussa A, Lovecchio T, Kourda N, Najjar T, Ben Jilani S, El Gaaied A, Porchet N, Manai M, Buisine MP (2009) Identification and characterization of a novel MLH1

632

E. Hassen and L. Chouchane

genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination. Fam Cancer 8:119–126 Al-Abdulkareem AA, Ballal SG (1998) Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse health effects on the offspring. J Community Health 23:75–83 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, al-Khayat AI, Gaber T (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Arfa I, Abid A, Malouche D, Ben Alaya N, Azegue TR, Mannai I, Zorgati MM, Ben Rayana MC, Ben Ammar S, Blousa-Chabchoub S, Ben Romdhane H, Zouari B, Dellagi MK, Abdelhak S (2007) Familial aggregation and excess maternal transmission of type 2 diabetes in Tunisia. Postgrad Med J 83:348–351 Ayadi H, Hadj Kacem H, Rebai A, Farid NR (2004) The genetics of autoimmune thyroid disease. Trends Endocrinol Metab 15:234–239 Ayed K, Gorgi Y, Ayed-Jendoubi S, Bardi R (2004) The involvement of HLA -DRB1*, DQA1*, DQB1* and complement C4A loci in diagnosing systemic lupus erythematosus among Tunisians. Ann Saudi Med 24:31–35 Baccar Harrath A, Yacoubi Loueslati B, Troudi W, Hmida S, Sedkaoui S, Dridi A, Jridi A, Ben Ayed F, Ben Rhomdhane K, Ben Ammar Elgaaied A (2006) HLA class II polymorphism: protective or risk factors to breast cancer in Tunisia? Pathol Oncol Res 12:79–81 Bayoumi RA, Nur-E-Kamal MS, Tadayyon M, Mohamed KK, Mahboob BH, Qureshi MM, Lakhani MS, Awaad MO, Kaeda J, Vulliamy TJ, Luzzatto L (1996) Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenase deficiency in Al-Ain District, United Arab Emirates. Hum Hered 46:136–141 Belguith-Maalej S, Hadj-Kacem H, Kaddour N, Bahloul Z, Ayadi H (2010) DNase1 exon2 analysis in Tunisian patients with rheumatoid arthritis, systemic lupus erythematosus and Sjo¨gren syndrome and healthy subjects. Rheumatol Int 30:69–74 Belmahi L, Sefiani A, Fouveau C, Feingold J, Delpech M, Grateau G, Dode´ C (2006) Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol 329:71–74 Ben Abdelaziz A, Drissi L, Tlili H, Gaha K, Soltane I, Amrani R, Ghannemr H (2006) Epidemiologic and clinical features of patients with type 2 diabetes mellitus in primary care facilities (Sousse, Tunisie). Tunis Med 84:415–422 Ben Arab S, Hmani M, Denoyelle F, Boulila-Elgaied A, Chardenoux S, Hachicha S, Petit C, Ayadi H (2000) Mutations of GJB2 in three geographic isolates from northern Tunisia: evidence for genetic heterogeneity within isolates. Clin Genet 57:439–443 Ben Arab S, Masmoudi S, Beltaief N, Hachicha S, Ayadi H (2004) Consanguinity and endogamy in Northern Tunisia and its impact on non-syndromic deafness. Genet Epidemiol 27:74–79 Ben Hamida M, Attia N, Chaabouni H, Fardeau M (1983) Autosomal recessice severe, proximal myopathy in children, common in Tunisia. Rev Neurol 139:289–297 Ben Hamida C, Doerflinger N, Belal S, Linder C, Reutenauer L, Dib C, Gyapay G, Vignal A, Le Paslier D, Cohen D et al (1993) Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 5:195–200 Ben Khalifa F, Mekaouar A, Taktak S, Hamhoum M, Jebara H, Kodia A, Zouari B, Chakroun M (1997) A five-year study of the incidence of insulin-dependent diabetesmellitus in young Tunisians (preliminary results). Diabetes Metab 23:395–401 Ben Othmane K, Ben Hamida M, Pericak-Vance MA, Ben Hamida C, Blel S, Carter SC, Am B, Petruhkin K, Gilliam TC, Ad R, Hentati F, Vance JM (1992) Linkage of Tunisian autosomal recessive Duchenne-like muscular dystrophy to the pericentromeric region of chromosome 13q. Nat Genet 2:315–317 Ben Rebeh I, Benzina Z, Dhouib H, Hadjamor I, Amyere M, Ayadi L, Turki K, Hammami B, Kmiha N, Kammoun H, Hakim B, Charfedine I, Vikkula M, Ghorbel A, Ayadi H, Masmoudi S (2008) Identification of candidate regions for a novel Usher syndrome type II locus. Mol Vis 14:1719–1726

21

Genetic Disorders in Tunisia

633

Ben Rekaya M, Messaoud O, Talmoudi F, Nouira S, Ouragini H, Amouri A, Boussen H, Boubaker S, Mokni M, Mokthar I, Abdelhak S, Zghal M (2009) High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis. J Hum Genet 54:426–429 Bener A, Hussain R (2006) Consanguineous unions and child health in the State of Qatar. Paediatr Perinat Epidemiol 20:372–378 Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, Benjemaa L, Zemni R, Vinet MC, Francis F, Couvert P, Gomot M, Moraine C, Van Bokhoven H, Kalscheuer V, Frints S, Gecz J, Ohzaki K, Chaabouni H, Desportes V, Fryns JP, Beldjord C, Chelly J (2002) ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 11:981–991 Blibech R, Gharbi Y, Mrad A, Zahra H, Mahjoub T, Belhaj A, Laatiri Z, Kastally R, Rosa R (1989) Incidence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in Tunisian populations. Nouv Rev Fr Hematol 31:189–191 Bouchlaka C, Abdelhak S, Amouri A, Ben Abid H, Hadiji S, Frikha M, Ben Othman T, Amri F, Ayadi H, Hachicha M, Rebaı¨ A, Saad A, Dellagi K, Tunisian Fanconi Anemia Study Group (2003) Fanconi anemia in Tunisia: high prevalence of group A and identification of new FANCA mutations. J Hum Genet 48:352–361 Bougatef K, Marrakchi R, Ouerhani S, Sassi R, Moussa A, Kourda N, Blondeau Lahely Y, Najjar T, Ben Jilani S, Soubrier F, Ben Ammar Elgaaied A (2009) No evidence of the APC D1822V missense variant’s pathogenicity in Tunisian patients with sporadic colorectal cancer. Pathol Biol 57:67–71 Chaabouni H, Chaabouni M, Maazoul F, M’Rad R, Jemaa LB, Smaoui N, Terras K, Kammoun H, Belghith N, Ridene H, Oueslati B, Zouari F (2001) Prenatal diagnosis of chromosome disorders in Tunisian population. Ann Genet 44:99–104 Chaabouni HB, Ksantini M, M’rad R, Kharrat M, Chaabouni M, Maazoul F, Bahloul Z, Ben Jemaa L, Ben Moussa F, Ben Chaabane T, Mrad S, Touitou I, Smaoui N (2007) MEFV mutations in Tunisian patients suffering from familial Mediterranean fever. Semin Arthritis Rheum 36:397–401 Chaabouni-Bouhamed H (2008) Tunisia: communities and community genetics. Community Genet 11:313–323 Chakraborty P, Hadj Kacem H, Makni-Karray K, Jarraya F, Hachicha J, Ayadi H (2003) The A/T mutation in exon 2 of the DNASE1 gene is not present in Tunisian patients with systemic lupus erythematosus or in healthy subjects. Arthritis Rheum 48:3297–3298 Chalabi N, Bernard-Gallon DJ, Bignon YJ, Breast Med Consortium, Kwiatkowski F, Agier M, Vidal V, Laplace-Chabaud V, Sylvain-Vidal V, Bertholet V, De Longueville F, Lacroix M, Leclercq G, Remacle J, Sibille C, Zammateo N, Ben Jaafar N, Sefiani A, Ouldim K, Me´garbane´ K, Jalkh N, Mahfoudh W, Troudi W, Ben Ammar-El Gaı¨ed A, Chouchane L (2008) Comparative clinical and transcriptomal profiles of breast cancer between French and South Mediterranean patients show minor but significative biological differences. Cancer Genomics Proteomics 5:253–261 Chalbi N, Zakaria D (1998) Models of family, endogamy and consanguinity in Tunis. Essais de mesure Famille et population 1:39–59 Chelli D, Dimassi K, Chaabouni M, Ben Saad M, Mssaed H, Bchir F, Zouaoui B, Sfar E, Gaigi S, Chelli H, Chanoufi B (2008) Prenatal diagnosis of trisomy 21: the Tunisian experience. Sante 18:199–203 Chibani J, Vidaud M, Duquesnoy P, Berge´-Lefranc JL, Pirastu M, Ellouze F, Rosa J, Goossens M (1988) The peculiar spectrum of b-thalassemia genes in Tunisia. Hum Genet 78:190–192 Chouk I, Daoud BB, Mellouli F, Bejaoui M, Ge´rard N, Dellagi K, Abbes S (2004) Contribution to the description of the beta-thalassemia spectrum in Tunisia and the origin of mutation diversity. Hemoglobin 28:189–195 Daoud BB, Mosbehi I, Pre´hu C, Chaouachi D, Hafsia R, Abbes S (2008) Molecular characterization of erythrocyte glucose-6-phosphate dehydrogenasedeficiency in Tunisia. Pathol Biol 56:260–267

634

E. Hassen and L. Chouchane

Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl HH, Middleton A, Houseman MJ, Dode´ C, Marlin S, Boulila-El Gaı¨ed A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E, Aubois A, Joannard A, Petit C (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6:2173–2177 Douik H, Ben Chaaben A, Attia Romdhane N, Romdhane HB, Mamoghli T, Fortier C, Boukouaci W, Harzallah L, Ghanem A, Gritli S, Makni M, Charron D, Krishnamoorthy R, Guemira F, Tamouza R (2009) Association of MICA-129 polymorphism with nasopharyngeal cancer risk in a Tunisian population. Hum Immunol 70:45–48 Farhat K, Hassen E, Bouzgarrou N, Gabbouj S, Bouaouina N, Chouchane L (2008a) Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients. Cytokine 43:132–137 Farhat K, Hassen E, Gabbouj S, Bouaouina N, Chouchane L (2008b) Interleukin-10 and interferon-gamma gene polymorphisms in patients with nasopharyngeal carcinoma. Int J Immunogenet 35:197–205 Fattoum S (2006) Hemoglobinopathies in Tunisia. An updated review of the epidemiologic and molecular data. Tunis Med 84:687–696 Fattoum S, Guemira F, Oner C, Oner R, Li HW, Kutlar F, Huisman TH (1991) Beta-thalassemia, HB S-beta-thalassemia and sickle cell anemia among Tunisians. Hemoglobin 15:11–21 Fredj SH, Messaoud T, Templin C, Des Georges M, Fattoum S, Claustres M (2009) Cystic fibrosis transmembrane conductance regulator mutation spectrum in patients with cystic fibrosis in Tunisia. Genet Test Mol Biomarkers 13:577–581 Gouider-Khouja N, Belal S, Hamida MB, Hentati F (2000) Clinical and genetic study of familial Parkinson’s disease in Tunisia. Neurology 54:1603–1609 Gozukara EM, Khan SG, Metin A, Emmert S, Busch DB, Shahlavi T, Coleman DM, Miller M, Chinsomboon N, Stefanini M, Kraemer KH (2001) A stop codon in xeroderma pigmentosum group C families in Turkey and Italy: molecular genetic evidence for a common ancestor. J Invest Dermatol 117:197–204 Guilford P, Ayadi H, Blanchard S, Chaib H, Le Paslier D, Weissenbach J, Drira M, Petit C (1994a) A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum Mol Genet 3:989–993 Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, Petit C (1994b) A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet 6:24–28 Haj Khelil A, Laradi S, Miled A, Omar Tadmouri G, Ben Chibani J, Perrin P (2004) Clinical and molecular aspects of haemoglobinopathies in Tunisia. Clin Chim Acta 340:127–137 Hamamy H, Jamhawi L, Al-Darawsheh J, Ajlouni K (2005) Consanguineous marriages in Jordan: why is the rate changing with time? Clin Genet 67:511–516 Hassen E, Farhat K, Gabbouj S, Jalbout M, Bouaouina N, Chouchane L (2007) TAP1 gene polymorphisms and nasopharyngeal carcinoma risk in a Tunisian population. Cancer Genet Cytogenet 175:41–46 Hassen E, Ghandri N, Bouaouina N, Chouchane L (2010) The human leukocyte antigen class I genes in nasopharyngeal carcinoma risk. Mol Biol Rep 37:119–126 Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175 Hsairi M, Fakhfakh R, Ben Abdallah M, Jlidi R, Sellami A, Zheni S, Hmissa S, Achour N, Nacef T (2002) Assessment of cancer incidence in Tunisia 1993–1997. Tunis Med 80:57–64 Jalbout M, Bouaouina N, Gargouri J, Corbex M, Ben Ahmed S, Chouchane L (2003) Polymorphism of the stress protein HSP70-2 gene is associated with thesusceptibility to the nasopharyngeal carcinoma. Cancer Lett 193:75–81 Jemaa LB, des Portes V, Zemni R, Mrad R, Maazoul F, Beldjord C, Chaabouni H, Chelly J (1999) Refined 2.7 centimorgan locus in Xp21.3–22.1 for a nonspecific X-linked mental retardation gene (MRX54). Am J Med Genet 85:276–282

21

Genetic Disorders in Tunisia

635

Jenhani F, Bardi R, Ayed K, Chammakhi S, Jeddi M, Labonne MP, Gebuhrer L, Betuel H (1990) Extended HLA haplotypes in multiplex families with insulin dependent diabetes mellitus in Tunisian population: HLA serological typing and RFLP analysis. Dis Markers 8:327–331 Kammoun I, Chaabouni M, Trabelsi M, Ouertani I, Kraoua L, Chelly I, M’rad R, Ben Jemaa L, Maaˆzoul F, Chaabouni H (2008) Ann Endocrinol (Paris) 69:440–445 Kefi M, Amouri R, Driss A, Ben Hamida C, Ben Hamida M, Kunkel LM, Hentati F (2003) Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521T mutation. Neuromuscul Disord 13:779–787 Kerkeni E, Monastiri K, Saket B, Guediche MN, Ben Cheikh H (2007) Interplay of socioeconomic factors, consanguinity, fertility, and offspring mortality in Monastir, Tunisia. Croat Med J 48:701–707 Khan SG, Oh KS, Shahlavi T, Ueda T, Busch DB, Inui H, Emmert S, Imoto K, Muniz-Medina V, Baker CC, DiGiovanna JJ, Schmidt D, Khadavi A, Metin A, Gozukara E, Slor H, Sarasin A, Kraemer KH (2006) Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27:84–94 Kharrat M, Tardy V, M’Rad R, Maazoul F, Jemaa LB, Refaı¨ M, Morel Y, Chaabouni H (2004) Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab 89:368–374 Kharrat M, Tardy V, M’rad R, Maazoul F, Morel Y, Chaabouni H (2005) A novel 13-bp deletion in exon 1 of CYP21 gene causing severe congenital adrenal hyperplasia. Diagn Mol Pathol 14:250–252 Kharrat N, Al’Fadhli S, Rebai M, Aifa MS, Kallel I, Khabir A, Sellami-Boudawara T, Frikha M, Rebai A (2007) (AC) dinucleotide repeat polymorphism in intron 1 of human EGFR shows ethnic specificities and high evidence for association with breast cancer. Int J Biol Markers 22:258–264 Khedhaier A, Remadi S, Corbex M, Ahmed SB, Bouaouina N, Mestiri S, Azaiez R, Helal AN, Chouchane L (2003) Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma. Br J Cancer 89:1502–1507 Khedhaier A, Hassen E, Bouaouina N, Gabbouj S, Ahmed SB, Chouchane L (2008) Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer 18:109 Khemir S, Tebib N, Nasrallah F, Ben Nour F, Mizouni H, Elasmi M, Sanhaji H, Jemaa R, Feki M, Ben Dridi MF, Mebazaa A, Kaabachi N (2009) Phenylketonuria in Tunisian institutions for the mentally handicapped. Arch Dis Child 94:647–648 Khlat M (1988) Consanguineous marriage and reproduction in Beirut, Lebanon. Am J Hum Genet 43:188–196 Kifagi C, Makni K, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Rebaı¨ A, Granier C, Jarraya F, Ayadi H (2008) Association of calpain-10 polymorphisms with type 2 diabetes in the Tunisian population. Diabetes Metab 34:273–278 Lambert JC, Pasquier F, Cottel D, Frigard B, Amouyel P, Chartier-Harlin MC (1998) A new polymorphism in the APOE promoter associated with risk of developing Alzheimer’s disease. Hum Mol Genet 7:533–540 Li X, Ghandri N, Piancatelli D, Adams S, Chen D, Robbins FM, Wang E, Monaco A, Selleri S, Bouaouina N, Stroncek D, Adorno D, Chouchane L, Marincola FM (2007) Associations between HLA class I alleles and the prevalence of nasopharyngeal carcinoma (NPC) among Tunisians. J Transl Med 5:22 Lombardi F, Gasparini M, Gianni C, De Marie M, Molinari R, Pilotti S (1982) Nasopharyngeal carcinoma in childhood. Med Pediatr Oncol 10:243–250 Louhichi N, Triki C, Quijano-Roy S, Richard P, Makri S, Me´ziou M, Estournet B, Mrad S, Romero NB, Ayadi H, Guicheney P, Fakhfakh F (2004) New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 5:27–34

636

E. Hassen and L. Chouchane

Louhichi N, Richard P, Triki CH, Meziou M, Ayadi H, Guicheney P, Fakhfakh F (2006) Novel mutations in LAMA2 gene responsible for a severe phenotype of congenital muscular dystrophy in two Tunisian families. Arch Inst Pasteur Tunis 83:19–23 Maalej M, Frikha H, Ben Salem S, Daoud J, Bouaouina N, Ben Abdallah M, Ben Romdhane K (1999) Le cancer du sein en Tunisie: e´tude clinique et e´pide´miologique. Bull Cancer 86:302–306 Maalej A, Makni H, Ayadi F, Bellassoued M, Jouida J, Bouguacha N, Abid M, Ayadi H (2001) A full genome screening in a large Tunisian family affected with thyroid autoimmune disorders. Genes Immun 2:71–75 Maalej M, Hentati D, Messai T, Kochbati L, El May A, Mrad K, Romdhane KB, Ben Abdallah M, Zouari B (2008) Breast cancer in Tunisia in 2004: a comparative clinical and epidemiological study. Bull Cancer 95:5–9 Mabrouk I, Baccouche S, El-Abed R, Mokdad-Gargouri R, Mosbah A, Saı¨d S, Daoud J, Frikha M, Jlidi R, Gargouri A (2003) No evidence of correlation between p53 codon 72 polymorphism and risk of bladder or breast carcinoma in Tunisian patients. Ann N Y Acad Sci 1010:764–770 Mahindra P, DiGiovanna JJ, Tamura D, Brahim JS, Hornyak TJ, Stern JB, Lee CC, Khan SG, Brooks BP, Smith JA, Driscoll BP, Montemarano AD, Sugarman K, Kraemer KH (2008) Skin cancers, blindness, and anterior tongue mass in African brothers. J Am Acad Dermatol 59:881–886 Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D (2005) The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum 34:813–818 Makni H, Daoud J, Ben Salah H, Mahfoudh N, Haddar O, Karray H, Boudawara T, Ghorbel A, Khabir A, Frikha M (2010) HLA association with nasopharyngeal carcinoma in southern Tunisia. Mol Biol Rep PMID:19714482 (in press) Makni K, Mnif F, Boudawara M, Hamza N, Rekik N, Abid M, Rebaı¨ A, Jarraya F, Granier C, Ayadi H (2008) Association of glucose transporter 1 polymorphisms with type 2 diabetes in the Tunisian population. Diabetes Metab Res Rev 24:544–548 Mehri S, Koubaa N, Nakbi A, Hammami S, Chaaba R, Mahjoub S, Zouari B, Abid M, Arab SB, Baudin B, Hammami M (2009) Relationship between genetic polymorphisms of angiotensinconverting enzyme and methylenetetrahydrofolate reductase as risk factors for type 2 diabetes in Tunisian patients. Clin Biochem 43:259–266 Messaoud T, Bel Haj Fredj S, Bibi A, Elion J, Fe´rec C, Fattoum S (2005) Molecular epidemiology of cystic fibrosis in Tunisia. Ann Biol Clin 63:627–630 Mrad R, Dorboz I, Ben Jemaa L, Maazoul F, Trabelsi M, Chaabouni M, Mlaiki B, Miladi N, Hentati F, Chaabouni H (2006) Molecular analysis of the SMN1 and NAIP genes in 60 Tunisian spinal muscular atrophy patients. Tunis Med 84:465–469 Nafa K, Reghis A, Osmani N, Baghli L, Benabadji M, Kaplan JC, Vulliamy TJ, Luzzatto L (1993) G6PD Aures: a new mutation (48 Ile>Thr) causing mild G6PD deficiency is associated with favism. Hum Mol Genet 2:81–82 Niazi GA, Adeyokunnu A, Westwood B, Beutler E (1996) Neonatal jaundice in Saudi newborns with G6PD Aures. Ann Trop Paediatr 16:33–37 Nishigori C, Zghal M, Yagi T, Imamura S, Komoun MR, Takebe H (1993) High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. Am J Hum Genet 53:1001–1006 Nishioka K, Kefi M, Jasinska-Myga B, Wider C, Vilarino-Guell C, Ross OA, Heckman MG, Middleton LT, Ishihara-Paul L, Gibson RA, Amouri R, Yahmed SB, Sassi SB, Zouari M, Euch GE, Farrer MJ, Hentati F (2010) A comparative study of LRRK2, PINK1 and genetically undefined familial Parkinson disease. J Neurol Neurosurg Psychiatry PubMed PMID: 19726410 (in press) Ouerhani S, Tebourski F, Slama MR, Marrakchi R, Rabeh M, Hassine LB, Ayed M, Elgaaı¨ed AB (2006) The role of glutathione transferases M1 and T1 in individual susceptibility to bladder cancer in a Tunisian population. Ann Hum Biol 33:529–535

21

Genetic Disorders in Tunisia

637

Ouerhani S, Oliveira E, Marrakchi R, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, Amorim A, El Gaaied AB, Prata MJ (2007) Methylenetetrahydrofolate reductase and methionine synthase polymorphisms and risk of bladder cancer in a Tunisian population. Cancer Genet Cytogenet 176:48–53 Ouerhani S, Marrakchi R, Bouhaha R, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, El Gaaied AB (2008) The role of CYP2D6*4 variant in bladder cancer susceptibility in Tunisian patients. Bull Cancer 95:1–4 Ouerhani S, Rouissi K, Marrakchi R, Ben Slama MR, Sfaxi M, Chebil M, ElGaaied AB (2009) Combined effect of NAT2, MTR and MTHFR genotypes and tobacco on bladder cancer susceptibility in Tunisian population. Cancer Detect Prev 32:395–402 Ouragini H, Cherif F, Daoud W, Kassar S, Charfeddine C, Rebaı¨ A, Boubaker S, Ben OsmanDhahri A, Abdelhak S (2008) Haplotypic classification of dystrophic epidermolysis bullosa in Tunisian consanguineous families: implication for diagnosis. Arch Dermatol Res 300:365–370 Ouragini H, Cherif F, Kassar S, Floriddia G, Pascucci M, Daoud W, Osman-Dhahri AB, Boubaker S, Castiglia D, Abdelhak S (2009) Dystrophic epidermolysis bullosa phenotypes in a large consanguineous Tunisian family. J Dermatol Sci 54:114–120 Piscopo P, Manfredi A, Malvezzi-Campeggi L, Crestini A, Spadoni O, Cherchi R, Deiana E, Piras MR, Confaloni A (2006) Genetic study of Sardinian patients with Alzheimer’s disease. Neurosci Lett 398:124–128 Raygani AV, Zahrai M, Raygani AV, Doosti M, Javadi E, Rezaei M, Pourmotabbed T (2005) Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran. Neurosci Lett 375:1–6 Rejeb I, Saillour Y, Castelnau L, Julien C, Bienvenu T, Taga P, Chaabouni H, Chelly J, Ben Jemaa L, Bahi-Buisson N (2008) A novel splice mutation in PAK3 gene underlying mental retardation with neuropsychiatric features. Eur J Hum Genet 16:1358–1363 Richard P, Gaudon K, Haddad H, Ammar AB, Genin E, Bauche´ S, Paturneau-Jouas M, M€ uller JS, Lochm€uller H, Grid D, Hamri A, Nouioua S, Tazir M, Mayer M, Desnuelle C, Barois A, Chabrol B, Pouget J, Koenig J, Gouider-Khouja N, Hentati F, Eymard B, Hantaı¨ D (2008) The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 71:1967–1972 Riou S, El Younsi C, Chaabouni H (1989) Consanguinite´ dans la population du nord de la Tunisie. Tunis Med 67:167–172 Sfar S, Hassen E, Saad H, Mosbah F, Chouchane L (2006) Association of VEGF genetic polymorphisms with prostate carcinoma risk and clinical outcome. Cytokine 35:21–28 Sfar S, Saad H, Mosbah F, Gabbouj S, Chouchane L (2007) TSP1 and MMP9 genetic variants in sporadic prostate cancer. Cancer Genet Cytogenet 172:38–44 Sfar S, Abid A, Mahfoudh W, Ouragini H, Ouechtati F, Abdelhak S, Chouchane L (2009a) Genetic analysis of hereditary multiple exostoses in Tunisian families: a novel frame-shift mutation in the EXT1 gene. Mol Biol Rep 36:661–667 Sfar S, Saad H, Mosbah F, Chouchane L (2009b) Combined effects of the angiogenic genes polymorphisms on prostate cancer susceptibility and aggressiveness. Mol Biol Rep 36:37–45 Siala O, Kammoun Feki F, Louhichi N, Hadj Salem I, Gribaa M, Elghzel H, Saad A, Triki C, Fakhfakh F (2008) Molecular prenatal diagnosis of muscular dystrophies in Tunisia and postnatal follow-up role. Genet Test 12:581–586 Slor H, Batko S, Khan SG, Sobe T, Emmert S, Khadavi A, Frumkin A, Busch DB, Albert RB, Kraemer KH (2000) Clinical, cellular, and molecular features of an Israeli xeroderma pigmentosum family with a frameshift mutation in the XPC gene: sun protection prolongs life. J Invest Dermatol 115:974–980 Smach MA, Charfeddine B, Lammouchi T, Harrabi I, Ben Othman L, Dridi H, Bennamou S, Limem K (2008) CSF beta-amyloid 1-42 and tau in Tunisian patients with Alzheimer’s disease: the effect of APOE epsilon4 allele. Neurosci Lett 440:145–149 Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Chouchane L (2005) Genetic variation in pro-inflammatory cytokines (interleukin-1beta, interleukin-1alpha and interleukin-6)

638

E. Hassen and L. Chouchane

associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw 16:253–260 Stayoussef M, Benmansour J, Al-Jenaidi FA, Nemr R, Ali ME, Mahjoub T, Almawi WY (2009) Influence of common and specific HLA-DRB1/DQB1 haplotypes on genetic susceptibilities of three distinct Arab populations to type 1 diabetes. Clin Vaccine Immunol 16: 136–138 Teebi AS, Al-Awadi SA, Farag TI, Naguib KK, el-Khalifa MY (1987) Phenylketonuria in Kuwait and Arab countries. Eur J Pediatr 146:59–60 Tlili A, Masmoudi S, Dhouib H, Bouaziz S, Rebeh IB, Chouchen J, Turki K, Benzina Z, Charfedine I, Drira M, Ayadi H (2007) Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB63 to chromosome 11q13.3-q13.4. Ann Hum Genet 71:271–275 Troudi W, Uhrhammer N, Sibille C, Dahan C, Mahfoudh W, Bouchlaka Souissi C, Jalabert T, Chouchane L, Bignon YJ, Ben Ayed F, Ben Ammar Elgaaied A (2007) Contribution of the BRCA1 and BRCA2 mutations to breast cancer in Tunisia. J Hum Genet 52:915–920 Troudi W, Uhrhammer N, Romdhane KB, Sibille C, Amor MB, Khodjet El Khil H, Jalabert T, Mahfoudh W, Chouchane L, Ayed FB, Bignon YJ, Elgaaied AB (2008) Complete mutation screening and haplotype characterization of BRCA1 gene in Tunisian patients with familial breast cancer. Cancer Biomark 4:11–8 Uhrhammer N, Abdelouahab A, Lafarge L, Feillel V, Ben Dib A, Bignon YJ (2008) BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases. Int J Med Sci 5:197–202 Warren L, Gibson R, Ishihara L, Elango R, Xue Z, Akkari A, Ragone L, Pahwa R, Jankovic J, Nance M, Freeman A, Watts RL, Hentati F (2008) A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson’s disease. Parkinsonism Relat Disord 14:77–80 Zghal M, Fazaa B, Kamoun MR (2006) Xeroderma pigmentosum. EMC (Elsevier SAS, Paris). Dermatologie 10:98–660 Zorai A, Harteveld CL, Bakir A, Van Delft P, Falfoul A, Dellagi K, Abbes S, Giordano PC (2002) Molecular spectrum of alpha-thalassemia in Tunisia: epidemiology and detection at birth. Hemoglobin 26:353–362 Zouari Bouassida K, Chouchane L, Jellouli K, Che´rif S, Haddad S, Gabbouj S, Danguir J (2004) Polymorphism of stress protein HSP70-2 gene in Tunisians: susceptibility implications in type 2 diabetes and obesity. Diabetes Metab 30:175–180

Chapter 22

Genetic Disorders in the United Arab Emirates Lihadh Al-Gazali and Bassam R. Ali

The Country and Population The United Arab Emirates (UAE) was founded in 1971 as a federation of seven emirates on the Arabian Gulf. It is bounded by Qatar on the northwest, Saudi Arabia on the west and southwest, Oman on the east and northeast, and the Arabian Gulf on the north. It occupies an area of 83,600 km2 and Abu Dhabi is the capital of the state. Six of the emirates lie on the southern shore of the Arabian Gulf and present a continuous coastline stretching some 600 km. The six emirates in geographical order from west to east are Abu Dhabi (which comprises 87% of the entire area of the UAE), Dubai, Sharjah, Ajman, Um Al-Quween, and Ras Al Khaimah. Fujairah is the only emirate without a coastline on the Arabian Gulf; it lies entirely on the Gulf of Oman. The UAE population was 1,043,225 in 1980 according to the 1980 population census. Since then, the population almost doubled every 10 years to reach 2,011,400 in 1992 and 3,750,000 in 2002. Currently, the population is estimated to be 5.3 million. The growth rate varied considerably from year to year with an annual growth of 5.9%. About 30% of the growth was due to natural increase and the rest due to inflow of expatriates (Alwash and Abbas 1999).

Population History The ancestors of this tribal population have not always lived in this region. They took possession of this land during successive waves of population movement, which brought Arab tribes from Yemen by way of Oman as well as by way of L. Al-Gazali (*) Department of Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates e-mail: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_22, # Springer-Verlag Berlin Heidelberg 2010

639

640

L. Al-Gazali and B.R. Ali

Central and Northern Arabia. They would have found people already settled in the economically viable locations, and there were probably some nomadic groups here as well, combining herding, hunting, and fishing (Heard-Bay 1999). There is in fact archaeological evidence of fairly well to do communities who lived in the area as far as 5,000 years ago. The descendants of this original population were probably absorbed, although some were for a long time identifiable as separate communities particularly in the mountains of Oman (Heard-Bay 1976). The local society was and is still tribal in nature. This implies that every individual in the society belongs to one of the 70 tribes which can now be identified in the UAE. This also means that traditionally his or her existence was largely regulated by the tribal community. Through the tribe and its hierarchy, the individual had protection, and the system also served as a strong defense for small, weak groups on their own in the desert. The tribe also provides economic security for individuals and within the family, and tribal unit tasks as well as resources are shared. The traditional tribal system even makes a young man’s choice of his bride largely unnecessary because he had in any case a first option for the daughter of his paternal uncle (Heard-Bay 1999). Most marriages were between close relatives to guarantee the continuity of the economic unity of the family (Heard-Bay 1976). Thus before the advent of oil, the entire population formed one homogenous society. Significant intermixing has probably only occurred with adjacent Arabs of the peninsula and with Persians and East Africans of the Omani Empire territories. Persian intermixing resulted from the alternating Arab and Persian domination of both coasts of the Arabian Gulf (Abdulla 1978). The slave traffic from Africa resulted in many blacks later being absorbed into the local community (Ramahi 1973). There has also been continuous exodus of Baluchis to Oman and the UAE. These people originate from Baluchistan which is across the Strait of Hormuz and are now in Iran, Afghanistan, and Pakistan. These people have a history that goes back over 2,000 years. In fact, attention has been drawn to the earliest inhabitants of Baluchistan, who moved across the gulf to Arabia after being defeated by Iranian Gedrasians sometime before Alexander’s conquest (Quaife et al. 1994). Although many of the Baluchis are now UAE nationals, they remain isolated with high level of inbreeding. Many do not speak Arabic and do not send their female children to school and therefore form very isolated communities.

Current Population Currently after several decades of immigration by foreign experts and laborers, the UAE society as a whole is anything but homogenous. It consists of, in addition to the original local population, a mixture of immigrants from Oman, Yemen, other Middle Eastern countries, North Africa, Iran, India, Pakistan, Bangladesh, Baluchistan, and Europe. Intermarriages with these immigrants are limited but increasing, although the majority of the Bedouins still form tribal communities which are

22

Genetic Disorders in the United Arab Emirates

641

quite isolated. Belonging to a well respected local tribe or an influential family is still of prime importance in today’s local society. Because of the large number of expatriates, the population pyramid in the UAE shows a unique composition. It has a normal base during childhood, and then the pyramid broadens in the age group 20–50 years (mainly males) constituting about 42.8% of the whole population. This feature is mainly due to the influx of young expatriate male workers. The pyramid gets narrower as the age exceeds 50 years constituting less than 2% of the population above 60 years (Alwash and Abbas 1999). The local population is also characterized by a consistently high fertility rate which is considered desirable by the government and various measures are in place to encourage fertility among the national population. The government does not support the provision of contraception, but there are no major limits on access to birth control options except abortion which is illegal (Annual Report Ministry of Health 1993). The family size is therefore large with an average of five children per family. Women continue to reproduce well after the age of 40 years and men well into their 60s. There has been steady decline in the death rate among nationals for all age groups, which is reflected in longer life expectancy, currently estimated at 74 years for males and 76 years for females. There has also been a significant decline in mortality among infants and children under 5 years of age which reached 8.19/ 1,000 and 10.5/1,000, respectively, in 2,000. With the decreasing incidence of child and infant mortality, congenital and hereditary diseases are receiving increased attention especially as such problems have been recorded as the fourth leading cause of death in the country during the last decade (Annual Report, Ministry of Health 2000).

Consanguinity The rate of consanguineous marriages in the UAE is high, estimated at 50.5% and the average coefficient of inbreeding up to second cousin is 0.0222 (Al-Gazali et al. 1997). The commonest type of consanguineous marriages is first cousin (26%). Furthermore, type 1 (paternal) first cousin constitutes 17% of all marriages and 64% of first cousin marriages. This is similar to that in other Arab countries and reflects the cultural practice among the Arab families of consulting with paternal uncles before accepting the marriage of a girl from a non-consanguineous partner (Al-Gazali et al. 1997). Other types of consanguineous marriages include double first cousin (3.5%), first cousin once removed (3.1%) and second cousin (3%) (Al-Gazali et al. 1997). There are also families with very complex consanguinity with very high coefficient of inbreeding particularly among the Bedouins and other isolates like Baluchis and Yemenis. The custom of consanguineous marriage is due to cultural and historical, rather than religious reasons. Such marriages are considered to be more stable and economically beneficial, through the maintenance of family fortune within the

642

L. Al-Gazali and B.R. Ali

family structure. This tradition is deeply rooted in the Arab culture and therefore is very difficult to change and is in fact, increasing rather than decreasing (Al-Gazali et al. 1997). The reason for this trend is not known, but a recent study assessing the attitude of the population toward consanguinity showed that the majority of people in this country still prefer this type of marriage for themselves and their children (Al-Gazali 2005).

Genetic Services In spite of the high frequency of genetic disorders in the UAE, genetic services are still fragmented and not very well established. Currently genetic services are provided by three centers. The first one is the Genetic and Thalassemia Center which is based in Dubai and was established by the Dubai Department of Health in 1989. This center provides services for thalassemia patients from all over the UAE. It is supported by cytogenetic, molecular, and biochemical diagnostic laboratories. The second one is based in Al-Ain in the Faculty of Medicine and Health Sciences (FMHS). It was established in 1990 and also provides service for patients from all Emirates. It is supported by a small cytogenetics laboratory and a developing molecular genetics laboratory. The third service is located in Abu Dhabi and it is under the Maternity and Child Health Department of the Ministry of Health. It was established in 1999 and the service is provided through two genetic clinics located in two primary health care centers supported by a cytogenetics laboratory. Genetic counseling in the three genetic centers is provided by clinical geneticists (three in total) who are not supported by genetic counselors, health visitors, or social workers. Premarital genetic counseling, mainly for thalassemia and sickle cell anemia, is also offered at the two primary health care centers in Abu Dhabi where the genetic clinics are run. Premarital testing for these disorders is currently compulsory. However, there are no options available for carriers as prenatal diagnosis is still not widely available and abortion is still not legal in this country. National screening for phenylketonuria (since 1995) and congenital hypothyroidisim (since 1998) is provided by the Maternity and Child Health Department. Sickle cell anemia screening at birth was added in 2001 in Abu Dhabi Emirate and implemented at the national level in 2005. Congenital adrenal hyperplasia screening program was initiated in 2005 in Abu Dhabi and implemented at the national level in 2007. The Maternity and Child Health Department also run a national registry for congenital abnormalities which was established in 2000, and a national registry for genetic diseases which was established in 2002. In addition, a registry for birth defects covering Al Ain Medical District was established in 1995 by members at the FMHS which subsequently became a member of the International Clearing House for Birth Defects (ICBD).

22

Genetic Disorders in the United Arab Emirates

643

Prenatal diagnosis service in general is not well established in the UAE as abortion is still not legal in this country. Antenatal diagnosis of fetal anomalies by ultrasonography is offered in Al Ain and Dubai and amniocentesis is also done in some cases in these centers. Chorionic villus sampling is not currently available but it is being developed in Al Ain. However, as there are no options available for couples, the benefits of prenatal diagnosis in the UAE remain questionable. A genetic interest group “Genetic and Development Research Priority Group” was formed at the FMHS in 2002. The mission of the group is to provide the highest quality patient care, research into genetic diseases, and education of both professionals and the public. In addition, the newly formed National Research Foundation will fund a research center of excellence in “Genes and Diseases” based at FMHS. In 2003, a new initiative by Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences resulted in the establishment of the “Center for Arab Genomic Studies” in Dubai. The main objectives of this center are (1) to raise public awareness on the importance of genetic diseases in the Arab world, (2) to identify disease causing genes in the Arab population, (3) to develop a database of genetic diseases prevalent in the Arab world, (4) to prevent genetic diseases by providing comprehensive genetic services, and (5) to develop a center of excellence in Dubai for genetic research and clinical services in the Arab world. This project is still in its early stages of implementation but a database of genetics diseases in Arab populations has been established and is available to the public. The government is committed to provide children with special needs and handicapped individuals the education and care they require and therefore several centers for this purpose have been established in the country. However, apart from the Thalassemia and the Down Syndrome Associations there are no patients or parents associations or support groups in this country, and this issue needs to be addressed.

Genetic Disorders in the UAE Genetic diseases are an important cause of morbidity and mortality in the UAE. According to the Ministry of Health Annual Report 2002, birth defects are the fourth cause of death in the UAE. In addition, the UAE is currently ranked 6th out of 193 countries in terms of prevalence of birth defects, mainly as a result of genetic causes (Christianson et al. 2006). More than 270 genetic diseases have been reported in the UAE population with about 60% of those diseases being autosomal recessive (Fig. 22.1). The epidemiology of genetic disorders in the UAE is especially complicated as many families and tribal groups have descended from a limited number of main ancestors and the disease genes present reflect the sample carried by the founding members. Therefore, some conditions are confined to specific villages, families, and tribal groups. This has lead to the fact that some groups have unusual burden of genetic diseases while others are free of genetic diseases. On the other hand, there

644

L. Al-Gazali and B.R. Ali

Fig. 22.1 Number and classification of genetic disorders reported in UAE population. Data compiled from CTGA database of the Center for Arab Genomic Studies (www.cags.org.ae). Accessed on 24/02/2009

are certain disorders which are common throughout the UAE like the thalassemias and hemoglobinopathies and G6PD deficiency. In addition, different congenital malformations caused by recessive genes and several metabolic disorders are also common across the UAE.

b-Thalassemia b-Thalassemia constitutes a major health problem in the UAE. There are no accurate data regarding the exact b-thalassemia frequency in the country; nevertheless, between 1989 and 2003, more than 850 patients have been registered at the Dubai Genetic and Thalssemia Center (Baysal 2005). However, DNA based data indicate this number to be much higher when other emirates are taken into account. Previous surveys showed that the UAE exhibits one of the highest carrier frequency of b-thalassemia in the Gulf region with defective allele frequency of 8.3% (Baysal 2001). Mutation analysis among UAE nationals and expatriate b-thalassemia patients demonstrated that the UAE is the most heterogeneous b-thalassemia population in the world with more than 50 different mutations reported to date (Baysal 2005 and personal cummunication). The most common mutation in the UAE is IVS-1-5 (G > C) which is known to exist at very high frequencies in the Indian subcontinent

22

Genetic Disorders in the United Arab Emirates

645

Table 22.1 The 11 most common b-thalasaemia mutations with their Gene Frequency in the UAE Mutation Gene frequency (%) IVS-1-5(G>C) 44.5 25 bp del 8.6 Cd 8/9 (+G) 3.0 IVS-11-1 (G>A) 2.8 Cd 39 C>T 2.2 Cd 8 (-AA) 2.2 Hb D-Punjab 2.2 Cd 30 (G>C) 2.1 Cd 5 (CT) 2.1 IVS-1-6(T>C) 1.5 88 (C>A) 1.1 Addapted from Baysal et al. (2007)

and among populations surrounding India but not among the Middle East Arabs. It is very likely that IVS-1-5 (G > C) allele was introduced to the Arabian Peninsula by gene migration from Baluchistan (Quaife et al. 1994). Its low frequency in Kuwait and high frequency in the UAE and Oman favor the speculation that the gene was introduced into the Arabian Peninsula across the Strait of Hormuz. This navigational route still constitutes a major trade link between the Indian Subcontinent and the Gulf states (Baysal 2005). One of the most striking features of b-thalassemia distribution in the UAE is the diversity of mutations. Table 22.1 shows the 11 most common mutations and their frequencies. It is apparent from molecular studies of b-thalassemia in the UAE that gene flow and heterogeneity of b-thalassemia mutations represent complex anthropological influence from the East Mediterranean, Asia, India, Sub-Sahara and East Africa, supporting the the hypothesis that the diversity of b-thalassemia mutations may reflect historical events and gene migration in the region (Baysal 2005).

Sickle Cell Disease (SCD) and Other Haemoglobinopathies The frequency of sickle cell disease (SCD) carriers in the UAE is 0.014 which is much lower than that found in Oman (0.06) (White et al. 1993). The overall picture of SCD disease in the UAE is that of mild to moderate severity similar to that observed in Eastern Saudi Arabia (Awad and Bayoumi 1993). However, there are also reports of severe SCD similar to the African type (White et al. 1993; Kamel 1979). Haplotype studies showed that 68% of the SCD patients in the UAE were homozygous for the Saudi Arabian/Indian haplotype (31/31), whereas only 8% were homozygous for the Bantu haplotype (20/20) which signifies the African influence. No homozygous Benin (19/19) was observed (Baysal 2005). This is in contrast to the haplotypes of patients of Omani origin where 34% had the 19/19

646

L. Al-Gazali and B.R. Ali

type, 24% had 20/20, and 22% had 31/31 type indicating the East African influence on the Arabian Peninsula (Baysal 2005). Haplotype 31 was associated with elevated mean HbF levels, as compared to the other two haplotypes. This resulted in less severe clinical symptoms and a majority of the patients with this haplotype did not require blood transfusion at all. Most of the sickle cell patients had concomitant a-thalassemia, which in turn reduced the severity of their disease. El-Kalla and Baysal (1998) identified eight different b-thalassemia mutations in heterozygous condition with the HbS allele. Seven of these eight mutations were beta-zero (b ) and their coexistence with the sickle gene manifested severe clinical symptoms. It was concluded that the SCD phenotypes are genetically complex and multifactorial and that epistatic factors influence the severity of the disease to a large extent.Other Hb variants seen in the UAE include Hb D-Punjab, Hb C, Hb E, and HbO-Arab, Hb Al Ain, Abu Dhabi (White et al. 1986; Abbes et al. 1992).

a-Thalassemia The frequency of a-thalassemia in the UAE is one of the highest in the world (El-Kalla and Baysal 1998). Almost half (49%) of those screened for an a-globin gene defect were positive (El-Kalla and Baysal 1998). Molecular characterization showed that the gene frequency of the alpha 3.7 was 0.2847 and that of alpha 4.2 was 0.0072. In addition, four non-deletional a-thalassemia mutations were found, alpha PA-1, alpha PA - 2, HbCS, and alpha 5ntdel with gene frequencies of 0.0036, 0.0012, 0.0024, and 0.0072, respectively (El-Kalla and Baysal 1998). Clinically most of the compound heterozygotes due to deletional and non-deletional a-thalassemia–2 were categorized phenotypically as very mild HbH disease (El-Kalla and Baysal 1998). Bart’s hydrops fetalis (/) and non-mutational HbH (/alpha) to our knowledge have not been seen in the UAE, which is also the case for other Gulf countries (El-Kalla and Baysal 1998).

