Life Span Development in Genetic Disorders: Behavioral and Neurobiological Aspects

LIFE SPAN DEVELOPMENT IN GENETIC DISORDERS: BEHAVIORAL AND NEUROBIOLOGICAL ASPECTS

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LIFE SPAN DEVELOPMENT IN GENETIC DISORDERS: BEHAVIORAL AND NEUROBIOLOGICAL ASPECTS

ANNAPIA VERRI EDITOR

Nova Biomedical Books New York

Copyright © 2008 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Life span development in genetic disorders : behavioral and neurological aspects / Annapia Verri, editor. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60876-250-7 (E-Book) 1. Genetic disorders. 2. Developmental disabilities--Genetic aspects. 3. Developmental genetics. 4. Developmental psychology. I. Verri, Annapia. [DNLM: 1. Genetic Diseases, Inborn. 2. Developmental Disabilities--genetics. 3. Human Development. 4. Mental Retardation--genetics. QZ 50 L722 2008] RB155.5.L54 2008 616'.042--dc22 2008023058

Published by Nova Science Publishers, Inc.

New York

CONTENTS Intelligence: An Overview Timothy C. Bates Chapter I

Chapter II

Diagnostic Evaluation of the Child Affected with Intellectual Disability: a Clinical Genetic Perspective A. Cereda, A. Passarini, M. Cerutti, D. Milani, F. Menni and A. Selicorni Brain and Beyond the Brain: The Biological Profile of Down Syndrome Annapia Verri, Luigi Nespoli, Diego Franciotta and G. Roberto Burgio

1

9

33

Chapter III

Life Span Development in Turner Syndrome (TS) Annapia Verri, Valeria Destefani, Anna Cremante, Carla Uggetti and Daniela Larizza

65

Chapter IV

Life Span Development in Klinefelter Syndrome Luigi Tarani

85

Chapter V

Life Span Development in XYY Mirta Vernice and Anna Cremante

93

Chapter VI

Neurobiological Advances in the Fragile X Family of Disorders and Targeted Treatment Randi Hagerman and Michele Ono

107

Chapter VII

Life Span Development in Nance-Horan Syndrome (NHS) Silvia Russo, Annapia Verri, Valeria Destefani, Francesca Cogliati and Maria Teresa Dotti

123

Chapter VIII

Idiopathic Hypoparathyroidism and Chromosome 10p Deletion Annapia Verri and Paola Maraschio

135

Chapter IX

Life Span Development in Interstitial Deletion Chromosome 21 Annapia Verri, Anna Cremante and Biancardi Caterina

147

vi

Contents

Chapter X

Cognitive Enrichment Issue Valeria Destefani

157

Chapter XI

Rehabilitation Issues Michelangelo Bartolo, Monica Dulio, Ennio Pucci and Giorgio Sandrini

173

Chapter XII

Narrative Based Medicine in Genetic Syndromes with Intellectual Disability Ciro Ruggerini, Federica Vezzosi, Angela Solmi and Sumire Manzotti

Index

195

213

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

INTELLIGENCE: AN OVERVIEW Timothy C. Bates∗ Department of Psychology, University of Edinburgh, Edinburgh, UK.

INTRODUCTION Studies on the genetics of human cognitive ability provide a powerful tool for understanding human cognition. The goal of this brief introduction to intelligence is to provide an overview of topical intelligence research and theory, in terms that can be integrated with the results and theory of neuropsychology. A consensus definition of intelligence amongst over 50 researchers in the area was proposed as the “very general mental capability that, among other things, involves the ability to reason, plan, solve problems, think abstractly, comprehend complex ideas, learn quickly and learn from experience. It is not merely book learning, a narrow academic skill, or testtaking smarts. Rather, it reflects a broader and deeper capability for comprehending our surroundings—‘catching on,’ ‘making sense’ of things, or ‘figuring out’ what to do” (Gottfredson, 1997). Across all the hundreds of tests and at least dozens of separable abilities studied in neuropsychology, two findings have been especially salient to researchers since the turn of the last century: All these abilities are correlated with each other (Spearman, 1927); and quite astounding double dissociations often accompany acquired or developmental disorders (Rapp, 2002). Both of these approaches (of association and double-dissociation) reflect key conceptual and statistical breakthroughs in psychological modelling (Shallice, 1988) and a goal of this introduction is to render the findings of both into a single framework of genetic neuropsychology. In this brief introduction to intelligence, I first discuss the relationship between information from associations and information from dissociations. I then summarise a large literature indicating that a general latent ability factor accounts for around half of differences in cognition and that this is a highly heritable trait. Finally, I note the biological and genetic

∗

Correspondence concerning this article should be addressed to: Professor Timothy C. Bates, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ Scotland, UK.

2

Timothy C. Bates

findings in intelligence, again with an emphasis on linking the concepts of intelligence to neuropsychology.

Association and Dissociation: A Rapprochement through Structural Modelling An audience of neuropsychologists needs no reminder that people differ widely in their abilities to create and manipulate mental representations and that these differences are prime data for understanding cognition. The idea that the brain and neuronal integrity are critical to these abilities and that genetic differences impact powerfully on the development of a broad range of mental differences are also fairly universal among neuropsychologists. Thus far, the goals and interests of neuropsychology and of intelligence researchers appear identical: the use of individual differences in cognition (responding to information, solving, understanding, manipulating, memorising, etc.) to understand the structure of the mind and the biological basis of this structure. Where intelligence research differs from the typical approach of neurology and neuropsychology is in its focus on the associations amongst tasks, rather than dissociations and double-dissociations between tasks. Represented graphically in Figure 1 and Figure 2, there seems at times a looming gulf between the respective views from neuropsychology (with its box-and-arrow diagrams of painstakingly accumulated from patient studies of dissociations in the mind: See Figure 1) and intelligence research, with its hierarchical tree diagrams built largely from the relationships of performance on tasks in larger group of normally developing individuals (See Figure 2). Despite appearances, both of these models are compatible: the same modules would ultimately appear as boxes in both diagrams as the data driving their creation is in both cases the existence of between-task correlations significantly less than one, not explainable by scaling factors such as difficulty. Where they differ is that the latent variable model of intelligence preserves the raw association data (at the cost of losing the wiring diagram), while the neuropsychological boxand-arrow model preserves connectivity information at the cost of losing information on shared processes. Surprisingly, recent research is revealing that normal variation in tasks reveals the same structure double dissociations patient data contribute critical data on the separability of dissociations modelled as boxes fact that the abilities do not correlate 1.0 Figure 2 shows a representative finding of the structure of intelligence research from the WAIS (Wechsler, 1997), a test common to both neuropsychology and intelligence research. It can be seen that the 13 WAIS sub-tests correlate 0.49 (range .26 to .77). Since the first formal mental test was devised (Binet, 1905/1916), structures closely related to that shown in Figure 2 emerge from all of the many hundreds of test batteries devised and administered to many millions of test-takers (Ian J. Deary, 2001).