G6PD Deficiency The frequency of G6PD deficiency in men in the UAE ranges from 11 to 15% (Bayoumi et al. 1996; Abdulrazzaq et al. 1999) while in females it is 5% (Bayoumi et al. 1996). This level is lower than that reported from neighboring Gulf countries such as Bahrain 21% (Mohammed et al. 1992) and Oman 27% (White et al. 1993); however, variable frequencies within different ethnic groups were found with UAE nationals and Yemenis at low frequency of 3–6% while Baluchis had a high frequency of 28–45% (Bayoumi et al. 1996). Among the non deficient subjects, the major normal phenotype was Gd B phenotype (Bayoumi et al. 1996). Of 18 deficient subjects, 14 had the B type mobility of G6PD Mediterranean and four had the A type mobility of G6PD.

22

Genetic Disorders in the United Arab Emirates

647

The Mediterranean mutation (563 C>T, 188 Ser>Phe) was found to be the most common mutation causing G6PD deficiency in the UAE. Other mutations detected include the African mutation 202 G>A, 68Val>Met and G6PD-Aures (143 T>C, 48 lle>Thr) (Bayoumi et al. 1996).

Cystic Fibrosis (CF) (MIM 219700) Several cases of CF from the UAE have been identified since its first report in the UAE (Benson et al. 1987; Abdul Aziz et al. 1991; Frossard et al. 1999a, b; Dawson and Frossard 1994). Twenty three patients with CF were investigated at the molecular level. Two mutations were found, del F508 and S549R (T>G) accounting for 46 out of 52 (88%) alleles and characterizing 95% (18 out of 19) of the affected families. All patients were homozygous for either of the two mutations (Frossard et al. 1999a, b). Both these mutations identified have been shown to affect the processing of the CFTR protein, leading to its degradation, and therefore, resulting in very severe forms of the disease. In addition, all patients of Bedouin origin (16) were homozygous for S549R (T>G) and all patients of Baluchi origin (7) were homozygous for del F508 (Frossard et al. 1999a). The authors also screened 400 asymptomatic UAE nationals for these mutations to establish the carrier frequency of these two mutations. The carrier frequency of S549R (T>G) was 1:100 and for del F508 was 1:200. From these figures, the carrier frequency of any CF mutation was estimated to be 1:63 and the frequency of affected CF subjects in the emirates population was 1:15,876. This figure was thought to be a conservative estimate (Frossard et al. 1999b). The clinical severities associated with the two cystic fibrosis (CF) mutations S549R (T>G) and deltaF508 were also compared (Dawson and Frossard 2000). Clinical and biochemical variables of CF were compared in two age- and sexmatched groups of CF children in the United Arab Emirates. The clinical severities of mutations S549R (T>G) and deltaF508 were very similar, with very low Shwachman scores and high sweat chloride levels indicating that patients homozygous for either of these mutations have a severe clinical presentation and illness, and are indistinguishable on clinical grounds. It was also suggested that the founding chromosomes for the S549R (T>G) may have originated in Bedouins of eastern Arabia (Dawson and Frossard 2000). Saleheen and Frossard (2006) reported an Emirati CF patient homozygous for the 3120þ1 G>A mutation.

Deafness Non-syndromic autosomal recessive deafness is common in the UAE. A genetic etiological survey of children attending classes for the deaf in the UAE, in whom a known acquired cause for their deafness had been excluded, showed that overall

648

L. Al-Gazali and B.R. Ali

there was a high prevalence of AR deafness (92%) in the study group with autosomal dominant deafness constituting 7% and sporadic deafness 1% (Al-Gazali 1998). Non-syndromic deafness was present in 81% of cases and most of those (98%) had autosomal recessive type. The frequency of connexin 26 mutation is not known in the UAE; however, two genes were mapped in two consanguineous families and a novel mutation in the otoferlin gene was found in another family from the UAE (Campbell et al. 1997; Pulleyn et al. 2000; Houseman et al. 2001).

Malformation Syndromes Several studies on the pattern of congenital anomalies in the UAE population have shown increased frequency of rare recessive syndromes or disorders (Al-Gazali et al. 1995a, 1999a, 2003a; Al-Talabani et al. 1998). It has also been shown that malformation syndromes are an important cause of morbidity and mortality in this community. For example a study to determine the causes of neonatal death in Al-Ain Medical District found that lethal malformations were the second cause of death, being responsible for 70% of deaths in normal-weight infants and almost half of these malformations were multiple anomalies that were due to specific autosomal recessive syndromes (Dawodu et al. 2000). Some of these syndromes are common throughout the population while others cluster in certain communities and some are restricted to one or two families. In addition, there are several new or previously not described syndromes. Examples of these syndromes include the following:

Bardet–Biedl Syndrome (MIM 209900) This autosomal recessive syndrome is known to be common in the Arab Bedouins (Teebi 1994). Several families from the UAE with this syndrome were evaluated. All affected children had polydactyly, retinitis pigmentosa, and obesity. In two families, the affected female children presented with hydrometrocolpos in the neonatal period. The molecular basis of this syndrome has not been established in the UAE.

Cohen Syndrome (MIM 216550) Seven children from three families with Cohen syndrome were evaluated. All presented with microcephaly with mental retardation and the typical facial appearance. Molecular study in two of these families revealed two different mutations in the COH1 gene [homozygous c.6530_6732del (deletion axon 37), (p.Val2245fsX16), homozygous mutation in axon 9 c.1225G > T (p.Glu409X)] (Taban et al. 2007).

22

Genetic Disorders in the United Arab Emirates

649

Donnai–Barrow Syndrome (MIM 222448) This autosomal recessive disorder is characterized by congenital diaphragmatic hernia, agenesis of corpus callosum, craniofacial dysmorphology, high myopia, sensorineural hearing loss, and developmental delay. This disorder was diagnosed in one large consanguineous family of Yemini origin and UAE nationality. There were five affected children in two branches. Molecular study revealed a homozygous mutation in LRP2 (Megalin) (7564T > C) (Kantarci et al. 2007).

Sanjad–Sakati Syndrome (MIM 241410) This autosomal recessive syndrome is characterized by severe failure to thrive, developmental delay, dysmorphic features, and hypoparathyroidism. It is known to be common in the Arabs and is caused by mutations in the TBCE gene. Seven children from six families all from the UAE were seen with this syndrome. However, no molecular studies were done on these children (Al-Gazali and Dawodu 1997; Al-Gazali unpublished data).

Hennekam Syndrome (MIM 235510) This is an autosomal recessive syndrome characterized by lymphangiectasia, severe peripheral lymphedema, facial anomalies, seizures, mild growth retardation, and variable mental retardation (Hennekam et al. 1989). Six children from five different families (four published) with this syndrome were evaluated. All had flat mid face with hypertelorism but only two of them had dysplastic ear with atretic ear canal. (Al-Gazali et al. 2003b, unpublished data). Intestinal lymphangectasia was present in five of the six patients. Three of the six had mild-borderline mental retardation and one had moderate retardation. (Al-Gazali et al. 2003b, unpublished data).

Fraser Syndrome (MIM 219000) In a family of UAE origin in which the parents were first cousins, five children out of a total of six had features of Fraser syndrome. All of them either died immediately after birth or were stillborn. All had cryptophthalmos, renal agenesis,

650

L. Al-Gazali and B.R. Ali

syndactyly, and abnormalities of the genitalia. Genetic study revealed a homozygous mutation in FRAS1 gene (c.9524A>C; p.3175Y>S) (van Haelst et al. 2008).

Mowat–Wilson Syndrome (MIM 235730) Mutation analysis of homeo box 1 B in a child with this syndrome ( Hirschsprung disease, distinct facial appearance, microcephaly, agenesis of corpus callosum, and mental retardation) revealed a de novo 7 bp deletion (1773 delTGGCCCC) resulting in a termination codon at aminoacid residue 604 (604X) in exon 8 (Sztriha et al. 2003).

Down Syndrome The birth prevalence of Down syndrome in Al-Ain medical district varied from 14.84 in 10,000 in 1996 to 26.30 in 10,000 in 2001 (Al-Gazali 2005). This increase is probably due to better ascertainment. Another study from Dubai found a birth prevalence of 22 per 10,000 in the national and expatriate population and 31 per 10,000 in the national population (Murthy et al. 2007). The mean maternal age of UAE national mothers was 33.48 8.08 with 41.66% of the mothers being in the advanced maternal age group (>35 years). The prevalence of the translocation and mosaic type of Down syndrome was very low (Murthy et al. 2007).

Brain Malformation Syndromes Brain malformation syndromes are common in the UAE. A prospective study of the pattern of CNS anomalies in 9,610 births in Al-Ain Medical District showed that 42% of the babies with congenital anomalies of the CNS had syndromic type of anomalies and 92% of these syndromes were inherited as autosomal recessive. Examples of such syndromes include microlissencephaly, micrencephaly and pontocerebellar hypoplasia with arthrogryposis, agyria-pachygyria, complex brain malformation with dense bones, and microcephaly caused by peroxismal defect (Al-Gazali et al. 1999a). Other recessively inherited brain malformation syndromes seen in the UAE include Walker–Warburg syndrome, eye-brain-muscle syndrome, AR cerebellar hypoplasia with cerebral gyral simplification, AR Dandy –Walker malformation, and bilateral frontal polymicrogyria (Guerrini et al. 2000). In a review of 25 patients with a spectrum of hindbrain malformations, Sztriha and Johansen (2005) found that 11 patients from six families had malformation of the hindbrain and midbrain with molar tooth sign (ten from five families had typical Joubert syndrome), five patients showed severe supratentorial anomalies in addition to hindbrain malformations, five patients had ponto-cerebellar or cerebellar hypoplasia with anterior horn cell disease in the

22

Genetic Disorders in the United Arab Emirates

651

spinal cord, and four patients showed malformations affecting predominantly the hindbrain without substantial involvement of other systems. Sztriha et al. (2004) reviewed the MRI findings and the clinical features of 14 children with the combination of microcephaly and abnormal gyral pattern. Seven patients showed features of simplified gyral pattern with relatively preserved posterior fossa structure, two had a cortical malformation in the agyria-pachgyria spectrum with agenesis of corpus callosum and cerebellar hypoplasia in one of them, two had polymicrogyria and leukoencephalopathy and cortical dysplasia, one had callosal and pontocerebellar dysplasia, and another had a simplified gyral pattern with severe cerebellar hypoplasia. In a child with X-linked recessive CRASH syndrome (corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus) Sztriha et al. (2000) identified a novel missense mutation in LICAM gene (c.604G>T; p.D202Y). The following are examples of brain malformation syndromes seen frequently in the UAE:

Joubert Syndrome (MIM 213300) Joubert syndrome is an autosomal recessive disorder characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. The neuroradiological hallmark of the disorder is a malformation of the midbrain–hindbrain junction known as the “molar tooth sign” consisting of cerebellar vermis hypoplasia or dysplasia, thick horizontally-oriented superior cerebellar peduncles, and abnormally deep interpeduncular fossa. This syndrome is seen frequently in the UAE. The birth prevalence in the UAE is estimated to be 1 in 5,000 (Al-Gazali et al. 1999a). Thirty eight cases from 15 families with Joubert syndrome were evaluated. Using homozygosity mapping, several genes and mutations were identified in some of these families. Gene AHI 1 CEP290 INPP5E

Exon 8 41 7 9

Mutation c.787dupC (p.Q263fs) c.5668G>T (p.G1890X) c.1534C>T (p.R512W) c.1543C>T (p.R515W) c.1688G>A (p.R563H)

Origin Palestinian UAE UAE (Omani origin) UAE (Omani origin) UAE (Omani origin)

References Dixon-Salazar et al. (2004) Valente et al. (2006) Biels et al. (2009)

Meckel Syndrome (MIM 249000) Another commonly seen syndrome is Meckel syndrome. This autosomal recessive syndrome has a birth prevalence of 1/5,000 in the UAE (Al-Gazali et al. 1999a) and is known to be common in Bedouins in Kuwait and in Palestinian Arabs (Teebi 1997). One family, originally from Oman, was studied at the molecular level and was found to have a homozygous mutation in mecklin (MKS3) gene (383384delAC, p.H128fsX140 (Smith et al. 2006).

652

L. Al-Gazali and B.R. Ali

AR Microcephaly (MIM 608716) This type of microcephaly is common in the UAE but no prevalence figures are available. Molecular study in one consanguineous family with eight affected children in two branches showed a mutation in ASPM gene (c.9751delA) (AlGazali unpublished data). One of the affected children in this family died of acute myeloid leukemia. Genetic study in another UAE family in which two affected children had severe microcephaly, and one of them had in addition, persistent vitreous and retinal detachment, revealed a homozygous mutation in ASPM gene (c.3067T>G) (Al-Gazali unpublished data). Seckel syndrome was diagnosed in two inbred UAE families. Three children were affected in the first family and two children in the second family. These children had severe microcephaly with receding forehead, bilateral radial dislocation, and short stature (Al-Gazali unpublished data).

Osteochondrodysplasias Osteochondrodysplasias are relatively common in the UAE. In a study of 38,084 births in Al Ain medical district, 36 cases of skeletal dysplasias were found (9.46 in 10,000) (Al-Gazali et al. 2003a). There was high prevalence of dysplasias caused by autosomal recessive genes (4.7/10,000 births) and new dominant mutations (2.62/ 10,000). Some of the dysplasias seen frequently in the UAE include the following:

Stuve–Wiedemann Syndrome (MIM 601559) This rare autosomal recessive syndrome is relatively common in the UAE (AlGazali et al. 1996a, 2003c). The syndrome is characterized by camptomelia, camptodactyly with pursing of the mouth on stimulation. The course of the disorder is complicated by hyperthermia, feeding and swallowing difficulties leading to frequent aspirations, and respiratory problems. Most children die in the first year of life. However, if they survive, they develop progressive spinal deformity associated with insensitivity to pain leading to self mutilating behavior and corneal scarring (Al-Gazali et al. 2003a, c). Thirty five cases from 21 families have been evaluated. Most of these families originated from Oman and Yemen. Molecular study revealed a founder mutation in the leukemia inhibitory factor receptor gene (LIFR) [c.653_654 insT at exon 6] in these families (Dagoneau et al. 2004; Al-Gazali unpublished data).

22

Genetic Disorders in the United Arab Emirates

653

Microcephalic Osteodysplastic Primordial Dwarfism Type II (MIM 210720) This disorder is seen in the UAE most commonly in families of Omani and Pakistani origin. Six children from six families have been evaluated. Using homozygosity mapping, the gene and mutations were identified in some of these families. Two mutations in pericentrin gene were identified in some of these families c.5767C > T (p.R1923X), c.1336C > T (p.Q446X) (Rauch et al. 2008).

Fibrochondrogenesis (MIM 228520) This disorder was found to be relatively common in the UAE with a birth prevalence of 1.05/10,000 births (Al-Gazali et al. 2003a). This disorder was thought to be lethal in the neonatal period. However, two out of the eight children evaluated in the UAE have survived, one is 3 years old and the other is 18 months old at the time of writing. Both have severe short stature and developmental delay.

Raine syndrome (MIM 279775) Raine syndrome is a lethal bone dysplasia characterized by generalized osteosclerosis with periosteal new bone formation and distinctive facies (Al-Gazali et al. 2003d). Four consanguineous families with several affected children were seen in Al-Ain. (Al-Gazali et al. 2003d, unpublished data) Molecular study in one of these families revealed a mutation in FAM20C gene (c.915-3C > G) (Simpson et al. 2007).

Dygve–Melchior–Clausen Syndrome (MIM 304950) This disorder was diagnosed in two families living in the UAE. One family was of Lebanese origin and the other one of Palestenian origin. Both had the typical clinical and radiological features. Molecular study showed a homozygous mutation in dymeclin gene (IVS II 1252-1G > A at exon 12 in one of these families (El Ghouzzi et al. 2003).

654

L. Al-Gazali and B.R. Ali

Ellis-van-Creveld (MIM 225500) and Jeune Syndromes (MIM 208500) Ellis-van-creveld syndrome is seen frequently in the UAE. Five families with this syndrome were studied at the clinical and molecular level. Molecular study revealed a homozygous mutation in exon 13 of EVC1 Q605X in one family, a homozygous deletion (c.981delG) in exon (8) of EVC2 in the second, and splice site homozygous change (IVS13-1G > T) in intron 13 of EVC2 gene in the third (Ali et al. in preperation). Two families with Jeune syndrome were evaluated. In one family, the child died in utero while the second family had two affected children, and both had the typical clinical and radiological features, but one was mildly affected and is doing well at the age of 13 years with no renal and retinal complication while the other child had a stormy neonatal course requiring management in the ICU but is doing well currently at the age of 7 years.

Larsen (MIM245600) and Desbuquois (MIM 251450) Syndromes Autosomal recessive Larsen syndrome was diagnosed in an inbred UAE family (Topley et al. 1994). Both children had severe intrauterine growth retardation, genu recruvatum, and multiple joint dislocations with limited extension of both elbows. In 1996, Al-Gazali et al reported a consanguineous Arab Bedouin family with Desbuquois syndrome. Affected members of the family had typical Desbuquois syndrome features including a midface hypoplasia and joint laxity. This was probably the first report on Desbuquois syndrome in Arab Bedouins. Using homozygosity mapping, the gene responsible for Desbuquois syndrome was mapped to chromosome 17q25.3 with a possible genetic homogeneity of the clinical subtype with hand anomalies (Faivre et al. 2003). Another consanguineous family from the UAE with one child affected with Desbuquois syndrome without hand anomalies was also seen (Al-Gazali unpublished data).

Acromesomelic Dysplasia Two families with acromesomelic dysplasia, Maroteaux type (MIM 602875), were evaluated. One was originally from Oman and had two affected sibs. One of the affected had in addition cervical spina bifida and died in the first few months of life. Molecular study in this family showed c.2869C > T change leading to p.R957C missense mutation in NRP2 gene (Bartels et al. 2004).

22

Genetic Disorders in the United Arab Emirates

655

Another family had Langer mesomelic dysplasis (MIM 249700) which was confirmed by molecular study showing homozygous deletion encompassing CA SHOX, GA SHOX, and CT SHOX (Al-Gazali unpublished data).

Limb/Pelvis/Hypoplasia/Aplasia Syndrome (MIM 276820) One family, originally Syrian Bedouins, had three children in two branches with the typical phenotype of this syndrome. This included ectrodactyly of the right hand with nail dysplasia, contractures at the right elbow joint, and no elbow joint on the left with left arm ending in an appendage which looked like a deformed finger with dysplastic nail; lower limbs were absent and replaced by a stick like appendage more severe on the right side. The second child had no elbow joints bilaterally and complete absence of the lower limbs. Molecular study in this family revealed a homozygous missense mutation in exon 4 in Wnt7 gene c.1179C > T leading to substitution of arginine for cysteine (Woods et al. 2006).

Wollcott–Rallison Syndrome (MIM 226980) Al-Gazali et al. 1995b reported an Omani family with two children affected with this syndrome. Molecular study revealed a homozygous mutation in E1F2Ak3 gene (IVS14+1G>A (Brickwood et al. 2003).

Miscellaneous Bone Dysplasias Other bone dysplasia seen in the UAE include short-rib-polydactyly type III, Schneckenbecken dysplasia, osteopetrosis, micromelic dwarfism (Al-Gazali et al. 2003a), OSMED (Al-Gazali and Lytle 1994), spondylometaepiphyseal dysplasia, abnormal calcification type (Al-Gazali et al. 1996b), omodysplasia (Al-Gazali and Abo saad 1995), chondrodysplasia puctata, thanatophoric dysplasia, and achondroplasia. In addition, several new forms of bone dysplasia were also described from the UAE (Al-Gazali et al. 2003a, 2001, Al-Gazali et al. 1996c).

Neurometabolic Disorders Inborn errors of metabolism comprise a wide range of autosomal recessive disorders which show defects in metabolism of carbohydrates, amino acids, organic acids, and fatty acids. Although the incidence of each of the inborn errors of metabolism is relatively low, the overall number of inborn errors of metabolism is rather high, affecting more than 2% of all live newborns. Reports from the Gulf

656

L. Al-Gazali and B.R. Ali

region indicate that metabolic diseases constitute a significant cause of neonatal and infant death and mental retardation. Most of the work in the Gulf region has been generated from Saudi Arabia, where 15 common metabolic diseases have been identified through a universal screening program (Afifi and Abdul-Jabbar 2007). The prevalence of this group of genetic diseases in UAE populations is believed to be high, but the molecular causes are not well established. A recent retrospective study on metabolic disorders at Al-Wasl Hospital in Dubai conducted by the Centre for Arab Genomic Studies Work Group (Al-Ali et al. 2006) between 1995 and 2004 and an audit by Al-Wasl Hospital indicated the presence of at least 30 metabolic disorders including phenylketonuria (PKU), homocystinuria, propionicacidemia, maple syrup urine disease (MSUD), kabbe disease, and galactosemia. In addition, Tawam Hospital (Tawam Hospital web site) indicates the presence of PKU, MSUD, b-ketothiolase, tyrosinaemia (Type2), isovaleric acidaemia, methylmalonic aciduria, homocystinuria, arginosuccinic, aciduria, and galactosaemia. It is clear that the most common metabolic disorder in the UAE is PKU with incidence of 1:20050 (Al-Hosani et al. 2003). The molecular basis and epidemiology of most inborn errors of metabolism disorders are not well established for Emirati population. Abdulrazzaq et al. (2009) screened 2,981 school children for homogentisic acid and identified a family with high levels of this metabolite indicating alkaptonuria. Molecular studies revealed a homozygous single nucleotide deletion at c.342 delA in exon 3 leading to a frame-shift at amino acid position 58 in all affected children (Abdulrazzaq et al. 2009). In the second study, a homozygous single nucleotide deletion in ARG1 gene in three affected siblings with arginase deficiency was identified and the carrier status of other members of the family was established (Herticant et al. 2009). Molecular study on three children from UAE (2 sibs and 1 unrelated child) with infantile GM1-gangliosidosis showed two novel mutations. The first one was a homozygous missense mutation in exon 4 of GLB1 gene, c.451G > T, and the second mutation was a splicing mutation in intron 8, c.914þ4A > G (Georgiou et al. 2004). Mevalonic aciduria was described in two very low birthweight sibs with unspecific clinical signs and recurrent septicaemia. Both were homozygous for a T > C transition at nucleotide 104 of mevalonate kinase gene (L35S) (Raupp et al. 2004). Hamdan et al. 2008 reported a 35 week part -of-twin neonate with Pompe disease. There was a history of an older sib who died with the same condition. Mutation analysis of GAA gene revealed homozygosity for c.1327-2A (GAA intr 8) (Hamdan et al. 2008).

Genodermatosis Ehlers–Danlos Syndrome VIA (EDSVIA) (MIM 225400) Ehlers–Danlos Syndrome Type VIA is an inherited connective tissue disorder characterized by severe muscular hypotonia and kyphoscoloisis at birth, joint hypermobility, and skin fragility. It is caused by a deficiency of collagen lysyl

22

Genetic Disorders in the United Arab Emirates

657

hydroxylase deficiency due to mutations in PLOD1 gene. Sixteen children from 12 Bedouin UAE families were identified as having this disorder. Some of them were diagnosed initially as Nevo syndrome. However, molecular study showed that in fact Nevo syndrome and EDSVIA are allelic. A founder mutation In the PLOD1 gene was found in these families (p.R319X nonsense mutation) (Giunta et al. 2005 and Al-Gazali unpublished data).

Epidermolysis Bullosa Epidermolysis bullosa is a group of inherited disorders of the skin and characterized by blistering of the skin and mucous membranes even with minor trauma. The disease is traditionally classified into three groups: (1) epidermolysis bullosa simplex results from separation of the skin above the basement membrane, (2) junctional epidermolysis bullosa (MIM 226700) is manifested by blister formation within the basement membrane, and (3) in dystrophic epidermolysis bullosa (MIM 226600), blisters appear below the basement membrane. Two major clinical variants of junctional epidermolysis bullosa subtype have been reported, namely, the Herlitz and the moderately severe non-Herlitz junctional epidermolysis bullosa. The Herlitz type is associated with extensive skin and mucosal blistering, nail dystrophy, exuberant granulation tissue, enamel defects, and a high perinatal mortality resulting from overwhelming infections and respiratory complications. The non-Herlitz type on the other hand is characterized by localized to generalized blistering, nail dystrophy, scarring alopecia, and mucosal involvement. The different types of epidermolysis bullosa are seen frequently in the UAE. In their seminal study, Al-Talabani et al. (1998) observed two cases of generalized atrophic benign epidermolysis bullosa in consanguineous families from the UAE. They also reported the recurrence of this condition in other members of the family. Non-Herlitz junctional epidermolysis bullosa was identified in a consanguineous family originating from the UAE (Nakano et al. 2002). The affected child turned out to be heterozygote for two mutations, Q1083X and 1296insA, in the LAMB3 gene. Interestingly, both the grandmothers of the child originated from Palestine. Several families with pyloric atresia-junctional epidermolysis bullosa (MIM226730) were seen in the UAE (Lestringant et al. 1992; Al-Gazali unpublished data). Molecular study in one of these families showed missense mutation (S47L) in ITAG6 gene resulting in rapid decay of alpha 6 integrin (Allegra et al. 2003a, b). In a consanguineous UAE family, two children were affected with epidermolysis bullosa-muscular dystrophy, and one of them died at the age of 4 months. The children presented with blistering in the neonatal period involving the limbs and face and were severely hypotonic with increased CPK (Al-Gazali unpublished data).

658

L. Al-Gazali and B.R. Ali

Atopic Dermatitis Atopic dermatitis is an allergic hypersensitivity inflammation reaction affecting skin. In some patients, the condition may also be associated with allergic rhinitis, food allergy, urticaria, and/or increased IgE production. Lestringant et al. (1996) described three patients from the UAE with an association of lichen nitidus and atopic dermatitis.

Congenital Ichthyosis and Related Conditions Congenital ichthyosis is a clinically and genetically heterogeneous group of disorders of keratinization characterized by a significant and incapacitating scaling of the skin. Most forms are congenital and display different modes of inheritance. Al-Talabani et al. (1998) observed one case of autosomal recessive lamellar ichthyosis in a consanguineous family from the UAE out of 24,233 consecutive live and stillbirths at Corniche hospital in Abu Dhabi. Lestringant et al. (1998) reported five UAE sibs from a consanguineous family with normal stature, diffuse congenital ichthyosis, generalized and diffuse non-scarring hypotrichosis, and marked hypohidrosis. On the dorsum of the wrists and around the elbows and knees there was a zone where ichthyosis progressively transformed into follicular atrophoderma. The ichthyosis was present at birth; there were no collodion babies. Steroid sulfatase activity was normal and this excluded the possibility of an X-linked recessive ichthyosis and the authors concluded that this family may suffer from a previously described autosomal recessive genodermatosis. Molecular study in the family revealed a homozygous splice site mutation (c.2269þ1G > A) in the gene suppression of tumorigenicity-14 (ST14) (Alef et al. 2009).

Waardenburg–Shah Syndrome (MIM 277580) Waardenburg–Shah syndrome is divided into four distinct types on the basis or absence of dystopia canthorum: (1) type I with dystopia canthorum, (2) type II without dystopia canthorum, (3) type III without dystopia canthorum but with a one-sided ptosis, and (4) type 4, patients presenting with aganglionosis in association with hypopigmentation. Abdulrazzaq (1989) reported a full term baby boy with Waardenburg’s syndrome in the UAE of Omani origin with long segment Hirschsprung’s disease, who was born to a non-consanguineous Omani family. Two male siblings who died during the neonatal period had long segment Hirschsprung’s disease.

22

Genetic Disorders in the United Arab Emirates

659

Erythrokeratodermia Variabilis (MIM 133200) Erythrokeratodermia variabilis is a rare genetic disorder that is inherited through an autosomal dominant gene with variable expressivity. Erythrokeratodermia variabilis is characterized by two distinct morphologic features: erythematous patches and hyperkeratotic plaques. In 2004, Galadari and Galadari described a 4-year-old girl with a history of erythematous skin lesions on her face, extremities, forearms, and joints that started a few months after birth and the condition progressed over a period of time. There was no family history of a similar problem, although her older brother showed marginal hair loss without any skin lesions. The hair showed normal appearance, but there was no hair growth on the margins of the scalp. No molecular data are available about this family.

Mal de Meleda Disease (MIM 248300) Mal de Meleda is a rare autosomal recessive disorder characterized by diffuse transgressive palmoplantar keratoderma, keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities. Hyperkeratosis soon appears after birth and progresses with age and extends from the palms and soles onto the dorsal surface of the hands and feet, elbows, and knees without involvement of other organs. Lestringant et al. (1992, 1997) reported families from the UAE with Mal de Meleda with unusual features including prominent knuckle pads, peculiar finger-nail anomalies, and pseudo-ainhum on both fifth fingers. Patients of one of the families were the product of consanguineous marriages. Four years later, Lestringant et al. (2001) examined five patients and reported that the patients had diffuse erythrodermic PPK and transgressive erythrodermic keratosis, often with scaly borders, plaques of erythrodermic keratosis on the knees, and red nails with preserved lunula; none had hyperhidrosis. The MDM interval on chromsome 8q was excluded by homozygosity mapping in all three families. Lestringant et al. (2001) concluded that the MDM phenotype is due to at least two different genotypes. When the oldest patient was aged 23, keratoderma palmoplantaris was grayish, diffuse and waxy, and smooth and reported mutations affecting the initiation codon in SLURP-1 gene (Ecckl et al. 2003).

Restrictive dermatopathy (MIM 275210) Restrictive dermatopathy (RD) is a severe neonatal skin syndrome characterized by intrauterine growth retardation, taut translucent and easily eroded skin, and multiple joint ankylosis. Affected children usually die shortly after birth. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24 that

660

L. Al-Gazali and B.R. Ali

are predicted to cause loss of function of the encoded zinc metalloproteinase STE24. Two distantly related families from the UAE were reported to have two children with RD. The diagnosis was confirmed by skin biopsy. Both died at the age of 2 months. In both patients, a homozygous splice site mutation c.627+1G > C in ZMPSTE24 was identified. Accumulation of prelamin A could be detected at the nuclear envelope of the patient’s blood lymphocyte (Sander et al. 2008).

X-Linked Dyskeratosis Congenita (MIM 305000) This is a rare multisystem disorder characterized by lesions in the skin and appendages. Pulmonary manifestation is another rare feature. It is caused by mutations in DKC1 gene on Xq28.Two sibs originally from Egypt were studied at the molecular level and were found to have a novel missense mutation 5C > T (A > V) in exon 1 of the DKC1 (Dyskerin) gene (Safa et al. 2001).

Neuromuscular Disorders Spinal Muscular Atrophy, Type I (MIM 253300) In their study, Al-Talabani et al. (1998) reported three cases of type I spinal muscular atrophy born to first cousin couples from the UAE. No molecular data are available about this condition in UAE populations. Four children with congenital spinal muscular atrophy were identified during a 2 year prospective study of congenital malformations in the UAE (Al-Gazali et al. 1995a, b). All presented with arthrogryposis multiplex at birth. Similarly, in a prospective study on the pattern of CNS anomalies in the UAE, Al-Gazali et al. (1999a, b) found 1 affected child in 9,610 births. No molecular studies were performed on these children.

Muscular Dystrophy, Congenital, 1B (MIM 604801) Congenital muscular dystrophy 1B represents a heterogeneous group of conditions characterized by proximal girdle weakness, generalized muscle hypertrophy, and rigidity of the spine and contractures of the tendo Achilles. Muntoni et al. (1998) described a form of autosomal recessive congenital muscular dystrophy characterized by proximal muscle weakness, generalized muscle hypertrophy, rigidity of the spine, and contractures of the Achilles tendons in children from a UAE consanguineous family. Severe diaphragmatic involvement was responsible for the early respiratory failure in children. Serum creatine kinase levels were grossly elevated,

22

Genetic Disorders in the United Arab Emirates

661

and muscle biopsy samples showed dystrophic changes. Biochemical data from muscle indicated that affected individuals have laminin alpha-2 deficiency (LAMA2). However, linkage analysis excluded the LAMA2 gene locus on 6q22-q23. Further genome-wide linkage studies by Brockington et al. (2000) performed on the same family found a homozygous region on 1q42, spanning 6–15 cM in two affected children. The two affected sisters died as a result of respiratory complications at the ages of 4 and 7 years.

Myotonic Dystrophy 1 (MIM 160900) Myotonic dystrophy 1 is the most common dominant inherited neuromuscular disease in adults, with incidence rates of about 1 in 7,400 live births. The disorder shows a very wide range of presentations and progressions. The adult onset form typically presents with distal dystrophy and myotonia after 20 years of age and progress leading to significant disability. Characteristic facial changes are also common including low-set ears, a hatchet chin, and drooping of the lips and ptosis. Severe cases of adult-onset myotonic dystrophy may also show presenile cataracts, testicular atrophy, diabetes, kidney failure, and early frontal balding in males. Anwar et al. (1986) reported a 35 year old Emirati man with dystrophia myotonica and characteristic appearance of a long and haggard face with bilateral partial ptosis, atrophy of the temporalis and masseter muscles, atrophy of the sternomastoids, and premature frontal baldness. Tests in this patient revealed increased insertional activities with frequent fibrillations, myotonic discharges, primary gonadal failure, typical diabetic curve, and marked testicular atrophy. In a UAE family, a mother was affected with myotonic dystrophy confirmed by molecular study. She had five children with congenital myotonic dystrophy. All presented with severe hypotonia and arthrogryposis multiplex. Two died in the neonatal period and the other three are alive at the age of 15, 12, and 10 years. All are severely retarded (Al-Gazali unpublished data).

Neurogenetic Disorders Other than Neurodegenerative Disorders Congenital Insensitivity to Pain Sixteen children from six families with congenital insensitivity to pain were evaluated. One was of Palestinian origin, one of Baluchi origin, and the rest were UAE Bedouins. All had self mutilating behavior with repeated infections, fractures, and joint dislocations. Some presented with hyperthermia in the first few weeks of life because of the lack of sweating. In one family, the children had normal

662

L. Al-Gazali and B.R. Ali

intelligence, in one there was severe developmental delay, and the rest had mild-moderate delay. Molecular study showed a mutation in the NGFB gene in one of these families. In another UAE family, one affected child with congenital insensitivity to pain associated with anhydrosis (Sztriha et al. 2001) was found to have homozygosity for 30 splice site mutation G > C in the first position of intron 4 (IVS4-1G > C) of NTRK1 gene (Mardy et al. 1999). In addition, the child had C > A transversion at nucleotide 337 in exon 2, which causes an Arg > Ser substitution at aminoacid 85. The authors suggested that the phenotype in this child is probably caused by these double mutations although the IVS4-1G > C is likely to be the main cause considering the effect of exon skipping or alternative splicing (Mardy et al. 1999).

AR Spastic Paraplegia with Thin Corpus Callosum This condition was diagnosed in one large consanguineous family with six affected children in two branches and two small families with two affected in one and one affected in the other. Homozygosity mapping in the large family localized the gene to chromosome 8p12-p11.21 between marker D8S1820 and D8S532 with a LOD Score of 7.071, but candidate gene analysis was negative so far (Al-Yahyaee et al. 2006).

Crisponi Syndrome (MIM 601378) This rare autosomal recessive disorder is characterized by congenital muscular contraction of facial muscles, with trismus in response to stimuli, dysmorphic features with bilateral camptodactyly, major feeding and respiratory difficulties, and hyperthermia leading to death in the first few months of life. It overlaps with Stuve–Wiedemann syndrome (SWS) but there is no congenital lower limb bowing which is characteristic in SWS. Three families were seen with this syndrome and molecular study in one family showed a homozygous mutation in cytokine related factor CRLF1 (c.527þ5G>A) (Dagoneau et al. 2007).

Progeriod Syndromes Several syndromes leading to premature aging have been diagnosed in the UAE.

22

Genetic Disorders in the United Arab Emirates

663

Generalized Lipodystrophy of Seip (MIM 269700) Four families, each with one affected child with this disorder, were evaluated. All had the typical features except one child who presented at birth with lipodystrophy and had high serum lipids. Molecular study in three families revealed mutations in AGPAT2 in two families (CG 8100, del 158G homozygous [H52sx59]) and a mutation in BSCL2 gene (658 del GTATC [F105fsx111] (Agarwal et al. 2003; Al-Gazali unpublished data).

Neonatal Progeria (Wiedemann-Rautenstrauch Syndrome) (MIM 264090) Four children from two families with this condition were seen. One family with one affected child was originally from Yemen. The child presented at birth with growth retardation (weight, height, and head circumference were all below 3rd centile), aged facial appearance, prominent scalp veins with wide sutures and fontanelle, scaphocephaly with triangular face, small eyes with sparse eyebrows and eyelashes, curved profile of the nose, small pointed chin and contractures at the elbow joints, and large hands and feet with generalized deficient subcutaneous fat. Serum cholesterol and triglycerides were elevated (Al-Gazali unpublished data). The other family was originally from Lebanon and had three affected children. All had the typical features presenting from birth. The eldest is 22 years old now and is probably one of the few patients with this syndrome who survived till adulthood (Al-Gazali unpublished data). Mutation analysis in both LMNA gene and ZMPSTE24 gene were negative (Ali unpublished data).

SHORT Syndrome (MIM 269880) This syndrome is characterized by short stature, hyperextensibility of the joints, hernias, ocular depression, Rieger anomaly, and teething delay. In a UAE family four children and their father had features suggestive of this syndrome. The parents were first cousins once removed and the parents of the father were distantly related. One sister of the father had similar phenotype. All affected had failure to thrive since birth with dysmorphic features which included old looking appearance of the face, large eyes which were deep set, pinched nose and small mouth, and prominent forehead and ears. The teeth were small and there was reduced subcutaneous fat all over the body. Ophthalmological examination was normal. There was no Rieger anomaly. It is likely that this syndrome is inherited as autosomal recessive disorder in this family. However, autosomal dominant inheritance cannot be ruled out (Al-Gazali unpublished data).

664

L. Al-Gazali and B.R. Ali

Gerodermia Osteodysplastica (GO) (MIM 231070) Go is an autosomal recessive disorder characterized by lax wrinkled skin, joint laxity, and a typical face with a prematurely aged appearance. Skeletal signs include severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia, and a variable degree of growth retardation. Four families from the UAE (1 Palestinian, 1 Syrian, 1 UAE of Bahraini origin, 1 from Qatar) with a phenotype overlapping GO and the wrinkly skin syndrome characterized by congenital skin wrinkling, most pronounced on the dorsum of the hands and feet, triangular face with a progeroid appearance with hypoplasia of the jaw resulting in a prominent chin, and generalized connective tissue weakness with fingers contractures (Al-Gazali et al. 2001, Revesade et al. 2009). SCYL1B1 mutations were excluded in these families. Genetic studies on these families identified four different mutations in the PYCR1 gene c.617_633þdel, c.797þ2_797þ 5del (p.Lys215_Asp139del), c.535G > A(p.Ala179Thr), c.616G > A (p.Gly206Arg) (Revesade et al. 2009).

Leprechaunism and Leprechaunism-like Syndromes (MIM 246200) In a Yemeni family living in the UAE, five out of eight children were affected with a syndrome very similar to leprechaunism but a milder phenotype was evaluated (Al-Gazali et al. 1993). All the affected individuals are still alive in their 20s. Molecular study revealed a new mutation in the insulin receptor gene (Ile119Met) (Hone et al. 1994). Two other families of UAE origin had two affected children each with classical leprechaunism.

Setleis Syndrome (MIM 227260) This syndrome is characterized by distinctive bitemporal scar-like depression resembling forceps marks, lateral deficiency of the eyebrows, double row eyelashes, and of course, aged facial appearance. An inbred family from the UAE had two children and an uncle from the father side affected with this syndrome (Al-Gazali and Al Talabani 1996). Molecular study in this family identified a nonsense mutation in the TWIST1 gene (p.Q119X) (Desnick et al. 2004).

Genetic Disorders of the Kidneys Congenital nephrosis is seen frequently in the UAE. Molecular study in three families with congenital nephrosis showed a homozygous mutation in exon 9 of NPHS1 gene (c.1134G > A, p.W378X) in one family and a homozygous missense

22

Genetic Disorders in the United Arab Emirates

665

mutation in exon 6 of NPHS2 gene (p.V260E) in the other two families (Al-Gazali unpublished data). Abou-Chaaban et al. (1997) studied the pattern of pediatric renal diseases among children in the Dubai Emirate during the period from 1991 to 1996. In this period, a total of 712 pediatric patients, including 230 nationals of the United Arab Emirates, were seen with various renal problems. Of a total of 13 patients with congenital nephrotic syndrome, three were nationals from the United Arab Emirates. These patients either expired, within the first two weeks of life, or were on conservative treatment awaiting cadaveric donor renal transplantation. Abou-Chaaban et al. (1997) noted that consanguineous parents were a striking feature among their patients with congenital nephritic syndrome. In a family originally from Pakistan with childhood onset glomerular kidney disease and ocular abnormalities affecting seven children, a compound heterozygosity for two novel mutations in LAMB2 gene was found (p.Q1728X, p.DV79) (Matejas et al. 2006). Proximal renal tubular acidosis associated with ocular abnormalities was diagnosed in a family originally of Jordanian Bedouin origin. Molecular study showed a homozygous mutation in NBC1 gene (R881C) (Horita et al. 2005). Two families with renal tubular acidosis associated with deafness were seen but no molecular studies were performed.

Genetic Disorders of the Eyes Several genetic disorders affecting the eyes have been identified in the UAE. Examples include retinitis pigmentosa with and without mental retardation, congenital glaucoma and cataract, and congenital Leber’s amourosis. In one UAE family in which the parents were first cousins, three out of seven children were diagnosed with osteoporosis-pseudoglioma syndrome presenting with blindness at birth and developing fractures during childhood. Autosomal recessive anophthalmia/microphthalmia is also seen frequently in the UAE. Al-Gazali et al. (1994b) reported on a child of consanguineous parents with microphthalmia and distal limb abnormalities. The authors suggested that the features in this child represent a milder manifestation of ophthalmo-acromelic syndrome. No molecular studies have been done so far to identify the genes involved in all of these disorders. In a consanguineous UAE family, two sibs were affected with Goldmann syndrome (MIM 268100). Both had poor vision and night blindness since early childhood. Ophthalmoscopy showed macular and peripheral retinoschisis as well as clumps of pigment and subretinal changes along the temporal vascular arcades and in the mid-peripheral fundus (Chavala et al. 2005). Molecular study revealed a homozygous mutation in exon 6 of the NR2E3 gene (c.932G > A, p.Arg311Gln) (Chavala et al. 2005). Two families from the UAE were diagnosed with achromatopsia (MIM 262300) which is also known as rod monochromacy or total color blindness (Ahuja et al 2008). This is an autosomal

666

L. Al-Gazali and B.R. Ali

recessive disorder with an incidence of less than 1in 30,000. It presents in infancy with poor vision, pendular nystagmus, severe sensitivity to light, and complete lack of color perception (Ahuja et al. 2008). Two mutations in the CNGA3 gene were found in these families (c.847C > T p.Arg283Trp and c.1190G > T p.Gly397Val (Ahuja et al. 2008). In the first family, one branch was homozygous for p.Gly397Val mutation and the second branch was compound heterozygous for p.Gly397Val and p.Arg283Trp while the second family was homozygous for p.Arg283Trp mutation (Ahuja et al. 2008).

Miscellaneous Genetic Disorders In a family originally from Oman, one child was diagnosed with infantile systemic hyalinosis (MIM 2364900). This is an autosomal recessive disorder in which the main clinical symptoms include painful joint contractures, generally thickened skin with livid-red hyper pigmentation over bony prominence, fleshy nodules in the perianal region, gingival hypertrophy, and increased susceptibility to bone fractures and infections. The child presented with joint contractures, restlessness, and pain on handling. He had livid-red macular lesions over bony prominences. Genetic study revealed homozygous mutation in the CMG2 gene (p.L45P) (Al-Gazali unpublished data). In an inbred UAE family, four children were diagnosed as having combined immune deficiency microcephaly of Cemunnous/XLF type (Al-Gazali unpublished data). Multiple pterygium syndrome (MIM 265000) was diagnosed in one UAE national family originally from Pakistan. Two children were affected. Both presented with joint contractures at birth and developed pterygia with time. Both had expressionless face and had normal intelligence. Genetic study revealed a homozygous mutation in the embryonal acetylcholine receptor subunit (CHRNG) (IVS4-9T > C) (Morgan et al. 2006). Autosomal recessive Russell-silver syndrome was seen in nine children from two inbred UAE families originally from Oman. Features included Intrauterine Growth Retardation (IUGR), triangular face, large eyes, depressed nasal bridge, short neck, short thorax with pectus excavatum, asymmetric length of limbs, clinodactyly, and normal intelligence. There was poor response to growth hormone therapy (Al-Gazali unpublished data). Examples of other genetic disorders reported or seen in the genetic clinic include ataxia telengectasia, Chediac-Higashi syndrom, Cornelia de Lange syndrome, Noonan syndrome, neurofibromatosis, tuberous sclerosis, Crouzon and Saethre-Chotzen syndrome, Cockayne syndrome, Beckwith-wiedemann syndrome, Coffin-Seris syndrome, hypophosphatasia, Williams syndrome, Prader-Willi and Angelman syndrome, Bruck syndrome, Holt-Oram syndrome, split hand/foot malformation with long bone deficiency (Naveed et al. 2007), and Sotos syndrome (Table 22.2).

CHIME-like syndrome (MIM 612379) Catechoaminergic polymorphic ventricular tachycardia Peters plus like syndrome

Bifid nose, renal and rectal Malformation (MIM 608980) Bamforth-like syndrome

Macrocephaly-multiple epiphyseal dysplasia (MIM607131)

Retinopathy, aplastic anemia, CNS abnormalities with IUGR (MIM 268130) Agyria-pacygyria with agenesis of corpus callosum Al-Gazali syndrome (MIM 609465)

þ þ þ

UAE

Sudanese

Syrian

þ

Palestinian

þ þ

Palestinian Omani

7p14-p22

FREM1 c.2721delG (p.V907fs)

Ch.15q26

þ

Sudanese

þ

þ

Palestinian

Egypt

?

Gene and mutation

Sudanese

Table 22.2 New genetic disorders diagnosed in the UAE Disorder Ethnic origin Consanguinity

Anterior segments anomalies of eye, growth retardation, endocrine abnormalities

Choanal atresia,athelia/ hypothelia and thyroid gland anomalies Ichthyoisis, ocular coloboma, brain malformation Sudden death

Macrocephaly with absence of corpus callosum and multiple epiphyseal dysplasia Nasal defect with renal agenesis and rectal atresia

Anterior segment anomalies of the eye with clefting and skeletal abnormalities

Same as in title

Manifestation

Genetic Disorders in the United Arab Emirates (continued)

Al-Gazali et al. 2009

Bhuiyan et al. 2007

Al-Gazali et al. 2008

Al-Gazali et al. (2002a, b)

Al-Gazali et al. 2002a, Alazami et al. 2009

Al-Gazali and Bakalinova (1998), Bayoumi et al. (2001)

Al-Gazali et al. 1994a, 1999b

Sztriha et al. 1998

Revesz et al. (1992)

References

22 667

Manifestation

As in title

As in title

þ

þ

þ

UAE

UAE of Omani origin

Sudanese

Micrencephaly with simplified gyral pattern with abnormal myelination and arthrogryposis Optic nerve coloboma and renal anomalies associated with arthrogryposis multiplex Congenital bowing associated with camptodactyly and agenesis of corpus callosum

þ

UAE (Baluchi origin)

TORCH-like syndrome

þ

þ

Flat face with joint dislocation and congenital heart disease Macrocephaly, webbed neck, CHD, distinctive face Scalp defect, abnormal ear and hypoplastic nipple with developmental delay Developmental delay, brain calciffication and destruction, cataract, CHD. Brain malformation , microcephaly and arthrogryposis

Gene and mutation

þ

Consanguinity

UAE

UAE (Iranian origin) UAE

Ethnic origin

Scalp-ear-nipple like syndrome

Noonan-like

Larsen-like

Table 22.2 (continued) Disorder

Al-Gazali et al. (2000b)

Al-Gazali et al. (2000a)

Sztriha et al. 1999

Al-Gazali et al. (1999c), unpublished data

Al-Gazali et al. 2007

Al-Gazali et al. (1996a, b, c)

Baasanjav et al. 2009

References

668 L. Al-Gazali and B.R. Ali

22

Genetic Disorders in the United Arab Emirates

669

Future Directions It is clear that genetic disorders have a great impact on morbidity and mortality in the UAE creating a burden on the health system and financial resources. Despite the progress in genetics research and the establishment of several prevention programs for genetic diseases in this country, genetic disorders continue to be a big problem in this country and genetic counseling has not been very effective in the control of these disorders. This is probably due to the cultural and religious beliefs of the community, the unchanging traditional practice of consanguineous marriages, and most importantly to the lack of options available to carrier couples. For any prevention program to be effective, options need to be made available for the community. This point need to be addressed and the current legal and religious attitudes in this country need to be discussed and reviewed. In addition, effective genetic counseling requires an appropriate infrastructure with adequate genetic diagnostic facilities. For a small population like that of the UAE, there should be one national center to deal with referred cases, implement research projects, and develop expertise in disorders which are prevalent in this community. The center should also provide specialist training for clinical genetics, molecular genetics, and cytogenetics in addition to training genetic counselors. The newly established “Genes and Disease Research Center” in the FMHS is a step in the right direction. The government should also promote the development of education programs and materials for the community and encourage collaboration with non-government organizations with emphasis on patients and parents organizations ensuring the care for individuals with handicap or chronic illness and their integration into society. In addition, more research on the molecular causes of single-gene disorders should be prioritized in view of the immediate impact of such findings on diagnosis and prevention approaches.

References Abbes S, Rad A, Fitzgerald P, Dormer P, Blouquit Y, Kister J, Galacteros F, Wajeman H (1992) HB Al Ain Abu Dhabi [a 18(A16)Gly!Asp]: A new haemoglobin variant discovered in an Emirati family. Haemoglobin 16:355–362 Abdul Aziz S, Salem F, Gohary A (1991) Cystic fibrosis in the United Arab Emirates. Emerg Med J 9:202–204 Abdulla MM (1978) The United Arab Emirates: a modern history. Harper and Row, New York, pp 221–243 Abdulrazzaq YM (1989) Waardenburg’s syndrome with long segment Hirschsprung’s disease in an Omani family. Emirates Med J 7:26–29 Abdulrazzaq YM, Micallef R, Qureshi MM, Dawodu A, Ahmed I, Khidr A, Bastaki SMA, Al-Kayat AI, Bayoumi RA (1999) Diversity in expression of glucose-6-phosphate dehydrogenase deficieny in females. Clin Genet 55:13–19 Abdulrazzaq YM, Ibrahim A, Al-Khayat AI, Nagelkerke N, Ali BR (2009) R58fs Mutation in the HGD Gene in a Family with Alkaptonuria in the UAE. Ann Hum Genet 73:125–130

670

L. Al-Gazali and B.R. Ali

Abou-Chaaban M, Al Murbatty B, Abdul Majid M (1997) Spectrum of pediatric renal diseases in Dubai. Saudi J Kidney Dis Transpl 8:310–313 Afifi AM, Abdul-Jabbar MA (2007) Saudi newborn screening. A national public health program: needs, costs, and challenges. Saudi Med J 28:1167–1170 Agarwal A, Simha V, Arioglu Oral E, Gordon P, O’Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A, Ricker A, White NH, Bindl L, Herbst K, Kennel K, Patel S, Al-Gazali L, Garg A (2003) Pheotypic and Genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840–4847 Ahuja Y, Kohl S, Traboulsi EI (2008) CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis 14:1293–1297 Alazami AM, Shaheen R, Alzahrani F, Snape K, Saggar A, Brinkmann B, Bavi P, Al-Gazali LI, Alkuraya FS (2009) FREM1 mutations cause bifid nose, renal agenesis and anorectal malformations syndrome. Am J Hum Genet 85:414–418 Al Talabani J, Shubbar AI, Mustafa KE (1998) Major congenital malformations in United Arab Emirates (UAE): need for genetic counselling. Ann Hum Genet 62(Pt 5):411–418 Al-Ali MT, Al-Hashmi H, Mohammed N, Ahmed Z (2006) New perspectives in inborn errors of metabolism: the Dubai experience. In Genetic Disorders in Arab World-Bahrain, Centre for Arab Genomic Studies Work Group Alef T, Torres S, Hausser I, Metze D, Tursen U, Lestringant GG, Hennies HC (2009) Ichthyosis, follicular atrophoderma and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J Invest dermatol 129:862–869 Al-Gazali LI (1998) A genetic aetiological survey of severe childhood deafness in the United Arab Emirates. J Trop Paed 44:157–160 Al-Gazali LI (2005) Attitudes towards genetic counseling in the United Arab Emirates. Community Genet 8:48–51 Al-Gazali LI, Abo Saad F (1995) Autosomal Recessive Omodysplasia. Clin Dysmorphol 4: 52–57 Al-Gazali LI, Al Talabani J (1996) Setleis Syndrome: Autosomal Recessive or Autosomal Dominant Inheritance. Clin Dysmorphol 5:249–254 Al-Gazali LI, Dawodu A (1997) The syndrome of hypoparathyroidism growth retardation, developmental delay and distinctive facies. Clin Dysmorphol 6:233–237 Al-Gazali LI, Bakalinova D (1998) Autosomal recessive syndrome of macrocephaly multiple epiphyseal dysplasia and distinctive facial appearance. Clin Dysmorphol 7:177–184 Al-Gazali LI, Khalil M, Devadas K (1993) A Syndrome of Insulin Resistance Resembling Leprechaunism in Five Sibs of Consanguineous Parents. J Med Genet 30:470–475 Al-Gazali LI, Lytle W (1994) Otospondylomega epiphyseal dysplasia (OSMED) report of three sibs and review of the literature. Clin Dysmorphol 3:46–54 Al-Gazali LI, Al-Talabani J, Mosawi A, Lytle W (1994a) Anterior segment anomalies of the eye, clefting and skeletal abnormalities Michls syndrome or new syndrome? Clin Dysmorphol 3:238–244 Al-Gazali LI, Sabarinathan K, Khidir A (1994b) Micropthalmia and distal limb abnormalities. Clin Dysmorphol 3:258–262 Al-Gazali LI, Dawodu AH, Sabarinathan K, Varghese M (1995a) The profile of congenital abnormalities in UAE population. J Med Genet 32:7–13 Al-Gazali LI, Makia S, Azzam A, Hall C (1995b) Walcott-Rallison Syndrome. Clin Dysmorphol 4:227–234 Al-Gazali L, Varghese M, Varady E, Al Talabani J, Scorer J, Bakalinoval D (1996a) Neonatal Schwartz-Jampel syndrome: a common AR syndrome in the UAE population. J Med genet 33:203–211 Al-Gazali LI, Bakalinova D, Sztriha L (1996b) Spondylo Metaepiphyseal Dysplasia Abnormal Calcification type. Clin Dysmorphol 5:197–206 Al-Gazeli LI, Aziz SA, Bakalinova D (1996c) Desbuquois syndrome in an Arab Bedouin family. Clin Genet 50(4):255–259

22

Genetic Disorders in the United Arab Emirates

671

Al-Gazali LI, Aziz SAA, Salem F (1996d) A syndrome of short stature, mental retardation, facial dysmorphism, short webbed neck, skin changes and congenital heart disease. Clin Dysmorphol 5:321–327 Al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, Al-Kayat AI, Gaber T (1997) Consanguineous marriages in the United Arab Emirates. J Biosoc Sci 29:491–497 Al-Gazali LI, Sztriha L, Dawodu A, Varady E, Bakir M, Khadir A, Johansen J (1999) Complex consanguinity associated with short rib polydactyly syndrome III and congenital infection like syndrome: a diagnostic problem in dysmorphic syndromes. J Med Genet 36:461–466 Al-Gazali LI, Sztriha L, Dawodu A, Bakir M, Varghese M, Varady E, Scorer J, Abdulrazzaq YM, Bener A, Padmanabhan R (1999a) Pattern of central nervous system anomalies in a population with a high rate of consanguineous mattiages. Clin Genet 55:95–102 Al-Gazali LI, Bakir M, Sedaghatian MN, Nath R, Hass D (1999b) Anterior segment anomalies of the eye with multiple skeletal anomalies and early lethality: confirmation of an autosomal recessive syndrome. Clin Dysmorphol 8:81–92 Al-Gazali LI, Dawodu A. The syndrome of hypoparathyroidism growth retardation, developmental delay and distinctive facies. (1997) Clin Dysmorphol 6 :233–237 Al-Gazali LI, Bakir M, Hamid MY, Haas D, Amirlak I, Rushdi R (2000a) A new syndrome of optic nerve colobomas and renal abnormalities associated with arthrogryposis multiplex. Clin Dysmorphol 9:183–189 Al-Gazali LI, Bakir M, Hamid MY, Nath R, Haas D (2000b) Congenital bowing of the long bones associated with camptodactyly and agenesis of corpus callosum. Clin Dysmorphol 9:93–99 Al-Gazali LI, Sztriha L, Sakaff F, Hass D (2001) Gerodermia Osteodysplatica and wrinkly skin syndrome: are they the same. Am J Med Genet 101:213–220 Al-Gazali LI, Bakir M, Hamud OA, Gerami S (2002a) An autosomal recessive syndrome of nasal anomalies associated with renal and ano-rectal malformations. Clin Dysmorphol 11:33–38 Al-Gazali LI, Hamid Z, Hertecant J, Bakir M, Nath KA (2002b) An autosomal recessive syndrome of choanal atresia, athelia/hypothelia and thyroid gland anomalies overlapping Bamforth’s syndrome ANOTHER syndrome and methimazole emberyopathy. Clin Dysmorphol 11:79–85 Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghese M, Haas D, Bener A, Padmanabhan R, Abdulrazzaq YM, Dawodu A (2003a) Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Res (Part A) 125:125–132 Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R (2003b) Further delineation of Hennekam syndrome. Clin Dysmorphol 12:227–232 Al-Gazali LI, Ravenscroft A, Feng A, Shubber A, Al-Saqqaf A, Haas D (2003c) Stuve-Wiedemann syndrome in children surviving infancy: clinical and radiological features. Clin Dysmorphol 12:1–8 Al-Gazali L, Jehier K, Nazin B, Abtin F, Haas D, Sadagahatian R (2003d) Further delineation of Raine syndrome. Clin Dysmorpholo 12:89–94 Al-Gazali LI, Alwash R, Abdulrazzaq YM (2005) United Arab Emirates: Communities and Community Genetics. Community Genet 8:186–196 Al-Gazali L, Nath R, Iram D, Al Malik H (2007) Hpotonia, developmental delay and features of scalp-ear-nipple syndrome in an inbred Arab kindred. Clin Dysmorphol 16:105–107 Al-Gazali L, Hertecant J, Algawi K, El Teraifi H (2008) A new autosomal recessive syndrome of ocular colobomas. Ichhthyosis, brain malformations and endocrine abnormalities in an inbred emirati family. Am J Med Genet A 146A:813–819 Al-Gazali L, Shather B, Kaplan W, Algawi K, Ali B (2009) Anterior segment anomalies of the eye, growth retardation associated with hypoplastic pituitary gland and endocrine abnormalities: Jung syndrome or new syndrome? Am J Med Genet 149:251–256 Al-Hosani H, Salah M, Saade D, Osman H, Al-Zahid J (2003) United Arab Emirates National Newborn Screening Programme: an evaluation 1998-2000. East Mediterr Health J 9:324–332 Allegra M, Gagnoux-Palacios GY, Roques S, Lestringant G, Ortonne J, Meneguzzi G (2003a) Rapid decay of alpha 6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J Invest Dermatol 121:1336–1346

672

L. Al-Gazali and B.R. Ali

Allegra M, Gagnoux-Palacios GY, Roques S, Lestringent G, Otonne J, Meneguzzi G (2003b) Rapid decay of alpha 6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia. J Invest Dermatol 121:1336–1346 Alwash R, Abbas A (1999) Public Health practice in UAE. Public Health Med 1:113–117 Al-Yahyaee S, Al-Gazali LI, Al-Barwany H, Al-Kindi M, Chand P, Khoul R, Poovathor J, Guru Raj A, Sztriha L, Parrado A, Ott J, De Jonghe P, Van Broeckhoven C, Timmerman V, Bayoumi RA (2006) A novel locus for autosomal recessive hereditary paraplegia with thin corpus callosum and epilepsy. Neurology 66:1230–1234 Anwar S, Afify H, Hussein A (1986) Dystrophia myotonica presenting as infertility. Emirates Med J 4:137–139 Awad M, Bayoumi R (1993) Sickle cell disease in adult Bedouins of Al Ain District, UAE. Emerg Med J 11:21–24 Baasanjav S, Al-Gazali L, Hashiguchi T, Mizumoto S, Fischer B, Horn D, Seelow D, Ali BR, Aziz SA, Langer R, Becker C, Nurnberg G, Cantagrel V, Gleeson JG, Linder TH, Nurnberg P, Sugahara K, Mundlos S, Hoffmann K (2009) Faulty initiation step (GIcAT-I) of proteoglycan synthesis causes joint dislocations, facial abnormalities and congenital heart defect, a distinct disease that overlaps with Larsen syndrome, multiple hereditary exostosis, Ehlers-Danlos syndrome and progeria (submitted) Bartels CF, Bukulmez H, Padayatti P, Rhee DK, Ravenswaaiji-Arts CV, Pauli RM, Mundlos S, Chitayat D, Shih L, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, KirkJ MGR, Akker FVD, Warman ML (2004) Human skeletal growth is regulated by transmembrane natriuretic peptide receptor NPR-B. Am J Hum Genet 75:27–34 Bayoumi RA, Nur-E-Kamal MSA, Tadayyon M, Mohamed KKA, Mahboob BH, Qureshi MM, Lakhani MG, Ausiad MO, Kaeda J, VullamyTJ LL (1996) Molecular characterization of erythrocyte glucose –6-phosphate dehydrogenase deficiency in Al Ain District, United Arab Emirates. Hum Hered 46:136–141 Bayoumi R, Saar K, Nurnberg G, Reis A, Nur-E-Kamal M, Al-Gazali LI (2001) Localization of a gene for an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED) and distinctive facies to chromosome 15q26. J Med Genet 38:369–373 Baysal E (2001) Hemoglobinopathies in the United Arab Emirates. Hemoglobin 25:247–253 Baysal E (2005) Molecular heterogeneity of b thalassemia in the United Arab Emirates. Community Genet 8:35–39 Baysal E, Yousef I, Zeinali M, Abdulla H, Essa M, Taleb M (2007) Molecular basis oh haemoglobinopathies in the UAE: implication for prenatal diagnosis and prevention programmes. Emerg Med J 25:7–21 Benson PF, Fahmy NA, Vaswani K, Semrin A (1987) Cystic Fibrosis in the United Arab Emirates. A Case report. Emerg Med J 5:156–157 Bhuiyan ZA, Hamdan M, Shamsi E, Postma AV, Mannens MM, Wilde A, Al-Gazali L (2007) A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22. J Cardiovasc Electrophysiol 8:1060–1066 Biels SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki M, Rosti O, Kayserili H, Scott LC, Field SJ, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG (2009) Mutations in the inositol polyphosphate-5-phosphatase E gene link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41:1032–1036 Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn D, Wolson DI, Hanley NA (2003) Wolcott-Rallison syndrome: pathogenic insight into neonatal diabetes from new mutation and expression studies of ELF2Ak3. J Med Genet 40:685–689 Brockington M, Sewry CA, Herrmann R, Naom I, Dearlove A, Rhodes M, Topaloglu H, Dubowitz V, Voit T, Muntoni F (2000) Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Am J Hum Genet 66:428–435 Campbell DA, McHale DP, Brown KA, Moynihan LM, Houseman M, Karbani G, Parry G, Janjua AH, Newton V, Al-Gazali LI, Markham AF, Lench NJ, Mueller RF (1997) A new locus for non-syndromal autosomal recessive sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22. J Med Genet 34:1015–1017

22

Genetic Disorders in the United Arab Emirates

673

Chavala SH, Sari A, Lewis H, Pauer GJT, Simpson E, Hagstrom SA, Traboulsi EIT (2005) An Arg311GIN NR2E3 mutation in a family with classic Goldmann-Favre syndrome. Invest Ophthalmol Vis Sci 46: E-abstract 1824 Christianson A, Modell B, Howson C (2006) March of Dimes global report on birth defects: the hidden toll of dying and disabled children. White Plains, NY: March of Dimes Birth Defects Foundation Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A, Marrinovic J, Raas-Rothschild A, Sigaudy S, Unger S, Nicole S, Fontaine B, Taupin J, Moreau J, Superti-Furga A, Le Merrer M, Bonaventure J, Munnich A, Legeai-Mallet L, Cormier-Daire V (2004) Null Leukemia Inhibitory Factor Receptor (LIFR) mutations in Stuve-Wiedemann/ Schwartz-Jampel 2 syndrome. Am J Hum Genet 74:298–305 Dagoneau N, Bellais S, Blanchet P, Srda P, Al-Gazali L, Di Rocco M, Huber C, Goff L, Munnich A, Cormier-Daire V (2007) Mutations in Ctytokine-Like Factor 1 (CRLF1) account for both Crisponi and Cold Induced Sweating syndromes. Am J Hum Genet 80:966–970 Dawodu A, Vardy E, Varghese M, Al-Gazali LI (2000) Neonatal audit in the United Arab Emirates: a country with rapidly developing economy. East Mediterr Health J 6:55–64 Dawson K, Frossard P (1994) Cystic Fibrosis in the UAE: Clinical presentation. Emerg Med J 12:245–247 Dawson KP, Frossard PM (2000) The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Paediatr 159:496–499 Desnick RJ, Tukel T, Diaz N, Al-Gazali LI, Marion RW, Clark RD, Cadilla C (2004) Homozygous nonsense mutations in TWIST2 gene cause Setleis syndrome. Am Hum Genet Meeting, Toornto Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, Gleeson GG (2004) Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75:979–987 Ecckl KM, Stevens HP, Lestringant G, Westenberger-Treumann M, Traupe H, Hinz B, Frossard PM, Stadler R, Leigh IM, Nurnberg P, Reis A, Hennies HC (2003) Mal de Meleda caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates. Hum Genet 112:50–56 El Ghouzzi V, Dagoneau N, Kinning E, Thauvin-Robinet C, Chemaitilly W, Prost-Squarcioni C, Al-Gazali L, Verloes A, Le Merrer M, Munnich A, Trembath R, Cormier-Daire V (2003) Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchoir-Clausen Syndrome. Hum Mol Genet 12:357–364 El-Kalla S, Baysal E (1998) Alpha thalassemia in the United Arab Emirates. Acta Haematol 100:49–53 Faivre L, Le Merrer M, Al-Gazali LI, Ausems MG, Bitoun P, Bacq D, Maroteaux P, Munnich A, Cormier-Daire V (2003) Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3. J Med Genet 40:282–284 Frossard P, Hertecant J, Bossard Y, Dawson KP (1999a) Genotype-phenotype correlations in Cystic Fibrosis: clinical severity of mutation S549R (T>G). Eur Respir J 13:100–102 Frossard P, Lestringant G, Girodon E, Goossens M, Dawson KP (1999b) Determination of the prevalence of Cystic Fibrosis in the United Arab Emirates by genetic carrier screening. Clin Genet 55:496–497 Galadari I, Galadari H (2004) Case study: erythrokeratodermia variabilis. Skin med 3:231–232 Georgiou T, Drousiotou A, Campos Y, Caciotti A, Sztriha L, Gururaj A, Ozand P, Zammarchi E, Morrone A, D’Azzo A (2004) Four novel mutations in patients from the middle east with infantile form of GM1-gangliosidosis. Hum Mutat 24:352 Giunta C, Randolph A, Al-Gazali LI, Brunner HG, Kraenzlin ME, Steinmann B (2005) The Nevo syndrome is allelic to the kyphoscoliotic type of Ehlers-Danlos syndrome VIA (EDS VIA)expansion of the phenotype. Am J Med Genet 133A:158–164 Guerrini R, Barkovich AJ, Sztriha L, Dobyns WB (2000) Bilateral frontal polymicrogyria: a newly recognized brain malformation syndrome. Neurology 54:909–913

674

L. Al-Gazali and B.R. Ali

Hamdan MA, Almalik MH, Mirghani HM (2008) Early administration of enzyme replacement therapy for Pompe disease: short term follow up results. J Inherit Metab Dis [Epub ahead of print] Heard-Bay F (1976) The people of the UAE. Em Nat Hist Group (Abu Dhabi) 5:11–15 Heard-Bay F (1999) The Tribal society of the UAE and its traditional economy. In: Edit Gareeb E, Al Abed I (eds) Perspectives on the UAE. Trident Press Ltd, London, pp 254–272 Hennekam RCM, Geerdink RA, Hamel BCJ, Hennekam FAM, Kraus P, Rammeloo JA (1989) Autosomal recessive intestinal lymphangiectasia and lymphedema with facial anomalies and mental retardation. Am J Med Genet 34:593–600 Herticant J, Al-Gazali L, John A, Karuvantevida NS, and Ali BR (2009) A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family. Saudi Med J 12:160–163 Hone J, Acillin D, Al-Gazali LI, Lestringant G, Orban T, Taylor SI (1994) Homozygosity for a new mutation Ile 119 – met in the insulin receptor gene in 5 siblings with familial insulin resistance. J Med Genet 9:715–717 Horita S, Yamada H, Inatomi J, Moriyama N, Sekine T, Igarashi T, Endo Y, Dasouki M, Ekim M, Al-Gazali L, Shimadzu M, Seki G, Fujita T (2005) Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. J Am Soc Nephrol 16:2270–2278 Houseman MJ, Jackson AP, Al-Gazali LI, Badin RA, Roberts E, Mueller RF (2001) A novel mutation in a family with non-syndromic sensorineural hearing loss that disrupt the newly characterized OTOF long isoform. J Med Genet 38:E25 Kamel K (1979) Heterogeneity of sickle cell anaemia in Arabs: review of cases with various amounts of fetal haemoglobin. J Med Genet 16:428–430 Kantarci S, Al-Gazali L, Hill R, Donnai D, Black G, Bieth E, Chassaing N, Lacombe D, Devriendt K, Teebi A, Loscertales M, Robson C, MacLaughlin DT, Noonan K, Russell M, Walsh C, Donahoe PK, Pober B (2007) Mutations in megalin, a multiligand receptor, cause DonnaiBarrow syndrome and facio-oculo-acoustic-renal syndromes. Nat Genet 39:957–959 Lestringant GG, Hadi SM, Qayed KI, Blayney BJ (1992) Mal de Meleda: recessive transgressive palmoplantar keratoderma with three unusual facultative features. Dermatology 184:78–82 Lestringant GG, Frossard PM, Adeghate E, Qayed KI (1997) Mal de Meleda: a report of four cases from the United Arab Emirates. Pediatr Dermatol 14:186–191 Lestringant GG, Kuster W, Frossard PM, Happle R (1998) Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am J Med Genet 75:186–189 Lestringant GG, Frossard PM, Eckl KM, Reis A, Hennies HC (2001) Genetic and clinical heterogeneity in transgressive palmoplantar keratoderma. J Invest Dermatol 116:825–827 Lestringant GG, Piletta P, Feldmann R, Galadari I, Frossard PM, Saurat JH (1996) Coexistence of atopic dermatitis and lichen nitidus in three patients. Dermatology 192(2):171–173 Mardy S, Miru Y, Endo F, Mastsuda I, Sztriha L, Frossard P, Moosa A, Imail EAR, Macaya A, Andria G, Toscano E, Gibson W, Graham GE, Indo Y (1999) Congenital insensitivity to pain with anhydrosis: novel mutations in the TRKA (NTRK1) gene encoding a high affinity receptor for nerve growth factor. Am J Hum Genet 64:1570–1579 Marsh SE, Leeflang EP, Woods CG, Guru Raj A, Al-Gazali LI, Sztriha L, Gleeson JG (2003) Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 73:656–662 Matejas V, Al-Gazali L, Amirlak I, Zenker M (2006) A syndrome comprising childhood-onset glomerular kidney disease, cataract, anterior chamber abnormalities, and progressive loss of vision is caused by mutated LAMB2. NDT Nephrol Dial Transplant 21:3283–3286 Ministry of Health, United Arab Emirates (1993). Annual Report Ministry of Health, United Arab Emirates (2000). Annual Report Mohammed AM, Al-Hilli F, Nadkarni KV, Bhagwat GP, Bapat JP (1992) Hemoglobinopathies and glucose – 6 – phosphate dehydrogenase deficiency in hospital births in Bahrain. Ann Saudi Med 12:536–539

22

Genetic Disorders in the United Arab Emirates

675

Morgan N, Brueton L, Cox P, Greally M, Tolmi J, Pasha S, Aligianis IA, van Bokhoven H, Marton T, Al-Gazali L, Morton JEV, Oley C, Johnson CA, Trembath RC, Brunner HG, Maher ER (2006) Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and escobar variants of multiple pterygium syndromes. Am J Hum Genet 79:390–392 Muntoni F, Taylor J, Sewry CA, Naom I, Dubowitz V (1998) An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22. Eur J Paediatr Neurol 2:19–26 Murthy SK, Malhortra AK, Mani S, Shara ME, Al-Rowaished EE, Naveed S, Alkhayat AI, Alali MT (2007) Incidence of Down syndrome in Dubai, UAE. Med Princ Pract 16:25–28 Nakano A, Lestringant G, Paperna T, Bergman R, Greshoni R, Frossard P, Kanaan M, Meneguzzi G, Pulkkinen L, Sprecher E (2002) Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. J Am Acad Dermatol 46:510–516 Naveed M, Nath SK, Gaines M, Al-Ali MT, Al-Khaja N, Hutchings D, Golla J, Deutsch S, Bottani A, Antonarakis SE, Ratnamala U, Radhakrishna U (2007) Genome wide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1. Am J Hum Genet 80:105–111 Pulleyn LJ, Jackson AP, Roberts E, Carridice A, Muxworthy C, Houseman M, Al-Gazali LI, Lench NJ, Markham AF, Mueller RF (2000) A new locus for autosomal recessive nonsyndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23-q31. Eur J Hum Genet 8:991–993 Quaife R, Al-Gazali LI, Abbes S, Fitzgerald P, Old J (1994) Spectrum of B thalassemia mutations in the UAE national population. J Med Genet 34:59–61 Ramahi SA (1973) Economic and political evolution in the Arabian Gulf States. Carlton Press, New York, pp 42,45,57,81,203 Rauch A, Theil CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dorfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, VoB E, Wilson L, Hennekam R, de Zegher F, Dorr HG, Reis A (2008) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319:816–819 Raupp P, Varady E, Duran M, Wanders RJ, Waterham HR, Houten SM (2004) Novel genotype of mevalonic aciduria with fatalities in premature siblings. Arch Dis Child Fetal Neonatal Ed 89 (1):F90–F91 Revesade B, Escandle-Beillard N, Dimopoulou A, Fischer B, Chng SC, Li Y, Shboul M, Tham PY, Kayserili H, Al-Gazali L, Shahwan M, Brancati F, Lee H, O’Connor B, Schmidt-von Kegler M, Merriman B, Nelson SF, Masri A, Guerra D, Ferrari P, Nando A, Rajab A, Markie D, Gray M, Nelson J, Grix A, Sommer A, Savarirayan R, Janecke AR, Steichen E, Sillence D, HauBer I, Budde B, Nunberg P, Seeman P, Zambruno G, Dallapiccola B, Schuelke M, Robertson S, Hamamy H, Wollink B, Maldergem LV, Mundlos S, Kornak U (2009) Mutations in the PYCR1 gene cause Cutis Laxa with progeroid features. Nat Genet 41(9):1016–1021 Revesz T, Fletcher S, Al-Gazali LI, DeBuse P (1992) Bilateral retinopathy aplastic anaemia and central nervous system abnormalities. Possibly a new syndrome. J Med Genet 29:673–675 Safa WF, Lestringant GG, Frossard PM (2001) X-linked dyskeratosis congenital:restrictive pulmonary disease and a novel mutation. Thorax 56:891–894 Saleheen D, Frossard PM (2006) 3120+1 G!A: a rare variant in Emirati CF patients. J Coll Physicians Surg Pak 16:139–140 Sander CS, Salman N, van Geel M, Broers JL, Al-Rahmani A, Chedid F, Hausser I, Oji V, Al Nuaimi K, Berger TG, Verstraeten VL (2008) A newly identified splice site mutation in ZMPSTE24 causes dermatopathy in the Middle East. Br J Dermatol 159:961–967 Simpson MA, Hsu R, Keir LS, Hao J, Sivapalan G, Ernst LM, Zackai EH, Al-Gazali LI, Hulskamp G, Kingston HM, Prescott TE, Ion A, Patton MA, Murday V, George A, Crsby AH (2007)

676

L. Al-Gazali and B.R. Ali

Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. Am J Hum Genet 81:906–912 Smith UM, Tee JT, Consugar M, Tee LJ, McKee BM, Maina E, Whelan S, Morgan NV, Gissen P, Goranson E, Aligianis IA, Lilliquist S, Ward CJ, Pasha S, Sharif SM, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Punyashthiti R, Cox P, AlGazali L, Trembath RC, Torres VE, Kelly DA, Attie-Bitach T, Maher ER, Gattone VH, Harris PC, Johnson CA (2006) Meckelin (MKS3), a novel transmembrane protein is mutated in MeckelGruber syndrome and the wpk rat. Nat Genet 38:191–196 Sztriha L, Al-Gazali LI, Dawodu A, Bakir M, Chandran P (1998) Agyria-Pachygria, a genesis of the corpus callosum and crebellar hypoplasia: Autosomal recessive inheritance with neonatal death. Neurology 50:1466–1469 Sztriha L, Al-Gazali LI, Varady E, Goebel H, Nork M (1999) Autosomal recessive Micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis. Neuropediat 30:141–145 Sztriha L, Frossard P, Hofstra RM, Verlind E, Nork M (2000) Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis and hydrocephalus. J Child Neurol 15:239–243 Sztriha L, Lestringant GG, Hertecant J, Frossard PM, Masouye I (2001) Congenital insensitivity to pain with anhydrosis. Pediatr Neurol 25:63–66 Sztriha L, Espinosa-Parrilla Y, Gururaj A, Amiel J, Gerami S, Johansen JG (2003) Frameshift mutation of the zinc finger homeo box 1 gene in syndromic corpus callosum agenesis (MowatWilson syndrome). Neuropediatrics 34:322–325 Sztriha L, Daodu A, Gururaj A, Johansen JG (2004) Microcephaly associated with abnormal gyral pattern. Neuropediatrics 35:346–352 Sztriha L, Johansen JG (2005) Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity. Am J Med Genet 135:134–141 Taban M, Memoracion-Peralta DSA, Wang H, Al-Gazali L, Traboulsi EI (2007) Cohen syndrome: report of nine cases and review of the literature with emphasis on ophthalmic features. J AAPOS 11:431–437 Teebi AS (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 Topley JM, Varady E, Lestringant GG (1994) Larsen syndrome in siblings with consanguineous parents. Clin Dysmorphol 3(3):263–265 Valente EM, Silhavy JL, Brancati F, Marsh SE, Barrano G, Krishnaswami SR, Castori M, Boltshauser BL, Al-Gazali L, Fazzi E, Bellaccchio E, Signorini S, Bertini E, Dallapiccola B, Gleeson JG (2006) Mutations in the CEP290 gene, encoding a putative centosomal protein, cause pleotropic forms of Joubert Syndrome. Nat Genet 38:623–625 van Haelst MM, Maiburg M, Baujat G, Jadeja SMonti E, Bland E, Pearce K, Fraser Syndrome Collaboration Group, Hennekam RC, Scambler PJ (2008) Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet 146A:2252–2257 White JM, Byrne M, Richards R, Buchanan T, Katsoulis E, Weerasingh K (1986) Red cell genetic abnormalities in Peninsular Arabs: sickle haemoglobin, G6PD deficiency, and alpha and beta thalassaemia. J Med Genet 23:245–251 White JM, Christie BS, Nam D, Daar S, Higg DR (1993) Frequency and clinical significance of erythrocyte genetic abnormalities in Omanis. J Med Genet 30:396–400 Woods CG, Person S, Sherridan E, Roberts E, Springell K, Scott S, Stern R, Cox J, Karbani G, Malik S, Toombes C, Kumar D, Al-Gazali L, Mundlos S (2006) Mutations in WNT7A cause a range of limb malformations including Furhman-syndrome and Al Awadi/Raas Rothchild/ Schnzil phocomelia syndrome. Am J Hum Genet 79:402–409

Chapter 23

Genetic Disorders Among Jews from Arab Countries Efrat Dagan and Ruth Gershoni-Baruch

History of Jews from Arab Countries The Jewish Diaspora dates back to the Assyrian and Babylonian conquests in the Levant and is portrayed by complex migratory trajectories over the ensuing millennia. Considerable conversion of autochthonic populations to Judaism, which took place during ancient times, has been offset by numerous expulsions and forced conversion of Jews to Christianity and Islam, resulting in a drastic reduction of large Jewish populations and even extermination of Jewish-ethnic communities (Khaibar (Hedjaz) in the seventh century C.E.). Some Jewish societies in Arab countries remained virtually isolated for over 1,000 years (e.g., in Yemen) whereas others were enriched by the influx of Jews from outside the Arab world. A major change includes the settling of a large number of exiled Spanish and Portuguese Jews in the Mediterranean countries at the end of the fifteenth century. Later, up into the twentieth century, cross-migration of Jews expanded some pre-existing Jewish communities in Arab countries, for example, Turkish, Kurdish, and Iranian Jews who joined the ancient Babylonian community and European Jews (Ashkenazi Jews) who settled in Libya and in Egypt. In the last 100 years, Jews originating from Arab countries, namely, the Arabian peninsula, Mesopotamia, the Levant or North Africa have emigrated to Europe, USA, and Israel (Goodman et al. 1989; Behar et al. 2008). The greater part settled in Israel and constitutes the non-Ashkenazi Jewish population, of about three million, comprising among other North African, Iraqi, Iranian, Yemenite, and Iberian Exile Jewish communities. (http://www.cbs.gov.il/ishuvim/demographic_report.pdf).

R. Gershoni-Baruch (*) Institute of Human Genetics, RAMBAM Health Care Campus and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Institute of Technology, Haifa, Israel email: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_23, # Springer-Verlag Berlin Heidelberg 2010

677

678

E. Dagon and R. Gershoni-Baruch

This chapter seeks to provide information on the profile of genetic diseases that characterize Jewish communities from Arab countries. The genetic data presented are mainly supplied by studies from Israel. Diseases will be referenced and identified both by their commonly used names and by their numbers in McKusick’s catalogs (MIM) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim).

Pan Ethnic Diseases The diseases described in this subsection are found at high frequencies in Jews from Arab Countries.

Familial Mediterranean Fever (FMF, MIM 249100) Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by dramatic episodes of fever and serosal inflammation. It affects primarily people of Mediterranean extraction, mostly Sepharadic Jews, Armenians, Arabs, and Turks. The disease is characterized by painful, recurrent, self-limited attacks of fever with sterile peritonitis, pleurisy, and/or synovitis. Most patients (90%) begin to suffer before 20 years of age, and 60% before 10 years of age (Sohar et al. 1967). Some patients develop systemic amyloidosis (Pras et al. 1982). FMF is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. Mutation M694V is frequent in North African Jews (carrier rate 11%) while mutation V726A is prevalent among all patients other than North African Jews (carrier rate 7%). It has been assumed that these mutations originated in Israel some 2,000 years ago, and the convergence of intragenic SNP haplotypes for both the M694V and the V726A chromosomes, bearing different microsatellite haplotypes, indicates an ancient founder effect at the origin of a large fraction of FMF cases from the Mediterranean basin (French FMF consortium 1997; International FMF consortium 1997; Gershoni-Baruch et al. 2001).

Cystic Fibrosis (CF, MIM 219700) Cystic fibrosis (CF) is an autosomal recessive disease that affects the exocrine glands of the lungs, liver, pancreas, and intestines and cause progressive disability due to multisystem failure. CF is attributed to mutations in the CF transmembrane conductance regulator (CFTR). The product of this gene is a chloride ion channel important in creating sweat, digestive juices, and mucus. The incidence of CF and the frequency of disease-causing mutations vary among different ethnic and geographic populations. Among Ashkenazi Jews, the frequency of CF is 1:3,300,

23

Genetic Disorders Among Jews from Arab Countries

679

similar to the frequency observed in Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a frequency of 1:2,700 among Jews from Libya, but is rare in Jews from Yemen (1:8,800), Morocco (1:15,000), Iraq (1:32,000), and Iran (1:39,000). In each Jewish ethnic group, the disease is caused by a different repertoire of mutations. About 20 mutations have been identified in non-Ashkenazi Jews enabling the identification of 90% of the CF chromosomes in this subpopulation. With this in mind, carrier screening of healthy individuals has become feasible for Jews originating from Arab countries and is currently undertaken by the ministry of health (Kerem et al. 1995; Quint et al. 2005).

Fragile X (MIM 309550) Fragile X syndrome is the second most common inherited form of mental retardation, and the carrier frequency in the general population is approximately 1 in 250 females (Rousseau et al. 1995). Fragile-X syndrome is caused by the expansion, in excess of 200 repeats (full mutation expansion) of a trinucleotide element, (CGG)n, located in the 50 untranslated region of the FMR1 gene at Xq27. Normal individuals have a range of approximately 5 to 54 repeats. Carriers of premutations (intermediate alleles in the range of 55–200 repeats) are at risk of bearing children with fragile X syndrome as such alleles can undergo expansion to the full mutation on transmission from mother to offspring. Full mutation expansions are generally accompanied by silencing of the FMR1 gene, with attendant lack of FMR1 protein synthesis, leading to fragile X syndrome. In Jews of Tunisian descent, fragile X syndrome is more prevalent than in the general population and has been attributed to a founder effect of a rare haplotype, consisting of FMR1 CGG repeats which are completely devoid of AGG interruptions that normally serve to stabilize the repeats and prevent their expansion (Falik-Zaccai et al. 1997; Toledano-Alhadef et al. 2001).

Non syndromic Deafness (MIM 121011) The DFNB1 locus, which is located on chromosome 13q11-12, was the first deafness recessive locus to be discovered. DFNB1 was initially identified by linkage analysis in a large Tunisian family exhibiting recessive hearing loss (Ben Arab et al. 1990). Disruptions at this locus are mainly attributed to mutations in the GJB2 gene, responsible for up to 50% of all cases of autosomal recessive nonsyndromic hearing impairment, with prelingual onset in most populations (Kelsell et al. 1997). GJB2 is a small gene that encodes the gap junction protein connexin 26 which is involved in potassium (k+) homeostasis in the cochlea of the inner ear. One mutation, 35delG (also referred to as 30delG), accounts for the majority of mutant alleles and its prevalence among all ethnic groups amounts to 1:30 (Sobe et al. 2000).

680

E. Dagon and R. Gershoni-Baruch

Spinal Muscular Atrophy (SMA, MIM 253300) Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by progressive muscle weakness. It is caused by a mutation in the survival motor neuron gene 1 (SMN1). SMA has a carrier frequency of 1:33–1:60 in most populations (Basel-Vanagaite et al. 2008). A multicentric study in Israel has derived a carrier prevalence of 1:50 in the various ethnic groups (unpublished data).

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD, MIM 305900) Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common human enzyme deficiency, with an estimated 400 million people affected, worldwide. The highest prevalence rates were reported in malaria-endemic areas. G6PD is an X-linked trait almost entirely attributable to a single widespread mutation, G6PD Mediterranean. G6PD deficiency renders erythrocytes susceptible to hemolysis under conditions of oxidative stress. Although most affected individuals are asymptomatic, exposure to oxidative stressors (drugs or infection) can elicit acute hemolysis. The ingestion of fava beans induces an oxidative stress leading to acute hemolysis (Mason et al. 2007).

Thalassemias (MIM 141800, 141850, 141900) Thalassemias are inherited autosomal recessive blood diseases that result from reduced synthesis of one of the globin chains that make up hemoglobin and constitute the most common single-gene disorder in the world. The most common types in clinical practice are those that affect either a or b chain synthesis. A selective advantage for survival in individuals with the thalassemia trait, in regions where malaria is endemic, reflects the balance between the premature death of homozygotes and the increased fitness of heterozygotes. Two active a genes, located on each chromosome 16, give a-thalassemia the unique feature of gene duplication contrasted to only one active b-globin gene on chromosome 11.

Alpha Thalassemia (MIM 141800, 141850) Alpha thalassemia is rare and is more common in Southeast Asia. Absent of one or two a genes define silent carriers with two or three, of the four genes, active. The patients are hematologically healthy, except for mild anemia and occasional low

23

Genetic Disorders Among Jews from Arab Countries

681

RBC indices. In contrast, HbH disease (a-thalassemia intermedia) which results from the deletion or inactivation of three a-globin genes features mild to moderate anemia, splenomegaly, icterus, and abnormal RBC indices. Alpha-thalassemia major, attributed to complete deletion of the a gene cluster on both copies of chromosome 16, leads to the severe form of a-thalassemia, which is usually incompatible with life and causes hydrops fetalis. Other than deletions of the a-globin genes, a-thalassemia has been occasionally ascribed to missense or frameshift mutations (identified in a family of Turkish Jewish extraction and in a Kurdish family) (Oron-Karni et al. 2000).

b-Thalassemia (MIM 141900) Beta-thalassemia is due to reduced production of b chains and the formation of abnormal hemoglobin molecules. Excessive a chains, unable to form Hb tetramers, precipitate in the RBC precursors and interact with the membrane (causing significant damage). For clinical purposes, b thalassemia is divided into thalassemia major (Cooley anemia or transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic). Clinical symptoms include anemia, massive splenomegaly, bone deformities and growth retardation. Beta-thalassemia is caused by a repertoire of mutations in the b-globin gene that mirror migration events that occurred in the past millennium. Most of the encountered mutations are single-base changes, small deletions, or insertions of 1–2 bases. Beta-thalassemia alleles include the common Mediterranean type and other founder mutations originating in Jews from Kurdistan and Samaritans. Only one mutant allele-nonsense codon 37- appears to be indigenous to Israel. Among Kurds, Iraqis, and Yemenites, a variability of unique mutations including both deletions and point mutations were reported (Filon et al. 1994; Rund et al. 1997).