Intelligence: An Overview

Figure 1. Reading, Language and Working Memory in Cognitive Neuropsychology. On the right hand side are shown components of the dual-route cascaded system for reading (Coltheart, Rastle, Perry, Langdon, & Ziegler, 2001). Data from patients supports dissociations between the ability to read aloud pseudo-words such as “SLINT” and the ability to read-aloud irregular words such as “YACHT” (A. Castles, Bates, Luciano, Martin, & Coltheart, 2005; Anne Castles & Holmes, 1996). In the center we see semantics and the executive components of working memory (Baddeley, 2007). These are represented as separate modules because dissociations again suggest that there are patients with acquired brain damage who retain the ability to read but no longer access meaning from written language, and other patients who retain meaning despite losing the ability to read. Finally on the left hand side of the model are components of mind implicated in specific language disorder, specifically the systems for speech sound analysis, for brief storage of phonological strings, independent of meaning, and connections supporting rehearsal in short-term memory (Baddeley, 2007).

Figure 2. Factor Structure of ability as measured in the Wechsler Adult Intelligence Scale III.

3

Timothy C. Bates

4

The genetic and environmental influences on mental abilities have now been examined in a diverse range of genetically informative studies totally over 200,000 monozygotic (MZ) and dizygotic (DZ) twin-pairs (Summarized in Table 1). Two key findings from this research are that ability is highly heritable and that genetic influences increase rather than decrease over time, while the influence of within-family effects decreases over time, so that by adulthood and into old age, 70-80% of the differences observed in test performance in adulthood and old age are genetic (See Figure 3). Crucially for neuropsychological research, genetic studies of normal adolescents and adults indicate clearly that this correlation is almost entirely genetic in origin (Plomin & Spinath, 2004). Table 1. Summary of world literature on familial effects on IQ (adapted from Bouchard & McGue, 1981)

Cousins

0.15

Siblings (apart)

0.24

Relationship

Siblings (together)

0.47

Dizygotic twins reared together

0.6

Midparent – offspring together

0.5

Monozygotic twins reared apart

0.72

Monozygotic twins reared together

0.86

0

0.2

0.4

0.6

0.8

1

Correlation

The Biology of g While general ability emerges very reliably as a heritable trait, it is only more recently that researchers have begun to uncover biological bases for general intelligence. Perhaps surprisingly, the key finding of the last 20 years of research has been the finding that the strongest physical brain correlate of intelligence is brain volume itself, with a meta-analysis of several thousand samples cases suggesting that brain volume difference explain 10% of IQ variance, with regional difference contributing further variance (McDaniel, 2005). Twin studies indicate both that brain volume is highly heritable (Thompson et al., 2001; Pennington et al., 2000) and that general ability and brain volume share a genetic correlation

Intelligence: An Overview

5

(Posthuma et al., 2003). This suggests that researchers on genetic syndromes should examine regional and global changes in brain volume as potential biological indicators (Gray & Thompson, 2004 ). In addition to the global volume of the brain, recent studies have highlighted the importance of regional variation in brain activity and volume in intelligence (Jung & Haier, 2007). This further supports the role of genetic analyses of brain volume variation as a tool to identify brain systems with shared genetic influences but diverse anatomical boundaries (Toga & Thompson, 2005). Case studies of genetic abnormalities can play a potential crucial role in this field.

1 0.9 0.91

0.8 % Variance

0.7

0.75

0.6 0.54

0.4 0.3 0.2

0.7

0.64

0.5

A C E

0.39 0.25

0.26

0.1 0 3

5

E 7

10 Age

C 12

26

A 65

82

Figure 3. Genetic and Environmental Components of Intelligence from age 3 to age 82. A (red) is the observed heritability, C (yellow) is the effect of shared or family environment factors such as SES and home, and E (green) is the remaining effects, which are unique to each individual and include measurement error. The Figure shows that at very young ages family environment has a large effect on cognitive ability, but that by young adulthood, this has been replaced with large effects of genes, which continue to rise in relative importance into old age, possibly declining again as people reach their 80s. The data are combined results from (Bartels, Rietveld, Van Baal, & Boomsma, 2002; McClearn et al., 1997; Danielle Posthuma, de Geus, & Boomsma, 2001; Reynolds et al., 2005; Spinath & Plomin, 2003).

MOLECULAR GENETICS While the heritability of intelligence implies the existence of genetic effects on ability, the limited research on intelligence to date has been less productive thn has similar research on more specific traits such as dyslexia and even normal variation in reading, where as many as 11 regions containing reading-related genes have been identified (Bates et al., 2007). By contrast, studies of general intelligence suggest that specific genes such as klotho (Ian J Deary et al., 2005) and COMT (catechol-O-methyl transferase) (Winterer & Goldman, 2003

6

Timothy C. Bates

134-163) have small effects, consistent with a polygenic view of the heritability of intelligence, i.e., a view in which the genes affecting intelligence number in the hundreds, with none having a large effect on population variation. This view that genes for intelligence will have small effects is further buttressed by the first genome-wide linkage studies for intelligence, which suggested that the genetic effects are widely distributed with none explaining more than 2-3% of the variance in IQ (Luciano et al., 2006), and by exploratory association studies, which suggest that a reasonable estimate for the average gene effect size might be on the order of .1% of the population variance (Butcher et al., 2005). These conclusions remain tentative, as all the studies to date have been modest in size, and genome coverage, and, importantly, have lacked the ability to detect genetic effects mediated by multiple uncommon mutations, as well as being unable to detect copy-number variations, both of which seem likely to harbour significant cognitive effects (Sebat et al., 2007). These results do, however, suggest that the results of studies of the neuropsychological effects of chromosomal abnormalities, as reported in the rest of this volume will prove to be a critical source of candidate genes for understanding general cognition (for instance the case of microcephaly related genes such as ASPM (Cox, Jackson, Bond, & Woods, 2006). The pace of this research suggests the likelihood that the next five years will see notable progress in both intelligence and neuropsychological genetics of specific and general genes through collaboration and replication of effects detected using the g approach, and those discovered through family-based syndromic studies. In conclusion, it is hoped that this introduction has made the approach of intelligence researchers more accessible to those in neuropsychology, and highlighted progress in this field using phenotypes such as brain volumes and the methods of association and linkage as well as the difficulties encountered in the search for genes affecting diverse cognitive and biological functions.

REFERENCES Baddeley, A. D. (2007) Working memory: Multiple models, multiple mechanisms. In H. L. Roediger, Y. Dudai & S. M. Fitzpatrick (Eds.), Science of Memory: Concepts. (pp. 151153). Oxford: Oxford University Press. Bartels, M., Rietveld, M. J., Van Baal, G. C., & Boomsma, D. I. (2002) Genetic and environmental influences on the development of intelligence. Behav Genet, 32, 237-249. Bates, T. C., Luciano, M., Castles, A., Coltheart, M., Wright, M. J., & Martin, N. G. (2007) Replication of reported linkages for dyslexia and spelling and suggestive evidence for novel regions on chromosomes 4 and 17. Eur J Hum Genet, 15, 194-203. Binet, A. (1905/1916). New Methods for the Diagnosis of the Intellectual Level of Subnormals L'Année Psychologique, 12, 191-244. (E. S. Kite, Trans.). In The development of intelligence in children. Vineland, NJ: Publications of the Training School at Vineland. Bouchard, T. J., Jr., & McGue, M. (1981) Familial studies of intelligence: a review. Science, 212, 1055-1059.