Usher Syndrome Type IIA (USH2A MIM 276901) Usher syndrome Type 2 (USH2) is a recessively inherited disorder, characterized by early onset, moderate-to-severe sensorineural hearing loss and vision impairment due to retinitis pigmentosa. The majority of USH2 cases are caused by mutations in the USH2A gene, encoding for usherin, an extracellular matrix protein, which plays an important role in the development and maintenance of neurosensory cells in both retina and cochlea. To date, over 70 pathogenic mutations of USH2A have been reported in individuals of various ethnicities. Many of these mutations are rare private mutations segregating in single families. USH2 which is occasionally diagnosed in Jewish patients of non-Ashkenazi descent is mainly due to four USH2A mutations (239–240insGTAC, 1000C > T, 2209C > T, and 12067-2A > G) accounting for 64% of mutant alleles underlying USH2 in non-Ashkenazi Jews (Auslender et al. 2008).

682

E. Dagon and R. Gershoni-Baruch

Iraq, Kurdistan and Iran Jewish settlements were established in Mesopotamia following the deportation of Israelites and Judeans by the Assyrians and Babylonians (722 B.C. and 586 B.C., respectively) and have been the leading cultural center of the Jewry world; probably, constituting the majority of living Jews. The number of their descendants at present is estimated to be 260,000. An isolated Jewish community with different linguistic, cultural, and genetics characteristics lived among the Kurds in northern Iraq and together with Kurdish Jews of south-eastern Turkey and western Iran, constitute a distinct community. Iranian Jewry comprises an ancient community with a very high degree of inbreeding. Although the community remained relatively isolated, it had strong ties with Babylonian Jewry in Iraq (Zlotogora 1995).

Beta-Thalassemia (MIM, 141900) and G6PD Deficiency (MIM 305900) Jews of Kurdistan have a high incidence of b-thalassaemia and G6PD deficiency. Beta-thalassaemia, in this population, shows an unusual mutational diversity; more than a dozen different mutations were identified, two of which account for over 50% of chromosomes studied. Four mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews, in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant Kurdish chromosomes carry the mutations unique to Kurdish Jews. Haplotype analysis suggests that thalassemia in central Kurdistan (Northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible (Rund et al. 1991). G6PD in this inbred population reaches the highest known incidence in the world, and affects about 70% of males, mostly, attributable to a single widespread mutation, G6PD Mediterranean. Among the Jewish populations in Shiraz and southern Iran, the most common mutation causing G6PD deficiency is G6PD Mediterranean (563 C > T). Occasional mutations include 1376 (G > T) and G6PD A- (Oppenheim et al. 1988, 1993; Karimi et al. 2008).

Factor XI Deficiency (PTA, MIM 264900) Factor XI deficiency is a rare disease; patients with the severe form of the disease are usually at risk of excessive bleeding after surgery and injury, particularly when trauma involves tissues rich in fibrinolytic activity. The disease is found predominantly in Ashkenazi Jews, in whom two different mutations were observed. One of

23

Genetic Disorders Among Jews from Arab Countries

683

them (type II mutation) was detected in four unrelated Iraqi Jewish families raising the possibility that the mutation was present in Jews already 2.5 millennia ago. The allele frequency among Iraqi Jewish patients was found to be 0.0167 (0.03%) (Shpilberg et al. 1995).

Glanzmann’s Thrombasthenia (MIM 273800) Glanzmann thrombasthenia (GT) is a rare bleeding disorder resulting from mutations in either glycoprotein (GP) IIb or GPIIIa genes. The disease is relatively frequent in Iraqi Jews and is caused by two different in GPIIIA mutations originating from two distinct founders. The most frequent mutation causing GT in Iraqi Jews (IJ-1) is an 11-bp deletion in exon 13 of the GP IIIa gene, resulting in the elimination of the disulfide bond and a premature termination codon. The second mutation is an 11.2-kb deletion between intron 9 and exon 13 of the GP IIIa gene. The mutant DNA is transcribed into mRNA in which exons 10 through 13 are absent. The allele frequencies of these mutations are 0.0043 and <0.0007, respectively (Rosenberg et al. 1997; Yatuv et al. 2001).

Familial Mediterranean Fever (FMF, MIM 249100) In Jews, FMF is mainly observed in North-African and Iraqi populations. M694V mutation is found in all FMF Jewish patients of non-Ashkenazi descent while the V726A mutation is detected mainly among Ashkenazi and Iraqi Jews and absent in North-African Jews (Medlej-Hashim et al. 2004). In Iranian Jews, with FMF, the spectrum of mutations includes a newly described mutation with a non-typical phenotype (G632S) and a rare mutation (R653H). More information can be found in the section of pan-ethnic diseases (Shinar et al. 2007).

Costeff Optic Atrophy Syndrome (MIM 258501) Costeff syndrome (3-methylglutaconic aciduria type 3), was described by a group of Israeli doctors in 1989. Most of the patients are of Iraqi Jewish origin. Costeff syndrome is a neuro-ophthalmologic syndrome that consists of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and mild cognitive deficit. An intronic G!C mutation in the OPA3 gene, located on chromosome 19q13.2–q13.3, is responsible for Costeff syndrome in Iraqi Jews and was detected in 8 of 85 anonymous Israeli individuals of Iraqi Jewish origin (allele frequency 0.05) (Anikster et al. 2001; Fink and Mouallem 2006).

684

E. Dagon and R. Gershoni-Baruch

Pituitary Dwarfism II (Laron type, MIM 262500) Laron syndrome (LS, congenital primary GH insensitivity), first described in Israel, is a form of dwarfism caused by deletions and mutations in the GH receptor gene, resulting in an inability to generate insulin-like growth factor-I (IGF-I); hence, leading to severe dwarfism, as well as skeletal and muscular underdevelopment. Most of the patients originate from Mediterranean and Middle Eastern countries. Laron syndrome is accounted for by more than forty mutations. Recurrent mutations in Jewish-Iraqi patients from Israel include the W15X and the R211H mutations, and a 5, 6 exon deletion (Shevah et al. 2003; Laron 2008).

Cystic Fibrosis (CF, MIM 219700) In Jewish patients from Iraq and Kurdistan, two mutations were identified; the 2571 þ 1insT and the 3121-1G > A, respectively (Quint et al. 2005). Data collected from genetic centers in Israel, derived after screening 2,499 healthy Iraqi Jewish individuals, revealed a carrier frequency of 1:68.5, 1:435, and 0, for the 31211G > A, Y1092X, and 2751 þ 1insT mutations, respectively (Reish et al. 2009).

Hereditary Breast-Ovarian Cancer (MIM 113705, 600185) The BRCA1 and BRCA2 genes were isolated in the 90s of the twentieth century (Miki et al. 1994; Tavtigian et al. 1996). Mutations in these two genes impose a lifetime risk for breast and/or ovarian cancer of 60–80% and 20–40%, respectively. In Ashkenazi Jews, three predominant founder mutations, with a combined frequency of 2–3% in the healthy population, were detected in 20% of breast cancer patients and 40% of ovarian cancer patients (Simchoni et al. 2006). Of these, the 185delAG in BRCA1 was identified in Iraqi Jews, with a carrier frequency of 0.5% (Sher et al. 1996). Another mutation in BRCA1, Tyr987X, occurs in less than 0.5% of healthy Iraqi, Kurdish, and Iranian Jews (Shiri-Sverdlov et al. 2001).

Congenital Myasthenia Syndrome (CMS, MIM 608931) Congenital myasthenic syndromes (CMS) are genetic disorders of the neuromuscular junction and can be classified, by the site of the transmission defect, as presynaptic, synaptic, or postsynaptic. In 14 Jewish patients from 10 families of either Iraqi or Iranian origin, congenital myasthenia associated with facial malformations, including an elongated face,

23

Genetic Disorders Among Jews from Arab Countries

685

mandibular prognathism, malocclusion, and a high-arched palate was described. Muscle weakness was restricted predominantly to facial and masticatory muscles. The course was mild and nonprogressive. Despite the early onset, half the patients had been diagnosed between the ages of 18 and 42 years (Goldhammer et al. 1990). Patients of Jewish Iraqi or Iranian origin harbor the -38A!G mutation in the RAPSN gene which encodes rapsyn, a 43 kDa postsynaptic peripheral membrane protein that clusters the nicotinic acetylcholine receptor at the motor endplate. Haplotype analysis shows that -38A!G arises from a common founder (Ohno et al. 2003). Otherwise, two novel E-box mutations in the RAPSN promoter region in eight other congenital myasthenic syndrome patients were found.

Corticosterone Methyloxydase Deficiency Type II (CMO-II, MIM 610600) CMO type II deficiency is an autosomal recessive disorder caused by a defect in the terminal step of aldosterone biosynthesis and characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone and impaired aldosterone biosynthesis. Patients present with manifestations of mineralocorticoid deficiency during the first weeks of life. CMO-II deficiency is frequent among Jews from Iran (1 in 4,000 births). All individuals affected were double homozygotes for two missense mutations in CYP11B2. The first, in exon 3, codon 181, CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas asymptomatic subjects who were homozygous for R181W alone or homozygous for V386A alone were asymptomatic. These findings confirm that P450XIB2 is a major enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in vitro assays is sufficient to synthesize normal amounts of aldosterone (Ro¨sler and White 1993; Leshinsky-Silver et al. 2006).

Dubin–Johnson Syndrome (DJS, MIM 237500) Dubin–Johnson syndrome (DJS) is a rare autosomal recessive disorder in the excretion of conjugated bilirubin by hepatocytes. It is characterized by chronic jaundice and hyperbilirubinemia, alteration in coproporphyrin metabolism, and intracellular deposition of a dark melanin-like pigment giving the liver a typical black cast. The disorder is caused by mutations in MRP2 gene and is relatively frequent among Iranian and Moroccan Jews. DJS is caused by two founder

686

E. Dagon and R. Gershoni-Baruch

mutations, I1173F and R1150H, in the MRP2 gene, specific for Iranian and Moroccan Jewish patients, respectively. The estimated age of the I1173F mutation is approximately 1,500 years (Mor-Cohen et al. 2007).

Factor VII Deficiency (FVII, MIM 227500) Factor VII is part of the initiating complex of the extrinsic coagulation pathway. Laboratory diagnosis is easy, given that FVII deficiency is the only congenital bleeding disorder characterized by isolated prolonged prothrombin time. Clinical manifestations are heterogeneous, ranging from severe life-threatening hemorrhages, such as cerebral, gastrointestinal, and joint hemorrhages, to miscellaneous minor bleeding. Factor VII (FVII) deficiency is a rare autosomal recessive disorder caused by mutations in FVII gene. The disorder is relatively frequent among Iranian and Moroccan Jews. FVII deficiency in both populations is caused by a founder A244V mutation in the FVII gene. The estimated age of the A244V mutation is approximately 2,600 years (Mor-Cohen et al. 2007).

Achromatopsia II (MIM 216900) Achromatopsia belong to a genetically and phenotypically heterogeneous group of retinal degenerations. This rare disorder, that primarily affects the cone photoreceptor system, is caused by mutations in several genes, CNGA3, CNGB3, and GNAT2. As infants, the patients have nystagmus, which decreases later. Photophobia and restricted vision in ordinary light were described. Vision in dim light is relatively better. The disease was identified among Iraqi, Iranian, and Moroccan Jews (Zlotogora 1995; Kohl et al. 2005).

Colobomatous Microphthalmia (MIM 610092) Colobomatous microphthalmia is a common ocular malformation with a heterogeneous phenotype, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Most cases are isolated and have an autosomal dominant inheritance pattern (MIM 605738). A few cases with autosomal recessive transmission have been described in multiple relatives of five families of Jewish Iranian descent. In these families, a mutation in CHX10 gene on 14q24.3 chromosome was described. A relatively high incidence of this recessive allele is found in this community (Zlotogora et al. 1994).

23

Genetic Disorders Among Jews from Arab Countries

687

Polyglandular Syndrome (PGA I, MIM 240300) Polyglandular Syndrome is mainly characterized by hypoparathyroidism, candidiasis, and adrenal insufficiency (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome-APCED). Nineteen families of Iranian Jewish descent, manifesting PGA I with hypoparathyroidism, rarely candidiasis and no keratopathy, were described. The inheritance is autosomal recessive. The prevalence among Iranian Jews was estimated to be between 1:6,500 and 1:9,000. Among Iranian Jews, the disease is due to a mutation Y85C in exon 2 of the APECED-related autoimmune regulator (AIRE) gene (Zlotogora and Shapiro 1992).

Inclusion Body Myopathy 2 (IBM2, MIM 600737) A progressive proximal and distal muscle weakness and wasting of the upper and lower limbs resulting in severe incapacitation within 10–20 years characterize the disorder. Disease onset is usually after 20 years of age and before the middle of the fourth decade of life. It was first described in Jews of Iranian descent (Argov and Yarom 1984) and later in Jews originating from other Middle Eastern countries, as well as in non-Jews. Homozygosity for the GNE M712T mutation was identified in 129 Middle Eastern patients with IBM2 from 55 families. Eleven patients with atypical features and five unaffected individuals from five different IBM2 families (including two who were 50 and 68 years old) were homozygous for the mutation. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. This founder mutation is approximately 1,300 years old and is not limited to patients of Jewish descent (Argov et al. 2003).

The Near East Jews from Syria, Lebanon, and Egypt emigrated to Israel after World War II. The composition of these communities was tinted by immigrant Jews from the west (Spain and Maghreb), the east (Iraq), and the north (Turkey and Europe). Consequently, these communities are not characterized by a significant frequency of genetic conditions. Yet, FMF and G6PD are relatively common in these communities as well.

Yemen The number of Yemenite Jews is estimated at 180,000, both from North and from South Yemen (Aden and Habban, Hadramaut). There were two major centers of population for Jews in southern Arabia besides the Jews of Northern Yemen, one in

688

E. Dagon and R. Gershoni-Baruch

Aden and the other in Hadramaut. The Jews of Aden lived in and around the city, and flourished during the British protectorate. The Jews of Hadramaut lived a much more isolated life, and the community was not known to the outside world until the early 1900s. In the early twentieth century, they numbered about 50,000; they currently number only a few hundred individuals and reside largely in Sa’dah and Rada’a. The greater part of both communities were airlifted to Israel after the declaration of the state, in 1948 (Operation Magic Carpet). The distribution of various polymorphic genes in the Yemenite community reveals a special genetic identity, defined by African marker genes with adaptive advantage (Weingarten 1992).

Thalassemia (HBA2, MIM 141850) A deletion that involves the two a-globin genes is found in Yemenites. The deletion was found in four unrelated Israeli patients with HbH disease, all originating in Yemen, and has been designated – YEM (Shalmon et al. 1994, 1996; Oron-Karni et al. 1997; Tamary et al. 1998).

Phenylketonuria (PKU, MIM 261600) Hyperphenylalaninemia (HPA) is a group of diseases characterized by persistent elevation of phenylalanine levels in tissues and biological fluids. The most frequent form is phenylalanine hydroxylase deficiency (PAH), causing phenylketonuria (PKU). PKU is an autosomal recessive inborn error of metabolism. The disease is very rare among Ashkenazi Jews and relatively frequent among Jews from Yemen, the Caucasian Mountains, Bukhara, and Tunisia. The mutation responsible for the high frequency among Yemenite Jews is deletion of exon3 in the PAH gene (Bercovich et al. 2008).

Metachromatic Leukodystrophy (MLD, MIM 250100) Late infantile metachromatic leukodystrophy (MLD) is a neurodegenerative disease, most commonly caused by the deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Late infantile MLD is frequent (1/75 live birth) in a small isolated Jewish community which lived in Habban. Three mutations were detected, of which the P377L allele is predominant both in Habbanite and Yemenite Jews, denoting a common ancestor for most MLD carriers in this community. The origin

23

Genetic Disorders Among Jews from Arab Countries

689

and the means by which the mutation spread between the two communities remain unknown (Zlotogora et al. 1995).

Chronic Familial Neutropenia (Benign FL, MIM 162700) Benign autosomal dominant hereditary leukopenia–neutropenia has been reported in several ethnic groups, including Yemenite and Ethiopian Jews, Blacks of South African extraction, West Indians, and Arab Jordanians. The subjects with benign familial neutropenia were shown not to have an increased incidence of infections, and their response to infection does not differ from subjects with normal white blood cell counts. The suggested mechanism of this type of neutropenia is a defect in the release of mature WBC from the bone marrow to the peripheral circulation. Screening of 780 Yemenite Jewish individuals revealed 16 with neutropenia and 80 of 104 of their relatives had neutropenia (Berrebi et al. 1987; Shoenfeld et al. 1988).

Peroxidase and Phospholipid Deficiency in Eosinophils (MIM 261500) Autosomal recessive inheritance of an anomaly of eosinophils characterized by nuclear hypersegmentation, hypogranulation, and negative peroxidase and phospholipid staining was described in Yemenite Jews in Israel (Joshua et al. 1970).

Hereditary Breast-Ovarian Cancer (MIM 113705, 600185) In Jews from Yemen a founder mutation, 8765delAG, was found in the BRCA2 gene with a population frequency of 0.7% (Lerer et al. 1998). Haplotype analysis revealed that this mutation has an independent origin in geographically and ethnically distinct populations, acting as a founder mutation in Yemen (Manning et al. 2001). Mutations in BRCA2 gene predominantly predispose to breast and/or ovarian cancer. More information on these genes appears in the section on Iraq.

Myotonic Dystrophy I (MIM 160900) Myotonic dystrophy (DM) is an autosomal dominant disorder characterized mainly by myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG changes. The genetic defect in DM1 results from an amplified trinucleotide

690

E. Dagon and R. Gershoni-Baruch

repeat in the 30 untranslated region of a protein kinase gene. Disease severity varies with the number of repeats: normal individuals have 5–30 repeats, mildly affected persons have 50–80 repeats, and severely affected individuals have 2,000 or more copies. Amplification is frequently observed after parent-to-child transmission, but extreme amplifications are not transmitted through the male line. This mechanism causes genetic anticipation and the occurrence of the severe congenital form almost exclusively in the offspring of affected women. In a comprehensive epidemiologic survey among Jews living in Israel, an average prevalence of DM of 15.7 per 100,000 (1 case in 6,369) was found with intercommunity variations. Ashkenazi Jews had the lowest rate (1 case in 17,544) compared to Sephardic and Yemenites Jews (1 in 5,000 and 1 in 2,114 cases, respectively). The intragenic haplotype of the DM alleles is the same as that of DM patients in many populations worldwide (including Ashkenazi Jews); however, 2 markers closely linked to DM, D19S207, and D19S112, were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan extractions. This observation indicated a common ancestral origin for the DM premutation as a consequence of a founder premutation in these non-Ashkenazi Jewish communities (Segel et al. 2003).

Retinitis Pigmentosa (RP, MIM 608381) Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration, with a worldwide prevalence of 1 in 4,000. RP actually encompasses a heterogeneous group of retinal dystrophies characterized by night blindness followed by visual field loss, often resulting in severe visual impairment. A related form of retinal dystrophy is cone–rod degeneration (CRD). Besides being clinically heterogeneous, both RP and CRD are genetically heterogeneous. In most patients, the disease is limited to the eye (nonsyndromic RP/CRD), suggesting that the genes involved encode largely eye- and retina-specific products. A novel homozygous splice-site mutation, 238 þ 1G > A in CERKL gene on chromosome 2q31.3.3 was found in a Yemenite Jewish family. Further investigation revealed a carrier frequency of 4.4% in this population. The 238 þ 1G > A underlies approximately one-third of autosomal recessive retinal degeneration cases in the Yemenite Jewish population (Auslender et al. 2007).

Cystic Fibrosis (CF, MIM 219700) CF in Yemenite Jews is due to a founder mutation, namely, mutation I1234V in the CFTR gene with a carrier frequency of 1:45 (Kerem et al. 1995; Quint et al. 2005).

23

Genetic Disorders Among Jews from Arab Countries

691

Rare Diseases FMF and G6PD deficiency are relatively rare in Yemenite Jews compared to Jews born in other Arab countries (Weingarten 1992). The mutation underlying FMF in Yemenite Jews remains unknown.

North African Jews Jews from Libya, Tunisia, Algeria, and Morocco are designated North African Jews and/or Sephardic and/or non-Ashkenazi Jews. This population is noted for its high frequency of mutations, in MEFV, causing FMF (Gershoni-Baruch et al. 2001) and low frequency of G6PD deficiency. The different disorders associated with each subgroup will be referenced below.

Familial Mediterranean Fever (FMF, MIM 249100) As described earlier in this chapter, North African and Iraqi Jews are the two largest ethnic Jewish communities enduring FMF in Israel. North African Jews have a more severe disease manifested by earlier age of onset, increase in frequency and severity of joint involvement, higher incidence of erysipelas-like erythema, and higher doses of colchicine required to control symptoms (Pras et al. 1998). M694V and E148Q are the most prevalent mutation in this population with a carrier frequency of 1:5 (Gershoni-Baruch et al. 2001).

Glycogen Storage Disease III (GSD, MIM 232400) Glycogen storage disease type III (GSD III) is an autosomal recessive disease caused by the deficiency of glycogen-debranching enzyme. The overall incidence of the disease is about 1:100,000 life births in the USA; however, it is unusually frequent among North African Jews in Israel (prevalence 1:5,400, carrier prevalence 1:35). All North African Jewish GSD III patients examined have both liver and muscle involvement. While all patients showed the characteristic features related to the liver enzyme deficiency, the peripheral muscular impairment varied from minimal to severe, with neuromuscular involvement. A single mutation in the AGL gene, the deletion of T at position 4,455 (4,455delT) in homozygous form, was found in this patient population. The mutation appears to be ethnic-specific (Parvari et al. 1997).

692

E. Dagon and R. Gershoni-Baruch

Libya Libyan Jews retain genetic signatures distinguishable from those of the other populations. This finding is in agreement with some historical records on the relative isolation of this community. The lowest differentiation involving Libyan Jews is with Moroccan Jewry which may reflect shared ancestral Iberian Jewish or Berber contribution to these population, or gene flow between them (Rosenberg et al. 2001).

Creutzfeldt–Jakob Disease (CJD, MIM 123400) Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder. Various mutations in the prion protein (PrP) gene are associated with the disease. Among Libyan Jews, CJD is a familial disease with an incidence of about 100 times higher than in the worldwide population. After age adjustment, the mean annual incidence rate per million was 43 among Libyan-born and 0.9 in other populations. Among Jews born in Egypt and Tunisia, countries neighboring Libya, the adjusted rates were higher than in the other Israeli Jewish communities (3.5 and 2.3 per million, respectively). CJD in the Libyan community segregates with a point mutation at codon 200 of the PrP gene which causes the substitution of lysine for glutamate. Homozygous patients have the same disease pattern and age of onset as heterozygous patients, which argues that CJD associated with the codon 200 lysine mutation, is a true dominant disorder. Among Libyan Jews, there was no association between incidence rate of CJD and age at immigration, that is, duration of exposure to a hypothetical infectious factor in Libya (Zilber et al. 1991; Gabizon et al. 1994; Rosenmann et al. 1998; Frenkel et al. 1999).

Cystinuria (MIM 220100) Cystinuria is an autosomal recessive disease characterized by the development of kidney stones. The disease is caused by a defect in a renal tubular amino acid transporter resulting in impaired reabsorption of cystine and the dibasic amino acids, lysine, arginine, and ornithine. Mutations in SLC3A1 cause type I disease, while mutations in SLC7A9 are associated with non-type I disease with similar clinical manifestations. In Israel, cystinuria is especially common among Libyan Jews who suffer from non-type I disease with an estimated prevalence of 1:2,500. A founder mutation, V170M in the SLC7A9 gene, with a carrier rate of 1:25 was found in Libyan Jews and account for the disease in most of the patients (Sidi et al. 2003).

23

Genetic Disorders Among Jews from Arab Countries

693

Muscular Dystrophy Type 2B (Limb-Girdle MD (LGMD), MIM 253601) LGMD is an autosomal recessive heterogeneous disease. LGMD2B is caused by mutations in the dysferlin gene. In Jews of Libyan origin, LGMD2B, attributed to mutation 1624delG in the dysferlin gene, is prevalent with a carrier frequency of approximately 5% and disease prevalence of at least 1 per 1,300 adults. In 29 patients from 12 families, homozygosity for the same mutation was found. However, clinical features were heterogeneous even within the same family; in half of the patients, onset was in the distal muscles of the legs while in others onset was in the proximal muscles of the legs, similar to other forms of limb-girdle dystrophies. Progression is slow regardless of age of onset, patients remaining ambulatory until at least 33 years. The variable features in this ethnic cluster contribute to the definition of the clinical spectrum of dysferlinopathies in general. The cause of the observed heterogeneity remains unclear (Argov et al. 2000).

Cystic Fibrosis (CF, MIM 219700) CF is common in Libyan Jews with a carrier frequency of 1:25. In this population, CF is due to two mutations, namely, mutations F508 and 405 þ 1G!A. (Kerem et al. 1995; Quint et al. 2005).

Tunisia Between 1945 and 1970, around 100,000 Jews emigrated from Tunisia, mainly to Israel and France. This community is an Ancient Jewish congregation that lived in the region, including a small isolate on the island of Jerba whose tradition claims for continuous existence since the sixth century B.C.

Phenylketonuria (PKU, MIM 261600) and Hyperphenylalaninemia (MIM 612349) Among Tunisian Jews, the L48S mutation causing PKU was found (Bercovich et al. 2008). In Jews from Morocco and Tunisia, a missense mutation, TCASer!CCAPro, at codon 349 in exon 10 of the phenylalanine hydroxylase gene was detected. A homozygote for this mutation showed the most severe (“classical”) type of PKU, while compound heterozygotes showed two other types of HPA – “atypical” PKU and “high benign” HPA – illustrating the interplay between different mutations that

694

E. Dagon and R. Gershoni-Baruch

gives rise to various HPAs (Weinstein et al. 1993). Further information on the disease can be seen under Yemenite Jews.

Brittle Cornea Syndrome (BCS, MIM 229200) Brittle cornea syndrome (BCS) is characterized by blue sclera and hyperextensible joints. In Israel, five families of Tunisian Jewish origin characterized by red hair in all affected individuals were identified (Zlotogora et al. 1990). Linkage to chromosome 16q24 surrounding the hair color gene, MC1R, has been shown (Abu et al. 2006). The gene 2NF469 and the causing mutations were subsequently identified (Abu et al. 2008).

Cystic Fibrosis (CF, MIM 219700) The estimated carrier rate of CF among Tunisian Jews is 1:60. In this population, CF is due to four mutations, namely, mutations 405 þ 1G!A, F508, W1282X and 3849 þ 10KbC!T, in descending order of prevalence (Kerem et al. 1995; Quint et al. 2005).

Algeria Following the independence of Algeria in 1962, about 130,000 Jews emigrated, mainly to France. In Israel, there are about 30,000 Algerian Jews. Like in other Maghreb communities, FMF is common in this ethnic community. Other genetic diseases are described in individual families.

Morocco The largest community of Jews from Arab countries emigrated from Morocco (750,000). Most of them live in Israel and the rest in France and elsewhere. Twenty thousand came from Iberia and maintained a separated and isolated community. This group is different from the classic Moroccan Jewry and has a higher frequency of G6PD deficiency.

Oculocutaneous Albinism (MIM 203100) Oculocutaneous albinism is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin, and eyes. Albinism is characterized by specific ocular changes resulting from reduced amounts of

23

Genetic Disorders Among Jews from Arab Countries

695

melanin in the developing eye; the abnormalities in the eye and optic system being specific and pathognomonic. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus. Among Moroccan Jews with type IA (i.e., tyrosinasenegative) OCA, a highly predominant mutant allele of the tyrosinase (TYR) gene, with a carrier frequency of 1:40, harboring a missense substitution, Gly47Asp (G47D), was identified. This mutation occurs on the same haplotype as in patients from the Canary Islands and Puerto Rico, suggesting that the G47D mutation in these ethnically distinct populations may stem from a common origin (GershoniBaruch et al. 1994).

Ataxia Telangiectasia (AT, MIM 208900) The ATM gene is responsible for the autosomal recessive disorder ataxia-telangiectasia (AT), characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. A wide variety of AT mutations, most of which are unique to single families, were identified in various ethnic groups, precluding carrier screening with mutation-specific assays. However, a single mutation, 103C!T, was observed in 32/33 defective ATM alleles in Jewish AT families of North African origin, from various regions of Morocco and Tunisia. This mutation results in a stop codon at position 35 of the ATM protein. The carrier frequency of this mutation in Jews from Morocco and Tunis is about 1% (Gilad et al. 1996).

Tay Sachs (TSD, MIM 272800) Classical Tay-Sachs disease (TSD) is characterized by the onset in infancy of developmental arrest, followed by paralysis, dementia, and blindness, with death in the second or third year of life. The disease is one of the four lysosomal storage diseases prevalent among Ashkenazim; TSD, Gaucher disease type I, NiemannPick disease, and mucolipodosis type IV. TSD is caused by mutations in the alpha subunit of the hexosaminidase A gene (HEXA). Moroccan Jewry is the only nonAshkenazi Jewish community in which TSD is not extremely rare with an estimated frequency of 1 in 140. Seven mutations were found in Moroccan Jews, three of which (deltaF 304/305, R170Q, IVS-2A!G) were more frequently observed and not described in Ashkenazi Jews (Kaufman et al. 1997).

Adrenal Hyperplasia IV (MIM 202010) Congenital adrenal hyperplasia due to 11-b-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess,

696

E. Dagon and R. Gershoni-Baruch

virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursor’s 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension. In Jews of Moroccan descent, the prevalence of steroid 11-b-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated at approximately 1 in 40. A single mutation in the CYP11B1 gene (encoding 11beta-hydroxylase), R448H, accounts for the disease in this population. However, screening of more than 200 Moroccan Jews revealed an allele frequency lower than was assumed previously (Paperna et al. 2005).

Fanconi Anemia A (MIM 607139) Fanconi anemia (FA) is an autosomal recessive disorder affecting all bone marrow elements and associated with cardiac, renal, and limb malformations, as well as dermal pigmentary changes. FA is a genetically heterogeneous disease with at least eight complementation groups (A–H). In the non-Ashkenazi population in Israel, four ethnic-specific mutations were identified in FA group A (FANCA): two “Moroccan mutations,” the 2172–2173insG (exon 24) and the 4275delT (exon 43); a “Tunisian mutation” 890–893del (exon 10); and an “Indian mutation” 2574C > G (S858R). The tetranucleotide CCTG motif, previously identified as a mutation hotspot in FANCA and other human genes, was found in the vicinity of 2172–2173insG and 890–893del. The four mutations account for the majority (88%) of the FANCA alleles in the Israeli Jewish non-Ashkenazi FA population. Two “Indian mutation” carriers were identified among 53 Indian Jews. All carriers within each ethnic group had the same haplotype, suggesting a common founder for each mutation (Tamary et al. 2000).

Phenylketonuria and Hyperphenylalaninemia (MIM 612349) In Jews from Morocco and Tunisia, a missense mutation, TCASer!CCAPro, at codon 349 in exon 10 of the phenylalanine hydroxylase gene was detected (Weinstein et al. 1993). Further information can be found under Yemen and Tunisia.

Cerebrotendinous Xanthomatosis (CTX, MIM 213700) Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a

23

Genetic Disorders Among Jews from Arab Countries

697

pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Plasma cholesterol concentrations are low-normal in CTX patients. In Moroccan Jews, the estimated carrier rate is 1 in 108 (Berginer and Abeliovich 1981). The defect in cerebrotendinous xanthomatosis was shown to reside in the CYP27A1 gene (Cali et al. 1991). Two mutations were identified, deletion of a thymidine in exon 4 and a G-to-A transition at the 30 splice acceptor site of intron 4, in patients of four families (three families were consanguineous and the fourth was nonconsanguineous) (Leitersdorf et al. 1993).

Dubin–Johnson Syndrome (DJS, MIM 237500) As described earlier (under Iraq and Iranian Jewry), DJS is a rare autosomal recessive disease caused by mutations in MRP2 gene. It is relatively frequent among Iranian and Moroccan Jews. DJS is caused by two founder mutations, I1173F and R1150H, specific for Iranian and Moroccan Jewish patients, respectively (Mor-Cohen et al. 2007).

Factor VII Deficiency (FVII, MIM 227500) Factor VII is part of the initiating complex of the extrinsic coagulation pathway. Factor VII (FVII) deficiency is rare autosomal recessive disorder caused by mutations in FVII gene. The disorder is relatively frequent among Iranian and Moroccan Jews. FVII deficiency in both populations is caused by a founder A244V mutation in the FVII gene. The estimated age of the A244V mutation is approximately 2,600 years (Mor-Cohen et al. 2007).

Muscular Dystrophy I (MIM 253600) In Jews living in Israel, the average prevalence of myotonic dystrophy (DM) is 15.7/10.000 (1:6,369); Ashkenazi Jews have the lowest rate, 5.7/100.000 (1 case in 17,544) compared to the rate in Sephardic Jews 20/10(5) (1:5,000) and Yemenite Jews 47.3/100.000 (1:2,114). The difference in the incidence of DM was attributed to a higher mutation rate in non-Ashkenazi Jews compared to the rate in Ashkenazi Jews. Markers in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan extractions and not in the Ashkenazi patients indicate that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non-Ashkenazi Jewish communities (Segel et al. 2003).

698

E. Dagon and R. Gershoni-Baruch

Concluding Remarks This review portrays the genetic disease profile of the major Jewish communities that have emigrated to Israel from Arab countries. On the basis of population screening and family studies, information regarding clinical manifestation, disease, and mutation frequency is provided. In most cases, these frequencies reflect the relative genetic isolation of Jewish communities from each other and from their respective Arab host populations. In addition to the relatively common diseases mentioned here, rare conditions that have been documented in few families are also mentioned. Accumulating data in molecular genetics indicate that hereditary diseases are marked by clinical and genetic heterogeneity. In Israel, population screening programs have been set to identify carriers of genetic diseases. Mutation detection has become affordable to couples at risk. On the basis of disease severity and mutation frequencies within the various communities, genetic diagnosis is recommended aiming at health promotion and disease prevention. It must be stressed, however, that this synopsis is by no means exhaustive, partially because we have probably failed to retrieve all the relevant data from the medical literature.

References Abu A, Frydman M, Marek D, Pras E, Stolovitch C, Aviram-Goldring A, Rienstein S, Reznik-Wolf H, Pras E (2006) Mapping of a gene causing brittle cornea syndrome in Tunisian Jews to 16q24. Invest Ophthalmol Vis Sci 47:5283–5287 Abu A, Frydman M, Marek D, Pras E, Nir U, Reznik-Wolf H, Pras E (2008) Deleterious mutations in the zinc-finger u69 gene cause brittle cornea syndrome. Am J Hum Genet 82:1217–1227 Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O (2001) Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet 69:1218–1224 Argov Z, Yarom R (1984) “Rimmed vacuole myopathy” sparing the quadriceps: A unique disorder in Iranian Jews. J Neurol Sci 64:33–43 Argov Z, Sadeh M, Mazor K, Soffer D, Kahana E, Eisenberg I, Mitrani-Rosenbaum S, Richard I, Beckmann J, Keers S, Bashir R, Bushby K, Rosenmann H (2000) Muscular dystrophy due to dysferlin deficiency in Libyan Jews: Clinical and genetic features. Brain 123:1229–1237 Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S (2003) Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60:1519–1523 Auslender N, Sharon D, Abbasi AH, Garzozi HJ, Banin E, Ben-Yosef T (2007) A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 48:5431–5438 Auslender N, Bandah D, Rizel L, Behar DM, Shohat M, Banin E, Allon-Shalev S, Sharony R, Sharon D, Ben-Yosef T (2008) Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. Genet Test 12:289–294 Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, Zlotogora J, Shohat M (2008) Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel. Genet Test 12:53–56

23

Genetic Disorders Among Jews from Arab Countries

699

Behar DM, Metspalu E, Kivisild T, Rosset S, Tzur S, Hadid Y, Yudkovsky G, Rosengarten D, Pereira L, Amorim A, Kutuev I, Gurwitz D, Bonne-Tamir B, Villems R, Skorecki K (2008) Counting the founders: the matrilineal genetic ancestry of the Jewish Diaspora. PLoS One 3:e2062 Ben Arab S, Bonaı¨ti-Pellie´ C, Belkahia A (1990) An epidemiological and genetic study of congenital profound deafness in Tunisia (governorate of Nabeul). J Med Genet 27:29–33 Bercovich D, Elimelech A, Yardeni T, Korem S, Zlotogora J, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y (2008) A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. Ann Hum Genet 72:305–309 Berginer VM, Abeliovich D (1981) Genetics of cerebrotendinous xanthomatosis (CTX): an autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin. Am J Med Genet 10:151–157 Berrebi A, Melamed Y, Van Dam U (1987) Leukopenia in Ethiopian Jews. N Engl J Med 316:549 Cali JJ, Hsieh C-L, Francke U, Russell DW (1991) Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 266: 7779–7783 Falik-Zaccai TC, Shachak E, Yalon M, Lis Z, Borochowitz Z, Macpherson JN, Nelson DL, Eichler EE (1997) Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to the absence of AGG interruptions on a rare Mediterranean haplotype. Am J Hum Genet 60:103–112 Filon D, Oron V, Krichevski S, Shaag A, Shaag Y, Warren TC, Goldfarb A, Shneor Y, Koren A, Aker M et al (1994) Diversity of beta-globin mutations in Israeli ethnic groups reflects recent historic events. Am J Hum Genet 54:836–843 Fink N, Mouallem M (2006) Costeff syndrome: a syndrome that was described in Israel and the responsible gene discovered by an Israeli doctor. Harefuah 145:402–403, 472 French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31 Frenkel YR, Ben-Israel J, Korczyn AD, Chapman J (1999) Penetrance and phenotypic expression of a mutation linked to Creutzfeldt-Jakob disease in the elderly. Dement Geriatr Cogn Disord 10:47–50 Gabizon R, Rosenman H, Meiner Z, Kahana I, Kahana E, Shugart Y, Ott J, Prusiner SB (1994) Mutation in codon 200 and polymorphism in codon 129 of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease. Philos Trans R Soc Lond B Biol Sci 343:385–390 Gershoni-Baruch R, Rosenmann A, Droetto S, Holmes S, Tripathi RK, Spritz RA (1994) Mutations of the tyrosinase gene in patients with oculocutaneous albinism from various ethnic groups in Israel. Am J Hum Genet 54:586–594 Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9:634–637 Gilad S, Bar-Shira A, Harnik R, Shkedy D, Ziv Y, Khosravi R, Brown K, Vanagaite L, Xu G, Frydman M, Lavin MF, Hill D, Tagle DA, Shiloh Y (1996) Ataxia-telangiectasia: founder effect among north African Jews. Hum Mol Genet 5:2033–2037 Goldhammer Y, Blatt I, Sadeh M, Goodman RM (1990) Congenital myasthenia associated with facial malformations in Iraqi and Iranian Jews. A new genetic syndrome. Brain 113:1291–1306 Goodman RM, Bonne-Tamir B, Adam A, Voss R, Bach G, Shiloh Y, Katznelson MB, Barkai G, Goldman B, Padeh B et al (1989) Medical genetics in Israel. J Med Genet 26:179–189 International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807 Joshua H, Spitzer A, Presentey B (1970) The incidence of peroxidase and phospholipid deficiency in eosinophilic granulocytes among various Jewish groups in Israel. Am J Hum Genet 22:574–578 Karimi M, Yavarian M, Afrasiabi A, Dehbozorgian J, Rachmilewitz E (2008) Prevalence of betathalassemia trait and glucose-6-phosphate dehydrogenase deficiency in Iranian Jews. Arch Med Res 39:212–214

700

E. Dagon and R. Gershoni-Baruch

Kaufman M, Grinshpun-Cohen J, Karpati M, Peleg L, Goldman B, Akstein E, Adam A, Navon R (1997) Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat 10:295–300 Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387:80–83 Kerem E, Kalman YM, Yahav Y, Shoshani T, Abeliovich D, Szeinberg A, Rivlin J, Blau H, Tal A, Ben-Tur L et al (1995) Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum Genet 96:193–197 Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, J€agle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B (2005) CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 13:302–308 Laron Z (2008) Insulin-like growth factor-I treatment of children with Laron syndrome (primary growth hormone insensitivity). Pediatr Endocrinol Rev 5:766–771 Leitersdorf E, Reshef A, Meiner V, Levitzki R, Schwartz SP, Dann EJ, Berkman N, Cali JJ, Klapholz L, Berginer VM (1993) Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews of Moroccan origin. J Clin Invest 91:2488–2496 Lerer I, Wang T, Peretz T, Sagi M, Kaduri L, Orr-Urtreger A, Stadler J, Gutman H, Abeliovich D (1998) The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. Am J Hum Genet 63:272–274 Leshinsky-Silver E, Landau Z, Unlubay S, Bistrizer T, Zung A, Tenenbaum-Rakover Y, Devries L, Lev D, Hanukoglu A (2006) Congenital hyperreninemic hypoaldosteronism in Israel: sequence analysis of CYP11B2 gene. Horm Res 66:73–78 Manning AP, Abelovich D, Ghadirian P, Lambert JA, Frappier D, Provencher D, Robidoux A, Peretz T, Narod SA, Mes-Masson AM, Foulkes WD, Wang T, Morgan K, Fujiwara TM, Tonin PN (2001) Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered 52:116–120 Mason PJ, Bautista JM, Gilsanz F (2007) G6PD deficiency: the genotype-phenotype association. Blood Rev 21:267–283 Medlej-Hashim M, Loiselet J, Lefranc G, Me´garbane´ A (2004) Familial Mediterranean Fever (FMF): [from diagnosis to treatment]. Sante 14:261–266 Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71 Mor-Cohen R, Zivelin A, Fromovich-Amit Y, Kovalski V, Rosenberg N, Seligsohn U (2007) Age estimates of ancestral mutations causing factor VII deficiency and Dubin–Johnson syndrome in Iranian and Moroccan Jews are consistent with ancient Jewish migrations. Blood Coagul Fibrinolysis 18:139–144 Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG (2003) E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet 12:739–748 Oppenheim A, Cohen S, Goldfarb A, Katzhendler J, Deutsch J, Rachmilewitz EA (1988) Detection of specific beta-globin mutations in Kurdish Jews with beta-thalassemia. Hemoglobin 12:31–38 Oppenheim A, Jury CL, Rund D, Vulliamy TJ, Luzzatto L (1993) G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet 91:293–294 Oron-Karni V, Filon D, Rund D, Oppenheim A (1997) A novel mechanism generating short deletion/insertions following slippage is suggested by a mutation in the human alpha2-globin gene. Hum Mol Genet 6:881–885 Oron-Karni V, Filon D, Shifrin Y, Fried E, Pogrebijsky G, Oppenheim A, Rund D (2000) Diversity of alpha-globin mutations and clinical presentation of alpha-thalassemia in Israel. Am J Hematol 65:196–203

23

Genetic Disorders Among Jews from Arab Countries

701

Paperna T, Gershoni-Baruch R, Badarneh K, Kasinetz L, Hochberg Z (2005) Mutations in CYP11B1 and congenital adrenal hyperplasia in Moroccan Jews. J Clin Endocrinol Metab 90:5463–5465 Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT (1997) A single-base deletion in the 30 -coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. Eur J Hum Genet 5:266–270 Pras M, Bronshpigel N, Zemer D, Gafni J (1982) Variable incidence of amyloidosis in familial Mediterranean fever among different ethnic groups. Johns Hopkins Med J 150:22–26 Pras E, Livneh A, Balow JE Jr, Pras E, Kastner DL, Pras M, Langevitz P (1998) Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet 75:216–219 Quint A, Lerer I, Sagi M, Abeliovich D (2005) Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am J Med Genet A 136:246–248 Reish O, Borochowitz ZU, Adir V, Shohat M, Karpati M, Shtorch A, Orr-Urtreger A, Yaron Y, Shalev S, Fares F, Gershoni-Baruch R, Falik-Zaccai TC, Chapman-Shimshoni D (2009) Dynamic modification strategy of the Israeli carrier screening protocol: inclusion of the Oriental Jewish Group to the cystic fibrosis panel. Genet Med 11:101–103 Rosenberg N, Yatuv R, Orion Y, Zivelin A, Dardik R, Peretz H, Seligsohn U (1997) Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 89:3654–3662 Rosenberg NA, Woolf E, Pritchard JK, Schaap T, Gefel D, Shpirer I, Lavi U, Bonne-Tamir B, Hillel J, Feldman MW (2001) Distinctive genetic signatures in the Libyan Jews. Proc Natl Acad Sci USA 98:858–863 Rosenmann H, Vardi J, Finkelstein Y, Chapman J, Gabizon R (1998) Identification in Israel of 2 Jewish Creutzfeld-Jakob disease patients with a 178 mutation at their PrP gene. Acta Neurol Scand 97:184–187 Ro¨sler A, White PC (1993) Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. J Steroid Biochem Mol Biol 45:99–106 Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K (1995) Prevalence of carriers of premutation-size alleles of the FMRI gene–and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57:1006–1018 Rund D, Cohen T, Filon D, Dowling CE, Warren TC, Barak I, Rachmilewitz E, Kazazian HH Jr, Oppenheim A (1991) Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci USA 88:310–314 Rund D, Oron-Karni V, Filon D, Goldfarb A, Rachmilewitz E, Oppenheim A (1997) Genetic analysis of beta-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol 54:16–22 Segel R, Silverstein S, Lerer I, Kahana E, Meir R, Sagi M, Zilber N, Korczyn AD, Shapira Y, Argov Z, Abeliovich D (2003) Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder permutations. Am J Med Genet A 119A:273–278 Shalmon L, Kirschmann C, Zaizov R (1994) A new deletional alpha-thalassemia detected in Yemenites with hemoglobin H disease. Am J Hematol 45:201–204 Shalmon L, Kirschmann C, Zaizov R (1996) Alpha-thalassemia genes in Israel: deletional and nondeletional mutations in patients of various origins. Hum Hered 46:15–19 Sher C, Sharabini-Gargir L, Shohat M (1996) Breast cancer and BRCA1 mutations. N Engl J Med 334:1199 Shevah O, Borrelli P, Rubinstein M, Laron Z (2003) Identification of two novel mutations in the human growth hormone receptor gene. J Endocrinol Invest 26:604–608 Shinar Y, Kuchuk I, Menasherow S, Kolet M, Lidar M, Langevitz P, Livneh A (2007) Unique spectrum of MEFV mutations in Iranian Jewish FMF patients–clinical and demographic significance. Rheumatology 46:1718–1722

702

E. Dagon and R. Gershoni-Baruch

Shiri-Sverdlov R, Gershoni-Baruch R, Ichezkel-Hirsch G, Gotlieb WH, Bruchim Bar-Sade R, Chetrit A, Rizel S, Modan B, Friedman E (2001) The Tyr978X BRCA1 mutation in nonAshkenazi Jews: occurrence in high-risk families, general population and unselected ovarian cancer patients. Commun Genet 4:50–55 Shoenfeld Y, Alkan ML, Asaly A, Carmeli Y, Katz M (1988) Benign familial leukopenia and neutropenia in different ethnic groups. Eur J Haematol 41:273–277 Shpilberg O, Peretz H, Zivelin A, Yatuv R, Chetrit A, Kulka T, Stern C, Weiss E, Seligsohn U (1995) One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 85:429–432 Sidi R, Levy-Nissenbaum E, Kreiss I, Pras E (2003) Clinical manifestations in Israeli cystinuria patients and molecular assessment of carrier rates in Libyan Jewish controls. Isr Med Assoc J 5:439–442 Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, Kedar-Barnes I, ShiriSverdlov R, Dagan E, Tsabari S, Shohat M, Catane R, King MC, Lahad A, Levy-Lahad E (2006) Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci USA 103:3770–3774 Sobe T, Vreugde S, Shahin H, Berlin M, Davis N, Kanaan M, Yaron Y, Orr-Urtreger A, Frydman M, Shohat M, Avraham KB (2000) The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Hum Genet 106:50–57 Sohar E, Gafni J, Pras M, Heller H (1967) Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227–253 Tamary H, Klinger G, Shalmon L, Kirschmann H, Koren A, Bennet M, Zaizov R (1998) The diverse molecular basis and mild clinical picture of HbH disease in Israel. Ann N Y Acad Sci 850:432–435 Tamary H, Bar-Yam R, Shalmon L, Rachavi G, Krostichevsky M, Elhasid R, Barak Y, Kapelushnik J, Yaniv I, Auerbach AD, Zaizov R (2000) Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients. Br J Haematol 111:338–343 Tavtigian SV, Simard J, Rommens J et al (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12:333–337 Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, Drasinover V, Taub E, Halpern GJ, Ginott N, Shohat M (2001) Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69:351–360 Weingarten MA (1992) Changing health and changing culture: the Yemenite Jews in Israel. Praeger, London, pp 20–23 Weinstein M, Eisensmith RC, Abadie V, Avigad S, Lyonnet S, Schwartz G, Munnich A, Woo SLC, Shiloh Y (1993) A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in North African Jews with phenylketonuria. Hum Genet 90:645–649 Yatuv R, Rosenberg N, Zivelin A, Peretz H, Dardik R, Trakhtenbrot L, Seligsohn U (2001) Identification of a region in glycoprotein IIIa involved in subunit association with glycoprotein IIb: further lessons from Iraqi-Jewish Glanzmann thrombasthenia. Blood 98:1063–1069 Zilber N, Kahana E, Abraham M (1991) The Libyan Creutzfeldt-Jakob disease focus in Israel: an epidemiologic evaluation. Neurology 41:1385–1389 Zlotogora J (1995) Hereditary disorders among Iranian Jews. Am J Med Genet 58:32–37 Zlotogora J, Shapiro MS (1992) Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet 29:824–826 Zlotogora J, BenEzra D, Cohen T, Cohen E (1990) Syndrome of brittle cornea, blue sclera, and joint hyperextensibility. Am J Med Genet 36:269–272 Zlotogora J, Legum C, Raz J, Merin S, BenEzra D (1994) Autosomal recessive colobomatous microphthalmia. Am J Med Genet 49:261–262 Zlotogora J, Bach G, Bo¨senberg C, Barak Y, von Figura K, Gieselmann V (1995) Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews. Hum Mutat 5:137–143

Part V Cultural and Religious Attitudes Towards Genetic Issues

Chapter 24

Prevention and Care of Genetic Disorders: An Islamic Perspective Aida I. AL Aqeel

Islam and Ethics Islam is the continuum and the culmination of, not an alternative to, the sister Abrahamic faiths of Judaism and Christianity. In the Quran, they are links of the one chain of God’s message to humanity. The Quran, which Muslims believe is God’s very word, says: The same religion He enjoined on you as the one He enjoined on Noah, and this We reveal unto you and that We enjoined upon Abraham, Moses and Jesus, that you should uphold the faith and break-not your unity therein (The Holy Quran 42:13). This commonality we respect, although we are aware that on further comparison it is natural to find differences and distinct schools of thought between the faiths, and even within one faith. Islam is the predominant religion in the developing world; however, it is not an “Arab” religion. In fact, out of the 1.6 billion Muslims in the world, <20% of Muslims are Arabs. Among the 57 Islamic countries that make up the Organization of the Islamic Conference (OIC), the specific religious and cultural values of each country’s population have a significant impact on the health, education, and social policies, which drives the healthcare or models of care that patients receive (Al-Aqeel 2005, 2007). Islam has a moral code as well as a civil law with a unifying ethical framework. A universal foundation of practices and beliefs creates a monotheistic culture, the aim of which is to create peace in one’s self, family, and society by actively submitting to and implementing the will of God. This culture is further refined by various cultures on the basis of their inclinations and sensitivities. Some

A.I. AL Aqeel Pediatrics, Medical Genetics and Endocrinology, Department of Pediatrics, Riyadh Military Hospital, P. O. Box 7897, Riyadh 11159, Kingdom of Saudi Arabia e-mail: [email protected], [email protected] Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_24, # Springer-Verlag Berlin Heidelberg 2010

705

706

A.I. AL Aqeel

differences among Muslims are attributable to differences of opinion expressed by various schools of jurisprudence, of which there are seven major ones: Hanbali, Maleki, Hanefi, Shafe’i, Ja’fari, Zaidi in Yemen, and Abadyaha in Oman. Others are not Islamic but ethnic, and may even violate Islamic norms (Al-Aqeel 2005, 2007). Medical practice and research involving human subjects raises complex ethical, legal, and social issues. Islamic teachings carry a great deal of instructions for health promotion and disease prevention, including hereditary and genetic disorders; therefore, we will discuss how these teachings play an important role in the diagnostic, management, and preventive measures including genomic research; population genetic screening, including premarital screening, preimplantation genetic diagnosis, and newborn screening; assisted reproduction technology; stem cell therapy; and genetic counseling (Al-Aqeel 2005). Islamic bioethics derives from a combination of principles, duties, and rights, and, to a certain extent, a call to virtue. In Islam, bioethical decision-making is carried out within a framework of values derived from revelation and tradition. It is intimately linked to the broad ethical teachings of the Quran and the tradition of the Prophet Mohammad (Sunna), and thus to the interpretation of Islamic law “Shariai’ha.” In this way, Islam has the flexibility to respond to new biomedical technologies. Islamic bioethics emphasizes prevention and teaches that the patient must be treated with respect and compassion and that the physical, mental, and spiritual dimensions of the illness experience be taken into account (Daar and Al Khitamy 2001). Development of Shariai’a in the Sunni branch of Islam over the ages has also required Ijtihad, the law of deductive logic. Where appropriate, consideration is also given to maslaha (public interest) and urf (local customary precedent) (Kamali 1991). The four main concerns of Islamic ethics are similar to that of Western ethical systems: autonomy, beneficence, nonmaleficence, and justice. Islamic law (Shariai’a), is in spirit dynamic and flexible, exemplified by the principle that “necessity renders the prohibited permissible” (Al Aqeel 2007). The Islamic “Shariai’ha” law has established many principles which can be applied to therapy and treatment. In “Shariai’ha” there are judicial rules that encourage achieving ends, warding off corruption, and avoiding harm and evil, e.g., when removal of harm is followed by an after-effect harm, a balance has to be sought to reach the lesser degree of the two harms. These general judicial rules are only entrusted to the jurisdiction of the scholars of Jurisprudence, yet the doctor is required to be, to some degree, knowledgeable of the “Shariai’ha” laws of which he is in need to practise his profession in order to put into effect the Islamic characteristics of medicine represented in a comprehensive view point, fair judgement, and righteousness of work (Al Sayyad). Some of the Islamic Shariai’ha principles governing medicine, which are authoritative and agreed precedents, are included in (Box 1): (Ajlouni 2004; Al Othiamian 2006; Al Aqeel 2007).

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

707

Box 1: Islamic Shariai’ha Principles Governing Medicine 1. Physical well-being has precedence over religious well-being, “Sahat Al Abdan Mukadamaha Ala Sahat Al Adian” 2. Necessities override prohibitions, “Al Drawrat Tabieh Al mahdawrat” 3. Preventing harm is preferable to procuring benefits, “Draa Al Mafasad Mukadam Ala Jalab Al Manafaa” 4. The basic concept in useful matters is permissiveness, “Al Asal Fii Al Manafaa AL Abaha’a” 5. The basic concept in harmful matters is prohibition, “Al Asal Fii Al Madar Al Tahreem” 6. Human life protection is one of the main principles of Shariai’ha, “Al Mahafada’a Ala Al Nafas Al Bashariaha Ahda Al Maqasad Al Shariai’ha’a Al Raisayaha.” “If any one saved one life, it would be as if he saved the lives of all mankind” The Holy Qura’n 5:32

Impact of Genetic Diseases on the Muslim Population 1. Impact on the patient and the family. a. General Quality of life. l Patient suffering. l Parents’ enormous guilt/shame. l Burden of care. l Psychological distress. b. Adverse effects on the family dynamics. l Focus on sick child, less attention on normal children. l Marital stress. c. Genetic Stigmatization. 2. Impact on healthcare professionals. l Medical Care – limited to supportive care. l Frustration – untreatable diseases. l Genetic counseling (prenatal diagnosis/termination). l Desperate therapies (mixed outcome). 3. Impact on the Community and Society – Medical/supportive costs. – Community need to provide prevention and/or treatment.

Genetics Counseling Genetic counseling is the process in which an individual or a family obtains information and advice about a genetic condition that may affect the individual,

708

A.I. AL Aqeel

his/her progeny, his/her relatives, or the family as a whole. On the basis of this knowledge, he/she can take the pertinent decision regarding marriage, reproduction, abortion, and health management. A consanguineous marriage is usually defined as a marriage between people who are second cousins or closer, but leads to and increases birth prevalence of infants with severe recessive disorders (El-Hashemite 1997; Modell and Darr 2002). It is customary in Middle Eastern population, Irish travelers, Zoroastrians, some Jewish communities, and many tribes in subSaharan Africa and South East Asia. Although the custom is often perceived to be associated with Islam, in fact it is independent of religion. It is estimated that 20% of human population live in communities with preference for consanguineous marriage, and at least 8.5% of children have consanguineous parents (Modell and Darr 2002). Consanguineous unions account for 20–70% of all marriages in the Middle East, excluding Israel and Cyprus (Teebi and El-Shanti 2006). In spite of the fact that Islamic teachings discourage first-cousin marriages (Albar 1999), consanguineous marriage is integral to the structure of many Muslim societies, including those of the Arabian Peninsula, and is known to have many social and economic benefits. It is narrated that Omer Ibn Al-Khatab, the second khalifa, noticed that the progeny of the tribe of Bani Althaa’b had become weak and unhealthy because of intermarriage of cousins. He advised the tribe to avoid close-cousin intermarriage and to seek wives and husbands from tribes further afield. He said: “Marry from far away tribes; otherwise you will be weak and unhealthy” (Albar 1999; Al Aqeel 2007). Consanguinity, in combination with large family size and advanced maternal age, raises unique challenges and opportunities. It results in pedigrees with multiple affected individuals. This helps in homozygosity gene mapping of a multitude of novel Mendelian diseases (Al Aqeel et al. 2000; Martignetti et al. 2001). A review of the combined files of the Riyadh Military Hospital, Riyadh, over a 10-year period, documented more than 150 varieties of neurodegenerative disease among 2,000 children. Some autosomal recessive disorders are common, e.g., sickle cell anemia. Others are unique, e.g., Al Aqeel Sewairi syndrome. In these disorders, the exact molecular defect is found. Therefore, prevention is possible by either preimplantation genetics diagnosis or prenatal diagnosis according to the recommendation of our Islamic scholars (Al-Aqeel 2005, 2007). Islamic teaching encourages counseling. The Prophet Mohammed said: “Religion (Islam) is sincere counseling and good advice.” The Prophet Mohammed also said: “The counselor should be trustworthy.” Indeed a counselor cannot be trustworthy unless he or she is proficient in the field in which he or she is giving advice (Albar 1999). Counseling of families in the Muslim world must be done in accordance to our cultural and religious guidelines, to initiate treatment and to prevent these disorders. Counseling will include other family members as the impact of these disorders includes other family members with recurrence risk. However, treatment is either difficult or expensive or unavailable in some centers. Therefore, prevention is of utmost importance.

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

709

Medical Genetics and Genomics in Developing Countries Medical genetics involves the application of genetic knowledge and technology to specific clinical and epidemiologic concerns. Certain ethical and legal responsibilities accompany the flood of genetic knowledge into the current practice of medicine. This is because of three general characteristics of genetic information: the implications of genetic information are simultaneously individual and familial; genetic information is often relevant to future disease; and genetic testing often identifies disorders for which there are no effective treatments or preventive measures (Burgess et al. 1998). To insure that benefits of genomics are shared by developing countries, attention must be paid to complex ethical, legal, social, religious, and economic issues, as well as public education and engagement. Many of the advances in genomics were made, and in part are owned, by the developed world, which will further widen the equity gap in health between rich and poor nations (Luri and Wolfe 1994), which is one of the concerns of the World Health Organization. Although there is no single ethical issue that unifies the field of genetics, informed consent, confidentiality, and the potential for social harm and psychological distress are issues that physicians involved with testing should understand (Etchells et al. 1996). Essentially, the principles and components of consent that are generally acceptable in Western countries are also applicable to Muslims, although Muslims (depending on their level of education, background, and culture) will often want to consult with family members before consenting to major procedures. Particular care should be exercised when the consent involves abortion, end-of-life issues, or sexual and gynecological issues (Daar and Al Khitamy 2001). The 1989 Children’s Act states that the age of consent is when a child reaches his/her16th birthday, or younger, if a doctor deems a child capable of understanding and making decisions. In Islamic law, the age of majority (and hence full autonomy) taken by Shafi and Hanbali schools of Jurisprudence is 15 years, while Abu Hanifa and Maklik take the age of 18 years (Al-Aqeel 2005). Many examples in medical genetics and genomics are implemented by applying the Islamic Shariai’ha principle “Preventing harm is preferable to procuring benefits.” Therefore, the use of genomics research is encouraged in Islam, with a balance between potential benefits and harms, on the condition that such use does not cause further social damage (Al Aqeel 2007). The Islamic Jurisprudence Council of the Islamic World League (Organization of Islamic Countries) in Makkah Al-Mukarama regularly holds conferences in situations requiring specialist knowledge (for example, decisions concerning medical practice, or research), and the somewhat novel concept of a “consensus edict” (fatwa), an authoritative ruling on a point of Islamic law, is preferable. For rulings pertaining to medicine, these consensus groups will typically include a broad and diverse representation of Ulema (Islamic Jurists) and specialists, clinicians, and scientists from relevant disciplines, the latter responsible for providing the

710

A.I. AL Aqeel

necessary background information. The decision making process is typically transparent with members of the wider community able to scrutinize the arguments employed and the textual material underpinning these edicts. Counter arguments may be presented, and it is not unusual for two or more seemingly contrasting opinions to coexist. In such cases, individuals are, in principle, free to choose whichever judgment they find most agreeable, though in practice many will choose to remain loyal to their particular school of thought (Al-Aqeel 2005, 2007).

Genomic Research and Islam Genomics provides powerful means of discovering hereditary factors in disease. But even in the genomic era, it is not genes alone but the interplay of genetic and environmental factors that determines phenotype. However, as is true for much of the application of genomics, ethical, legal, and social issues complicate this era unless complex issues regarding the patenting and licensing of gene-based knowledge and techniques are dealt with more successfully than they are today. Another social issue, with particular relevance in the United States, is the understandable concern of many patients that obtaining genetic information important to their healthcare is not worth the risk of discrimination stemming from the use of such information by potential insurers or employers. Other social issues require our attention if genomic medicine is to benefit our patients. How should genetic tests be regulated? What, if any, are the appropriate uses of direct-to-consumer marketing of genetic tests? How will healthcare providers and the public distinguish between these and responsible testing services, and whether they are available through the Internet or in the hospital? It would be easy to assume that for the foreseeable future the benefits of genomic medicine will accrue only to people in developed countries (Collins et al. 2003). The benefits of molecular genetics and bio-engineering to Muslims have been discussed by the Islamic Jurisprudence Council of the Islamic World League (Organization of Islamic Countries) in Makkah Al-Mukarama in its 15th session (11th Rajab H/31 October 1998G), and it was decided as follows (Al-Aqeel 2005): 1. To use genetic engineering for disease prevention, treatment, or amelioration on the condition that such use does not cause further damage 2. To forbid the use of genetic engineering for evil and criminal uses or what is forbidden religiously 3. To forbid using genetic engineering and its tools to change human personality and responsibility, or interfering with genes to improve the human race 4. To forbid doing any research or therapy of human genes except in extreme need, after critical evaluation of its benefits and dangers and after an official consent of the concerned, respecting the extreme confidentiality of the information and human rights and dignity as dictated by Islamic Shariai’ha

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

711

5. To allow the use of bio-engineering in the field of agriculture and animals, on the condition that precautions are taken not to inflict harm (even in the long term) on humans, animals, or vegetation For DNA fingerprinting, the Islamic Jurisprudence Council of the Islamic World League (Organization of Islamic Countries) in Makkah Al-Mukarama in its 16th session (21–26.10.1422H/5–10 January 2002) has decided as follows: (Al-Aqeel 2005). 1. It is religiously allowed to use DNA fingerprinting on judges’ orders and performed in the state laboratories; in forensic interrogations to prove crimes which have no definite penalty in Islamic law (Shariai’ha) (Avoid punishment if there is any doubt, as doubt should always be used for the sake of the accused), this will lead to justice and to safety of the community, as the criminal will be punished and the innocent will be freed from guilt, which is one of the most important goals of Shariai’ha. 2. DNA fingerprinting may be used in lineage (genealogy) only with great caution and confidentiality as the Shariai’ha rules take precedence over DNA fingerprinting. 3. It is forbidden to use DNA fingerprinting in paternity (lineage) disputes, which should not precede the oath of condemnation (the sworn allegation of adultery committed by one’s spouse). 4. It is forbidden to use DNA finger printing to confirm or refute legally proven lineage; the state should forbid this and inflict punishment, in order to protect people’s honor and to preserve their lineage. 5. It is allowed to use DNA fingerprinting in proving lineage on the following conditions: – In cases of dispute about unknown lineage, as mentioned by the Islamic scholars because the evidence is either absent or equivocal, and to overcome the vagueness (suspicion) – In cases of disputes over babies in hospitals and nurseries or test-tube babies – In cases of children lost because of war, accidents, or natural disasters, where their family could not be found – To identify bodies or prisoners of war.

Population Genetic Screening Programs and Islamic Ethics Population genetic screening programs are public health programs targeted at populations or subgroups identified by their risk category. The goals are the detection and prevention of genetic disorders and birth defects at the population level (Donnai 2002). These screening programs are governed by several ethical principles: provision for the rights of an individual to access appropriate information and to make choices on participation in the program; avoidance of social stigmatization of persons found

712

A.I. AL Aqeel

to be at increased risk or of those declining screening; and avoidance of the misuse of information and of discrimination based on the test results. Economic criteria alone cannot be used to justify a screening program (WHO 1997, 1999). The Islamic “Shariai’ha” principle “The basic concept in useful matters is permissiveness” which indicates that everything is lawful, as long as it is useful to people, (unless otherwise stipulated in a religious provision or could be judged by analogy (Qiyas) with unlawful things) can be applied to all methods of treatment, or prevention (Al Sayyad).

Primary Prevention Strategies Control of Teratogens Apply the Islamic “Shariai’ha” principle “The basic concept in harmful matters is prohibition” which prohibits performing any medical procedure where harm is absolute or predominantly outweighing (Al Aqeel 2007). Therefore, Rubella is virtually eliminated in many countries by vaccinating girls of school age. Syphilis and other STD (sexually transmitted diseases) will not appear if all sexual desires are channeled through marriage as Islamic teachings imply. Fornication, adultery, and sodomy are all harshly punished in Islamic legal code, and religiously they are considered the greatest sins that each Muslim should avoid. Any substance that is going to be harmful to the baby (namely teratogen), e.g., alcohol and smoking, should be avoided as the prophet Mohammed said: “Do no harm” (Albar 2002).

Premarital or Prepregnancy Genetic Screening Genetic blood disorders (thalessemia and sickle cell anemia) and Tay–Sachs disease are the groups of disorders where there is extensive experience and where outcome data are available. The birth rate of children with thalassaemia major has fallen by at least 75% in Cyprus, Italy, and Greece where national programs promote premarital screening and where couples most at risk are identified before their first pregnancy (WHO 1999). These disorders are transmitted by autosomal recessive mode of inheritance, so they are quite common in the Islamic population. They include sickle cell anemia, thalassaemias, and glucose-6-phosphate dehydrogenase (G6PD) deficiency, which involves 20–25% of the whole population in Hofuf and Qatif (Eastern province of Saudi Arabia) and Jizan (South West province of Saudi Arabia); the carriers of the trait are one in four, or one in five in the whole community, and any carrier will have a high risk of marrying another carrier of the trait (Weatherall 1998). Applying the Islamic “Shariai’ha” principle “The basic concept in useful matters is permissiveness” the Islamic Jurisprudence Council of the Islamic World League

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

713

(Organization of Islamic Countries) in Makkah Al-Mukarama in its 17th session (19–23.10.1424H/13–17 December 2003G), after having looked into the legitimacy of premarital medical screening for genetic blood disorders, has decided as follows: First: The marriage wedlock contract is governed by conditions of the Islamic Shariai’ha, from which legal consequences follow. Thus, additional conditions, such as enforcing premarital medical screening, are not permissible under the Islamic Shariai’ha. Second: The Council recommends that governments and Islamic institutions spread understanding of the importance of premarital genetic tests and encourage their use. They should facilitate such tests for those who wish to use them, while ensuring confidentiality so that the results are not revealed except to the persons concerned. Therefore, informed premarital screening for genetic blood disorders, thalassaemia, and sickle cell anemia (which is not linked to any type of enforced prevention of marriage) has been mandatory in KSA for the past 4 years, after it was approved by a consensus edict. In the years 2004 and 2005, screening of almost a quarter million people from 130 Ministry of Health primary healthcare centers was carried out. Two thousand and three and 2,441 cases of incompatibility were identified respectively; in these sickle cell traits of 4.19% and 4.21%; sickle cell cases of 0.27% and 0.25%; b thalassaemia minor of 3.2% and 3.24%; and b thalassaemia major of 0.08% and 0.06% were identified. This screening has subsequently led to a decrease in consanguineous marriages in the screened population by 9.2% and 11.6% for the years 2004 and 2005, respectively (Alhamdan et al. 2007). Applying the same principle, prepregnancy genetic screening could be done if a genetic disorder is known in a family, and the mutation for such disorder is already known. Population wide prepregnancy carrier screening is possible, if the carriers’ mutations are known in the population for common genetic disorders like Tay–Sachs disease in the West. We have some experience with carrier screening for some of the common disorders in certain families in Saudi Arabia, for which prepregnancy screening is possible (Al Aqeel et al. 2000; Martignetti et al. 2001).

Secondary Prevention Strategies The aims of such screening programs are the early diagnosis of genetic disorders with a view to preventing or ameliorating their effects. Inborn errors of metabolism (IEMs) and other inherited Mendelian disorders are common in Saudi Arabia and throughout the Middle East, presumably because of the relatively high rates of consanguinity (Ozand et al. 1992). Twenty percent to 25% of all marriages in Saudi Arabia are between first cousins, another 20–25% are second cousins marriages, and 15–20% are family related, with a total of 60–65% of consanguineous marriages (El Hazemi 1996). Even in segregated communities, IEMs are estimated to account for as much as 20% of disease among full-term neonates not known to have been at risk and may

714

A.I. AL Aqeel

affect as many as one in 5,000 live births (Rashed et al. 1997). Many of the IEMs carry serious clinical consequences to the affected neonate or young infant, including mild to severe mental retardation, physical handicap, and even fatality. Although early diagnosis of some of these disorders has proven very effective in treatment or management, neonates are screened for only a handful of diseases, even in the developed world (Scriver 1996). Applying the Islamic “Shariai’ha” principle “The basic concept in useful matters is permissiveness,” such an important preventive measure to prevent mental handicap in children is highly recommended by Islamic jurists. Therefore, neonatal screening by tandem mass spectroscopy for 16 metabolic disorders and for endocrine disorders, on the basis of dried blood spots (DBS), was started in KSA in Ministry of Health hospitals in August 2005, and 1.2:1,000 newborns were found to be positive (Al Aqeel 2007).

Prevention Based on Reproductive Options Reproductive options which are ethically approved by Western standards vary according to the condition for which an individual is being screened and include prenatal diagnosis, preimplantation diagnosis, sperm or egg donation, the avoidance of further pregnancy, or adoption.

Contraception and Sterilization Applying the Islamic “Shariai’ha” principle “Preventing harm is preferable to procuring benefits” it is acceptable to use temporary means of contraception, if the couple is agreeable, and if no harm is likely to result. However, sterilization is not acceptable, unless the health of the mother would be endangered by pregnancy. However, in the situation where a couple already had two or three congenitallyaffected children and a lesser number unaffected, then they might choose sterilization. In such a case, they would find support from at least some Islamic jurists (Albar 1999; Husain 2003).

Adoption Adoption has a different interpretation in Islam. Though caring for orphan or children of unknown parents is encouraged and considered as a charity and a great act of worship, the lineage of the child should be kept to his biological parents. The Holy Quran says: God did not make your adopted ones your sons (33:4) (Albar 1999, 2002; Husain 2003).

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

715

Donation of a Sperm, Ovum, or Preembryo, or Motherhood Surrogacy Applying the Islamic “Shariai’ha” principle “The basic concept in harmful matters is prohibition” artificial insemination by a donor sperm, or egg donation, are all out of bounds in Islamic law. Procreation in Islamic law is limited to husband and wife, during the existence of matrimonial bondage. If divorce or death of a spouse occurs no procreation will be allowed, including surrogacy (Albar 1999, 2002; Husain 2003). A November 2000 workshop organized by the International Islamic Center for Population Studies and Research, Al-Zahra University, Cairo, considered use of assisted reproduction technologies (ART) in the Islamic world. The same above conclusions were drawn, including no embryo transplantation after husband death (Seroura and Dickens 2001).

Preimplantation Diagnosis Preimplantation genetic diagnosis (PGD) was introduced at the beginning of the 1990s as an alternative to prenatal diagnosis, to prevent termination of pregnancy in couples with a high risk for offspring affected by a sex-linked genetic disease (Sermon et al. 2004). PGD is an early form of prenatal diagnosis, where in vitro fertilization is carried out. The zygotes are grown to eight cell stage (Morella stage), and embryos created in vitro are analyzed for well-defined genetic defects; only those free of the defects are replaced into the womb. The technique is used mainly in two broad indication groups. The first group comprises individuals at high risk of having a child with a genetic disease e.g., carriers of a monogenic disease or of chromosomal structural aberrations, such as translocations. The second group consists of those being treated with in-vitro fertilization (IVF), who might have a low genetic risk but whose embryos are screened for chromosome aneuploidies to enhance their chance of an ongoing pregnancy (Sermon et al. 2004). The workshop organized by the International Islamic Center for Population Studies and Research, Al-Azhar University, Cairo recognized the importance of PGD, but was guarded about its use on non medical grounds such as sex-selection or family balancing, considering that each case should be treated on its own merits. Sex selection technologies have been condemned on the ground that their application is to discriminate against female embryos and fetuses (Seroura and Dickens 2001).

Ethically Difficult Indications For some diseases, PGD but not prenatal diagnosis can be defended from an ethical point of view. In nondisclosure PGD, which has been described for Huntington’s

716

A.I. AL Aqeel

disease but could also be applied to other late-onset diseases, patients do not wish to know their carrier status but want to have disease-free offspring (Stern et al. 2002). Another new indication for PGD involves the selection of embryos, according to their HLA type, so that a child born out of a PGD cycle can be a stem-cell donor for a sick sibling (Pennings et al. 2002). The use of PGD to diagnose risk of late-onset diseases (such as Huntington’s disease and Alzheimer’s disease) and to search for genes that predispose for cancer (BRCA1, BRCA2, Li-Fraumeni, neurofibromatosis 1 and 2) is also ethically debatable (Robertson 2003; Verlinsky et al. 2002). Finally, several reports have been published on the use of sexing for social reasons and have provoked mixed reactions (Ray et al. 2003). According to Islamic teaching, human life begins at the time of “inspiration of the soul” “Nafakh Al Rouh” which is stated in the holy Qur’an and Sunna, to be at the 120th day from the moment of conception (Fig. 24.1). Prior to that moment the embryo has sanctity but has not reached the status of a full human being (Al-Aqeel 2005). Each of you will have had his created existence brought together in his mother’s womb, as a drop (nutfa) for 40 days, then a leech like clot (alaqa) for the same period, then a piece of flesh (mughda) for the same period), after which God sends the angel to blow the spirit (ruh) into him (Hadith: Sahih Al-Bokhari and Muslim) (Seroura and Dickens 2001).

Applying the Islamic Shariai’ha principle “The basic concept in useful matters is permissiveness” PGD is ideal, as it is carried out in the preensoulment (prior to the inspiration of the soul) stage at 48 h of gestation (Al-Aqeel 2005). The important application for PGD is selecting the embryos, for a certain HLA type, so that a child born out of a PGD cycle can be a stem-cell donor for a sick sibling. Although this application of PGD is controversial in the West, applying the sixth Shariai’ha principle “human life protection,” such an indication is encouraged by Islamic scholars, on the assumption that the newly born child will be loved and well cared for by his parents and family. In Saudi Arabia, PGD is carried out for carriers of monogenic diseases or of chromosomal structural aberrations, such as translocations, with good results (Hellani et al. 2004; Al-Aqeel et al. 2006).

Fig. 24.1 Stages of embryo development as stated in the Holy Qura’n 23:14 (“Nutfah”: mixed drops of male and female sexual discharge, “AlAqa’a”: clot, “Mudgha’a”: lump, each for 40 days). On the basis of this text, and other texts in the Holy Qura’n and Sunna, many Muslim scholars conclude that fetal ensoulment occurs at 120 days postconception, when God says, “then we brought it forth as another creation”

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

717

Prenatal Diagnosis A number of ethical considerations arise with regard to screening for detecting and managing fetal anomalies. The ethical principle of beneficence gives rise to a duty of the obstetrician to provide emotional support when needed in relation to screening, confirmatory testing, giving bad news, making abortion decisions, making management decisions after viability, and dealing with the grieving process. Other issues involve ethical decision-making, such as deciding what recommendations to make concerning management of fetal anomalies after viability. The ethical principle of autonomy creates a duty of the obstetrician to help the pregnant woman make informed management decisions on the basis of her values, religion, and goals (Strong 2003). The fatwa #4 of the Islamic Jurisprudence Council of the Islamic World League (Organization of Islamic Countries) at its 12th session (15–22 Rajab 1410H/10–17 February, 1990G) in Makkah Al-Mukarama , agreed by a majority vote to allow for the option of abortion under certain specific conditions. The fatwa determined that an abortion may take place only if a committee of specialized, competent physicians has decided that the fetus is grossly malformed, and that its life would be a calamity for both the family and itself. The malformation must be untreatable, unmanageable, and very serious, and the abortion may only be carried out prior to the 120th day of conception (computed from the date of fertilization, not the last menstrual cycle), but not including Down’s syndrome or other serious conditions, like thalassaemia. Therefore, abortions due to serious fatal congenital disorders are carried out in some Muslim countries, legally so in Tunisia and Iran (Al-Gazali et al. 2006). However, applying the two principles, Physical well-being has precedence over religious well-being; Necessities override prohibitions, abortion is allowed after 120 days, if there is a danger to maternal life, regardless of whether the fetus is normal or abnormal. In this case, termination of pregnancy is against religious wellbeing, but it is done for the mother’s physical health (Al Aqeel 2007).

Cloning and Stem Cell Research Currently, the international community agrees that human cloning for reproductive reasons should not be attempted. The rationale cites safety considerations in view of the many difficulties and defects reported in the cloning of animals (Wakayama 2004). Others maintain that cloning might be ethically acceptable under certain conditions, for example, if it were the only way for couples with fertility difficulties or a genetic disorder to have a healthy genetically related child (Tauer 2004). Issues in public policy on cloning overlap somewhat with general stem-cell matters but have additional dimensions. Prohibition of cloning for reproductive reasons is directed at prevention of the birth of children who are genetic copies of already existing individuals (Tauer 2004).

718

A.I. AL Aqeel

Islam allows procreation between man and woman, only within marriage. Applying the Shariai’ha principle “the basic concept in harmful matters is prohibition,” human cloning (production of a human being whose genetic make-up is nearly identical to that of a currently or previously existent individual), is forbidden in any method that leads to human reproduction. Legislation on cloning for research, however, deals mainly with development of stem-cell lines through somatic cell nuclear transfer (SCNT), thus raising issues about specific type of stem-cell research. SCNT is achieved by injecting a nucleus from a somatic cell of an adult into an enculated egg (whose nucleus had been removed). The cell would then grow into a fetus that would be a true genetic copy of the adult from which the somatic cell nucleus was taken. In Islam SCNT is currently not permitted (Al Aqeel 2007). The Islamic Jurisprudence Council of the Organization of Islamic Countries in Jeddaha in its tenth session (23–28.2.1418H/28 June–3 July 1997G) declared Decree #100/2/D10, on cloning (Al-Aqeel 2005): 1. Human Cloning is forbidden in any method that leads to human reproduction. 2. It is forbidden in all cases to introduce a third party into marriage, be it an egg donor, a surrogate womb, a sperm donor, or a cloned cell. 3. It is permissible to use genetic engineering and cloning in the fields of germs, microorganisms, plants, and animals, following legitimate rules which lead to benefits and prevent harm. 4. All Muslim countries are called upon to formulate the necessary legislation to prevent foreign research institutes, organizations, and experts from directly or indirectly using Muslim countries for experimentation on human cloning or promoting it. 5. Specialized committees should be set up to look into the ethics of biological research and adopt protocols for study and research in Muslim countries. 6. Biological and bioengineering research institutions (other then cloning research) should be supported and established, according to the Islamic rulings, so that the Muslim world will not be dependent on others in this field. 7. The communication media are called upon to deal with recent scientific advances from an Islamic perspective in a faithful way and avoid employing their services against Islam, aiming to educate the public to be confident before any decision.

Cord Blood Transplantation Since the first successful use of cord blood as source of haemopoietic stem cells for transplantation in 1988, more than 2,000 patients with malignant or nonmalignant disorders have been treated with this procedure. Collection and storage of cord blood has prompted ethical considerations, mainly dealing with the issues of autonomy in making decisions about donation of cord blood, and of privacy and

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

719

confidentiality in the tests required before use of placental cells for transplantation (Burgio et al. 2003). Newborn babies are nonvoluntary donors of placental blood, and clinicians cannot use this blood without the informed consent of the mother (the father’s consent is usually not considered a legal requirement). The need to screen for the infectious and genetic diseases transmissible by transplantation of cord blood can cause problems in terms of privacy, professional confidentiality, and sometimes serious repercussions entailed by information about development of severe congenital diseases for which there is no cure (Burgio et al. 2003). Applying the Islamic Shariai’ha principle “The basic concept in useful matters is permissiveness” the Islamic Jurisprudence Council of the Islamic World League in Makkah Al-Mukarama in its 17th session (19–23.10.1424 H/13–17 December 2003G) have declared Decree #3 on Stem Cell Therapy (Al-Aqeel 2005): l

l l

l l

l

l

l l l

First: It is permissible to obtain stem cells, to be grown and used for therapy or for permissible scientific research, if its source is legitimate, as in examples given below: Adults, if they give permission, without inflicting harm on them. Children, provided that their guardians allow it, for a legal benefit and without inflicting harm on the children. The placenta or the umbilical cord, with the parents’ permission. A fetus if spontaneously aborted or when aborted for a therapeutic reason permitted by Sharia, with the parents’ permission. (Be reminded of decree #7 of the Council in its 12th session about abortion.) Left over zygotes remaining from in vitro fertilization, if donated by the parents, when it is ascertained that they will not be used in an illegal pregnancy. Second: It is forbidden to use stem cells, if their source is illegal, as in examples given below: Intentionally aborted fetuses (that is, abortion without a legal medical reason). Intentional fertilization between a donated ovum and sperm. Therapeutic human cloning.

Somatic Gene Therapy Somatic gene therapy (SGT) involves introducing an exogenous gene sequence into an organism, to act as a substitute for an endogenous gene that produces inadequate or aberrant protein. SGT currently lies in the uncertain gray area between novel research topic and therapeutic reality. Clinical trials began in the early 1990s, and attempts to provide SGT for a number of conditions notably cancer, acquired immune deficiency syndrome, and inherited diseases are underway. The clinical efficacy and safety of SGT, however, remain disputed, and no form of SGT is yet in routine use. In the years of professional discussion of human genetic manipulation, an ethical consensus has evolved. This views SGT as an extension of conventional

720

A.I. AL Aqeel

medical interventions, and identifies the predominant ethical issues associated with SGT as follows: (1) the anticipated risk/benefit balance, (2) the selection of appropriate patients, (3) the provision of information to patients so that informed consent can be given, (4) the preservation of patient confidentiality, and (5) the cost to the healthcare system (Scully and Rehmann-Sutter 2001; Scully et al. 2004). We (God) created Man in the most perfect form (The Holy Quran 95:4)

It is often used to explain that each human life has its own inherent value and goodness. While genetic research and gene therapy may have positive uses in serving to restore health (and in the process integrity), care must be taken to ensure that other Islamic principles are not violated. An accurate and complete knowledge of one’s pedigree is a fundamental human right; applying the Shariai’ha principle “Preventing harm is preferable to procuring benefits” only somatic cell lines should therefore be used in gene therapy as parental integrity is then not compromised and there is no question of hereditary characteristics being influenced (Gatrad and Sheikh 1999; Al Aqeel 2007).

Conclusions Genetic testing should be undertaken as part of public health measures to prevent disease, promote health-enhancing behavior, and to provide accurate and useful risk perception to a better informed public. Alliances of organizations supporting families affected by genetic disorders and individual groups should be major contributors, along with professionals, to the design of genetic services and development of appropriate measurement and valuation tools. Marked health improvements from integrating genomics into individual and public healthcare depend on the effective education of health professionals and the public about the interplay of genetic and environmental factors in health and disease. The media are crucial sources of information about genomics and its societal implications. Initiatives to provide the media with greater understanding of genomics are needed. High-school students will be both the users of genomic information and the genomics researchers of the future. Especially as they educate all sectors of society, high-school educators need information and materials about genomics and its implications for society to use in their classrooms (Collins et al. 2003). The majority of the populations in Asian and African countries are Muslims by religion. The Arabian Peninsula is the cradle of the Arabs, and Islam is their religion since it was established by Prophet Mohammed, in 622 AD in Madina (Gatrad and Sheikh 1999). Islamic teachings offer a great deal in the prevention and control of genetic diseases to Islamic community. It is important to educate people about the danger of consanguinity, which is very common in these countries. Premarital examination should be encouraged, which may detect the trait in those intending to get married. Proper counseling should be provided, the dangers explained, and the options discussed. Prenatal diagnosis and the option of abortion for serious

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

721

devastating diseases (prior to 120 days from conception) will reduce the incidence of such diseases. Neonatal screening can avert devastation by simple measures, namely, specific diets. Avoiding teratogens and provision of folate and iodine in the diet will help in reducing congenital diseases. Stem cell and gene therapy are very promising if used within the Islamic context. A minimum level of cultural awareness is a necessary prerequisite for the delivery of care that is culturally sensitive. Once equipped with such understanding it is possible to move beyond the “recipe book” approach to dealing with minority traditions, offering the opportunity for experiential learning. In this paper, we have simplified and highlighted certain key teachings in Islamic medical genetics ethics and explored their applications. We hope that the insights gained will aid clinicians to better understand their Muslim patients and deliver care that pays due respect to their beliefs. Strategic plans need to be made by establishing a strong international leadership by the scientific community, international organizations, governments, and industry, with critical analysis and systems development, and actually health system must balance two purposes. In the short term, they must respond to the demands of the public for access to existing services. At the same time, they must try to improve the health of the whole population. In genetics, population screening programs for detection and prevention of genetic disorders and birth defects with genetic data registry and systemic follow up of the probands are of utmost importance. Acknowledgments I would like to thank Dr Mohammed A. Al Bar, Consultant in Islamic Medicine, King Fahad Medical Research Center, Jeddaha, Saudi Arabia, for providing the Arabic version of the Islamic Fatwas and for his expert advice.

References Al Aqeel AI, Al Sewairi W, Edress B et al (2000) Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family. Am J Med Genet 93:11–18 Al Aqeel AI, Ruiter JPN, Ijlst L, Wanders RJA (2003) A novel molecular defect of carnitine acylcarnitine translocase (CACT) gene in a Saudi patient. Clin Genet 64(2):163–165 Al-Aqeel AI (2005) Ethical guidelines in genetics and genomics: an Islamic perspective. Saudi Med J 26(12):1862–1869 Al-Aqeel AI, Serdar C, Jaroudi K, Ozand PT, Hellani A (2006) Pre-implantation genetic diagnosis (PGD) for genetic disorders in Saudi Arabia. J Inherit Metab Dis 29(1):63 Al Aqeel AI (2007) Islamic ethical framework for research into and prevention of genetic disease. Nat Genet 39(11):1293–1298 Albar MA (1999) Counselling about genetic disease: an Islamic perspective. East Mediterr Health J 5(6):1129–1133 Albar MA (2002) Ethical considerations in the prevention and management of genetic disorders with special emphasis on religious considerations. Saudi Med J 23(6):627–632 Al-Gazali L, Hamamy H, Al-Arrayad S (2006) Genetic disorders in the Arab world. BMJ 333:831–834 Alhamdan NA, Almazrou YY, Alswaidi FM, Choudhry AJ (2007) Premarital screening for thalassemia and sickle cell disease in Saudi Arabia. Genet Med 9(6):372–377

722

A.I. AL Aqeel

Ajlouni K (2004) MS 1425H/2004G. In: Cloning between science and religion, vol. 31. Ajial, Amman, Jordan, pp 163–165 (Available in Arabic) Al Othiamian (2006) MS1427H/2006G. In: Fundamentals of islamic jurisprudence (Isul AFagih). Abn Al Jawzi, Damam, KSA (Available in Arabic) Al Sayyad IA Legal directives for medical practice procedures: an Islamic approach to medicine http://www.islamicmedicine.org/SayadBook2.htm Burgess MM, Laberge Claude M, Knoppers Bartha M (1998) Bioethics for clinicians: 14. Ethics and genetics in medicine. Can Med Assoc J 158:1309–1313 Burgio GR, Gluckman E, Locatelli F (2003) Ethical reappraisal of 15 years of cord-blood transplantation. Lancet 361:250–252 Collins FS, Green ED, Guttmacher AE, Guyer MS (2003) A vision for the future genomic research. Nature 422(6934):835–847 Daar AS, Al Khitamy A (2001) Binsumeit. Bioethics for clinicians: 14. Islamic bioethics. Can Med Assoc J 164(1):60–63 Donnai D (2002) Genetic services. Clin Genet 61:1–6 El Hazemi M, Warsy A (1996) Genetic Disorders among Arab Populations. Saudi Med J 17:108–123 El-Hashemite N (1997) The Islamic view in genetic preventive procedures. Lancet 350 (9072):9223 Etchells E, Sharpe G, Walsh P, Williams JR, Singer PA (1996) Bioethics for clinicians: 1. Consent. Can Med Assoc J 55:177–180 Gatrad AR, Sheikh A (1999) Medical ethics and Islam: an Islamic perspective. East Mediterr Health J 5(6):1129–1133 Hellani A, Al Aqeel AI, Jaroudi K, Ozand P, Coskun S (2004) Pregnancy after pre-implantation genetic diagnosis for Sanjad Sakati Syndrome. Prenat Diagn 24(4):302–306 Husain FA (2003) Reproductive issues from the Islamic perspective. Hum Fertil 3(2):124–128 Kamali MH (1991) Urf (custom). In: Principles of Islamic jurisprudence. Islamic Texts Society, Cambridge, pp 283–296 Luri P, Wolfe SM (1994) Unethical trials of interventions to reduce perinatal transmission of human immunodeficiency virus in developing countries. N Engl J Med 331:1173–1180 Martignetti J, Al Aqeel AI, Al Sewairi W et al. (2001) Mutations of matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Nat Genet 28: 261–265 Modell B, Darr A (2002) Genetic counseling and customary consanguineous marriage. Nat Rev Genet 3:225–229 Ozand PT, Devol EB, Generoso GG (1992) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Pennings G, Schots R, Liebaers I (2002) Ethical considerations on pre-implantation genetic diagnosis for HLA typing to match a future child as a donor of haematopoietic stem cells to a sibling. Hum Reprod 17(534–538):54–59 Rashed MS, Bucknall MP, Little D, Awad A, Jacob M, Alamoudi M, Alwattar M, Ozand PT (1997) Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automed flagging of abnormal profiles. Clin Chem 43(7):1129–1141 Ray P, Munnich A, Nisand I, Frydman R, Vekemans M, Viville S (2003) Sex selection by preimplantation genetic diagnosis: should it be carried out for social purposes? Is pre-implantation genetic diagnosis for “social sexing” desirable in today’s and tomorrow’s society? Hum Reprod 18:463–464 Robertson J (2003) Extending pre-implantation genetic diagnosis: the ethical debate – ethical issues in new uses of pre-implantation genetic diagnosis. Hum Reprod 18:465–471 Scriver CR (1996) Genetic screening, testing and treatment: how far can we go? J Inherit Metab Dis 19:401–411

24

Prevention and Care of Genetic Disorders: An Islamic Perspective

723

Scully JL, Rehmann-Sutter C (2001) When norms normalize. The case of genetic enhancement. Hum Gene Ther 12:87–95 Scully JL, Rippberger C, Rehmann-Sutter C (2004) Non-professionals’ evaluations of gene therapy ethics. Soc Sci Med 58:1415–1425 Sermon K, Van Steirteghem A, Liebaers I (2004) Pre-implantation genetic diagnosis (Review). Lancet 363:1633–1641 Seroura GI, Dickens BM (2001) Ethical and legal issues in reproductive health. Assisted reproduction developments in the Islamic World. Int J Gynecol Obstet 74:187–193 Stern H, Harton G, Sisson M et al (2002) Non-disclosing pre-implantation genetic diagnosis for Huntington disease. Prenat Diagn 22:303–307 Strong C (2003) Fetal anomalies: ethical and legal considerations in screening, detection, and management. Clin Perinatol 30(1):113–126 Tauer CA (2004) International policy failures: cloning and stem-cell research. Lancet 364: 209–214 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research, and policy. Lancet 367:970–971 Verlinsky Y, Rechitsky S, Verlinsky O, Masciangelo C, Lederer K, Kuliev A (2002) Pre-implantation genetic diagnosis for early-onset Alzheimer disease caused by V717L mutation. JAMA 287:1018–1021 Wakayama T (2004) On the road to therapeutic cloning. Nat Biotechnol 22:399–400 Weatherall D (1998) Some aspects of the hemoglobinopathies of particular relevance to Saudi Arabia and other parts of the middle east. Saudi Med J 9:107–115 World Health Organization (1997) Proposed international guidelines in ethical issues in medical genetics and genetic services, WHO/HGN/GL/ETH/98.1 World Health Organization (1999) Services for the prevention and management of genetic disorders and birth defects in developing countries, WHO/HGN/GL/WAOPBD/99.1

Chapter 25

Genetic Counseling in the Middle East Shelley J. Kennedy and Muna Al-Saffar

Genetic counseling is a new profession in the Middle East – and one that is highly in demand, given the demographics and health issues of the populations in this region. The practice of genetic counseling can be differentiated from the larger field of clinical genetics due to its intrinsic focus on communication and psychosocial issues. Although genetic counseling and clinical genetic services are closely interwoven, and typically offered together, the provision of genetic testing may not encompass the genetic counseling process in its entirety.