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7

Butcher, L. M., Meaburn, E., Knight, J., Sham, P. C., Schalkwyk, L. C., Craig, I. W., et al. (2005) SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children. Hum. Mol. Genet., 14, 1315-1325. Castles, A., Bates, T. C., Luciano, M., Martin, N. G., & Coltheart, M. (2005) Two different sets of genes for reading (and spelling). Australian Journal of Psychology, 57, 47-47. Castles, A., & Holmes, V. M. (1996). Subtypes of developmental dyslexia and lexical acquisition. Australian Journal of Psychology, 48, 130-135. Coltheart, M., Rastle, K., Perry, C., Langdon, R., & Ziegler, J. (2001) DRC: A dual route cascaded model of visual word recognition and reading aloud. Psychological Review, 108, 204-256. Cox, J., Jackson, A. P., Bond, J., & Woods, C. G. (2006) What primary microcephaly can tell us about brain growth. Trends Mol Med, 12, 358-366. Deary, I. J. (2001) Human intelligence differences: Towards a combined experimentaldifferential approach. Trends in Cognitive Sciences, 5, 164-170. Deary, I. J., Harris, S. E., Fox, H. C., Hayward, C., Wright, A. F., Starr, J. M., et al. (2005) KLOTHO genotype and cognitive ability in childhood and old age in the same individuals. Neuroscience Letters, 378, 22-27. Gottfredson, L. S. (1997) Mainstream science on intelligence: an editorial with 52 signatories, history, and bibliography. Intelligence, 224, 13-23. Gray, J. R., & Thompson, P. M. (2004) Neurobiology of intelligence: Science and ethics. Nature Reviews Neuroscience, 5, 471-482. Jung, R. E., & Haier, R. J. (2007) The Parieto-Frontal Integration Theory (P-FIT) of intelligence: converging neuroimaging evidence. Behav Brain Sci, 30, 135-154; discussion 154-187. Luciano, M., Wright, M. J., Duffy, D. L., Wainwright, M. A., Zhu, G., Evans, D. M., et al. (2006). Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q. Behavior Genetics, 36, 45-55. McClearn, G. E., Johansson, B., Berg, S., Pedersen, N. L., Ahern, F., Petrill, S. A., et al. (1997) Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science, 276, 1560-1563. McDaniel, M. A. (2005) Big-brained people are smarter: A meta-analysis of the relationship between in vivo brain volume and intelligence. Intelligence, 33, 337-346. Plomin, R., & Spinath, F. M. (2004) Intelligence: genetics, genes, and genomics. J Pers Soc Psychol, 86, 112-129. Posthuma, D., Baare, W. F. C., Pol, H. E. H., Kahn, R. S., Boomsma, D. I., & De Geus, E. J. C. (2003) Genetic correlations between brain volumes and the WAIS-III dimensions of verbal comprehension, working memory, perceptual organization, and processing speed. Twin Research, 6, 131-139. Posthuma, D., de Geus, E. J., & Boomsma, D. I. (2001) Perceptual speed and IQ are associated through common genetic factors. Behav Genet, 31, 593-602. Rapp, B. (Ed.). (2002) The Handbook of Cognitive Neuropsychology: What Deficits Reveal About the Human Mind. New York: Psychology Press.

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Reynolds, C. A., Finkel, D., McArdle, J. J., Gatz, M., Berg, S., & Pedersen, N. L. (2005) Quantitative genetic analysis of latent growth curve models of cognitive abilities in adulthood. Dev Psychol, 41, 3-16. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007) Strong association of de novo copy number mutations with autism. Science, 316, 445449. Shallice, T. (1988) From Neuropsychology to Mental Structure. Cambridge, UK: Cambridge University Press. Spearman, C. (1927) The abilities of man. New York NY: Macmillan. Spinath, F. M., & Plomin, R. (2003) Amplification of genetic influence on g from early childhood to the early school years. Paper presented at the IVth Meeting of the International Society for the Study of Intelligence, Irvine, USA, 4-6 December. Toga, A. W., & Thompson, P. M. (2005) Genetics of brain structure and intelligence. Annu Rev Neurosci, 28, 1-23. Wechsler, D. (1997) Wechsler Adult Intelligence Scale III. San Antonio: Psychological Corporation. Winterer, G., & Goldman, D. (2003) Genetics of human prefrontal function. Brain Res Brain Res Rev, 43, 134-163.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter I

DIAGNOSTIC EVALUATION OF THE CHILD AFFECTED WITH INTELLECTUAL DISABILITY: A CLINICAL GENETIC PERSPECTIVE A. Cereda, A. Passarini, M. Cerutti, D. Milani, F. Menni and A. Selicorni∗ Ambulatorio Genetica Clinica, I Clinica Pediatrica, IRCCS Fondazione Policlinico Milano, Italy.

ABSTRACT Diagnostic evaluation of the child affected with intellectual disability represent a challenge for the clinicians. The possible range of the causes is extremely wide, varying from genetic conditions to environmental, infective, toxic factors. Again after a detailed clinical work-up the number of patients without a specific etiologic diagnosis remains high, between 30 to 50%. Children with intellectual disability more commonly have malformations and other structural anomalies than individuals without intellectual disability. In many cases, the associated anomalies comprise recognizable syndromes caused by genetic or environmental insults. To co-occurrence of structural anomalies with intellectual disability thus assists in the diagnostic evaluation, particularly in infants and young children. Aim of this paper is to suggest a correct methodological approach to a patient with psychomotor or intellectual disability, underlying the useful contribution of laboratory evaluation to the diagnostic pathway. Variability of phenotype expression and genetic heterogeneity are addressed as open problems. A clinical genetic perspective is the modern approach best addressing the complexity of diagnostic evaluation.

Keywords: genetic syndromes, intellectual disability.

∗

Correspondence concerning this article should be addressed to: Dr. Angelo Selicorni, Ambulatorio Genetica Clinica, I Clinica Pediatrica, IRCCS Fondazione Policlinico Milano, e-mail: [email protected].

10

A. Cereda, A. Passarini, M. Cerutti et al.

INTRODUCTION Intellectual disability (ID) is usually defined as a disability which origins in paediatric age (before the age of 18 years) and it is characterized by a significant limitation in intellectual functioning and adaptive behaviour of the affected child. Intellectual functioning is defined by intelligence quotient (IQ) and adaptive behaviour refers to how an individual responds to the demands of everyday life. Severity of the ID can be extremely variable, ranging from borderline mental development/mild intellectual disability to profound mental deficiency. Facing with a child with psychomotor delay and/or intellectual disability is an important diagnostic problem for every paediatrician. The reasons are variable. First of all the problem is quite frequent epidemiological data from different studies suggest a prevalence from 1 to 10 % of the paediatric population with a sex ratio (male to female) of 1,5. Then the possible range of the causes is extremely wide, varying from genetic conditions to environmental, infective, toxic factors. Again after a detailed clinical work-up the number of patients without a specific etiologic diagnosis remains high, between 30 to 50%. Figure 1 outlines this concept and figure 2 describes the various etiologic categories as recently summarized recently by Stevenson et al. in 2003. Figure 1 tells us also that when we are able to identify a new cause, in the great majority of the cases it will be a genetic one thank to the improved knowledge in clinical genetics (definition of new phenotypes) or in the cytogenetic/molecular genetic fields (discovery of new genes or of new, more detailed, cytogenetic - molecular techniques).

Genetics (15-60%)

Unknown (30-50%)

Environment (10-35%) Figure 1. Causes of intellectual disability (modified from Curry et al., 1997).