What is Genetic Counseling? The term “genetic counseling” was first introduced by Sheldon Reed, a geneticist at the University of Minnesota, in 1947, who described the new field of genetic counseling as a type of social work (Reed 1980). Since this first description, many definitions of genetic counseling have been proposed. In 1974, genetic counseling was succinctly defined by Fraser as “a communication process that deals with the human problems associated with occurrence or risk of occurrence of a genetic disorder in a family (Fraser 1974)”. This was further expanded in 1975 by an ad hoc committee reporting to the American Society of Human Genetics (ASHG). This committee developed the following definition of genetic counseling that was broadly utilized for over 30 years: A communication process which deals with the human problems associated with occurrence, or the risk of occurrence, of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to:

S.J. Kennedy (*) Certified Genetic Counsellor, Ontario Newborn Screening Program & Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada email: [email protected]

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_25, # Springer-Verlag Berlin Heidelberg 2010

725

726 l

l

l l

l

S.J. Kennedy and M. Al-Saffar

Comprehend the medical facts, including the diagnosis, probable cause of the disorder, and the available management; Appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified relatives; Understand the alternatives for dealing with the risk of recurrence; Choose the course of action which seems to them appropriate in view of their risk, their family goals and their ethical and religious standards, and to act in accordance with that decision; and Make the best possible adjustment to the disorder in an affected family member and/or to risk recurrence of that disorder

While the ASHG definition captures many important aspects of genetic counseling it lacks specific reference to the counseling elements (Biesecker and Peters 2001). The definition has been described as lengthy and complex – and more critically, does not reflect changes in medical care and genetics that have occurred during the past 30 years (Resta 2006). In 2006, the Genetic Counseling Definition Task Force of the National Society of Genetic Counselors (2006) developed a slightly more succinct and modern definition: Genetic Counseling is the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. This process integrates the following: l

l

l

Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. Education about inheritance, testing, management, prevention, resources and research. Counseling to promote informed choices and adaptation to the risk or condition.

This definition emphasizes that genetic counseling is a psycho-educational process centered on the provision of genetic information (Kessler 1997) with the goal being to facilitate a client’s ability to use genetic information in a personally meaningful way in order to minimize psychological distress and increase perceived personal control (Biesecker and Peters 2001). No definition of genetic counseling will apply to all those that practice this profession – as a definition inherently reflects the values, ethics, goals and medical practices of the person or group defining the practice (Resta 2006). This is a critical factor for those practicing genetic counseling in the Middle East to consider, as the majority of the definitions of genetic counseling have been developed in North America, the United Kingdom, and Australia. As the profession of genetic counseling expands in the Middle East, a definition, or possibly definitions, reflective of practice in this region will likely be developed.

Development of the Genetic Counseling Profession The profession of genetic counseling, that is, a non-physician with graduate level training in both genetics and counseling, began in North America. The first genetic

25

Genetic Counseling in the Middle East

727

counseling training program was established at Sarah Lawrence College in 1969. Since then over 34 Masters of Science genetic counseling training programs have been established in the USA, Canada, the United Kingdom, Australia and South Africa. The majority of these programs take less than ten trainees per year, making this a competitive profession to join. The majority of genetic counseling training program are 2-year graduate programs that typically include coursework in clinical genetics, population genetics, cytogenetics, molecular genetics, psychosocial theory, ethics and counseling techniques in addition to clinical practicums and laboratory rotations. Most trainees enter the field from a variety of disciplines including molecular genetics, biology, nursing, psychology, public health or social work. Professional certification, upon completion of training, is available through a number of country specific certification bodies, such as the American Board of Genetic Counseling in the United States and the Canadian Association of Genetic Counsellors in Canada. In the United States, a number of states have established licensure for practicing genetic counselors. Currently there are over 2,000 genetic counselors in practice in North America, with the majority working in clinical environments such as hospitals, medical practices and universities. In 2006, the first international meeting of genetic counselor educators, spear headed by Janice Edwards, Director of the Genetic Counseling Training Program at the University of South Carolina School of Medicine, was held in Manchester England with delegates from 18 countries, representing 45 genetic counseling programs – reflecting the rapid growth and interest in genetic counseling training programs at an international level. In addition to the United States, Canada, the United Kingdom and South Africa, genetic counseling training programs from the following countries were represented: Cuba, Cyprus, France, India, Ireland, Israel, Italy, Japan, Netherlands, Norway, Portugal, Saudi Arabia, Spain, and Taiwan. Founding partners formed the Transnational Alliance for Genetic Counseling (TAGC). The TAGC’s mandate is to foster communication and collaboration among the international genetic counseling community and enhance genetic counseling education transnationally (http://tagc.med.sc.edu).

The Genetic Counseling Profession in the Middle East Many countries in the Middle East will report that genetic counseling services are currently available through their health care systems. It is important to note that although these countries may offer genetic counseling services via their clinical geneticists, primary health care providers and/or nurses – as of 2008, the Kingdom of Saudi Arabia and the United Arab Emirates are the only countries in the Middle East to have trained genetic counselors in practice. In terms of training programs, The Kingdom of Saudi Arabia is the only country in the Middle East to have had a formal genetic counseling training program. This training program was established in 2004 – as a 2.5 year post-graduate diploma at King Faisal Specialist Hospital and Research Centre in Riyadh. Currently, the genetic counselors practicing in the Kingdom of Saudi Arabia are a mixture of

728

S.J. Kennedy and M. Al-Saffar

individuals trained locally in Riyadh, and Saudi nationals who returned to the Kingdom after training overseas. Currently there is a lack of genetic counseling training programs in the Middle East. As a result, the majority of individuals interested in this career must pursue their training overseas. Jordan currently has two nationals completing their training at Sarah Lawrence College in New York. These individuals are expected to return to Jordan in 2009 where they will begin to establish the profession of genetic counseling in their country. It is anticipated that additional training programs in genetic counseling will be started in the Middle East in the next few years to meet the health care needs of these populations. Although it is possible for individuals from the Middle East to obtain training as a genetic counselor overseas, this is not ideal for a number of reasons. These new genetic counselors often return to completely different health care systems from the one in which they trained – in terms of resources, standards of practice, and a lack of recognition of the role of a genetic counselor in the provision of patient care. In addition, they frequently return to a country with vastly different cultural and religious norms, and significantly different prevalence rates for genetic disorders. As a result, there is a growing recognition amongst the genetic counseling community of the potential benefits of training genetic counselors in the country, or at least region, where they would like to practice. In the past, some countries in the Middle East have employed genetic counselors who are foreigners, typically from the West, to provide patient care. Again, this is not ideal for a number of reasons. Utilization of a genetic counselor who is a foreigner raises the probability that a patient will mask their true feelings due to concerns of how they will be perceived by an outsider, increases the potential for a misunderstanding of cultural norms and hampers effective communication secondary to the use of a translator (Panter-Brick 1991). However, until a sufficient number of individuals from the Middle East can be trained as genetic counselors, hospitals will likely continue to utilize genetic counselors who are foreigners. The remainder of this chapter will review religious and cultural factors relevant to the practice of genetic counseling in the Middle East. This summary is designed to be assistance for foreigners practicing as genetic counselors in the Middle East and may also be helpful for genetic counselors practicing in the West who see clients from this region.

Islam and Genetic Counseling While the term Arab includes individuals who are Christians, Jews and other minorities, the vast majority of Arabs are Muslim (Teebi and Teebi 2005). Given that genetic counselors strive to respect the religious beliefs of the individuals and families they work with, when practicing in the Middle East, a genetic counselor should be aware of Islamic teachings and fatwas, in order to best meet the needs of their patient population.

25

Genetic Counseling in the Middle East

729

A fatwa is an Islamic religious ruling or scholarly opinion on a matter of Islamic law. For rulings pertaining to medicine, the consensus group that develops the fatwa typically includes a broad and diverse representation of Islamic jurists and specialists, including clinicians and scientists from relevant disciplines, with the latter being responsible for providing the necessary background information (Al-Aqeel 2007). In Islam, bioethical decision making is carried out within the framework of the teachings of the Holy Qura’n and the hadiths (statements) and sunnah (traditions) of the Prophet Mohammed – and therefore are based on the interpretation of shari’a (Islamic Law) (Al-Aqeel 2007). A number of fatwas have been issued that have direct relevance to genetic counseling.

Assisted Reproduction Islamic teachings do not prohibit in vitro fertilization as long as the egg, sperm and uterus, are from a couple during the existence of a matrimonial bond. If divorce or death of a spouse occurs the use of any stored gametes or embryos, or a surrogate is not permissible. All forms of reproductive technology that involve a donor egg or sperm are outlawed in Islam (Albar 1999). When Preimplantation Genetic Diagnosis (PGD) technology first became available in the Middle East it was assumed by many policy makers that it would be preferred by all Muslim couples over prenatal diagnosis as it bypassed the issue of termination. However, when couples at increased risk for a genetic disorder were advised of the technical aspects of PGD, including ovarian stimulation, ooycyte retrieval, and the in vitro process, many opted to pursue prenatal testing with the option of termination of an affected pregnancy. In a study conducted in Saudi Arabia, 38% of couples expressed an interest in PGD – however acceptance rates varied significantly based upon which condition was discussed. Only 3 of 11 parents of children with cystic fibrosis were interested in PGD, whereas all seven parents of a child with thalassemia expressed an interest (Alsulaiman and Hewison 2006). Of interest, individuals with graduate and postgraduate education were observed to have fewer concerns about PGD than those with less or no education. This may be due to better-educated parents having more knowledge about new reproductive technology and also having a better understanding of the Islamic law, which allows these procedures in certain circumstances. In summary, as is the case in the West, the acceptability of reproductive technologies must be established on an individual basis (Alsulaiman and Hewison 2006).

Termination of Pregnancy In 1990, The Islamic Jurisprudence Council of Makkah Al-Mukaramah passed a fatwa on termination of pregnancy that states:

730

S.J. Kennedy and M. Al-Saffar

If the fetus reached 120 days counted from conception date, abortion is not allowed even if the medical diagnosis proved that the fetus is malformed, except only if it is proved by report from a committee formed of competent trustworthy physicians that continuance of the pregnancy has a confirmed risk to the mother’s life. If this is the case it is allowed to abort, whether the fetus is malformed or not to drive away any larger harm (hurt, damage or detriment). Before 120 days of pregnancy counted from date of conception, if this is proved and confirmed by a report from a committee formed of competent trustworthy physicians and on the basis of laboratory means that the fetus is grossly malformed with untreatable severe condition and if he stays and is born on his time, his life will be vicious and painful for him and his family, then it is allowed to be aborted on the basis of the parents requisition (Albar 2002).

In summary – this fatwa advises that after 120 days of conception, termination cannot be performed unless the mother’s life is deemed to be in danger by a committee of physicians. Prior to 120 days post-conception, termination can be performed under very specific circumstances. It should be noted that 120 postconception is equal to 134 days (19 weeks) from the last menstrual period. The issuance of this fatwa was of major significance for families who would consider pregnancy termination following the identification of a genetic condition. Prior to this fatwa being passed termination of pregnancy could not be performed after 40 day of pregnancy post-conception – a time frame which made it difficult to identify the majority of genetic conditions. Islam views the growing embryo and fetus as passing through different stages of sanctity. The date of 120 days post-conception was chosen based on a hadith which states that human life begins at the time of ensoulment on the 120th day from the moment of conception (Al-Aqeel 2005) giving it greater sanctity and subjecting it to additional legal stipulations (Alkuraya and Kilani 2001). The fatwa does, however, stipulate that the fetus must be grossly malformed – currently placing a limitation on the types of conditions that can be terminated. Many severe metabolic genetic conditions do not cause structural abnormalities and therefore would not be appropriate for termination as stipulated by the current wording of this fatwa. Families that are at risk to have a child with a severe metabolic condition have been able to seek individualized approval for termination of a given pregnancy from Islamic scholars. Medical experts within the Arab world are working with Islamic scholars to increase their understanding of the variability in presentation of genetic disorders during pregnancy to broaden the types of disorders that can be terminated. Those individuals living in extremely conservative countries in the Middle East, who cannot terminate a pregnancy locally, will often travel to more permissive neighboring countries to gain access to termination services. However, this option is self-limiting to those individuals with the financial means. The majority of studies on the acceptance of prenatal diagnosis, and the acceptance of termination, have been conducted in the West (Lipmann et al. 1985; McGovern et al. 1986; Spencer and Cox 1988; Julian-Reynier et al. 1993; Haddow and Palomaki 1996). However, based on the experiences of the authors and the findings of a limited number of studies performed in the Middle East, it has been

25

Genetic Counseling in the Middle East

731

confirmed that the acceptance of the termination of pregnancy in the Arab world is as complex and individualized as it is in many other countries (Alsulaiman and Hewison 2007). A survey of families in the Kingdom of Saudi Arabia, where an extremely conservative form of Islam is commonly practiced, found that 88% of mothers and 92% of fathers would consider termination of pregnancy for at least 1 of the 30 conditions investigated (Alsulaiman and Hewison 2007). The 30 conditions presented to the study participants varied in severity from severe to mild, e.g., anencephaly, cleft lip, coronary heart disease at 50 years of age. Of interest, overall the attitudes toward termination of pregnancy were more favorable amongst mothers than fathers. It was speculated that given the lack of social services available within the Kingdom, and given that most women do not work outside the home and therefore take a greater role in childcare, mothers had a greater appreciation than fathers of the day-to-day challenges of raising a child with a disability. Many Muslim individuals are not yet aware of this fatwa and will out-right reject the option of termination of pregnancy. One study found that 50% of respondents who initially rejected the idea of termination of pregnancy changed their attitude after education regarding the fatwa (Alkuraya and Kilani 2001). The majority of respondents indicated they had initially rejected the option of termination due to their religious beliefs – highlighting the influential role of education. A second study found that 37% of respondents believed that Islam does not allow termination of pregnancy under any circumstances (Neter et al. 2005). The authors of this study highlighted the importance of having informed clerics and physicians available to educate the public about this fatwa.

Teratogens Islamic teachings specify that any substance which is harmful to a baby should be avoided (Albar 2002). Alcohol, which if consumed during pregnancy can result in fetal alcohol spectrum, is completely prohibited by Islam. Smoking is also prohibited.

Adoption In the West, one option for couples at risk to have a child with a genetic disorder is adoption. Although Islam strongly encourages caring for orphans or children of unknown parents, as this is viewed as an act of charity, the child would never be incorporated into the family in such a way that the lineage to their biological parents is masked nor would the couple caring for the child be viewed by others to be the

732

S.J. Kennedy and M. Al-Saffar

true parents of the child. This is based on the teaching of the Holy Qur’an which says: “God did not make your adopted ones your sons”. (Albar 1999).

Contraception and Sterilization Islamic teachings advise that temporary means of contraception are permissible if the couple is in agreement and no harm is likely to occur. However, sterilization is not permissible unless the health of the mother would be endangered by pregnancy. Individual cases of sterilization, such as a couple that has a number of children affected with a severe genetic disorders and also has unaffected children, may be supported by at least some Islamic jurists (Albar 1999).

Cloning The cloning of humans is not permitted in Islam as the process does not follow the “Fitrah of Allah” – sexual reproduction (El-Hazmi 2004).

Premarital Screening The Islamic Jurisprudence Council of the Islamic World League in Makkah Al-Mukarama in its 17th session in 13–17 December 2003 examined the legitimacy of pre-marital medical screening of Genetic Blood Disorders and decided: The marriage wedlock contract is governed by conditions of the Sharia, from which legal consequences follow. Enforcing pre-marital medical screening is not permissible under the Sharia. The Council recommends that governments and Islamic institutions spread understanding of the importance of pre-marital genetic tests and encourage their use. They should facilitate such tests for those who wish to use them, while ensuring confidentiality so the results are not revealed except to the persons concerned. Pre-pregnancy genetic screening could only be carried out if a genetic disorder is known in a family, and the mutation for such disorder is already known. Population wide pre-pregnancy carrier screening is possible if the mutations are known for common genetic disorders (Al-Aqeel 2005).

The Cyprus Thalassemia Control Program has succeeded in reducing the prevalence of b-thalassemia major in the country through measures such as health education, carrier screening, premarital counseling and prenatal diagnosis (Angastiniotis et al. 1988). This success has encouraged other countries in the Middle East to adopt the same measures as in Bahrain (Al-Arrayed 2005). Additional fatwas from The Islamic Jurisprudence Council of the Islamic World League (Organization of Islamic countries) in Makkah Al-Mukarama addressing

25

Genetic Counseling in the Middle East

733

(1) Molecular genetics and bio-engineering, (2) DNA fingerprinting, (3) Cord Blood transplantation, and (4) Somatic Gene Therapy are summarized in Al-Aqeel (2005) and Al-Aqeel’s chapter in this book for those who are interested in additional review of pertinent rulings.

Impact of Faith on the Individual In general, Arabs are strong spiritual believers – and many report finding comfort in their religious beliefs during difficult and stressful experiences. Parents of children with genetic disease typically believe that Allah (God) determined their child’s fate in granting health or illness. While Mendelian inheritance stipulates that carriers will have a given proportion of affected children, it cannot specify why a particular child is spared while another is affected. A mother of a child with a genetic condition expressed this as: “the disease runs in my family. But only God knows why some children are fine and others are not”. (Panter-Brick 1991). This belief system can help to alleviate parental feelings of guilt – as the final decision regarding a child’s health is perceived to be in the hands of Allah. Foreign health care professionals who work in the Middle East often note the remarkable outward serenity projected by parents caring for children with serious genetic disorders (Panter-Brick 1992). Many parents have strong faith that having sick children is associated with God’s reward. Sickness is not understood as punishment rather God states that these afflictions are to examine a human’s faith. God is with those who patiently persevere (Qur’an 2:153).

The above should not be mistaken for a lack of grief, or absence of the grief response. Parents in the Middle East report experiencing the common phases of grief upon the receipt of bad news, just as parents in the West typically do – denial, anger, depression and acceptance (Panter-Brick 1991). Referrals to a psychologist are often required to assist family members experiencing depression secondary to coping with losing a pregnancy and/or child, having an affected child, or more commonly, multiple affected children. Genetic counselors practicing in the Middle East should be aware that patients referred to genetics clinics may not easily surrender their lay or personal theories about the causes of their own or their child’s condition and their understandings of genetic risk (Panter-Brick 1992; Shaw and Hurst 2008). Often parents will not accept the inheritance of disease unless the family history is obvious to them (Al-Gazali 2005). Autosomal recessive inheritance is often hard for families to comprehend – and they will frequently ask how can a condition be inherited when it has never before been seen in their family. Families will often repeatedly stress to the genetic counselor that other family members married a cousin and had healthy children, or that individuals who married outside of the family had affected children.

734

S.J. Kennedy and M. Al-Saffar

Genetics counselors may need to identify, work with and at times challenge patients’ understandings of illness causality and inheritance (Shaw and Hurst 2008). This is especially critical when the patient’s understanding is factually inaccurate, and may lead to decisions made on errant information. However, on occasion, despite all attempts, some individuals’ personal belief systems regarding causation of disease will not be amenable to change – as was the case of a gentleman who was a carrier of an isochromosome 21, and therefore at a 100% risk in each pregnancy to have a child with Down syndrome, who repeatedly remarried in an attempt to find a woman who could give him a child without Down syndrome despite the provision of extensive genetic counseling (N. Sakati, pers. commun.).

Cultural Issues Consanguinity Consanguinity is common within the Middle East, with 20% to 70% of marriages being consanguineous, excluding Israel and Cyprus (Teebi and El-Shanti 2006). An average figure of about 40% appears to hold for most Arab countries (Teebi and Teebi 2005). This is elevated above the global estimate of 20% of communities having a preference for consanguineous marriage and an estimated 8.5% of children having consanguineous parents. The most common form of consanguineous marriage in the Middle East is between first cousins, particularly paternal first cousins. A young man has the first right to marry his first cousin, and if she marries someone else, he will likely be entitled to some sort of compensation from her family (El-Badramany et al. 1997). Many additional forms of consanguineous marriage, such as second cousin marriages, also occur. However, it should be noted that uncle–niece/aunt–nephew marriages are forbidden in Islam and are prohibited by law in all Arab countries (Teebi and Marafie 1988). In addition, it is common for individuals belonging to the same tribe to prefer to marry within the same tribe (El-Hazmi 2004). While these individuals may not be related as cousins, they do share the same gene pool, placing them at increased risk to have offspring homozygous for a variety of genetic conditions. The tradition of marrying one’s cousins is deeply rooted in Arab culture. This practice is not a religious one; in fact, consanguinity is not promoted by Islam – which advises to “seek outsiders for marriage, so that your progeny does not become weak”. The practice of consanguineous marriage is known to have many social and economic benefits – the families know each other, and they view that this practice strengthens the relationship between them. The role of the extended family is integral to family functioning in the Middle East. Traditionally a young couple will share the husband’s parents’ house, join them for meals and recreation.

25

Genetic Counseling in the Middle East

735

The support of extended family is critical in assisting individuals cope with emotional upheavals (Droopy 1960). In a study in the United Arab Emirates in 2005, 45% of parents reported that they would prefer for their children to marry within the family, many indicating “a cousin takes better care of you” (Al-Gazali 2005). In 1997, a study from the United Arab Emirates revealed that consanguineous marriages are increasing versus decreasing – demonstrating that this is a deeply embedded cultural tradition that is resistant to change (Al-Gazali et al. 1997). Genetic disorders are quite common in the Middle East due to the contributing factors of consanguinity, relative homogeneity of the gene pool and large family size (Teebi 1994). Consanguinity is recognized to lead to an increased birth prevalence of severe autosomal recessive disorders and have a smaller impact on homozygosity for autosomal dominant and X-linked disorders, such as familial hypercholesterolemia and glucose-6-phosphage dehydrogenase deficiency, respectively (Modell and Darr 2002; Teebi and Teebi 2005). It is estimated that metabolic conditions occur at a frequency of five times the West (Ozand et al. 1992) – with the dietitian at King Faisal Specialist Hospital and Research Centre in Riyadh following over 320 active cases of Maple Syrup Urine Disease, more than most dietitians in the West will see in their entire career (N. Sakati, pers. comm.). Although many individuals purport that a reduction in consanguineous marriages is key to reducing the incidence of genetic disorders in the Middle East, the practicality of changing a cultural practice that has been in place for centuries is underestimated. In addition, the support of the extended family is critical in the raising of a child with a genetic condition – and by undermining the very basis of the network that supports these families – the care of these children and their parents would be jeopardized. Marriage patterns can be very resistant to change – with an illustrative case being a father counseled in Saudi Arabia at King Faisal Specialist Hospital and Research Centre regarding autosomal recessive inheritance, divorcing his wife, a paternal first cousin, to only remarry a maternal first cousin (Panter-Brick 1991). In addition, advising individuals not to partake in consanguineous marriages is inconsistent with the ethical principles of genetic counseling which support autonomous choice. This in combination with the social importance of consanguineous marriages makes any program that tries to reduce the rate of genetic conditions by reducing consanguineous marriages destined for failure. In 1994 and 1996 the WHO’s Regional Office for the Eastern Mediterranean, which include the Middle East, convened two meetings of experts in medical and social sciences to review the place of genetics in medical services in the region. The participants agreed that consanguineous marriage is an integral part of culture and societal life in many areas, and that attempts to discourage it at the population level are inappropriate and undesirable. They concluded that the development of genetic services is a particularly high priority for such communities (Modell and Darr 2002). Effective genetic counseling to identify families at increase risk, and to provide them with risk information and carrier testing when feasible, is likely to have a much larger impact (Modell and Darr 2002).

736

S.J. Kennedy and M. Al-Saffar

Clinical Photography One has to keep in mind the diverse traditions and cultural habits among Arabs. According to the local customs and many of the traditional habits in the Arabic peninsula, photography is not encouraged. This is even more applicable when it involves young girls or women. Women in other Arabic countries may have different restrictions. In Saudi Arabia and the Gulf countries, usually women are veiled to all men beyond her close relatives within the family. Majority of Bedouin woman wear the specific face covering that is traditional of her people and according to the geographic location of the tribe. The veil predated Islam and could be traced to Indian and Persian Empire as an ancient custom; it was adopted by Arabia’s nomadic tribes during the seventh century, which imposed a severe code of female modesty. It became more desired during the lifetime of the Prophet Mohammed (peace and blessings be upon him), perhaps as an imitation of his wives who covered themselves in public (From “Women of Saudi Arabia”, October 1987). Religious scholars in Saudi Arabia fall into two groups about the general subject of photography, the first group recommends comprehensive ban on photographs while others allow it with certain restrictions and considerations. One of the Hadiths (sayings of the Prophet) forbids only representation which reproduce the acts of God. According to a senior scholar (Sheikh Ahmad Kutty, Islamic scholar at the Islamic Institute of Toronto, Ontario, Canada) “Photography does not fall under the category of forbidden Tasweer”. Tasweer means painting or carving images or statues of living creatures which is associated with Shirk (paganism) that was clearly condemned by the Prophet Mohammed (peace and blessings be upon him –pbuh-). We could also argue that photography taboo became rather a local tradition than a religious practice. As a matter of fact in our current days, many of the celebrations, or wedding attended by only women, cameras are not permitted. A woman photographer will be allowed to take the photos of the bride but with the condition that is not revealing of others. However, it all depends on the use and function of a photograph, and the depth and the trust of the relationship with the medical professionals. Through our own personal experience and practice in the Middle East, we found that majority of the families we encountered are willing to provide their consent to photograph the child and the rest of the family. Many parents are cooperative when you explain the reasons and the associated confidentiality by sharing the photos with the relevant medical professionals in the field. It is important to highlight the anonymous nature of the limited distribution of the photos. They have no objections when they understand the importance of discussing their condition in a scientific forum for the purpose of science and teaching. Many scholars agree that photography is permitted if it is for educational purposes and has not been tainted with other motives.

25

Genetic Counseling in the Middle East

737

Illness and Visitation of the Ill Islam as a religion is spiritual and recommends virtuous deeds such as visiting the sick (Iyadah) . The Arabic “iyadah” comes from the root that means ‘to return’ and it also means “clinic”. People are encouraged to return to visit the sick except when it is not recommended medically or when it imposes a burden on the patient. Visiting an ill person is a confirmed Sunnah (Inspired practice of the Prophet Mohammed–pbuh). It is not only culturally recommended but also religiously based on the following: 1. Empathy toward Muslim brothers. 2. Muslim’s responsibility to support each other. 3. Eternal rewards for such a practice. Numerous Hadiths (Saying of the Prophet Mohammed–pbuh-) emphasize this practice and empathy toward our Muslim brothers. The parable of the Believers in their mutual love and mercy is like that of a living body: if one part feels pain, the whole body suffers in sleeplessness and fever. (Saheeh Muslim)

It is also considered one of the main responsibilities of the practicing Muslim. One Hadith “The rights of one Muslim over another Muslim are six . . . When you meet him, you greet him with the salaam, when he invites you, you accept his invitation, when he consults you in a matter, you give him sincere advice, when he sneezes and praises God, you ask God to have mercy on him, when he is sick, you visit him, and when he passes away you accompany him (through his funeral)”. (By Abu Hurayra-Saheeh Bukhari)

In this narration, it is clear that the Muslim is encouraged to care for his brother in Islam during healthy time as well as in sickness and death. The iyadah should be brief and courteous as such it considers the patient’s situation according to the following Hadith “The most rewarding visitation of the sick is the one that is appropriately brief ”. According to many scholars and local traditions, the visitation of the sick is considered social obligation. On the other hand, the visitation in itself is selfpurification for the visitor. Also it is believed that the patient’s prayers are heard faster and have an effect, thus many visitors will ask the patient to pray for them for forgiveness. Many verses from Quran have a soothing effect for the afflicted person as well as their relatives. It is a reminder of God’s ability to heal the sick and ask for His forgiveness and Mercy to restore health. “. . . And in God should the believers put their trust”. (Qur’an 3:122)

By reciting the Quran, individuals are reminded of God’s immeasurable attributes. The human may have some of these attributes but needs to be identified and discovered within the self (nafs). The Qur’an directs man to this fact: By the nafs, and the proportion and order, given to it, and its inspiration, as to its wrong and its right; truly he succeeds that purifies it, and he fails, that corrupts it (Qur’an 91:7–10)

738

S.J. Kennedy and M. Al-Saffar

One is advised to say: “O Allah! There is no God but You. Glory be to You. I have been a wrong-doer.” This is called Dua’a. Some Muslims hang amulet containing Qur’an verses or Names and Attributes of Allah around the child or patient’s neck as safety and protection from evil eyes. This is a controversial matter among the Muslim scholars, but the general consensus is that it is prohibited to hang amulets in general.

Additional Cultural Beliefs Impacting Health Care Some individuals in the Middle East will attribute the occurrence of disease to supernatural agents, such as the devil, satan, or Jinn. Disease can also be attributed to a strange “look”, or an “evil”, or “jealous” eye (ayn) (El-Badramany et al. 1997; Panter-Brick 1991). The “evil eye” is often used as an explanation by families to explain why a child that was normal at birth, and growing well, suddenly becomes seriously ill – a well recognized and frequent occurrence with many metabolic conditions. Cultural beliefs can impact the way in which individuals in the Middle East seek medical treatment for a genetic disorder. Many families will often take children with a genetic condition to a traditional healer, or the Muslim equivalent of a priest, which goes by different names depending on the country (Mutawwa in Kuwait and Saudi Arabia, Sheikh in Lebanon, Jordan and Syria, Mula in Iraq or Al-Sayed in Egypt) in an attempt to cure and/or understand the condition (Maloner 1982). In a study of families in the United Arab Emirates, 40% of families reported that they had resorted to traditional methods of healing by taking their children to local healers – where they were often treated with cauterization. This practice was not limited to the poorly educated – as this practice was reported amongst families in which parents had university education – typically due to grandparents’ insistence (Al-Gazali 2005). Increasing openness between the Middle East and the West has led to younger generations in the Middle East acquiring Western attitudes and methods of thinking toward illness and medicine – in turn, this has led to intergenerational conflict when dealing with issues related to health care (El-Badramany et al. 1997). Cauterization is not prescribed by Islam – the Prophet Mohammed is said to have forbidden cauterization for an individual who is ill, yet this has become a cultural norm in the Middle East – similar to the practice of consanguineous marriage (Panter-Brick 1991). Some families will seek the advice and treatment of a local healer before hospital care, others seek help simultaneously or only after hospital care. This can become dangerous for a child if the family stops medical treatment in favor of traditional healing methods, as one father of a patient with Maple Syrup Urine Disease (MSUD) did – he interrupted the prescribed dietary treatment for 5 months as he felt cauterization was more effective in treating his child’s condition (Panter-Brick 1991).

25

Genetic Counseling in the Middle East

739

The practice of genetic counseling includes establishing patients’ prior knowledge of illness causality, inheritance and risk. Genetic counselors working in the Middle East will ultimately benefit by providing patients with the opportunity to describe their own perception of the condition and their understanding of its inheritance or etiology. Genetic counselors should be prepared to face the potentially challenging situation of trying to find a way to partner medical facts with errant personal beliefs. This is especially critical mistaken beliefs that will influence an individual or couple’s reproductive decision making and/or impact on risk communication among family members in an adverse manner. In summary, the magnitude of genetic disorders in the Middle East is immense, yet the availability of genetic services in general, let alone genetic counselors, is lacking. The impact of genetic disorders on the population is significant, – as many of these conditions, are, chronic with significant mental and physical involvement – and place a heavy social and financial burden on both families and the health care system (Teebi and Teebi 2005). As the Middle East prioritizes and expands genetic services – through the implementation of newborn screening program, premarital screening programs and enhanced clinical and diagnostic genetic services – the role of the genetic counselor will be in demand. The foundation for the profession of genetic counseling in the Middle East has already been established, with a handful of trained genetic counselors already in practice. The years to come will be exciting, as we witness the evolution of this profession to meet the health care and societal needs of the Middle East.

References Ad Hoc Committee on Genetic Counseling (1975) Report to the American society of human genetics. Am J Hum Genet 27:240–242 Al-Aqeel AI (2005) Ethical guidelines in genetics and genomics – an islamic perspective. Saudi Med J 26(12):1862–1870 Al-Aqeel AI (2007) Islamic ethical framework for research into and prevention of genetic diseases. Nat Genet 39(1):1293–1298 Al-Arrayed S (2005) Campaign to control genetic blood disease in Bahrain. Community Genet 8:52–55 Al-Gazali LI, Bener A, Abdulrazzaq Y, Micallef R, Al Kayat AI, Gaber T (1997) Consanguineous marriages in the UAE. J Biosoc Sci 29:491–497 Al-Gazali LI (2005) Attitudes toward genetic counseling in the United Arab Emirates. Community Genet 8:48–51 Albar MA (1999) Counseling about genetic disease: an Islamic perspective. Easter Med Health J 5:1129–1133 Albar MA (2002) Ethical considerations in the prevention and management of genetic disorders with special emphasis on religious considerations. Saudi Med J 23(6):627–632 Alkuraya FS, Kilani RA (2001) Attitude of Saudi families affected with hemoglobinopathies towards prenatal screening and abortion and the influence of religious ruling (Fatwa). Prenat Diagn 21:448–451 Alsulaiman A, Hewison J (2006) Attitudes to prenatal and preimplantation diagnosis in Saudi parents at genetic risk. Prenat Diagn 26:1010–1014

740

S.J. Kennedy and M. Al-Saffar

Alsulaiman A, Hewison J (2007) Attitude to prenatal testing and termination of pregnancy in Saudi Arabia. Community Genet 10:169–173 Angastiniotis M, Kyriakidou S, Hadjiminas M (1988) The Cyprus thalassemia control program. Birth Defects 23:417–432 Biesecker BB, Peters KF (2001) Process studies in genetic counseling: peering into the black box. Am J Med Genet 106(3):191–198 Droopy AS (1960) Changing child rearing patterns in the Middle Eastern family. J Med Liban: 13–50 El-Badramany MH, Farag TI, Al-Awadi SA, Teebi AS (1997) Psychosocial and medical aspects of genetic counseling among Arabs: the example of Kuwait. In: Teebi AS, Farag TI (eds) Genetic disorders among Arab populations. Oxford University Press, New York, pp 474–486 El-Hazmi MAF (2004) Ethics of genetic counseling – basic concepts and relevance to Islamic communities. Ann Saudi Med 24(2):84–92 Fraser FC (1974) Genetic counseling. Am J Hum Genet 15:1–10 Haddow JE, Palomaki GE (1996) Similarities in women’s decision-making in the US and UK during prenatal screening for Down syndrome. Prenat Diagn 16:1161–1162 Julian-Reynier C, Macquart-Mouline G, Matti JP et al (1993) Attitudes of women of childbearing age towards prenatal diagnosis in Southern France. Prenat Diag 13:613–627 Kessler S (1997) Psychological aspects of genetic counseling. XI. Nondirectiveness revisited. Am J Med Genet 72(2):164–171 Lipmann A, Perry TB, Mandel S, Cartier S (1985) Chorionic villi sampling: women’s attitudes. Am J Med Genet 22:395–401 Maloner GE (1982) Local healers of Qasim. In: Sebai ZA (ed) Community health in Saudi Arabia. Stanhope Press, London, pp 87–98 McGovern MM, Goldberg JD, Desnick RJ (1986) Acceptability of chorionic villi sampling for prenatal diagnosis. Am J Obstet Gynecol 155:25–29 Modell B, Darr A (2002) Science and society: genetic counseling and customary consanguineous marriage. Nat Rev Genet 3(3):225–229 Neter E, Wolowelsky Y, Borochowitz ZU (2005) Attitudes of Israeli muslims at risk of genetic diosrders towards pregnancy termination. Community Genet 8:88–93 National Society of Genetic Counselors’ Definition Task Force, Resta R, Biesecker BB, Bennett RL, Blum S, Hahn SE, Strecker MN, Williams JL (2006) A new definition of genetic counseling: National society of genetic counselors’ task force report. J Genet Couns 15(2):77–83 Ozand PT, Devol EB, Generoso GG (1992) Neurometabolic diseases at a national referral centre: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11 Panter-Brick C (1991) Parental responses to consanguinity and genetic disease in Saudi Arabia. Soc Sci Med 33(11):1295–1302 Panter-Brick C (1992) Coping with an affected birth: genetic counseling in Saudi Arabia. J Child Neurol 7:S69–S72 Reed S (1980) Counseling in medical genetics, 3rd edn. Alan R. Liss, New York Resta RG (2006) Defining and redefining the scope and goals of genetic counseling. Am J Med Genet C Semin Med Genet 142C(4):269–275 Shaw A, Hurst JA (2008) “What is this genetics, anyway?” Understandings of genetics, illness causality and inheritance among British Pakistani users of genetic services. J Genet Couns 17(4):373–383 Spencer JW, Cox DN (1988) A comparison of chorionic villi sampling and amniocentesis: acceptability of procedure and maternal attachment of pregnancy. Obstet Gynecol 72:714–718 Teebi AS (1994) Autosomal recessive disorders among Arabs: an overview from Kuwait. J Med Genet 31:224–233 Teebi AS, Marafie MJ (1988) Uncle-niece/aunt-nephew marriages are not existing among Muslim Arabs. Am J Med Genet 30:981 Teebi AS, El-Shanti HI (2006) Consanguinity: implications for practice, research and policy. Lancet 367(9515):970–971 Teebi AS, Teebi SA (2005) Genetic diversity among the Arabs. Community Genet 8:21–26

Index

A Aase–Smith syndrome, 231 Abboud, M.R., 381 Abdallat syndrome, 196 Abdelnoor, A.M., 383, 395 Abdul-Karim, R., 383, 395 Abifadel, M., 383, 413 A-b-lipoproteinemia, 378 Abu Bakr al-Razi, 39 Abu Feisal, K., 378 Abu Haydar, N., 387 Abyssinia, 575 Acanthosis negricans AD, 364 Acardi’s syndrome (XL), 366 ACE gene, 578 Achalasia-alacrimia syndrome, 186 Achondroplasia, 221, 274, 275, 277, 285, 288, 289, 292, 592, 655 Achromatopsia, 665 Acrocephalopolysyndactyly type II, 378 Acrodermatities enteropathica, 249, 335, 378, 507 Acrofrontofacionasal dysostosis, severe (AR), 365 Acromesomelic dysplasia, Maroteaux type, 654 Acroosteolysis, neurogenic, 186 Acro-reno-ocular syndrome, 182 Active X chromosome, 602 Adaimy, L., 385, 417 Adams–Oliver syndrome, 231 Addison’s disease, 378 Adenosine deaminase deficiency, 253, 548

Adhalin, 152, 154 a-Adhalin, 167 Adhalinopathies, 152 Adoption, 6, 714 Adrenal hyperplasia, 397 Adrenal hyperplasia congenital due to 12 hydroxylase deficiency (AR), 364 Adult-onset disease Alzheimer disease, 97 bipolar disease, 97 cancers, 96, 97 diabetes mellitus, 96 heart disease, 97 schizophrenia, 97 Advanced maternal age, 329 Afghanistan, 640 Afifi, A.K., 384, 386, 388 African continent, 575 African Nilotes, 576 African populations, 595 Agammaglobulinemia (XL), 366 Agenesis of corpus callosum, 650, 651 AGL alleles, 243 Agyria-pachygyria with agencies of corpus callosum, 202, 667 Ahmed, Z.M., 423 Aicardi–Goutieres syndrome, 184, 226 Akl, K.F., 387, 422 Alacrima–achalasia–addisonianism (triple-A syndrome), 544 Alagille syndrome I, 378 Al-Aqeel–Sewairi syndrome, 194, 708

741

742

Al-Awadi–Raas-Rothschild syndrome, 197, 233 Al-Awadi, S.A., 378, 384, 398, 413 Albinism, 249, 590 oculocutaneous, 397 Alexander, D.A., 382, 384, 390, 415 Al-Gazali syndrome, 200, 667 Algeria, 150 Algerian, 185, 196, 198 Alkalosis, hypokalemic, 378 Alkaptonuria, 378, 535, 590, 656 Allele frequencies, 578 Almawi, W.Y., 381, 385, 405, 416 Alopecia, 188, 339 Alopecia universalis, 200 Alpha-1-antitrypsin, 335, 496 Alpha-globin gene deletion, 235 Alpha-mannosidosis, 243 Alpha-one antitrypsin deficiency, 242 5-Alpha-reductase deficiency, 245 5-Alpha-reductase type2, 246 Alpha thalassemias, 7, 8, 236, 364 Iraq, 311, 312 Alport’s syndrome (XL), 366 Al-Ruhawi, 4 Alstrom syndrome, 543 Al-Tabari, 4 Al Taweel, 581 Al-Thani, 516 Al Zaiem Al Azhari University, 580 Alzheimer disease (AD), predisposing genetic risk factor, 621 Ambiguous genitalia, 602 Amelia, X-linked, 205 American University Hospital, 377, 419 Amino acid disorders, 590 Aminoacidopathies, 361, 503 Amniocentesis, 643 Amyloidosis, 112 Ancient Egypt, 221, 273–294 Anderson’s continuum, 72 Androgen end organ non responsiveness, 245 Androgen receptor (testicular feminization syndrome) (XL), 366 Anemia, dyserythropoietic congenital, Type I (AR), 365 Anencephaly, 597

Index

Anetoderma, 254 Angelman syndrome, 666 Angiotensin, 394–395 Angiotensin-converting enzyme (ACE) gene, 577 Ankylosing spondylitis, 397–398 Anophthalmia, 251 Antenatal care coverage, 78 Anterior hypopituitarism, 544 Anthropometry birth measurements, 93 childhood stature, 93 Antisense oligonucleotide (ASON), 236 a-1-Antitrypsin (a 1 AT), 553 deficiency, 548 Anus, imperforate, 378 APECED, 253 Apert syndrome, 221 Apnea of prematurity, 398 ApoB-100 R3500Q mutation, 378 Apolipoprotein E, 398 Apple-peel syndrome AR, 365, 507 Arab, 588 Arab Bedouins, 654 Arab countries, 4–8, 12, 14, 17, 20, 22 ancestry, 577, 586 culture, 6 diseases, 9, 10 family, 6, 16 fertility, 46, 49 history, 3 league, 4 minorities, 6 population dynamics, 40, 45–48 societies, 85–92, 97, 99 world, 4, 5, 8, 10, 12, 14, 18, 21–23 Arabia, 575, 577, 597, 640, 647 Arabian gulf, 4, 639, 640 states, 584 Arabian peninsula, 4, 9, 15, 16, 153, 645, 646 Arabic language, 4 Arabs, 575, 590, 640–643, 649 descent, 576, 583 nomads, 575 origin, 587, 588 populations, 643 tribes, 596, 639 world, 643

Index

Arachnodactyly, 228, 231 Arayssi, T.K., 379, 400 ARCI. See Autosomal recessive congenital ichthyosis Arginase deficiency, 535 Argininosuccinic aciduria (ASA), 367, 535 Aringa, 582 Aringa ethnic group, 582 Armenian, H.K., 382, 386, 408, 409 Armenians, 5, 8 Arnold, W.P., 417 Arranged marriage, 85, 98, 99 Arrhythmias, 167 Arterial tortuosity syndrome (ATS), 520, 523, 547 Arthrogryposis multiplex congenita, 230 Arthrogryposis, renal tubular dysfunction, and cholestasis (ARC) syndrome, 548 Arthropathy, progressive, pseudorheumatoid, 398 Arylamine N-acetyltransferase, 395 Arylsulphatase A pseudodeficiency, 242 Asphyxiating June thoracic dystrophy, 507 Aspirin, 588 Asthma, 252 Ataxia, cerebellar, congenital, 378, 379 Ataxia-deafness-retardation syndrome (AR), 186, 364 Ataxia-microcephaly-cataract syndrome, 186 Ataxia telangiectasia (AT), 331, 399, 447, 527 Ataxia telangiectasia-like disorder (ATLD), 541 Ataxia with oculomotor apraxia type 2 (AOA2, MIM No. 606002), 599 Ataxia with selective vitamin E deficiency (AVED), 197 Athabaskan brain stem dysgenesis syndrome, 198 Atopic dermatitis, 248, 658 Atrial septal defect with various cardiac and noncardiac anomalies, 182 Atrophic benign EB, 599 Autoimmune thyroid diseases (AITDs) linkage analysis, 622 susceptibility gene, 622

743

Auto-inflammatory, 111, 116, 126, 131 disorders, 8 Autosomal dominant (AD), 9, 20–21 condition, 483–484 hereditary paraplegia, 226 Autosomal recessive, 678–680, 685–693, 695–697 cerebellar hypoplasia with cerebral gyral simplification, 650 epidermolytic palmoplantar keratoderma, 186 gene, 247 microcephaly, 652 Robinow syndrome, 232 spastic paraplegia with thin corpus callosum, 662 Autosomal recessive anophthalmia/ microphthalmia, 665 Autosomal recessive cardiomyopathy and ophthalmoplegia (ARCO), 169 Autosomal recessive cerebellar ataxias, 599 Autosomal recessive congenital ichthyosis (ARCI), 248 Autosomal recessive cutis laxa (MIM No. 219200), 599 Autosomal recessive disease, 502 brain structural defects, genetic diseases, 481 childhood morbidity, mortality and handicap, 477 congenital blindness and deafness, 483 disorders, 7, 10, 11, 22, 327, 496–502 ethnic and genetic diversity, 477 hemoglobin disorders, 477 immunodeficiencies and chromosomal instability syndromes, 481 inborn errors of metabolism, 478 neurodegenerative disease, 480 neurogenetic disorders, 478–480 neurologic dysfunction, genetic diseases, 481 neuromuscular disorders, 480 neuromuscular disorders, genetic diseases, 481 seizure disorders, 480 skeletal dysplasias and bone structure diseases, 481

744

Autosomal recessive Ehlers Danlos syndrome (type I), 452 Ayoub, N., 382, 407 Azar, H.A., 387

B Bacterial infections, 585 Baggara, 577, 590, 592 Baggara tribal, 583, 588 Baghdassarian, S.A., 378, 379, 381–388 Bahrain, 4, 5, 7, 20 Bahraini, 664 Baluchistan, 645 Baluchis, 640, 646, 661 Bamforth-like syndrome, 667 Bangladesh, 640 Bantu, 586 Baraka, A., 378, 386, 387 Barakat, A.Y., 378, 386, 387 Barbari, A., 403 Bardet–Biedl syndrome 5 (AR), 366 Bardet–Biedl syndrome (BBS), 17, 254, 367, 399, 499–500, 542, 648 Bardet–Biedl syndrome 1990a (AR), 364 Bartsocas-Papas syndrome, 527 Bartter syndrome, type 4, 400 Batten’s disease, 522 Becker muscular dystrophy (BMD), 150, 161, 163, 331, 539 Beckwith–Wiedemann syndrome, 666 Bedouins, 5, 6, 11–13, 15–20, 22, 186–189, 191, 195–198, 200, 204, 640, 641, 647, 648, 651 Bedouin spastic ataxia, II (AR), 366 Bedouin spastic ataxia syndrome, 363, 366 Bedouin tribes, 499 Beh| et syndrome, 398, 400 Beighton, P., 406 Beirut, 389, 391, 393, 398, 402, 403, 411, 419–421, 425 Beja, 583, 588, 594 Beja tribal group, 594 Ben Ezra, D., 387 Benin, 586 Benin haplotype, 237 Berardinelli–Seip syndrome, type 2, 384

Index

Berber, 5 Beta thalassemias, 7, 8, 235, 367, 525 gene mutations, 235 Iraq, 311–312 phenotype, 235 Beutler, E., 410 Bidinost, C., 379, 400 Bifid nose renal agenesis and anorectal malformations, 200 renal and rectal malformation, 667 Bile acid synthesis defect, 536 Bilharzia-associated bladder cancer (BAC), 600 Bilharziasis, 580 Biliary malformations, 379 renal tubular insufficiency, 186 Binary polymorphisms, 577 Bio-engineering, 710, 711, 718 Bioethics, 706 Biotinidase deficiency, 242, 535 Biotin-responsive basal ganglia disease, 536 Birth defects, 596 Birth incidence of malformations, 223 Birt–Hogg–Dube syndrome, 249 Birth rate, 354 Births attended by skilled health professionals, 79 Bitar, E., 379, 383 Bitar, J.G., 380, 382, 388, 403 Bladder cancer case-control studies, 628 detoxification of xenobiotics, 627 disease susceptibility, 627 high risk, 628 polymorphism, 628 Bleeding disorders, 590 Blepharophimosis–ptosis–telecanthus– epicanthus inversus, 546 Blibech, R., 383, 420 Blindness, 332, 501 childhood, Iraq, 316 Blood groups, 495 Iraq, 300–303 Blue Nile, 580, 583 Bonafede, R.P., 406 Bone dysplasias, 655

Index

Borjeson–Forssman–Lehmann syndrome, 543 Bosley–Salih–Alorainy syndrome, 198, 550 Bou-Dames, J., 387, 421 Boustany, R.M., 423 Boyadjiev–Jabs–Eyaid syndrome, 183 Brachmann de Lange syndrome, 254 Brachydactyly, 228 type A1, 232 Brain malformation, 650 Branchial myoclonus with spastic paraparesis and cerebllar ataxia (AD), 364 Branchiogenic-deafness syndrome, 184 BRCA2 exon 11, 599 BRCA1-ineracting protein 1; BRIP1 (AD), 367 Breast cancer, 467, 599, 600 aggressiveness, 629 BRCA1, 629 BRCA2, 629 cancer risk, 629 genetic association, 629 increase in incidence rate, 629 low penetrance, 629 most frequent cancer, 629 North African founder allele, 629 overall disease survival, 630 penetrant genes, 629 sporadic cases, 629 susceptibility, 629 Tunisian index cases, 629 xenobiotic metabolizing enzyme, 630 Brenner, B., 424 Brittle cornea syndrome, 546 Broad beans (fava beans), 588 Brook, C.G., 385 Brother and sister marriages, 222 Brown–Vialetto–Van Laere syndrome, 400 Bruck syndrome, 666 Bullous congenital icthyosiform, 233 Bundle branch block, 182, 411 Buresi, C., 387 Burkina Faso, 580

C Cabannes, R., 387, 419 CADASIL, 542

745

CAHMR, 186, 204, 255 Calcinosis, tumoral, with hyperphosphatemia, 379 Callosal dysgenesis, 226 Camel milk, 595 Cameroon, 586 Camptodactyly, 188 Camptodactyly, arthropathy, and coxa vara (CAC syndrome), 544 Camptodactyly-arthropathy-coxa vara-pericarditis (CACP), 231, 544 Canaanites, 4 Canavan disease, 534, 535 Cancer, 504 breast, 506, 551 colorectal, 506 diffuse large B-cell lymphoma (DLBCL), 551 genetics, 599 incidence, 505 liver, 506 lung, 505 nervous system, 506 papillary thyroid cancer, 551 prostate, 506 Carbamoyl phosphate synthase deficiency, 367 Carbohydrate disorders, 591 Carbonic anhydrase II deficiency, 16 Cardiofaciocutaneous syndrome, 254 Cardiogenital syndrome, 187, 379 Cardiomyopathies, 166, 167, 546 congestive with hypergonadotropic hypogonadism, 187 congestive with hypogonadotrophic hypogonadism, 379 familial hypertrophic, 379 Cardioskeletal syndrome, Kuwaiti type (AR), 187, 363, 364 Carpenter syndrome, 235, 378 Carrier rate, 235 Carrier screening, 80, 235 Cartilage hair hypoplasia, 545 Cataract, 501 congenital, 379 microphthalmia, and nystagmus, 187 posterior polar, 400 Catechoaminergic polymorphic ventricular tachycardia, 667

746

Cathepsin C gene, 249 Caylor syndrome, 507 CBAVD. See Congenital bilateral absence of the vas deferens CDC42 gene, 165 Celiac disease, 379 Cenani–Lenz syndrome, 231 Center for Arab Genomic Studies, 100, 643, 644 Central Sudan, 587, 598 Cerebellar hypoplasia, 651 Cerebellar vermis hypoplasia, 651 Cerebro-oculo-facio-skeletal syndrome, 504 Cerebrooculofacioskeletal (COFS) syndrome, 254 Cerebrotendinous xanthomatosis, 536 Certification American Board of Genetic Counseling, 727 Canadian Association of Genetic Counsellors, 727 CFTR. See Cystic fibrosis transmembrane conductance regulator Chad, 588 Chad area, 582 Chaib, H., 380, 404 Charcot–Marie–Tooth disease, 379, 401, 463, 540, 597 CMT4F, 401 Chediak–Higashi syndrome (AR), 337, 364, 666 Chehab, F.F., 387, 420 Chelation therapy, 236 Childhood blindness, 249 Childhood epilepsy, 330 Childhood morbidity blindness, 94 congenital disorders, 94 deafness, 94 dental anomalies, 94 Childhood onset glomerular kidney disease, 665 CHIME-like syndrome, 667 Chloride diarrhea, familial (AR), 364 Chondrodysplasia anomalies of multiple systems, 401–402 Khaldi type, 202 multiple dislocations, 401

Index

Temtamy type, 202 Chondrodysplasia puctata, 655 Chorea-acanthocytosis, 541 Chorionic villus sampling, 643 Choueiri, R.N., 382, 407 Christianity, 6 Christian kingdom of Nubia, 575 Christians, 390–392, 397, 403, 404, 408, 409, 416, 419, 420, 422, 576 Chromosomal abnormalities, 224, 356, 357, 456–457, 496, 601 Chromosomal disorders, 329 Chromosomal G-bonding, 602 Chromosomal rearrangements, 477 Chromosome aberrations, Down syndrome, 95 Chromosome 3 and 5 translocation, 380 Chromosome (7)(p22.1pter) duplication, 380 Chromosome 1p36, 165 Chromosome 5p13.1, 166 Chromosome 22q12, 582 Chromosome 5q12 deletion, 380 Chromosome 6q22-q23, 581 Chronic infantile neurologic cutaneous and articular syndrome, 131 Chronic progressive external opthalmoplegia and skeletal muscle involvement, 447 Chronic recurrent multifocal osteomyelitis, 127–129, 201, 337 Chronic renal failure, 336 Chu, E.T., 384 CIAS1, 131 Ciliary discoordination due to random ciliary orientation, 187 Ciliary dyscoordination, 380 Ciliary dyskinesia, 335 Circassians, 5 Citrullinemia (Cit), 364, 535 Clasped thumb clubfoot syndrome, 230 Cleft lip and palate, 253, 334 Clinical anophthalmia (AR), 365, 367 Clinical presentations, 235 Cloning, 717–719 CLSD, 183 CMD. See Congenital muscular dystrophy CNS

Index

disorders, 224 malformations, 225 Coagulation defects, 238–239 Cockayne syndrome, 542, 666 Code, 705, 712 Coffin–Lowery syndrome (XL), 366 Coffin–Siris syndrome, 233, 251, 666 COFS syndrome. See Cerebrooculofacioskeletal (COFS) syndrome Cohen syndrome, 254, 402, 648 Coinheritance, 235 Colchicine therapy, 114, 239 Collagen VI, 160 Coloboma, 201, 251 Colorectal cancer, 467 constitutional mutations, 631 hereditary form, 631 sporadic, 631 Complementation types, 237 Complement profiles, 585 Complements C3 and C4, 586 Cone-rod dystrophy and amelogenesis imperfecta, 187 Congenital adrenal hyperplasia (CAH), 240, 339, 360, 367, 448, 465, 501, 642 CYP21, 622 homozygous, 622 3b-hydroxylase deficiency, 543 11b-hydroxylase deficiency, 543 3b-hydroxysteroid dehydrogenase type II deficiency, 543 21-hyroxylase deficiency, 543 mutational spectrum, 622 nonfunctional enzyme, 622 Congenital afibrinogenemia, 539 Congenital alopecia areata, 249 Congenital anomalies, 445, 449 Congenital atrichia, 547 Congenital bilateral absence of the vas deferens (CBAVD), 252 Congenital bowing disorder, 668 Congenital cataract, 250, 256 Congenital chloride diarrhea (CLD), 14–15, 367, 547 Congenital contractural, 231 categories, 230 Congenital cutis laxa, 547

747

Congenital deafness, 251–252, 361 Congenital diseases in Sudanese children, 601 Congenital dyserthropoietic anemia, 201 Congenital dyserythropoietic anemia type I, 539 Congenital erythropoietic porphyria (AR), 366 Congenital fibrosis of extraocular muscles (CFEOM), 545 Congenital/genetic disorders, 475 community genetic services, 476 consanguinity, 476 genetic disease prevention, 476 genetic technology value, 476 genomics application, 476 Congenital glaucoma, 247, 665 Congenital heart disease, 334, 601 Congenital hereditary endothelial dystrophy, 546 Congenital hypothyroidism (CH), 240, 333, 359–360, 448, 450, 452, 521, 543, 593, 601, 642 Congenital ichthyosis, 658 Congenital insensitivity to pain, 547, 661 Congenital Leber’s amourosis, 665 Congenital lipoid adrenal hyperplasia, 543 Congenital malformations (CMs), 223, 496, 596, 597 Iraq, 306–308 Congenital muscular dystrophy (CMD), 159–161, 331, 462, 539 Congenital muscular dystrophy 1B, 660 Congenital myasthenic syndromes (CMS), 447, 540, 598 consanguineous, 620 founder event, 621 North African, 620 Congenital myopathies, 166–168 Congenital nephrosis, 664 Congenital nephrotic syndrome, 336 Congenital sensorineural deafness, 451 Connexin 26 mutations, 18 Conotruncal malformations (AR), 365 Consanguineous, 6–7, 11, 16, 596 Consanguineous marriages, 222, 355–356 Iraq, 300–302 rate of, 377, 403, 420

748

Consanguinity, 7, 16, 18–20, 22, 327–328, 392–393, 398, 402, 403, 407, 411, 414, 418, 424, 445, 450, 451, 494–496, 576, 708, 710, 713. See also First cousin marriages consanguineous, 653, 657, 662 consanguineous marriages, 641 cultural practice, 734 economic factors, 734 impact on genetic conditions, 735 rates, 734 social factors, 734 social importance, 735 types, 734 WHO position on, 735 Consent, 709, 710, 719, 720 Consumer-centered care, 67 Contemporary attitudes, secular changes, 91 Contraception, 714 Contracture deformities, 228 Control of teratogens, 712 Convulsive disorders, 225 familial, with prenatal or early onset, 187 Cord blood transplantation, 718–719 Corneal dystrophy and perceptive deafness, 187, 380 Cornea plana, 546 Cornelia de Lange’s syndrome AD, 364, 602, 666 Coronary artery disease (CAD), 551, 552 Counseling, 708, 720 Courbage, Y., 392 COX, 170 COX6B1 gene, 170 Craniofacial dysmorphism, 187 Craniofacial–hair–finger caudal syndrome, 364 Craniolenticulosutural dysplasia, 183 Craniosysnostosis, 202 CRASH syndrome, 651 Creutzfeldt–Jakob disease, 446, 452 Crigler–Najjar syndrome, 548 Crisponi syndrome, 662 Crouzon carniofacial dysostosis AD, 364 Crusades, 5, 14, 492 Cryopyrinopathies, 131–132 C-terminal titin deletions, 597 Cultural awareness, 721

Index

Cultural beliefs cauterization, 738 evil eye, 738 intergenerational conflict, 738 traditional healers, 738 Cultural diversity, 39 Curative and preventative care, 66 Cushing disease, 380 Cutaneous and neurocutaneous disorders, 599 Cutaneous porphyria, 248, 249 Cutis verticis gyrata, 199 Cyclopia/holoprosencephaly, 507 CYP2C19, 334 CYP21 mutations, 245, 246 Cystic fibrosis (CF), 252, 334, 403, 468–469, 520, 547, 594, 647 carrier frequency, genetic variations, 623 helicobacter gastritis, megaloblastic anemia and subnormal mentality, 365 helicobacter pylori-gastritis, megaloblastic anemia subnormal mentality (AR), 365 incidence, 15, 498 mutations, 15, 499 novel mutations, 623 Cystic fibrosis transmembrane conductance regulator (CFTR), 647 Cystinuria (AR), 365, 367, 534, 535, 590 Cytogenetic, 80, 81, 327 Cytogenetic abnormalities, 601

D Dabbous, I.A., 419 DABI stain, 232 50 DAG adhalin, 152 35 kDa DAG deficiency, 156 Dagoneau, N., 388, 424 Danagla, 583 Dandy–Walker malformation, 650 Daraweesh village, 580 Darfur, 586 Darwish, M., 386 Database, 643, 644 D-CHRAMPS syndrome, 331

Index

Deafness, 202, 593, 596, 647 autosomal recessive 31, DFNB31, 200 autosomal recessive 33; DFNB33, 200 branchiogenic, 405 Iraq, 316–317 neurosensory, autosomal recessive, I, 188 sensorineural, 400, 402 sensorineural, autosomalmitochondrial, 186 DeAngelis, M.M., 388, 423 Deeb, Z., 378 Defect of tryptophan metabolism, 600 Definition of genetic counseling American Society of Human Genetics (ASHG), 725 Clarke Fraser, 725 National Society of Genetic Counselors, 726 Sheldon Reed, 725 Delague, V., 378–380, 397, 399, 401 De Laurenzi, V., 422 de Longh, R.V., 380 Delta beta thalassemia, 235 De Meeus, 379 De Moerloose, 382, 408 Demographic correlates, 90–91 Demographic transition, 37, 40, 47, 54, 61 Denaturing gradient gel electrophoresis (DGGE), 241 Denoyelle, F., 380, 404 Density of physicians and nurses, 69 Department of pediatrics, 590 Der Kaloustian, V.M., 377–425 Dermodistortive urticaria, 182, 380 De Sanctis–Cacchione syndrome, 380 De Sandre-Giovannoli, A, 379, 380, 401 Desbuquois syndrome, 654 Desgeorges, M., 380, 403 De Vaumas, E., 389–391 Developed nations, 67, 68, 72, 75 Developing countries, 75, 709–710 Dextrocardia, 188 DGGE. See Denaturing gradient gel electrophoresis D-glyceric acidurias, 535 DHA, 244 Dhaini, H.R., 378, 379, 395 Diabetes insipidus, 424, 504, 593

749

Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD), 451, 593 Diabetes, Iraq, 315–316 Diabetes mellitus (DM), 338, 360, 405, 424, 551, 552, 593 neonatal, with congenital hypothyroidism, 183 Diaphragmatic hernia, 504 Diaphragm, 365 Diastrophic dysplasia, 233, 381 DIDMOAD. See Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness Digestive system, 594 Digitotalar dysmorphism, 230 Dilated cardiomyopathy, 167, 601 Dinka, Nuer, and Shilluk, 583 Disability, 291 Disease susceptibility, 580 Disorders of hemostasis, 590 Disorders of sexual differentiation (DSD), 245 Distal anterior compartment myopathy, 154 Distichiasis, 381 Diversity and Conflict of civilizations, 39 DMD. See Duchenne muscular dystrophy DNA fingerprinting, 711 Doctors and hospital beds ratios, 52 Donation of a sperm, 714, 715 Dongola, 575 Donnai–Barrow syndrome, 527, 543, 649 Donohue syndrome, 381 Dopa-responsive dystonia (Segawa disease)–like, 598 Dorfman–Chanarin syndrome, 248 Down’s syndrome, 356, 381, 446, 452, 595, 601, 643, 650 Iraq, 309–310 prenatal, 619 screening strategy, 618 termination of pregnancy, 619 Drousiotou, A., 387, 419 Druze, 5, 7, 14, 20, 390–395, 399, 403, 404, 406, 407, 409, 410, 419, 421, 494, 496 Duane/Radial dyplasia(DR), 255 Duchenne, 161–163 Duchenne-like autosomal recessive MD, 148

750

Duchenne-like muscular dystrophy (SARCMD), 367 Duchenne muscular dystrophy (DMD), 145–147, 149, 161, 162, 163, 227, 331, 366, 447, 539, 597 Dudin, G., 380, 386 Dudin–Thalji syndrome, 189 Duodenal atresia, pyloric, 188 Dup(1)(p36.1-36.2), 231 Du-pan syndrome, 232 Dupuytren contracture, 230 Dwarf, 274–278, 285–289, 293–294 Dwarfism, 221 dyssegmental, 504 Rhizomelic short limbed, 504 Dyggve–Melchior–Clausen syndrome, 229, 397, 406, 653 Dyschromatosis universalis hereditaria (DUH), 547 Dysferlin, 154 DYSF gene, 154 Dyshormonogenesis, 593 Dyskeratosis congenita, 249, 548 Dyslipidemia, 552 Dystonia 17, torsion, autosomal recessive DYT17, 202 a-Dystroglycan, 158, 160 b-Dystroglycan, 158, 167 b-Dystroglycan deficiency, 158 Dystroglycan gene, 158 Dystrophia myotonica, 661 Dystrophic epidermolysis bullosa (DEB), 237, 657 autosomal dominant, 626 consanguineous families, 626 deleterious mutation, 626 recessive, 626 type VII collagen gene, 625, 626 Dystrophin, 149–151, 154 50 kDa Dystrophin-associated glucoprotein, 152 Dystrophin associated proteins (DAPs), 158, 597 Dystrophin gene, 162–163 deletion, 228 Dystrophin–glycoprotein complex (DGC), 150 Dystrophinopathies

Index

Becker muscular dystrophy (BMD), 461 Duchenne muscular dystrophy (DMD), 458

E Early behavioural disorders intellectual disability, 96 intelligence quotient (IQ), 96 learning and reading difficulties, 96 Early onset cerebellar ataxia with retained tendon reflexes, 447 Early-onset myopathy, 601 Early onset PD (EOPD), 598 Early postnatal mortality, reproductive compensation, 94 East Africa, 577 Eastern Saudi Arabia, 584 Eastern Sudan, 580, 582 EB simplex, 599 EB simplex lethalis, 600 ECP 434 CC genotype, 581 Ectodermal dysplasia hidrotic, 381 hidrotic, autosomal recessive, 199 hypohidrotic, 406 with sensorineural deafness, 381 Ectopia lentis, 332, 406–407 Ectrodactyly, ectodermal dysplasia, macular dystrophy (EEM) syndrome, 231 EDA1 mutation, 381 EDAR mutation, 381 Edward syndrome, 602 EEC syndrome, 231 Effectiveness, 66, 77 Efficiency, 78 Egypt, 588 Egyptian, 7, 9, 12 Egyptian population, 581 Ehlers–Danlos syndrome (AR), 365, 382 Ehlers–Danlos syndrome, type IV-D, 189 Ehlers–Danlos syndrome type VIA (EDSVIA), 656–657 PLOD1, 656 Eldahdah, L.T., 425 El Ghouzzi, V., 406 Eljalde syndrome, 249 Ellis–van-Creveld syndrome, 229, 452, 654

Index

El-Rassy, I., 378 El-Shanti syndrome, 200 El-Zahabi, L.M., 382, 410 Embryo development, 716 Emiratis, 578 Encephalocele, 597 Encephalopathy, 168 Endemic diseases, 578 Endemic goiter, 592 Endocrine disorders, 359–360, 592 Endogamy, 6–7 clan, 92, 96, 99 hamula, 85 tribe, 92, 96, 99 Enterocolitis, necrotizing, 407 Enteropathy, protein losing, 189 Enzyme replacement therapy, 243 Eosinophil cationic protein (ECP), 581 Epidermolysis bullosa (EB), 407, 504, 507, 599, 657 with diaphragmatic hernia, 189 junctional, 524, 547 simplex, 547 simplex lethalis, Salih type, 189 Epstein, P.A., 380 ERIS, 332 Erythroderma, 233 lethal congenital, 189 Erythrokeratodermia variabilis, 659 Erythropathogocytic lymphohistiocytosis, 507 Ethics, 4, 705–707, 718, 721 Ethiopians, 577 Ethnic communities, 377, 394 Ethnic composition of the Sudanese population, 576 Ethnic diversity, 5 Ethnic groups, 586 Ethnic origins, 238 Europe, 640 European, 492, 496 EVC1, 654 EVC2, 654 EVC, EVC2, C4orf6 and STK32B, 229 Expatriates, 639 Extended family, 5 Extended metabolic screening, 240 Extracellular matrix protein 1 (AR), 366

751

Eye, anterior segment defects, clefting and skeletal anomalies, 200 Eye–brain–muscle syndrome, 650

F Facial anomalies, 649 Faciodigitogenital syndrome, 363 Kuwaiti type (AR), 189, 365 Facioscapulohumeral muscular dystrophy, 331, 447 Faciothoracogenital syndrome, 189 Factor V and factor VIII deficiency, 539 Factor VII deficiency, 590 Factor V Leiden, 407–408 Iraq, 314 Factor V R2 (H1299R) polymorphism, 408 Factor XI deficiency, 408 Factor XIII deficiency, 408 Faculty of medicine, 579, 582 Fadhil, M., 385, 417 Faivre, L., 388, 424 Falciparum malaria, 578, 579 Familial cold autoinflammatory syndrome, 131 Familial hypercholesterolemia, 465 Familial hypercholestrolemia type IIA AD, 364 Familial hypophosphatemic rickets, 360 Familial Leydig cell hypoplasia, 245 Familial Mediterranean fever (FMF), 111–117, 239, 337, 365, 367, 396, 408–410, 468, 545 Arabs, 624 autosomal recessive, 624 carrier rate, 239 incidence, 498 Iraq, 314–315 MEFV mutations, 624 migrations, 624 mutations, 8, 239, 498 Familial paroxysmal polyserositis (FPP), 396, 408–410 Family size, 5, 22 Fanconi anemia-like dysmorphic syndrome, 203 Fanconi’s anemia (FA), 231, 237, 251, 365, 382

752

autosomal recessive, 618 families, 618 new polymorphisms, 618 Fanconi’s syndrome, 592 Fares, F., 379, 399 Fargues, P., 392 Farra, C., 380, 403 Fascioscapulohumeral MD, 145 Fatty acid oxidation defects MSUD, 240 Fatty acid oxidation disorders (FAOD) carnitine acylcarnitine translocase deficiency, 536 carnitine palmityl transferase I deficiency, 536 carnitine transporter defect, 536 long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, 536 medium-chain acyl-CoA dehydrogenase deficiency (MCAD), 536 very long chain acyl-CoA dehydrogenase deficiency (VLCAD), 533, 536 Fatwas, 709, 717 adoption, 731 assisted reproduction, 729 bio-engineering, 733 cloning, 732 contraception, 732 cord blood transplantation, 733 definition, 729 DNA fingerprinting, 733 molecular genetics, 733 preimplantation genetic diagnosis, 729 premarital screening, 732 somatic gene therapy, 733 sterilization, 732 teratogens, 731 termination of pregnancy, 729 Fayad, M.N., 382 FC g receptor IIa (CD32) polymorphism, 580 Fcg RIIa-R/R131 genotype, 580 Female infertility, 358 Femoral-facial syndrome AD, 232, 364 Fertility, 641 Fertility rates, 4, 355–356 Fever familial lifelong, persistent, 190 persistent, 382

Index

FFU syndrome, 231 FGFR3 mutation, 229 Fibrochondrogenesis, 653 Fibrodysplasia ossificans progressiva AD, 364 Fibromatosis, juvenile hyaline, 382 Fibular aplasia or hypoplasia, 190 Figueiredo, M.S., 412 First cousin marriages, 494 First cousins, 6, 7, 494 Bint amm, 88, 89 Firzli, S.S., 419 Fischel-Ghodsian, N., 409 Fleck retina, familial benign, 190 Fluorescent in situ hybridization (FISH), 245, 254, 602 F508 mutation, 252 a-Foetoprotein, 599 Founder effect, 11, 15, 17, 20, 502 Founder gene, 246 Fragile X syndrome, 224, 541 Fraser syndrome, 649 Frayha, R.A., 378, 384, 386–388 Freeman, 230 Fregin, A., 388, 424 Freij, B.J., 386 Frequency of parental consanguinity, 223 Fresh legumes, 588 Fried, K., 407 Friedreich ataxia, 447 Fructose-1,6-diphosphatase deficiency (AR), 365, 382, 536 Fructosuria, nonalimentary, 382 Fryns, J.-P, 416 Fukushima, K., 404 Fukutin-related protein (FKRP), 158, 160 Fukuyama type, 159 Fulani group, 580 Fulani of West Africa, 580 Fuleihan, D.S., 387 Fundus albipunctatus, 546 Fur, 576, 588, 592

G Gaalyeen, 583, 590, 595 Gaalyeen tribe, 590 Gadarif state, 580

Index

Galactosemia, 240, 242, 448, 591, 656 Galactosialidosis, 535 Galactosyltransferase-I deficiency, 527 Galloway–Mowat syndrome, 336 Gamma globin gene polymorphisms, 235 GAPO syndrome, 249 Garcia, C.K., 383, 412, 413 Gastric sneezing, 182, 363 Gastrointerstinal atresias, 445 Gaucher disease, 240, 243, 449, 522, 535 Gaucher’s disease type I (AR), 365, 367, 382, 410 Gaza, 14, 19, 20, 492 GC/MS, 244 GDAP1, 379, 401, 459, 463 Geha, R., 384 Gene mapping, 708 Generalised lipodystrophy, 184 Genetic counseling, 80, 81, 706–708 carrier testing, 98–99 genetic counselors, 642 genetic education, 100 medical termination of pregnancy, 98, 99 premarital counselling and screening, 98 training programs Sarah Lawrence College, 727 Saudi Arabia, 727 Genetic disease autosomal recessive, 92, 94 homozygosity, 92, 94 Genetic disorders, 476–477, 677–698 of muscles, 227 Genetic diversity, 3–23 Genetic eye disorders, 249 Genetic facilities, 222 Genetic markers, 495–496 Genetic services, 65–82 Genetic stigmatization, 707 Genetic susceptibility to infectious diseases, 578 Genetic testing, 77, 78, 81, 82, 709, 710, 713, 720 Genodermatosis, 248–249, 339, 450–451, 658 Genomic research, 706, 709–711 Genomics, 709–710, 720 Genotype phenotype correlations, 250

753

Gerodermia osteodysplastica (GO), 452, 664 Gezira province, 580 Gezira scheme, 580, 581 Ghanem, I., 379, 385, 401, 416, 417 Ghanem, N., 384, 387, 396 Ghayad, E., 379 Gilbert syndrome, 382 GJB2 gene, 251 Glanzmann’s thrombasthenia, 501, 590 Glaucoma, 457–458, 501 congenital, 382 Global downturn, 45 Glomerulonephritis, 114 Glucose-6-phosphatase gene, 383 Glucose-6-phosphate dehydrogenase (G6PD) alleles, 579 Glucose-6-phosphate dehydrogenase (G6PD) deficiency, 21, 238, 333, 359, 382, 397, 410–411, 448, 520, 537, 538, 579, 587, 644, 646, 647 deficiency among Sudanese tribes, 588 Iraq, 313–314 mutations, 618 severe phenotype, 618 variant, 618 Glucose-6-phosphate dehydrogenasedeficient gene (G6PD), 588 Glutaric acidemia type I (GAI), 534, 535 Glutaric aciduria type II, 535 Glyceric aciduria, 534 Glycogenesis type 1 (Von Gierke’s disease), 591 Glycogenosis, 503 hepatic, 382 Glycogen storage diseases (GSD), 243, 383, 411, 448 Fanconi–Bickel syndrome, 536 phosphofrucokinase deficiency, 536 phosphorylase b kinase deficiency, 536 type I, 536 type III, 536 Glycosuria, renal, 383 GM1-gangliosidosis (AR), 365, 367, 535 GLB1, 656 GM2 gangliosidosis, 243 AB variant, 535 Sandhoff disease, 534

754

GMi gangliosidosis, 500 Goldenhar syndrome (GS), 231, 665 Gorlin–Goltz syndrome AD, 364 Gout, 383 G6PD deficiency. See Glucose-6-phosphate dehydrogenase (G6PD) deficiency Grebe-like chondrodysplasia, 186, 363, 502 Griscelli syndrome, 337, 548 G34R mutation, 246 Gross domestic product (GDP) growth, 43, 47 Growth and volatility, 40 Growth hormone (GH) deficiency, 543 Growth hormone insensitivity with immunodeficiency (AR), 365 Growth retardation, 649 Gulf Cooperation Council (GCC), 5, 517

H Haddad, R., 382, 407 Hajjar, E.T., 379 Halabi, S., 393 Hallermann–Streiff syndrome, 254, 365, 383 Hallervorden–Spatz syndrome, 244 Hamad Medical Corporation (HMC), 517 Hamitic, 576 Haplotypes, 8, 12, 17, 237 Hara, Y., 419 Harboyan, G., 380 Harfouche, J.K., 393 Hartnup’s disease, 590 Hawazma, 577, 583, 588 HbAA, 585 HbAA individuals, 579 HbAS, 579, 585 Hb Khartoum, 587 Hb Khartoum/g thalassemia, 587 HbS, 579 Hb S/beta-thalassemia, 235 HbS þ O, 587 HbSS, 584, 585 Health care inequalities, 50 Healthcare system(s), 65–67, 69, 82 Health expenditures, 40, 50–53 Health risk factors, 65–82 Health service(s), 65, 66, 69, 71, 75–78, 82

Index

Health systems, 38, 40, 50–53 Health workforce, 38, 52, 61 Hearing loss, 502 GJB2, 457 Hearing loss, non-syndromic, 383 Heart block, 411 Hechtman, P., 387, 422, 423 Hematological disorders, 234, 359 Hemimelia, 254 Hemoglobin HbO-Arabs, 498 HbS, 498 Hb Taybe, 498 Hemoglobin Beirut, 383 Hemoglobin C, Iraq, 312 Hemoglobin F, 584 Hemoglobin H (HbH) disease, 383, 411 Iraq, 312 Hemoglobinopathies, 7–8, 496–498, 644, 645 Hemoglobin S beta thalassemia, 235 Hemoglobin S/O Arab (Hb S/O-Arab), 586 Hemophilia, 464 Hemophilia A, 238, 590 Hemophilia B, 238 Hennekam syndrome, 649 Hennies, H.C., 380, 402 Henoch–Schonlein purpura (HSP), 113 Hepatic fibrosis, 580, 581 Hepatitis B surface antigen (HBsAg), 586 Hepatitis B virus (HBV), 586 Hereditary ataxias, 226, 599 Hereditary 1,25-dihydroxyvitamin D3-resistant rickets, 544 Hereditary emochromatosis gene, 548 Hereditary fructosuria, 591 Hereditary hemorrhagic telangiectasia, 539 Hereditary motor and sensory neuropathy (HMSN), 540 Hereditary multiple exostoses type I EXT1, 627 newly identified mutation, 627 novel frame-shift deletion, 627 Hereditary pyropoikilocytosis, 539 Hereditary sensory and motor neuropathy, 446, 447 Hereditary spastic paraplegia, 447, 541

Index

Hereditary tyrosinemia, 242 Herman, R.H., 382 Hexosaminidase A deficiency, 243 Hexosaminidase B deficiency, 243 H/H131 genotype, 580 Hirbli, K.I., 381 Hirschprung’s disease, 504 Historical background, 219–222 Hitti, P.K., 391, 392 HLA-B*27 new allele, 383 HLA. See Human leukocyte antigen Hochberg, Z., 386, 418 Holt-Oram syndrome, 231, 504, 666 Homocystinuria (HCU), 13, 240, 251, 365, 367, 383, 521–522, 535, 656 Homozygous HbSS, 583 Homozygous SCD, 584 Hospital-based data, 476 HPA-1 platelet antigen, 383, 396 HSN2, 385, 416 Human cytogenetic project in Sudan, 602 Human leukocyte antigen (HLA), 336 complex class I and II antigen, 383 gene variability, 495 markers, 383 typing, 247 Human life protection, 716 Humeroradial syntosis with craniofacial anomalies, 190 Hunter syndrome, 243 Huntington disease-like neurodegenerative disorder, 540 Hurler’s and Hurler–Scheie syndromes (AR), 365, 367 Hurler’s syndrome, 243, 383, 591 Hutchinson-Gilford progeria syndrome, 452 Hyaline body myopathy, 540 Hydrocephalus (AR), 17, 221, 225, 365, 383, 500–501, 507, 596 4-Hydroxybutyric aciduria, 535 21-Hydroxylase deficiency, 246, 397 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency, 535 Hypercholesterolemia autosomal recessive, 383, 412–413 familial, 383, 412

755

low-density lipoprotein receptor, Lebanese variant, 383, 412 Hyperekplexia, 330 Hyperhomocysteinemia, 413, 416 Hyperimmunoglobulinemia D with periodic fever syndrome, 130 Hyperinsulinism and hyperammonemia (HI/HA) syndrome, 522, 536 Hyperlipoproteinemia, Type I, 383, 413 Hyperornithinemia–hyperammonemia– homocitrullinuria (HHH) syndrome, 535 Hyperoxaluria I, 383 Hyperphenylalalinemia (HPA), 12–13, 241 Hyperphosphatasia, 233 Hyperprolinemia (AR), 240, 365 Hypertelorism, hypospadias polysyndactyly syndrome, 363 tetralogy of Fallot syndrome, 190, 363 Hypertelorism–Teebi type AD, 182, 364 brachycephalofrontonasal dysplasia, 363 Hypertension, 506 Iraq, 316 Hyperthyroidism, 601 Hypertrichosis, congenital anterior cervical, with peripheral sensory and motor neuropathy, 190 Hypertrophic pyloric stenosis, 247 Hypertrophic synovitis, 527 Hypoadrenocorticism with hypoparathyroidism and moniliasis, 384 Hypogonadism, 502 hypogonadotropic, and alopecia, 384, 414 hypogonadotropic, and partial alopecia, 384, 413–414 primary and partial alopecia, 191, 363 Hypogonadotropic hypogonadism alopecia, 203 MR, obesity, and minor skeletal abnormalities, 203 obesity, MR, and skeletal anomalies, 364 Hypohydrotic/anhydrotic ectodermal dysplasia, 466–467 Hypokalemic tubulopathy, 400 Hypomagnesemia with hypercalciuria, 548 Hypomelanosis of Ito(HI), 249 Hypoparathyroidism (XL), 366 short stature, mental retardation and seizures, 191

756

Hypophosphatemic rickets, 591 with hypocalciuria, 191 Hypoplastic tibiae and postaxial polysyndactyly (AD), 363, 364 Hypospadias, 189–191 Hypothyroidism, 601 congenital, 384

I Ichthyosiform erythroderma, 507 Ichthyosis congenita, 547 Ichthyosis, lamellar, 5, 384, 414 IDDM. See Insulin-dependent diabetes mellitus (IDDM) Idiopathic hypogonadotropic hypogonadism, 543 Idriss, Z.H., 378, 380, 383, 386, 403 IDU A deficiency, 242 IEM. See Inborn errors of metabolism IFN–gR1 gene, 581 IgA nephropathy, 120 IgG1 and IgG3 antibodies, 580 IgG subclass immune deficiency, 526 IgM nephropathy, 120 Illness hadiths, 737 recitation of the Quran, 737 visitation of the ill, 737 Imerslund-Gra¨sbeck syndrome, 384, 414 Immunized, 78 Immunodeficiency hyper-IgM, 548 severe combined-1, 384 Immunoglobulin lambda, 384 Immunoglobulins (IgG, IgA and IgM), 585, 586 Immunoglobulins IGHA2*M1 and IGHA2*M2 alleles, 384, 396 Impact of genetic diseases, 707 Improved drinking water, 76, 77 Improved sanitation, 76, 77 Inati, A., 420 Inborn errors of metabolism (IEM), 10–14, 224, 240, 361–368, 448, 449, 502, 590, 655, 713 Inbreeding, 4, 6, 19, 22 coefficient, 222, 576, 577 Incidence, 224

Index

Incidence of DSD, 245 Incontinenta pigmenti X-linked dominant, 366 India, 640 Indifference to pain (AR), 365 Inequity/Inequities, 66, 75, 76 Infant deaths, 223 Infantile metachromatic, 242 Infantile systemic hyalinosis, 544, 666 Infant mortality rate(s), 4, 72, 73 Infertility, 469 Iraq, 310–311 multitailed spermatozoa and excessive DNA, 190 Inflammatory linear verrucous epidermal nevus (ILVEN) (AD), 364 Inherited metabolic disorders, 590 Insensitivity to pain, congenital, with anhidrosis (AR), 365 Inspiration of the soul, 716 Institute of Endemic Diseases, 577, 582 Institute of Medicine (IOM), 66 Insulin-dependent diabetes mellitus (IDDM), 247–248, 450 DQB1, 623 HLA-DR, 623 multiplex families, 623 Insulin resistance leprechaunism-like syndrome, 192 Integrin, beta-3, ITGB3, 383, 396 Interferon-g (IFN-g), 581 Interleukin-1, 384 defective T-cell response to, 205 Interleukin-12 deficiency, 548 Interleukin-4 (IL-4) gene, 580 Interleukin-2 (IL-2) receptors, 579 Intestinal atresia, multiple level, 191, 384 Intracranial calcificaton, 526 Intrauterine growth retardation (IUGR), 666, 667 In vitro fertilization (IVF), 715, 719 IQ scores less than 94, 586 Iran, 640 Iranian, 640 Irani-Hakime, N., 382, 408 Iraq geography and history, 297 health services, 299–300 Iraqi, 20, 21, 182, 192, 198, 199

Index

population, 298–299 Islam, 4–6, 576, 705–711, 714, 718, 720 Islamic ethics, 706, 711–712 Islamic Jurisprudence Council, 709–712, 717–719 Islamic Jurists, 709, 714 Islamic law, 6 Islamic medicine, 4 Islamic Shariai’ha principles, 706, 709, 712, 714–716, 719 Islamic teachings, 706, 708, 712, 716, 720 Islamic World League (Organization of Islamic Countries), 709–712, 717, 719 Isolated ectopia lentis, 527 Isolates, 5, 6, 11, 18 Isovaleric acidemia, 448, 656 IUGR. See Intrauterine growth retardation I1234V mutation, 520

J Jaatoul, N.Y., 385 Jabal marra, 577 Jabir B. Hayyan, 39 Jalili syndrome, 187 Jalkh, N., 382, 409 Jancar’s syndrome, 504 Jarjouhi, L., 384 Jarrah, A., 378 Jeck, N., 379 Jejunal atresia, 192, 384 Jervell and Lange-Nielsen syndrome 2 (long-QT syndrome), 384, 414–415 Jeune syndrome, 654 Jews, 5, 8, 10, 14, 20–22 Johanson–Blizzard syndrome, 542 Jordan, 325–342 Jordanian, 8, 10, 11, 20, 188, 191, 196, 199–201, 378, 665 Joubert’s syndrome (AR), 364, 542, 650, 651 related disorders, 226 Junctional epidermolysis bullosa (EB), 599, 657 Jurisprudence, 706, 709 Juvenile hyaline fibromatosis, 249 Juvenile hypothyroidism, 593 Juvenile nephronophthisis, 548

757

Juvenile polyposis syndrome, 336

K Kabuki make up syndrome, 507 Kala-azar (KA), 582 Kallman syndrome, 339 Kawahla, 598 Kawahla tribe, 155 KBG syndrome AD, 364 Kearns–Sayre syndrome, 168 Kenny–Caffey syndrome, type I (AR), 365 Keratolysis exfoliative congenita, 195 b-Ketothiolase, 656 3-Ketothiolase deficiency, 535 Ketotic hyperglycenemia, 240 Keutel syndrome (AR), 365 Khachadurian, A.K., 378, 381–383, 386, 408, 409, 412 Khachadurian, L.A., 383, 412 Khaldi syndrome, 203 Khartoum, 581, 584, 587, 588, 595, 598 Khartoum teaching hospital, 586, 588 Khlat, M., 393 Khudr, A., 393 Kidd, D.D., 380 Kindler syndrome, 547 Kindreds, 5, 11–13, 16, 18, 20, 21 Klinefelter syndrome, 496 cytogenetic analysis, 619 extra X chromosome, 619 Klippel–Feil syndrome, 221 Klippel–Trenaunay syndrome AD, 364 Kniest dysplasia, 384 Kocher–Debre´–Se´me´laigne syndrome, 384 Kordofan, 586 Krabbe disease, 500, 656 Krause–Kivlin syndrome, 504 Kufor–Rakeb syndrome, 199, 330 Kuhl, W., 410 Kurban, A.K., 384, 387 Kurdi-Haidar, B., 382, 410, 411 Kurds, 5, 10 Kuwait, 5–9, 11–17, 19–22, 645, 651 Kuwaiti, 182, 183, 185–189, 191, 195, 196, 198, 204 Kuwaiti family, 149