The first question that we have to answer while looking at a child with ID is the following: the psychomotor/mental problem is an isolated problem or is part of a larger clinical condition such as a malformative syndrome? The importance of this answer is broader than that we can imagine. The correct diagnosis will give us some indication at prognostic level regarding both the evolution of the mental development itself and at clinical paediatric level; using a proper etiologic diagnosis we can organize a specific follow-up programme knowing exactly which can be the medical complications that must be searched. Furthermore a correct diagnosis will give us indications on the rehabilitation programme that has to be suggested to the parents; the classical example is Angelman syndrome as we know that a verbal communication is absolutely impossible for an affected patient. Clearly the stimulation in the communicative

Diagnostic Evaluation of the Child Affected with Intellectual Disability

11

area should keep into account this characteristic and has to be direct to the use of non verbal communicative methods instead of the classic speech therapy approach. ther enviromental insults

0,50%

other genetic syndromes

1%

genetic syndromes

1%

multifactorial

2%

chemical

2%

injury

5%

infections

5%

prematurity

5%

culturofamilial single gene chromosome

6% 8% 11%

unknown

53%

Figure 2. Causes of intellectual disability (modified from Stevenson et al., Am. J. Med. Genet).

We have said that a great part of the causes of ID are genetic if this is true another very important consequence of the etiologic diagnosis is the possibility of performing an adequate genetic counselling for the parents, for the relatives of the parents of the affected child. This is sometimes the only motivation that pushes the parents to search for a diagnosis for years and years also when the diagnosis itself will not give any relevant practical information for the patient. The last but not less important reason that gives importance to the etiologic diagnosis is that it is practically useful for the parents that, thank to the medical classification, can be put in contact with a specific parent support group with the possibility of sharing emotions, problems, practical solutions, medical or rehabilitative pathways with other parents who have faced and solved the same problems years before. Table 1 summarized all these reasons. Table 1. Importance of correct etiologic diagnosis Prognosis Medical follow-up Rehabilitation Genetic counselling Family support

Indications regard evolution of the intellectual disability Organization of specific follow-up programme Indications on the specific rehabilitation programme to suggest to the parents Adequate genetic counselling for the parents, for they families and for healthy brothers and sisters of the affected child Possibility of contact with a specific parent support group

12

A. Cereda, A. Passarini, M. Cerutti et al.

Some Useful Definitions Before describing the clinical genetic approach of the ID child we have to define if the neurological problem is isolated or not it is important to clarify some basic definitions. We consider as major malformation a morphologic anomaly of an organ or a larger part of the body due to a pathological process occurring within the organogenesis. On the contrary we define as minor anomaly a congenital defect of no medical/surgical relevance which can have, at maximum, an aesthetic meaning; the minor anomalies can be qualitative (shape of the nose, slanting of palpebral fissures etc) or can be measurable (inner or outer chantal distance, length of palpebral fissures, length of fingers etc) and are also called anthropometric defects. Figure 3 gives an example of the growth charts for inner and outer chantal distances as reported by J. Hall et al. They are important in the description of a patient and can have a great relevance in the diagnostic process.

Figure 3. Growth charts from Hall, J. et al. Handbook of normal physical measurements (1989).

Diagnostic Evaluation of the Child Affected with Intellectual Disability

13

Finally we define a malformative syndrome a medical condition in which we can find together, in every possible combination, the presence of major malformations, growth anomalies (both in defect and in excess), psychomotor/mental deficit and minor anomalies; this particular combination of problems is due to a unique cause, an anomaly in the DNA of the patient at chromosomal or single gene level. Table 2 describe the features of a malformative syndrome. Table 2. Features of a malformative syndrome Basilar defects

Occasional anomalies Medical complications

Clinical features (major defects or minor anomalies) which are present in the great majority of the affected patients (if not in all) and represent the best handle to suspect the clinical diagnosis Medical problems which are more frequent in that group of patients in comparison with the general population but whose presence/absence is not decisive for the clinical diagnosis Clinical paediatric problems which are more frequent in the affected patients compared to the general population. The knowledge of the natural history of every single syndrome is the starting point for elaborate protocols of medical follow-up

What is the Correct Methodological Approach to a Patient with Psychomotor or Intellectual Disability? We know that among the various causes of ID metabolic diseases, central nervous system isolated malformations or pure neurological diseases have a relevant weight. However they will not discussed in this chapter that is oriented specifically to a clinical genetic approach. The first important part of the clinical evaluation is a detailed history starting for family data that we will describe by building a three generation genealogic tree. This approach will give us the opportunity of describing in a clear way the presence of consanguinity between the parents or the evidence of other members of the family similarly affected giving also the opportunity of hypothesizing the possible genetic mechanism involved. Figure 4 summarizes the symbols that are internationally used for painting a genealogic tree while figure 5 shows an example of genealogic tree typical of a autosomal recessive disease. After the collection of familiar data, pregnancy history itself can give further important information regarding growth, motility, swallowing deficiency of the fetus or discovery, from the prenatal period, of some major malformations. It will also be important to record the results of all biochemical, cytogenetic and/or molecular tests eventually performed. Our collection of historical data will continue with the analysis of the neonatal period, in all its aspects, the postnatal growth with regards to the three major auxological parameters (weight length/height and head circumference) and the psychomotor evolution of the child. It is also absolutely important to ask about the presence of any other medical problem previously diagnosed in the child (in particular any major malformation or any sensorial, neurological or medical disease) and for results of every specialistic consultation, instrumental evaluation or metabolic/genetic tests performed by the child before our visit.

14

A. Cereda, A. Passarini, M. Cerutti et al. Male Female Male female affetted Heterozygous for an autosomal recessive mutation Heterozygous for an x-linked recessive mutation Death Unknown gender

Abortion Proband

Heterozygotic twins Monozygotic Twins

Marriage Consanguineous marriage

Figure 4. Symbols internationally used for painting a genealogic tree.

Figure 5. Example of genealogic tree typical of an autosomal recessive disease.

Now we are ready to perform a careful direct examination of the child. Our evaluation will start with a measurement of the basic auxological parameters and with a complete paediatric visit. After that we need to perform a dysmorphological evaluation of our patient. This consists in a thorough examination, from the head to the foot, looking for the presence of any possible minor anomaly that can be found. Most of these minor anomalies will be present at facial level however any part of the body (hair, skin, thorax, arms, joints, hands and feet) will give us useful information.

Diagnostic Evaluation of the Child Affected with Intellectual Disability

15

For professionals not particularly experienced in this kind of evaluation, it will be helpful to have a defined list of every part of the body that it is important to analyze starting from the forehead down to the other part of the face (in frontal and lateral view) and then continue to the neck, trunk and extremities.

Figure 6. Face traits, comparative drawings (frontal view) from POSSUM database.

Figure 7. Face traits, comparative drawings (lateral view) from POSSUM database.

In medical literature there are few bibliographic referrals specifically discussing this topic. The old book from John Aase remains the best textbook to consult. The main computerized databases for creating a differential diagnosis list (POSSUM and OMD) can be of help. In particular POSSUM offer some referral schemes (figures 6 and 7) which give practical information to analyze facial features. We must remind that if the minor anomaly

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identified is measurable it is possible to confirm the clinical impressions by using a specific charts. Some research societies in the field of medical genetics are working to create a complete and shared glossary of the definition of the single dysmorphic features that will be available through internet in the next months. An extremely accurate description of the minor anomalies of a specific patient is absolutely important, especially when a gestaltic diagnosis is not available, to continue on the search of the right diagnosis.

How to Arrive to the Correct Etiologic Diagnosis? After having performed all the various steps listed above we have to summarize the available information to hypothesize an etiological diagnosis. In some cases the diagnosis comes directly from the use of what we can call “basic genetic tests”. Apart from the presence of a clinical suspicion every patient affected with intellectual disability should perform a standard karyotype and, if microcephaly is absent, a molecular analysis of the FMR1 gene for Fragile X syndrome. The simple use of these tests can offer the final diagnosis showing a structural cytogenetic anomaly or an anomaly in FMR1 gene (pathological expansion of the CGG triplets sequence). In other cases the diagnosis can come from what we call a simple “gestaltic process”. In same situation, in fact, the global clinical features of the patient (dysmorphic signs, major malformations, growth pattern etc) are a clear indicator of specific condition (Down, Williams, Rubinbstein Taybi, Cornelia de Lange syndrome). This process is strongly conditioned by the experience of the paediatrician with the specific disease and, obviously, by the severity of the expression of the disease in the patient himself. Figures: 8, 9, 10, 11, 12, 13, 14, show some examples of syndrome for which a gestaltic diagnosis is quite easy while table 3 list a number of syndromes that should be part of the basic cultural background of a modern paediatrician. In these cases after the clinical hypothesis is made the paediatrician will try to confirm it through the application of the proper diagnostic genetic test when and if available. Clearly the paediatrician needs to know as well which is the genetic test that can confirm the clinical diagnosis and which is the detection rate of the various tests, to explain correctly the meaning of a negative result. We have to outline at this level that the most important clinical handles for gestaltic diagnosis are mainly represented by the global facial dysmorphisms whose severity can be extremely variable from patient to patient and from age to age also in the same child. For this reasons the same diagnosis could be simple in some patients, also in the newborn period while it could be extremely difficult in other subjects and not so evident in subjects of older ages thank to the evolution of the phenotype itself.

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Figure 8. Child with Cornelia de Lange syndrome.

Figure 9. Child with CHARGE association.

Figure 10. Child with deletion 22q11.

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Figure 11. Child with Kabuki syndrome.

Figure 12. Child with Noonan-LEOPARD syndrome.

The first two situations are the most favorable but unfortunately they are not so common. In the great majority of the cases an evident diagnosis is not available so it is necessary to study the clinical data. In these situation the using of computerized databases (POSSUM and OMD) is very helpful to suggest to the paediatrician a list of possible differential diagnosis. These systems permit to choose between a long panel of various symptoms which features are more adequate to describe the phenotype we are analyzing. The features chosen can be indifferently related to dysmorphisms, major malformations, growth pattern, psychomotor development, functional problems or paediatric medical complications. The search function of the system offers the paediatrician a list of all the syndromes/phenotypes which share a minimum number of features independently from the importance of the single feature in the disease (a major feature or an occasional one). For this reason the paediatrician has to analyze in a critical way every suggestion to decide if and which condition can be really considered as a possible etiologic diagnosis for his patient. If some diagnosis can be clear, the professionals have to complete the diagnostic pathway performing the specialistic evaluations and the genetic tests necessary to confirm or exclude the diagnosis. If no genetic and/or

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metabolic test is available to confirm the diagnosis it is mandatory to discuss the conclusion of the research with other experts in clinical genetic, looking for a concordance of the first hypothesis. As we have said at the beginning of our chapter the global detection rate of this process is between 60-70%. This percentage is proportionally lower in younger ages and in patients in which the psychomotor/mental development problems are not associated with clear dysmorphysms and/or major malformations and/or abnormal growth patterns.

Figure 13. Child with Rubinstein-Taybi syndrome.

Figure 14. Child with Williams syndrome.

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Table 3. List of the most common syndrome with their known genetic defect (if known) Sindrome Down syndrome Turner syndrome Klinefelter sindrome Cri du chat syndrome Edwards sindrome Patau sindrome Wolf-Hirschhorn syndrome Williams syndrome Prader-Willi sindrome

Angelman syndrome Microdeletion 22q sindrome (Di George syndrome) Noonan sindrome Cornelia de Lange sindrome S. di Rubinstein-Taybi Vater/Vacterl association CHARGE sindrome Treacher-Collins sindrome Sotos sindrome Beckwith-Wiedemann syndrome Bardet-Biedl syndrome Oculo-auricolo-vertebral spectrum Marfan syndrome Neurofibromatosis type 1 Achondroplasia Apert syndrome Crouzon sindrome Fragile X syndrome

Genetic defect Chromosome 21 trisomy Chromosome X monosomy Alteration of the number of sexual chromosome (47 XXY) Deletion/microdeletion 5p Chromosome 18 trisomy Chromosome 13 trisomy Deletion/microdeletion 4p Microdeletion 7q11.23 Absent paternal contribution for 15q11.2 region (different genetic mechanisms) Absent maternal contribution for 15q11.2 region (different genetic mechanisms) Microdeletion 22q11.2

Mutation of PTPN11, KRAS, SOS1 and RAF 1 genes Mutation of NIPBL, SMC1 and SMC 3 genes Microdeletion 16p13.3, mutazione gene CBP Clinical diagnosis Mutation in CHD7 gene Mutazione gene Treacle Deletion 5q35 or mutation NSD1 gene Microduplication 11p15.5/mutation of the genesi of 11p15.5 region Seven locus/genes knowns Clinical diagnosis Mutation of fibrillin 1 and TGF beta genes Mutation/microdeletion neurofibromin gene Mutatione FGFR3 gene Mutation FGFR2 gene Mutation FGFR3 e 2 genes FMR1 gene anomaly

Laboratory Help to the Diagnostic Pathway As we have quickly mentioned before, any child with a psychomotor/mental developmental problem needs to perform a standard karyotype and/or a molecular test for FMR1 gene (if not microcephalic). The genetic tests, both at cytogenetic-molecular or at molecular level, have a great importance to confirm a large group of diagnosis which were only clinically based a few years ago. Furthermore new technologies (such as subtelomeric studies and CGH array) are progressively available to deeply analyze patients with unknown complex phenotypes.

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Standard and Molecular Cytogenetic Techniques According Rauch et al. (2006) the standard karyotype has still today its weight in the diagnostic pathway; in their report in fact they stated that about 16% of mentally retarded patients have a chromosomal aneuploidy as cause of the disease. This is particularly thorough if we consider that standard cytogenetics has improved its resolution in the recent years (figure 15). For these reasons it is important to decide whether to repeat a cytogenetic analysis in a patient who has performed this kind of test too many years before. Apart from this example (the specific percentage is clearly dependent by the pre-test clinical selection) it is important to state that a standard cytogenetic study is recommended as starting point of the majority of patients with ID.

Figure 15. Example of standard karyotype.

Genetic tests are also very useful in confirming a specific diagnosis hypothesized at clinical level. FISH (fluorescent in situ hybridization) studies are in fact the easier and more direct way to confirm a diagnosis of one of the well known micro-deletion syndromes listed in table 4. Thank to the hybridization of a specific fluorescent probe, in fact, it is possible to detect the absence of one copy of a little piece of DNA in one of the two chromosomes studied and identified and thank to another probe it is possible to determine at which level they are located: at centromere or telomere level (figure 16). Rauch et al. (2006) suggested that around 5% of the mentally retarded patients analyzed by them had a chromosomal microdeletion as cause of the problem. In these cases the test is quite simple and quick and it can only confirm a correct clinical diagnosis.