758

L Lacombe, A., 386, 418 Lactose intolerance, adult, 384 Lactose malabsorption, 594 Lake Victoria region in Kenya, 583 Lalouel, J.M., 394 Lambotte syndrome, 192 Lamellar ichthyosis, 658 Laminin-a2 chain, 158, 160, 161, 167 Langer mesomelic dysplasis, 655 LARGE gene, 160 Laron’s syndrome (AR), 366, 543 Larsen-like disorder, 668 Larsen syndrome, 230, 253, 654 Late onset cerebellar ataxia, 446 with retinal pigmentary degeneration with autosomal dominant inheritance, 447 Laurence–Moon syndrome (AR), 365 Laurier, V., 379, 399 Lawrence-Seip syndrome, 249 Lay beliefs, 733 LDLR, CYS660TER, 383, 412 Leadership, 721 Least-developed, 68, 79 Lebanon, 377–425, 663 Lebanese, 8, 10, 11, 14, 20, 182, 184, 186–197, 199–203, 205, 377, 378, 390–425, 653 Leber congenital amaurosis, 332, 384, 458, 546 Leber optic atrophy, 384 Lefe`vre, C., 384, 414 Lefranc, G., 393, 394 Lehrman, M.A., 383, 412 Leigh syndrome, 244 Leishmania donovani, 582 Leishmaniasis, 578, 582 Lentigines, 184, 384 Lenz microphthalmia syndrome, 251 LEOPARD syndrome AD, 364 Leprechaunism, 381, 527, 664 Leprechaunism-like syndromes, 664 Lethal chondrodystrophies, 367 Lethal congenital contracture syndrome, 200 Leukemia inhibitory factor receptor (LIFR), 166

Index

Leukodystrophy, 243 Leukonychia, 186 Leukonychia totalis and skin changes, 203 Levodopa therapy, 598 Levy, G.N., 378, 379, 395 L-glyceric acidurias, 535 LGMD. See Limb-girdle muscular dystrophy L-2-Hydroxyglutaric aciduria, 535 Libya, 146, 148 Benghazi, 444, 445, 448–450, 452 genetic services, 445, 452 history, 443 Libyan, 443–446, 448, 449, 451, 452 Libyans (Temehu), 575 map, 444 population statistics, 444–448, 450, 451 screening programs, 448 Tripoli, 443–445, 448, 449, 452 Life expectancy, 4 Lightwood, R., 388 Limb and skeletal malformation clinic (LSMC), 233 Limb-girdle, 146 Limb-girdle muscular dystrophy (LGMD), 150, 331, 447 LGMD2C, 461 Limb-girdle muscular dystrophy (LGMD) 1A, B, C, 152 Limb-girdle muscular dystrophy (LGMD) 2A, B, 152 Limb-girdle muscular dystrophy 2B (LG-MD 2B), 154–155 Limb-girdle muscular dystrophy (LGMD) 2I, 158 Limb-girdle muscular dystrophy type 2C (LGMD2C), 155–158 Limb/pelvis-hypoplasia/aplasia syndrome (AR), 197, 363, 366, 502, 655 Limb reduction defects, 231 LINE1-mediated deletion of, 229 Linguistic groups, 586 Lipodystophy congenital, generalized, type 2, 384, 415 generalised with mental retardation and deafness, 184 Rajab type, 184

Index

Lipoid proteinosis, 251, 256, 384, 451, 549 Lissencephaly, 526 Loiselet, J., 384, 386, 393 Long QT syndrome, 546 Low density lipoprotein receptor (AD), 367 Lowe syndrome, 250 Lowry–Maclean syndrome (AD), 366 LPIN2, 128 Lymphoproliferative responses to SPAg, 579 Lysosomal disorders, 500 Lysosomal storage disorders, 242, 333, 448–449, 503

M Macrocephaly multiple epiphyseal dysplasia, 667 mutiple epiphyseal dysplasia and distinctive facies, 200 Macrodactyly, 228 Macrosomia microphthalmia and cleft lip/palate, 502 microphthalmia, lethal (AR), 192, 363, 365 Maghreb, 8, 9, 13, 16, 17 Maghrebian countries, 151 Magre´, J., 384, 415 Mahfouz, R.A.R., 378, 382, 398, 408 Mahmud, J., 380 Majdalani, E., 386 Majeed syndrome, 8, 128, 201, 337, 502 Major congenital anomalies (MCAs), 361, 445 Makhoul, N.J., 387, 421 Malaria, 578 Malaria antigens, 580 Mal de Meleda disease, 659 Male idiopathic infertility, 247 Male infertility, 357 Male pseudohermaphroditism, 19 Malformation, 494 Malformation syndromes, 17 Malonic aciduria, 535 Malouf, J., 379 Malouf syndrome, 187, 379 Mamo, J.G., 383 Managil area, 581

759

Manic depressive illnes (XL), 366 Mannose-6-phosphate receptor recognition defect, Lebanese type, 385, 415 Mansour, A.M., 380 Mansour, I., 382, 409 Maple syrup urine disease (MSUD), 385, 534, 535, 656 Marden-Walker syndrome, 385 Marenostrin, 115 Marinesco–Sjogren syndrome (AR), 226, 365 Market-maximized, 72 Market-minimized, 72 Maroteaux–Lamy syndrome, 243, 367 Marriage, 5–7 Martin–Bell syndrome (XL), 366 Masalit, 582 Masalit tribe, 583 MCADD. See medium chain acyl coenzye A dehydrogenase deficiency MCAs. See Major congenital anomalies McLaren, D., 388 MD congenital type 1A (MDC1A, or merosin-deficient (MD), 160 Meckel–Gruber syndrome (AR), 226, 365, 452, 542 Meckel syndrome, 17, 358, 367, 385, 500, 651 MECP2 gene mutation, 244 Medical genetics, 709–710, 721 Medical practice, 706 Medicine, 706, 709, 710 Mediterranean, 219, 377, 389, 392–394, 396, 407–411, 420 Mediterranean mutations, 241 Medium chain acyl coenzye A dehydrogenase deficiency (MCADD), 244 Medlej-Hashim, M., 382, 409 Medlej, R., 388, 424 MEFV, 114 Megalencephaly with dysmyelination, 192 Megalocornea/mental retardation syndrome (MMR2), 255 Me´garbane´, A., 378–382, 384, 385, 387, 399–402, 405–407, 413, 416, 422 Megarbane–Jalkh syndrome, 202 Me´garbane´ syndrome, 199, 385, 416 3-Mehylglutaconic aciduria, 535

760

Meier–Gorlin, 545 MENA, 44–48, 54 Mendelian disorders Iraq, 304–306 Menetrier’s disease, 504 Meningitis, 595, 596 Meningitis belt, 596 Mentally handicapped children, 595 Mental retardation (MR), 224, 358, 366, 496, 502, 593, 649, 650, 656 Iraq, 308–309 with optic atrophy, facial dysmorphism, microcephaly and short stature, 200 short stature, facial anomalies and joint dislocations, 199 skeletal dysplasia, abducent palsy (XL), 366 spastic diplegia (XL), 366 Merosin, 160 Mesangial sclerosis, 192 Mesomelic dysplasia, upper limb, 385, 416 Messeria, 583, 588 Metabolic and molecular testing strategy, 521 Metabolic bone disease, 591 Metabolic disorders, 644, 656 Metachromatic leukodystrophy (MLD), 243, 500 ASA-deficient MLD, 540 SAP-B deficiency (SAPBD), 540 Metaphyseal dysplasia, 192 Metaphyseal Spahr-type dysplasia, 385 3-Methylcrotonyl-CoA carboxylase deficiency, 535 Methylenene tetrahydrofolate reductase (MTHFR), 385, 413, 416, 535 Iraq, 314 polymorphisms, 383, 413 3-Methylglutaconic aciduria, 534 Methylmalonic acidemia (MMA), 448, 534 Mevalonate kinase, 130 Mevalonic aciduria, 656 Microcencephaly with simplified gyral pattern with abnormal myelination and arthrogryposis, 203 Microcephaly, 17, 200, 225, 330, 367, 650, 651

Index

brain calcification, developmental delay and small stature, 184 chorioretinopathy (AR), 365 hypogonadism syndrome, 192 hypogonadotrophic hypogonadism, 364 intracranial calcification (AR), 365 normal intelligence, 193, 363, 502 osteodysplastic primordial dwarfism type II, 653 simplified gyral pattern, 183 with abnormal myelination and arthrogryposis, 668 and early lethality, 199 Micromelic dwarfism, 655 Micromelic dysplasia, congenital with dislocation of radius, 193 Micropenis, 246 Microphthalmia, 188, 251, 501, 665 with myopia and corectopia, 385 Microphthalmos, 385 Micro syndrome, 254 Middle East, 4, 21, 23, 640 Migration of doctors, 38 Migration of health workers, 52 Mikaelian, D.O., 381 Mikati, M.A., 379, 385 Mikati syndrome, 192 Mild mutations, 235 Milk consumption, 594 Mishalany, H.G., 381, 384 Mitchell, G.A., 385 Mitochondrial abnormalities, 227 Mitochondrial disorders, 244, 448, 503, 536 cytochrome c oxidase deficiency, 536 MELAS, 536 Mitochondrial hepatopathy, 244 Mitochondrial myopathies, 168 Mitomycin C (MMC), 237 Mitonchondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), 169 Miyoshi myopathy (MM), 154 M-line protein complex, 168 M-line titin, 601 Mnaymneh, W.A., 387 Modifer gene, 125 Moebius’s syndrome AD, 364 Molecular characterization, 243

Index

Molecular studies, 227 Monogenic disorders, 223 Monotheistic culture, 705 Moroccan Human Mutation Database, 456 mutations, 459–461 Morocco, 7, 9, 150 consanguinity, 456 ethnic groups, 455 genetic services, 456 inhabitants, 455 Morquio’s disease, 243, 591 Mortality, 38, 46–49, 58–60 Mossman, J., 383, 387 Motherhood surrogacy, 715 Motor neuron disease, 446 Mowat–Wilson syndrome, 650 MPS type 1, 449 MPS type II, 449 MR, 203 mtDNA, 170 mtDNA-encoded cytochrome c oxidase (COX) genes, 170 MTHFR. See Methylenene tetrahydrofolate reductase MTM1 gene, 166 Muckle–Wells syndrome, 131 Mucolipidosis, 500 Mucolipidosis type II, 367 Mucopolysaccharidosis (MPS), 242, 465–466, 500, 591 Maroteaux–Lamy syndrome, 534 Morquio disease, 534 Mudawwar, F., 384 Mufarrij, I.S., 380 Mu¨llerian structures, 385 Multiple-acyl-CoA dehydrogenase deficiency (MADD), 590 Multiple congenital anomalies, MR, and happy nature, 203 Multiple endocrine neoplasia type 1 (MEN 1), 544 type 2, 468 Multiple intestinal atresia (AR), 365 Multiple pterygium syndrome, 230, 367, 666 Multiple sclerosis, 506 Multiple sulfatases deficiency (AR), 366, 367

761

Multiplex PCR, 162, 163 Mummy, 281–284, 287, 291 Mumtaz, G., 402 Murcs association, 233 Musallam, S., 378 Muscle specific kinase (MUSK) mutation, 598 Muscular dystrophies (MDs), 8–9, 22, 145–163, 446, 447 autosomal, 620 consanguineous families, 620 families, 619 fukutin-related protein gene (FKRP), 619 heterogeneous, 619 Muslims, 390, 392, 403–405, 408, 409, 416–421, 575, 576 Mustapha, M., 380, 383, 404, 405 Mutation analysis, 120 Mutation detection, 235 Myelomeningocele, 504, 597 Myofibrillar myopathies, 166, 527 Myopathy(ies), 8–9, 22 early-onset, with fatal cardiomyopathy (EOMFC, MIM 611705, Salih Myopathy), 167–168, 201 Myotonic dystrophy, 146, 331 Myotonic dystrophy 1, 661 Myotubulation, 166

N Nablus mask-like facial syndrome, 184, 504 Nabulsi, M.M., 403 Nachman, H.S., 384 Naffah, J., 377, 380, 381, 385, 387, 393, 394, 406, 408, 409 Nail-patella-like renal disease, 193 Najjar, F.B., 380, 384, 386 Najjar, S.S., 378, 379, 381, 384, 386, 387, 414, 415 Najjar syndrome, 187, 379 Nasopharyngeal carcinoma direct sequencing, 630 familial and sporadic, 630 human leukocyte antigen (HLA) haplotypes, 630 Nasr, F., 387

762

NAT1 genotypes, 385, 395 National strategies for the prevention and management definition, 487 genetic and ethics, 487 genetic and genomic research, 487 genetic diagnostic laboratory services, 487 medical education, 487 Natural resistance-associated macrophage protein-1 (NRAMP1), 582 Naxos disease, 547 NDH syndrome, 183 Neonata adrenoleukodystrophy, 251 Neonatal death congenital anomalies, 74, 76 other causes, 75 preterm births, 74 Neonatal jaundice, 587 Neonatal mortality rate/s, 72, 73 Neonatal-onset multisystem inflammatory disease, 131 Neonatal screening program, 241, 518, 714, 721 Nephrogenic diabetes insipidus (NDI), 548 Nephrosis, minimal change, 364 Nephrotic syndrome, 548 early onset with diffuse mesangial sclerosis, 193 minimal change, X-linked, 205 Nesidioblastosis, 502 Nesidioblastosis of pancreas (NP), 16 Netherton syndrome, 547 Neu–Laxova syndrome, 249 Neumann, L.M., 381, 406 Neural tube defects (NTDs), 225, 358, 446, 506, 596, 597 Neurogenetic disorders, 446, 595 Neurolipidosis, 243 Neurological disorders, 329–331 Neuromigrational disorders, 329 Neuromuscular disorders, 145, 597 Neuronal ceroid lipofuscinosis (NCL), 534 CLN1, 541 CLN2, 541 CLN6, 541 CLN7, 541 Neuronal lipofuscinosis, 242 Neuronal migration disorders, 225

Index

Neuropathy giant axonal, Tunisian form, 193 hereditary sensory and autonomic, 416 Neuroskeletal handicap, 595 Neutrophilic dermatitis, 201 New bone dysplasia, 254 New born screening (NBS), 65, 76–78, 81–82 New genetic syndromes, 502–504 New syndromes, 9, 10, 21, 22, 600 Newton, F.H., 384 New type of EB simplex, 599 Nezarati, M.M., 387, 422 Niemann–Pick disease, 500, 534 type A (AR), 365 type B, 367 Nigeria, 583 Night blindness and myopia, 385 Niikawa-Kuroki syndrome, 507 Nile Delta, 235 Nile valley, 575 Nilo-Hamitics, 576 Nilo-Hamitic tribes, 583 Nilotes, 576, 594 Nilotic Baria, 582 Nilotic Nuer, 582 NK2, drosophila, homolog of, 6; NKX2-6 (AR), 367 Nodulosis Osteolysis, Arthropathy (NOA) syndrome, 194 Noncompaction cardiomyopathy, 527 Non-disjunction (AR), 19, 365 Non-Herlitz junctional epidermolysis bullosa, 657 Noninsulin-dependent diabetes mellitus (NIDDM) familial aggregation, 624 health problem, 624 susceptibility gene, 624 Nonketotic hyperglycinemia (AR), 365, 367, 535 Nonketotic hypoglycemia, 244, 448 Nonsyndromal anencephaly (AR), 364 Non-syndromic autosomal recessive deafness, 647 Non syndromic congenital deafness consanguineous, 626 DFNB1, 626

Index

inbreeding, 626 linkage analysis, 626 novel locus, 626 Non-syndromic deafness, 18 Non syndromic microphthalmia/ anophthalmia, 520, 523, 524 Noonan’s syndrome (AD), 253, 364, 666, 668 Norrie disease, 250, 546 North Africa, 4, 8, 12, 13, 597, 640 Northern Nigeria, 588 Northern province of Sudan, 599 Northern Sudan, 595, 598 Northwestern Africa, 153 Novel deletion of PINK1 exons 4–8, 598 Novel early-onset myopathy with fatal cardiomyopathy, 597 Novel mutation, p.A217D, 598 Novel mutations, 246, 250, 253 Novel phenotypes and variants, and novel genotypes allopecia universalis congenita, 486 Bardet–Biedl syndrome, 486 brain calcifications, 485 cohen syndrome, 486 congenital generalized lipodystrophy, 484 congenital generalized lipodystrophy with deafness, 484 Escobar variant, new form, 485 geroderma osteodysplastica, 486 grebe acromesomelic dysplasia, 486 hemophagocytic Lymphohistiocytosis type 1, 486 hypopituitarism, 486 microcephaly, lethal form, 484 paroxysmal nonkinesigenic dyskinesia, 487 pontocerebellar hypoplasia, 485 Scwartz–Jampel syndrome, 486 spastic cerebral palsy, autosomal recessive form, 485 spinal muscular atrophy, 487 spondyloepiphyseal dysplasia, 485 three M syndrome, 486 wrinkly skin syndrome, 486 Novel syndromes, 254 NTDs. See Neural tube defects

763

Nuba, 576, 582, 583, 588 Nubians, 5, 7, 583, 594 Nuba mountains, 576, 583, 588 Number of clinics, 80 Nurses’ density, 70 Nutritional problems, 5 Nystagmus, 384 congenital, 385

O Obesity, 254, 338 Occulodentoosseous dysplasia, recessive, 193, 385 Oculomotor apraxia, 599 Oculotrichodysplasia, 250 Odontoonychodermal dysplasia, 194, 385, 417 Oil and natural resources, 38, 40 Oil prices, WTI, 38, 45, 54 Oldenburg, J., 424 Oman, 165, 166, 578, 588, 639, 640, 646, 651, 652, 666 Omanis, 183–185, 189, 194, 204, 578, 640, 653, 655, 658 Oman population family size, 473 growth rate, 473 yearly growth, 473 Omdurman, 596 Omenn syndrome, 253 Oppenheim, A., 412 Opthalmoplegia-plus, 447 Optic atrophy, 399, 417, 424, 501 congenital, 385 Optic nerve coloboma, 668 Organic acidemias, 13, 240, 367, 503 Organization of Islamic Countries, 718 Organization of Islamic Conference (OIC), 705 Oris, 249 Ornithine aminotransferase deficiency, 385 Orofaciodigital syndrome, 253 Osseous dysplasia, 385, 417 Osteochondrodysplasias, 18–19, 652 Osteogenesis imperfecta, 221, 279, 545, 592 Osteopetrosis (AR), 233, 365, 385, 417–418, 504, 655

764

carbonic anhydrase II (CA II) deficiency, 545 malignant osteopetrosis, 545 renal tubular acidosis (AR), 365 severe autosomal recessive, 367 syndromes, 16 Osteoporosis-pseudoglioma syndrome (AR), 366 Osteoporosis-pseudoglioma with congenital heart disease, a variant, 194 OTOF gene, 404 Otopalatodigital syndrome, 253 Outcome and process indicators, 76 Ovarian failure, premature, 386, 418 Ovum, 715, 719

P 1p22, 582 PAH mutations, 241 Pakistan, 640 Pakistani, 653 Palestine, 657 Palestinians, 7, 8, 10–20, 166, 184–197, 199–205, 391, 392, 419, 491–508, 651, 661, 664 Pallidopyramidal degeneration, 199 Palmoplantar keratoderma AD, 364 epidermolytic, 364 epidermolytic recessive form 2 Kuwaiti 144200*, 363 Pancytopenia with multiple congenital anomalies, 203 Papillon–Lefe`vre syndrome, 249, 333, 549 Parasite neutralizing immune mechanisms, 580 Parathyroid carcinoma, familial, 386 Parental consanguinity, 222, 242, 249, 254 PARK 6, 598 Parkinson’s disease (PD), 507, 542, 598 genetically heterogenous, 621 genetic characteristics, 621 neurodegenerative disease, 621 Parkman, R., 388 Partial androgen insensitivity, 247 Paupe, V., 406 Paw, B.H., 423 Pediatric service, 377

Index

Peeling skin syndrome (AR), 366 Pelizaeus–Merzbacher-like disease (PMLD), 242, 540 Pellagra-like skin rash, 600 Pellagra-like syndrome, 194 Pendred’s syndrome (MIM No. 274600), 593 Pentosuria, essential, 386 Pericenrtrin 2 mutation (Seckel syndrome) (AR), 367 Peripheral neuropathy, 599 Periportal fibrosis (PPF), 580 Perlecan (HSPG2), 165 Peroxisomal disorders, 244, 503 hyperpipecolic acidemia, 536 rhizomelic chondrodysplasia punctata type II, 536 X-linked adrenoleukodystrophy, 536 Zellweger syndrome, 536 Persians, 4, 640 Persistent hyperinsulinaemic hypoglycemia of infancy (PHHI), 543 Persistent hyperinsulinemic hypoglycemia, 16 Persistent mullerian duct syndrome (AR), 366 Persistent primary vitreous, 251 Peters plus like syndrome, 667 Peters plus syndrome, 526, 527 Petro-dollar surpluses, 44 Peutz–Jeghers syndrome, 386 P. falciparum antigens (SPAg), 579 P. falciparum infections, 580 Pfeiffer syndrome, 233 Pharmaceutical market issues, 54 Pharmaceutical trade, 54, 55 Phenylketonuria (PKU), 12–13, 240–241, 333, 366, 367, 386, 448, 449, 590, 642, 656 hyperphenylalaninemias, 499 incidence, 499 inherited metabolic disorder, 623 mutations, 499 6-pyruvoyl tetrahydropterin synthase, 535 Phenyl thiocarbamide (PTC) nontasters, 592 Phenylthiocarbamide (PTC) taste response, 592

Index

Phocomelia and ipsilateral asymetric crying face, 255 Phosphorylase kinase deficiency of liver and muscle, 195 Photography cultural attitudes, 736 medical photography, 736 women, 736 Physical growth, 585 Physicians’ density, 70 Piebaldism (AD), 364 Pilot, 65, 81 PINK1 gene mutation, 598 Pipkin, A.C., 384 Pipkin, S.B., 384 PKU. See Phenylketonuria Placental blood, 719 Plasminogen activator inhibitor-1, 386, 418 Plasmodium falciparum, 579 Poland syndrome (AD), 231, 364 Polycystic kidney disease, 548 Polygamy, 5 Polymorphism, 495–496, 580 IFN-receptor, 582 Pompe disease, 656 Pontocerebellar hypoplasia type 3, PCH3, 183 Popliteal pterygium syndrome, 253 Population, 219, 353–354 Population aging, 48–49 Population genetics, 577 Population genetic screening programs, 711–712 Population-screening, 65 Population stratification, 100 Porokeratosis punctata palmaris and plantaris, 185, 547 Porphyria, congenital erythropoietic, 386 Post-KA dermal leishmaniasis (PKDL), 582 Prader-Willi syndrome (PW), 254, 666 Pras, E., 409 Preembryo, 715 Preferred types, 86–89 Preimplantation diagnosis, 714, 715 Preim-plantation genetic diagnosis, 80, 328 Premarital, 706, 712–713, 720 examinations, 328 genetic counseling, 642

765

screening/counseling, 522, 526 testing, 642 Prenatal diagnosis, 80, 235, 328, 642, 643, 707, 708, 714, 715, 717, 720 Prenatal loss, 223 Prepregnancy genetic screening, 712–713 Prevalence, 86–91, 93, 95, 96, 100 falciparum malaria, 585 Prevention, 705–721 PRICKLE1, 331 Primary adhalinopathy (a-sarcoglycanopathy, LGMD2D), 156–157 Primary congenital glaucoma (PCG), 250, 545, 546 Primary cortisol resistance, 544 Primary hypomagnesemia (AR), 365 Primary lateral sclerosis, 541 Primary lateral sclerosis, juvenile (AR), 367 Primary prevention strategies, 712–713 Primordial dwarfism osteodysplastic variant, 542 Private expenditure on health, 71, 72 Progeriod syndromes, 662 generalized lipodystrophy of seip, 663 neonatal progeria (Wiedemann– Rautenstrauch syndrome), 663 Progressive external ophthalmoplegia (PEO), 169 Progressive motor and mental retardation, 243 Progressive myoclonus epilepsies, 331 Progressive pseudorheumatoid arthropathy, 544 Progressive pseudorheumatoid arthropathy of childhood (AR), 364 Prolidase deficiency, 386 Propionic acidmeia (PA), 448, 533, 534, 656 Prostate cancer aggressiveness, 628 angiogenic gene, 628 combined effect, 628 multifactorial, 628 onset, 628 Protein C deficiency, 507, 539 Protracted febrile myalgia, 116 Prune belly syndrome, 386 Pseudocholinesterase deficiency, 386

766

Pseudodominant inheritance, 229 Pseudohermaphroditism, 386, 418, 501 Pseudohypoparthyroidism, 251 Pseudo-TORCH syndrome, 198 Pseudotrisomy 13 syndrome, 194 Pseudoxanthoma elasticum, 386 Psoriasis, 248 Psoriasis vulgaris, 552 PSTPIP1, 131 Psychoses, affective, 386 Psychosocial impact of SCD, 586 PTEW-induced putative kinase 1 (PINK1), 598 p53 Tumor suppressor gene, 600 Public health geneticists, challenges cultural background, 487 definition, 487 healthy child, 487 legal system, 487 social circumstances and religious beliefs, 487 Public health service, 65, 82 Pulmonary alveolar microlithiasis, 335 Punctata, 251 Pyogenic arthritis, 131 Pyrin, 115 Pyroglutamic aciduria, 535 Pyruvate kinase deficiency, 333, 507

Q 6q27, 582 17q21, 157 Qatanani, M., 387, 421 Qatar, 7, 9, 11, 13, 15, 17–20, 22, 148, 639, 664 autosomal dominant disorders, 519 autosomal recessive disorders, 520 chromosomal disorders, 518–519 consanguinity, 518 endocrine disorders, 525 genetic disorders, 518–520 genetic services, 517–518 geography and history, 515–517 hemoglobinopathies, 525–526 inborn errors of metabolism, 521 map, 516 multifactorial birth defects, 519 population statistics, 517

Index

X-linked disorders, 520 2q31.1–q31.3, 168 Quasidominant inheritance, 231 Queen of Punt, 291–292 Quran, 705, 706, 714, 720

R Rahad river, 582 Raine syndrome, 653 Rambam–Hasharon syndrome, 195 Rapid progressive glomerulonephritis, 120 Rare cortical malformations, 226 Rare disorders, 226 Rawashda tribe, 581 RB1 gene, 250 Red blood cell abnormalities, 578 Red cell genes, 578 Red cell genetic disorders, 583 Red sea, 575 Red sea hills (Hamitic), 588 5-a-Reductase SRD52 deficiency, 386 Reduction defects, 228 Refsum disease, 243 Regional conflict, 61 Registry, 642 Reifenstein’s syndrome (XL), 366 Reimann, H.A., 382, 408 Religion Christianity, 89 grief, 733 illness, 733 Islam, 89 Renal and urinary tract anomalies, 386 with chromosome aberrations, 386 Renal-colobomaarthrogrposis syndrome, 185 Renal disease, 119 Renal tubular acidosis distal, 201 Renal tubular insufficiency, 379 Renpenning’s syndrome (XL), 366 Reproductive health abortion, 93 fertility, 92 miscarriage, 93 stillbirth, 93 Reproductive options, 714–717 Research, 706, 709–711, 715, 717–720 Resistant to falciparum malaria, 579 Resources, 65–82

Index

Restrictive dermatopathy (RD), 659 Reticulosis, familial, histiocytic, 386 Retinal, 501 Retinitis pigmentosa (RP), 199, 201, 250, 386, 423, 458, 507, 546, 665 Retinoblastoma, 250, 386 Retinopathy, 667 Rett’s syndrome (XL), 244, 366, 541 Revesz syndrome or retinopathy, 195 Rhabdomyolysis, acute recurrent (AR), 195, 366 Rheumatic heart disease (RHD), 253 Rhizomelic chondrodystrophia, 251 Rhizomelic dysplasia, 201 Rhizomelic syndrome, 195 Ribosomal RNA, mitochondrial, 12S, 205 Rickets-alopecia, 233 Rivie`re, J.-B., 385, 416 Roberts syndrome, 231, 504 Robinow syndrome, 504, 545, 548 autosomal recessive, 366 Roman Egypt, 222 ROR2 mutation, 232 Ro¨ssler, J., 384, 414 Rubinstein-Taybi syndrome, 232, 233 Rural-urban migration, 40 Russell-silver syndrome, 666 Rutland, J., 380 R1226X mutation, 599

S Saab, Y.B., 395 Sabbagh, A.S., 378, 382, 383, 395, 396, 409, 413 Saethre-Chotzen syndrome, 666 Sahel, 586 Salam, M., 383, 386 Salem, G.M., 384, 386 Salem, Z., 384, 414 Salih myopathy, 168, 201, 597, 601 SALLA disease, 244 Salmonella osteomyelitis, 584 Salti, I.S., 380, 384, 388, 414 Samaha, H., 395 Sand flies, 582 Sandhoff disease, 243, 367, 387, 397, 418–419, 522

767

Sanfilippo disease type B, 387 Sanjad–Sakati syndrome, 16, 191, 254, 549, 649 San philippo syndrome, 243 Santavouri CMD, 159 Saouda, M., 388, 423 a-Sarcoglycan, 152, 154 a-Sarcoglycan (adhalin), 156 b-Sarcoglycan, 156 Sarcoglycan complex, 597 b-Sarcoglycan deletion, 597 a-Sarcoglycan gene, 156 b-Sarcoglycan gene, 157 b-Sarcoglycan gene mutation, 147 a-, b-, g-, d-Sarcoglycan genes, 597 b-Sarcoglycanopathy (LGMD2E), 157–158 d-Sarcoglycans, 156 Sarcoglyconopathies, 152 Saudi Arabia, 6–9, 11–17, 19, 21, 22, 146, 164, 165, 575, 579, 595, 599, 639, 656 Saudi Arabian, 183, 185, 190–192, 194, 198, 201, 203, 205 Sayad, R., 382, 407 SCA. See Sickle cell anemia Scalp-ear-nipple like syndrome, 204, 668 Scalp hair abnormalities, 202 SCARMD in Saudis, Syrians, and Yemenis, 153 SCARMD. See Severe childhood autosomal recessive muscular dystrophy Scheie syndrome, 243 Schimke immun-osseous dysplasia, 548 Schistosoma mansoni, 580, 581 Schistosomiasis, 578, 580 Schneckenbecken dysplasia, 655 School performance, 585 Schools of jurisprudence, 702, 709 Schulze-Bahr, E., 384, 415 Schwabe, A.D., 408, 409 Schwartz–Jampel syndrome (SJS), 163–166, 231 Scoliosis, 201, 202 SC phocomelia syndrome, 387 Screening programs, 240 Seckel syndrome, 542, 652 Secondary prevention strategies, 713–714 Second cousin, 86, 166, 223, 256, 300, 302, 309, 355, 616, 643, 708, 713, 734

768

Segregation and genetic linkage analyses, 579 Seizures, 243, 649 Selective, 65, 66, 80 Semitic, 3, 491 Semitism, 492 Senataxin (SETX) gene, 599 Senegal haplotypes, 586 Sensorineural, 251 deafness, 199, 549 Septooptic dysplasia, 544 Serre, J.L., 383, 394 Setleis syndrome, 664 Severe childhood autosomal recessive muscular dystrophy (SCARMD) AR, 146–154, 156, 157, 162, 365, 539, 597 Severe childhood muscular dystrophy, 527 Severe hypertelorism, 201 Severe mutations, 235 Sex reversal, 496 Sex-revesed cases, 247 S gene, 586 Shahid, M.J., 382, 383, 387, 420 Shaigia, 583, 590, 595 Shammaa, D.M.R., 386, 418 Shammas, H.F., 381 Shamseddine, A., 382, 410 Shariai’a, 706 Shariai’ha principles, 716, 718, 720 Shawaf, S., 382, 406 Sheldon syndrome, 230 Shi’ite, 5 Sohat, M., 409 Short rib-polydactyly syndromes, 545 Short-rib-polydactyly type III, 655 Short stature and facioauriculothoracic malformations, 201 Short stature, Iraq, 317 SHORT Syndrome, 663 Sialic acid storage, 244 Sialidosis type 1, 535 Sialuria, 242 Sickle cell anemia (SCA), 221, 237–238, 366, 367, 448, 533, 537, 538, 579, 583, 586, 716, 720, 721 Iraq, 313 Sickle cell/b O thalassaemia (S-b0 thal), 583 Sickle-cell/bþ thalassemia (S-bþ thal), 583

Index

Sickle cell disease (SCD), 8, 359, 525, 526, 583, 585, 586, 645, 646 in Khartoum, 585 sickle cell anemia, 642 Sickle cell thalassemia, 587 Sickle-cell trait, 387, 419, 583 Sideroblastic anemia autosomal recessive, 195 Signal transducer and activator of transcription 5B, STAT5B (AR), 367 Sille´n, A., 387, 422 Silver–Russel syndrome, 253 Single gene defects, 477–487 Single nucleotide polymorphisms, 581 Sjo¨gren–Larsson syndrome, 248, 387, 422 SJS. See Schwartz–Jampel syndrome SJS type 1A, 165 SJS type 1B, 165 SJS type 2, 165 Skeletal and limb malformations, 228 Skeletal dysplasia, rhizomelic, with retinitis pigmentosa, 200 Skeletal dysplasias, 292, 592 Skin peeling, familial continuous, 195 SMA. See Spinal muscular atrophy Smith–Lemli–Opitz syndrome, 387, 422 Smith–McCort dysplasia, 229 Socioeconomic correlates, 90–91 Sohar, E., 409 Solh, H., 386 Somalis, 577, 578 Somatic cell nuclear transfer (SCNT), 718 Somatic gene therapy (SGT), 719–720 Somerville, I., 381 Sotos syndrome AD, 364, 543 Soua, Z., 384, 396 Souraty, N., 385, 417, 418 Soussou, I., 378 Southern Nilotes, 583 Southern Sudan, 582 Sovereign wealth funds (SWFs), 38, 45 Spahr metaphyseal chondrodyslasia (AR), 365 Spastic ataxia syndrome Bedouin type, 196 Bedouin type 2, 204 Spastic cerebral palsy with microcephaly and mental retardation, 204

Index

Spastic paraparesis, 196 Spastic paraplegia, 331, 502 Spastic paraplegia 26 (AR), 367 Spastic paraplegia 20, autosomal recessive (Troyer’s syndrome), 366 Spastic paraplegia-5B autosomal recessive, 198 Spina bifida, 221, 446 Spinal muscular atrophy (SMA), 227, 228, 447, 462–463, 502, 539, 660 autosomal recessive neuromuscular disorders, 620 mutation or deletion, 620 SMN gene, 620 Type I (AR), 365 Type II (AR), 365 Spinal muscular atrophy/Werdnig– Hoffmann disease, 367 Spinocerebellar ataxia, 226 autosomal recessive 5; SCAR5, 199 with axonal neuropathy (SCAN1), 541 Spinocerebellar degeneration and corneal dystrophy, 196, 387 with slow eye movement (AR), 196, 363, 366 Split hand/split foot, 507 autosomal recessive, 190 Spondylitis, 387 Spondylocostal dysostosis, 233 Spondyloepimetaphyseal dysplasia, 196, 229, 387, 422 Spondyloepimetaphyseal dysplasia, new variant (AR), 363, 366 Spondyloepiphyseal dysplasia, 545 Omani type, 183 Spondylometaepiphyseal dysplasia, 655 Spondylometaphyseal dysplasia, Algerian type, 185 Spranger, J., 381, 406 Sprengel disease, 222 Srouji, G., 386 SRY, 245, 246 SSCP, 246 Stargardt disease, 546 Stargart macular degeneration, 387 Stayoussef, M., 381, 405 Stem cell research, 717–718 Stem cell therapy, 706, 719, 721

769

Ste´phan, E., 379, 411 Sterilization, 714 Steroidogenic acute regulatory protein (AR), 366 Steroid resistant nephrotic syndrome, 253 Strahler, J.R., 383, 420 Sturge–Weber syndrome (AD), 364 Stuve–Wiedemann (SJS type 2) syndrome, 166 Stuve–Wiedemann syndrome (SWS), 652, 662 Sudan, 7, 9, 146, 153, 575, 578, 580–584, 586, 591, 592, 598 Sudanese, 189, 194, 195, 200, 201, 577, 578, 586 Sudanese family, 147, 591 Sudanese kindred, 157 Sudan Ministry of Health, 579 Sulfa preparation, 588 Sulfite oxidase deficiency, 536 Sulh, H.M., 382 Sunna, 706, 716 Sunni, 4, 5 Supplementary, 65 Susceptibility to human leishmaniasis, 582 Sustained growth, 44 Sutherland, J.V., 386 Sweat chloride test, 252 Swedish population, 581 Symphalangism, 228 Symphalangism with multiple anomalies of hands and feet, 185 Syndactyly, 504 Syndesmodysplastic dwarfism, 196 Synspondylism, congenital, 387 Syrian, 153, 655, 664 Systemic lupus erythematosus case-control studies, 625 deoxyribonuclease I (DNASE1), 625 HLA, 625 MHC class II, 625 polymorphisms, 624

T Tabbara, K.F., 378, 379, 381–383, 385–388 Taher, A., 382, 408 Takla, R., 382

770

Taleb, N., 381, 382, 387, 406, 410, 420 Tama-Messeria tribe, 581 Tamim, H., 378, 398 Tamouza, R., 378, 398 Tandem mass spectrometry, 590 TAR syndrome, 231 Tay-sachs disease (AR), 242, 243, 366, 507 juvenile, 387, 422–423 T-cell antigen receptor, gamma subunit, 387 a-Tectorin, 405 Teebi, A.S., 378, 398 Teebi hypertolerism syndrome, 182 Teebi–Shaltout syndrome (AR), 196, 366, 520, 524 Teeth, 506 Temtamy preaxial brachydactyly syndrome, 232, 255 Temtamy preaxial polydactyl syndrome, 199 Temtamy syndrome of ocular, 251 Teratogens, 224 Termination of pregnancy, 6 Testes, rudimentary, 196, 387 Tetra-amelia with pulmonary hypoplasia, 197 Tetralogy of Fallot and pulmonary atresia, 186, 387 a-Thalassemia, 537, 538, 646 haemoglobinopathies, 617 Hb H disease, 538 screening study, 617 b-Thalassemia, 533, 537, 644–646 mutational spectrum, 617 Thalassemias, 328, 359, 387, 397, 419–422, 448, 463–464, 496, 587, 642, 643, 712, 713, 717 antenatal diagnosis, 497 frequency, 497 genes, 579 incidence, 497 mutations, 497 premarital thalassemia screening, 497 Thanatophoric dysplasia, 655 Thauvin-Robinet, C., 406 Therapy, 236 Thiamine responsive megaloblastic anemia, 539 Thrombocytopenia, X-linked, 205

Index

Thyroglossal duct syndrome, 504 Thyroid disease, 601 Thyroid hormonogenesis (MIM No.274400), 593 Tibia, hypoplasia of, with polydactyly, 185 Tibial aplasia and ectrodactyly, 387 Titin gene, 168 Titinopathy, 540, 601 TNF receptor associated periodic syndrome (TRAPS), 126–127 TNFRSF1A, 126 Tohme, A., 379 Tomb, R., 381, 406 TORCH-like syndrome, 668 Torsion dystonia, 507 Total expenditure on health, 71, 72 Traboulsi, E.I., 383–386, 388 Trans-African migrations, 575, 586 Transnational Alliance for Genetic Counseling (TAGC), 727 Transposition of external genitalia, 247 Treacher Collins syndrome AD, 364 Tribal, 11, 13 Trigonobrachycephaly, 197, 363 syndrome, 502 Trimethylaminuria, 333 Trioche, P., 382, 411 Trisomy 13, 356 Trisomy 18, 357 Trisomy 21, 496 Trop, I., 387, 423 True hermaphroditism (TH), 246, 593 Tryptophan, 600 Tuberculin (PPD), 579 Tubulopathy, salt losing, 400 Tumor necrosis factor-a (TNF-a), 581 Tunisia, 146, 164, 165 abortions, 614 Africa, 614 Arab countries, 616 consanguineous marriages, 613, 616 contraception, 614 cross roads of Europe, 614 cytogenetic analyses, 616 different Mediterranean civilizations, 614 DNA analyses, 616 endogamy, 616 genetic counseling, 616, 631

Index

genetic diseases in Tunisians, 613 genetic disorders, 613, 631 genetic services, 616 growth rate is about 1%, 614 history of genetic conditions, 616 major national health problem, 631 Middle East, 614 monogenic, 631 mutational spectrum, 631 republic of, 615, 616 smallest country of the North African countries, 614 Tunisian, 9, 15–17, 188, 193, 196–198, 202, 203 Turks, 5, 10 Turner syndrome, 387, 496, 602 deletion of one chromosome X, 619 karyotyping, 619 mosaicism, 619 Tyrosinemia, 448, 656 type I, 367, 449, 534, 535 type II, 366, 535

U UAE Bedouins, 661 Uganda, 581 Ullrich CMD, 160 Ulnar hypoplasia, 204 Ulnar-mammary syndrome, 231 Ultrasonography, 581, 643 Ultrastructural changes, 243 Umzukra, 581 Undelineated neurodegenerative brain disorders, 367 Under five mortality rate/s, 72 Under-service, 67 United Arab Emirates (UAE), 7, 9, 15, 17–19, 22, 164, 166, 181, 577, 588, 639–645, 648, 651, 653, 657, 658, 664 United Nations (UN), 68, 76 University of Gezira, 580 University of Khartoum, 579, 580, 582, 590 Unusual facies, 188 Upper Nile province, 582 Urea cycle defects, 448 Urea cycle disorders, 503 Urinary schistosomiasis, 600 Urofacial syndrome (AR), 365

771

Usanga, E.A., 382, 411 Usher syndrome (USH), 388, 423 consanguineous, 627 heterogeneous, 627 novel gene, 627 Uthman, S.M., 382, 383, 412

V Vaccination, 78 van der Woode syndrome, 253 Vassoyan, J., 386 Very long chain fatty acids, 244 Vincenti, F., 387 Visceral leishmaniasis (VL), 582 Vitamin A metabolic defect, 197, 388 Vitamin D–dependent rickets (AR), 366 Vitamin D-dependent rickets type II, 591 Vitamin D resistant rickets, 233 Vitamin K-dependent clotting factor, 388, 424 Vitiligo, 198, 552 VL susceptibility gene on 22q12, 582 von Willebrand disease, 590 VPS13B mutation, 380 Vulliamy, T.J., 410 Vulnerability to VL, 582 Vure, E., 407

W Waardenburg recessive microphthalmia, 388 Waardenburg–Shah syndrome, 658 Waardenburg’s syndrome, 253, 507, 658 Waardenburg syndrome type 2, 451 Walker–Warburg syndrome (WWS), 159, 527, 542, 650 WAS, 548 Weaver-like syndrome (AR), 198, 363, 366 Weill–Marchesani syndrome, 388, 424, 544 Werding–Hoffmann disease (AR), 364, 597 Werner’s syndrome, 452 West African populations, 588 West Bank, 492 Western Sudan, 576, 581, 582, 586 White Nile, 580, 588 Wiedemann syndrome (MIM 601559), 165 Wiles, C.R., 387

772

Williams syndrome, 254, 666 Wilson’s disease (AR), 366, 367, 502, 548 Winchester–Torg syndrome, 233 Wiskott–Aldrich syndrome, 388, 538 Wolcott–Rallison syndrome, 527, 544 Wolfram syndrome (DIDMOAD), 332, 338, 388, 424, 544 Wollcott–Rallison syndrome, 655 Wolman’s disease, 507, 535 Woodhouse–Sakati syndrome, 190, 527 Workforce, 67, 69, 77 World Health Organization (WHO), 66 Wrinkly skin syndrome, 367, 507, 547 W70X, 383, 411 Wynne-Davies, R., 398

X Xanthinuria hereditary, 388 Type I (AR), 366 Xeroderma pigmentosa, 248 Xeroderma pigmentosum (XP), 17, 388, 450, 466 consanguineous marriage, 625 founder effect, 625 gene mutations, 625 homozygous deletion, 625 rare, 625 X-linked androgen insensitivity, 247 X-linked conditions, 484 X-linked dyskeratosis congenita, 660 X-linked hypophosphataemic rickets, 544

Index

X-linked lymphoproliferative disease, 548 X-linked mental retardations new locus, 627 PAK3 gene splice mutation, 627 X-linked myotubular myopathy, 166 X-linked recessive, 9 X-linked recessive ichthyosis, 658 XVII collagen, 599 46 XX DSD, 245 XY gonadal dysgenesis, 200

Y Yasunaga, S., 380, 404 Y chromosome, 577, 602 Y-chromosome diversity, 392–393 Yehya, A., 411 Yemen, 588, 639, 640, 652 Baluchis, 641 Yemenis, 153, 166, 641, 664 Yq(11) microdeletion, 247 Yunis, K., 412

Z Zaatari, G.S., 382, 408 Zahed, L., 378, 380, 387, 397, 420, 421 Zaire, 583 Zalloua, P.A., 392 Zaynoun, S.T., 384 Zekian, B., 388 Zirbel, G.M., 417