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A. Cereda, A. Passarini, M. Cerutti et al. Table 4. The most investigated microdeletion syndromes Sindrome Wolf-Hirschhorn Williams Langer-Giedion WAGR Smith-Magenis Angelman/Prader-Willi Di George Miller-Diecker

Microdeletion 4p16.3 7q11.23 8q24.1 11p13 17q11.2 15q11-q13 22q11.2 17p13.3

WAGR, Wilms tumour-aniridia-genitourinary anomalies-intellectual disability syndrome.

Figure 16. Example of FISH with microdeletion at 4p16.3.

In recent years the FISH technique has been used to perform another important type of molecular cytogenetic approach, the one of the study of subtelomeric rearrangements. The theoretical basis of this approach was the demonstration that telomeres are chromosomal regions very rich of genes. It has been hypothesized that subtle anomalies in those regions could be responsible for human disease associated with intellectual disability. What we can do practically is to study with specific and different probes the telomeric regions of every single chromosome (figure 17) searching for unbalanced rearrangements not evident at cytogenetic level. The probability to find an anomaly is higher if the patients has what is commonly called a “chromosomal phenotype” or if more than one individual within the family is affected by intellectual disability, also if the phenotype itself of the various affected patients is not overlapping. In the first case we consider a “chromosomal phenotype” a clinical combination of problems (major anomalies, dysmorphic signs, growth anomalies, psychomotor/intellectual disability) that strongly suggests to the paediatrician that a genetic cause could be the basis of the disease. The criteria of the familiarity for intellectual disability

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are independently from the similarity of the physical anomalies and are easily explained by thinking that within the same family a subtle balanced chromosomal rearrangement could segregate in different ways and in particular could bring to different types of unbalanced chromosomal pattern responsible for the clinical difference between the patients.

Figure 17. Example of subtelomeric rearrangements study.

Table 5. Clinical score for subtelomeric study as suggested by De Vries et al. (2001) Feature Family history of intellectual disability Compatible with mendelian inheritance Incompatible with mendelian inheritance Postnatal growth retardation or excessive growth Microcephaly, macrocephaly, short/tall stature More than two facial dysmorphic features Non-facial minor anomalies and/or major malformations

Score 1 2 2 2 1 point for each anomaly (maximum 2 points) 2

A score of 3 or more is an indication for performing a subtelomeric study.

Various papers have been published about the detection rate of this technique; generally speaking in the past a range between 2 and 29% have been reported with a mean of 6% As it is quite clear the higher detection rates were evident where the inclusion criteria of the patients were more appropriate. A more realistic rate can be obtained by the very wide study that was published by Ravnan et al. in 2005 reporting the results of 11688 cases referred for subtelomere FISH testing in three clinical cytogenetic laboratories. Their detection rate was approximately 2,5% confirming but not overestimating the importance of this kind of study. De Vries at al. in 2001 suggested a practical algorithm to select patients for subtelomeric analysis; table 5 shows it. Apart from the possibility to define in a discrete amount of patients the genetic base of the intellectual disability the sub-telomeric studies has shown us some quite frequent diseases relatively unknown before the introduction of this kind of analysis. We refer in particular to

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1p and 22q terminal micro-deletion which were between the most frequent rearrangements detected also in the wide research previously mentioned. In particular 1p terminal deletion seems to have quite specific phenotypes which permit now to be suspected also at clinical level and specifically searched and demonstrated. Molecular Tests If cytogenetics at all its levels helps the paediatrician to confirm a specific diagnosis or find a new one, also the molecular tests, directly oriented in demonstrating anomalies in the sequence of known genes, have a big role in facing the diagnostic challenge of a child with intellectual disability. One of the basilar test at this level is represented by the molecular analysis of the FMR1 gene whose anomalies are related to the Fragile X syndrome. We know in fact how subtle and variable is the phenotype of Fragile X syndrome, especially in the first years of life. For this reason the level of suspicion should be absolutely high. For practical indications De Vries et al. (1999) suggested that using their scoring system (described in table 6) in a wide population of mentally retarded patients and testing subjects with a score equal or superior of 5, they did not miss any diagnosis and they succeeded in avoiding to test a great amount of patients. The real utility of this score has never been formally evaluated in subsequent reports; it is certain that FMR1 molecular test must be considered in the diagnostic working process of any child affected with ID. Apart from the study of FMR1 gene a lot of common diagnosed syndrome have been classified at genetic level in recent years. Now it is possible to search for a confirmation of a clinical diagnosis of Rubinstein Taybi syndrome, Sotos syndrome, Cornelia de Lange syndrome, Rett syndrome, Cohen syndrome by studying the specific involved genes searching for known mutations. One important point that has to be considered at this level is that for the majority of these conditions the detection rate of the molecular tests available is not of 100 % and that mutations in more than one gene have been described for some of them. Two very clear examples are represented by Cohen and Cornelia de Lange syndrome. The first syndrome is an autosomal recessive disease characterized by peculiar facial dysmorphisms, psychomotor/intellectual disability, visual disability and intermittent neutropenia. The syndrome has been associated with mutation of COH1 gene on the long arm of chromosome 8 (8q22) but it is now evident this is true only for a proportion of the all clinically diagnosed patients. We have to say that exist a number of correctly diagnosed Cohen patients who are waiting for the discovery of a new genetic test to confirm the clinical diagnosis. Cornelia de Lange syndrome (CdLS) is characterized by typical facial dysmorphisms, prenatal and post natal growth retardation, hirsutism, small hands and feet or more severe limb reduction defects. Up to the middle of 2004 the diagnosis of the disease was only clinically based. In May 2004 two independent research groups showed that a variable percentage of CdLS had a mutation in NIPBL gene on the short arm of chromosome 5 (5p13); further reports from different countries outlined that NIPBL mutations are evident in a maximum of 50% of CdLS subjects. In 2006 a second gene (SMC1L1) was discovered being associated with the syndrome in a minority of similar patients (about 10%). A third

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gene, SMC3, has been recently defined but not definitively confirmed as pathogenetic for CdLS. In spite of all these important facts about 35-40% of CdLS people have still only the clinical diagnosis. Table 6. algorithm for fragile-X syndrome molecular testing from De Vries et al. (1999) Feature Familial history of intellectual disability • Affected brother, maternal uncle, nephew or cousin • Every affected relative (compatible with XL) Face • Elongated mandible/prominent and high forehead • One of the two previous signs Ears • Large and prominent • Only large Joints • Metacarpophalangeal laxity • 5th finger laxity Skin • Soft and redundant palmar skin • Soft palmar skin Testes • Both > 30 ml • One > 30 ml Behaviour • Shyness, poor visual contact, then friendly and hyperverbal • Some of these features

Score

2 1 2 1 2 1 2 1 2 1 2 2 2 1

This condition is not particularly surprising if we think of the Noonan syndrome for which a major gene (PTPN11) has been firstly discovered and, subsequently, other three different genes have shown to be related to this variable and complex phenotype. All these examples give us the important message that before applying a molecular test is very important to know exactly its detection rate and how many genes are involved in the genetic basis of the suspected syndrome for a correct interpretation of the results obtained. It is also very important to consider that there are also a discrete number of well known genes referred to what it is called “non syndromic X linked intellectual disability” in which the ID is the only relevant clinical problem of the child. The segregation of the disease within the family is typical of an X linked condition. The majority of them are responsible for a really small percentage of patients with ID. In a report from Ropers et al. (2006) 27 of these genes were identified but the number of these information is growing years by years. Array CGH (Comparative Genomic Hybridization) This technique represents the best approach for the genetic study of a patient affected with ID without a specific clinical diagnosis. Thanks to array CGH, it is possible to detect the presence of submicroscopic genomic imbalances, micro-deletions and micro-duplications,

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along all the chromosomes. This means that also very subtle interstitial anomalies can be diagnosed and not only those present at telomeric level as it happens with the FISH subtelomeric study. In this technique, test and normal reference DNA samples are labelled with two different colored fluorochromes and hybridized onto an extremely wide number of clones of mapped sequences. The presence of copy number changes at a particular locus is suggested by the deviation from the expected 1:1 fluorescence intensity ratio between the test and the normal samples at that chromosomal locus. The indications for the use of this technique are mainly the same that are used for the FISH subtelomeric studies. The detection rates of this approach is widely variable because of two independent reasons. It depends in fact from: - how good is the clinical selection of the patients to test. The more the patient has a “chromosomal phenotype” in the previously expressed sense the higher will be the percentage of positive patients - how strict is the level of resolution of the panel of probes used. At the beginning of the use of the technology the level of resolution was comprised between 5-10 Mb. In a few time the level of resolution becomes lower permitting to show more subtle rearrangements Very recently (June 2007) Hoyer at al. detected 9,1% apparently disease causing de novo aberrations in a group of 104 unselected patients affected with intellectual disability using 100k single nucleotide polymorphisms arrays. The application of this new procedure of analysis has permitted us to understand some new information. First of all it has been shown that interstitial anomalies are two-three times more frequent than sub-telomeric ones. Then it was possible to demonstrate that some de novo apparently balanced chromosomal translocation at cytogenetic level are in fact subtly unbalanced. The previously defined “normal” karyotype was in fact abnormal and related to the child’s disease. Again thank to this analysis it was possible to show some very atypical presentation of well-known micro-deletion syndromes that were not suspected with the clinical analysis. The last important information is that our genome has a level of normal variability wider than we have never thought. A pathological result of the array CGH in a ID patient should in fact be always compared with those of both parents to correctly explain the result itself. By doing this it has been shown the presence of a very high amount of non pathological copy number variations (CNV) in the humane genome. Not rarely the same variation is evident in one of the parents as the result of a segregation of a normal variant. Going a bit further the problem more complicated because if it is true that most of the CNV are in fact benign, it has also been postulated that in some individuals they can be pathogenetic even if they are inherited from a phenotypically normal parent due to possible epigenetic effects, position effects, gene dosages effects or the unmasking of recessive mutations.

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In conclusion the classification of CNV as benign findings on CGH need to be reevaluated as our understanding of the phenomena will improve.

Some Open Problems Variability of Phenotype It is very important to keep in mind that each single syndrome can have a wide variability of expression. This variability refers both to different patients and to the same patients during the years. As we have already said, for these reasons, some gestaltic diagnosis of well known dysmorphic syndromes can be absolutely easy or extremely difficult in different situations. Very commonly, for example, the neonatal phenotype or the phenotype of the first months of life cannot be always typical. So if the first clinical genetic evaluation of our patients did not give us any convincing conclusion it is part of the diagnostic pathway to suggest a follow-up examination to re-evaluate the clinical setting. The time distance from the first evaluation will be lower if our patient is younger (few months) and longer at older age (not less than one years apart from the onset of a new relevant medical problem). What do we expect to find in further observations? First of all, during the time, the facial phenotype can evolve and become more typical for a specific disease. A lot of examples of this kind of evolution can be done: Williams, Cornelia de Lange and Kabuki syndromes can be some of them but the list can be really wide. In other situations the natural history of the syndrome itself offer new important handles along the years because of the appearance of specific medical problems or clinical feature which are age related. A peculiar example are those syndromes with ID, sometimes associated with obesity (for example Bardet Biedl or Cohen syndrome), in which a retinal dysfunction classically appears later on. Genetic Heterogeneity We have already discussed in the lab section the possibility that a single disease can be caused by different genes’ mutations. It should also be stressed that sometimes the basic genetic defects of a single syndrome can be very different. A very clear example is represented by Angelman syndrome in which the great part of the patients show a microdeletion on the long arm of chromosome 15 (15q11.2) some others show an uniparental paternal disomy for chromosome 15, some others a mutation in the gene of the region which regulate the imprinting mechanism (IC gene) and another group of them show a mutation of further genes such as the UBE3A gene. Obviously the paediatrician needs to know all informations, needs to be aware that the great majority of the genetic defects can be pointed out through a methylation test that does not include only the UBE3A mutations. The paediatrician needs also to know that a small proportion of clinically diagnosed Angelman patients (about 10%) can have all these tests normal. Figure 18 summarizes the algorithm for the molecular diagnosis of this complex disease.

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Figure 18. Algorithm for the molecular diagnosis of Angelman syndrome.

What we have described for Angelman syndrome can be in a simplier way applied for other complex condition like Rubinstein Taybi or Smith Magenis syndrome in which some patients can have a micro deletion of a specific chromosomal region and some other (with different proportion) a mutation of a gene within the commonly deleted region. Table 7. Molecular defects described for syndromic craniosynostosis. Syndrome Crouzon syndrome Apert syndrome Pfeiffer syndrome Jackson-Weiss syndrome

Molecular defect FGFR 2 - FGFR3 (Crouzon syndrome+acanthosis nigricans) FGFR2 FGFR1 - FGFR2 FGFR2

After having discussed this relevant point we cannot forget the opposite phenomena, the situation in which mutation of one gene can be responsible for different clinical phenotypes. All of us know that MECP2 mutations are related with Rett syndrome phenotypes. There are some reports that suggest to test for mutations of this gene, patients with Angelman phenotype who are negative to all the over described genetic tests; moreover mutation of this gene was also found in male patients with non specific, severe intellectual disability. The most famous situation is still related to the FGFRs genes and their relationships with the Acrocephalo-polisyndactylies phenotypes. Clinically the story of these diseases has permitted to identify several different syndromes (Apert, Crouzon, Sathre-Chotzen, Pfeiffer syndrome) by analyzing the cranial, facial and extremities features. As soon as we had found their molecular basis, the overlapping between all these syndromes was impressive. Table 7 shows the molecular defects described for each conditions. We have to understand what is the point

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at practical level. As well outlined by R. Hennekam quite recently, the question is whether we have to face with the mutation or with the patient. I think that we can agree with the author when he states that “clinical genetics would not exist without patients” because all our efforts, also at research level, should be directed to improve heath of the patients and their families. Etiological Diagnosis: the Final or the Starting Point? If we agree with the last sentence of the previous paragraph the answer to the question is absolutely evident. Etiological diagnosis cannot be the final goal of our work, cannot be the word “end” of our interventions. We have said that the correct diagnosis gives us the opportunity of knowing natural history of the disease also in terms of medical complications, of deciding in some way the best approach for rehabilitation. This indicates us that after the diagnostic process it is mandatory to start the follow-up process in which paediatric neurologic and neuropsychiatric issues should run together and should be carefully coordinated. It is out of the aims of this presentation to go into details in this topics but it is very important to outline that paediatrician have to move at double level. We now know exactly that the great majority of patients with complex malformative syndrome can share common clinical problems: difficulties in feeding, growth retardation, gastro esophageal rephlux, constipation, recurrent pulmonary infections, tooth disease, orthopaedic complications, epilepsy, communication and behavioural problems. For all of them the modern approach should be able to create a common cultural background of what we can name “paediatrics of disability”. Apart from these common problems we should also be able to improve our knowledge on the natural history of the single rare diseases to apply the new information in the specific clinical follow-up of the various patients. Only with this approach we will be able to consider at practical level these children and their family as a part of the paediatric community and not as an isolated, far, particular world.

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Chelly, J., Mandel, J. (2001) Monogenic causes of X-linked mental retardation. Nat Rev Genet, 2, 669-680. Deardorff, M.A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodríguez, C., Arnedo, M., Loeys, B., Kline, A.D., Wilson, M., Lillquist, K., Siu, V., Ramos, F.J., Musio, A., Jackson, L.S., Dorsett, D. & Krantz, I.D. (2007) Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet, 80(3), 485-94. De Vries, B.B., Mohkamsing, S., van den Ouweland, A.M., Mol, E., Gelsema, K., van Rijn, M., Tibben, A., Halley, D.J., Duivenvoorden, H.J., Oostra, B.A. & Niermeijer, M.F. (1999) Screening for the fragile X syndrome among the mentally retarded: a clinical study. The collaborative fragile x study group. J Med Genet, 36, 467–470. De Vries, B.B., White, S.M., Knight, S.J., Regan, R., Homfray, T., Young, I.D., Super, M., McKeown, C., Splitt, M., Quarrell, O.W., Trainer, A.H., Niermeijer, M.F., Malcolm, S., Flint, J., Hurst, J.A. & Winter, R.M. (2001) Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J Med Genet, 38, 145–150. De Vries, B.B.A. et al. (2003) Telomeres: a diagnosis at the end of the chromosomes. J Med Gen, 40, 385-398 Hall, J. (1988) The value of natural history in genetic disorders and congenital anomaly syndromes. J Med Genet, 25, 434-444. Hoyer, J., Dreweke, A., Becker, C., Gohring, I., Thiel, C.T., Peippo, M.M., Rauch, R., Hofbeck, M., Trautmann, U., Zweier, C., Zenker, M., Huffmeier, U., Kraus, C., Ekici, A.B., Ruschendorf, F., Nurnberg, P., Reis, A. & Rauch, A. (2007) Molecular karyotyping in patients with mental retardation using 100K single-nucleotide polymorphism arrays. J. Med. Genet, 44, 629-636. Kirchhoff, M. et al. (2001) High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet, 38, 740-744. Kirchhoff, M., Pedersen, S., Kjeldsen, E., Rose, H., Duno, M., Kolvraa, S. & Lundsteen, C. (2004) Prospective study comparing HR-CGH and subtelomeric FISH for investigation of individuals with mental retardation and dysmorphic features and an update of a study using only HR-CGH. Am J Med Genet A, 127, 111–117. Krantz, I.D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L.A., Yaeger, D., Jukofsky, L., Wasserman, N., Bottani, A., Morris, C.A., Nowaczyk, M.J., Toriello, H., Bamshad, M.J., Carey, J.C., Rappaport, E., Kawauchi, S., Lander, A.D., Calof, A.L., Li, H.H., Devoto, M. & Jackson, L.G. (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet, 36(6), 631-5. Merks, J.H.M. et al. (2003) Phenotypic abnormalities: terminology and classification. Am J Med Genet, 123A, 211-230. Miyake, N., Shimokawa, O., Harada, N., Sosonkina, N., Okubo, A., Kawara, H., Okamoto, N., Kurosawa, K., Kawame, H., Iwakoshi, M., Kosho, T., Fukushima, Y., Makita, Y., Yokoyama, Y., Yamagata, T., Kato, M., Hiraki, Y., Nomura, M., Yoshiura, K., Kishino, T., Ohta, T., Mizuguchi, T., Niikawa, N. & Matsumoto, N. (2006) BAC array CGH reveals genomic aberrations in idiopathic mental retardation. Am J Med Genet A, 140, 205–211.

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Musio, A., Selicorni, A., Focarelli, M.L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P. & Larizza, L. (2006) X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet, 38(5), 528-30. Poss, A.F., Goldenberg, P.C., Rehder, C.W., Kearney, H.M., Koeberl, D.D. & McDonald, M.T. (2006) Clinical experience with array CGH: case presentations from nine months of practice. Am J Med Genet A, 140, 2050–2056. Rauch, A., Hoyer, J., Guth, S., Zweier, C., Kraus, C., Becker, C., Zenker, M., Huffmeier, U., Thiel, C., Ruschendorf, F., Nurnberg, P., Reis, A. & Trautmann, U. (2006) Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet, 140, 2063–2074. Ravnan, J.B., Tepperberg, J.H., Papenhausen, P., Lamb, A.N., Hedrick, J., Eash, D., Ledbetter, D.H. & Martin, C.L. (2006) Subtelomere FISH analysis of 11688 cases: an evaluation of the frequency and pattern of rearrangements in individuals with developmental disabilities. J Med Genet, 43, 478-489. Rio, M., et al. (2003) Spectrum of NSD1 mutations in Sotos and Weaver syndrome. J Med Genet, 40, 436-440. Ropers, H.H. (2006) X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev, 16, 260-269. Rosenberg, C., Knijnenburg, J., Bakker, E., Vianna-Morgante, A.M., Sloos, W., Otto, P.A., Kriek, M., Hansson, K., Krepischi-Santos, A.C., Fiegler, H., Carter, N.P., Bijlsma, E.K., van Haeringen, A., Szuhai, K. & Tanke, H.J. (2006) Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. J Med Genet, 43, 180–186. Slager, R.E., Newton, T.L., Vlangos, C.N., Finucane, B. & Elsea, S.H. (2003) Mutations in RAI1 associated with Smith–Magenis syndrome. Nat Gen, 33, 466 – 468. Stevenson, R.E., Procopio-Allen, A.M., Schroer, R.J., Collins, J.S. (2003) Genetic syndromes among individuals with mental retardation. Am J Med Genet, 123(1), 29-32. Tonkin, E.T., Wang, T.J., Lisgo, S., Bamshad, M.J. & Strachan, T. (2004) NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet, 36(6), 636-41. Varela, M.C., Kok, F., Otto, P.A. & Koiffmann, C.P. (2004) Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet, 12, 987–992. Xu, J., Chen, Z. (2003) Advances in molecular cytogenetics for the evaluation of mental retardation. Am J Med Gen, 117C, 15-24.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter II

BRAIN AND BEYOND THE BRAIN: THE BIOLOGICAL PROFILE OF DOWN SYNDROME Annapia Verri1, Luigi Nespoli2, Diego Franciotta3 and G. Roberto Burgio4 1

IRCCS Neurological Institute C. Mondino Foundation, Department of Behavioral, Neurology, Pavia, Italy; 2 Pediatric Clinic, University of Insubria, Varese, Italy 3 IRCCS Neurological Institute C. Mondino Foundation ,Laboratory of Neuroimmunology, Pavia Italy 4 Emeritus Professor of Pediatrics ,University of Pavia, ,Italy.

ABSTRACT Down’s syndrome (DS) is the most frequent genetic disorder associated with intellectual disability. The syndrome is the phenotypic result of a triplicated chromosome 21, or from a triplication of its restricted regions. Despite entire DNA sequence of human chromosome 21 is now complete, little is known about the mechanisms by which the increased gene copy number leads to the characteristic DS phenotype. The phenotype can be variable in severity, on the basis of allelic composition of chromosome 21 genes and of the interaction with environment and with expression of genes that are not located on chromosome 21. Dysregulation of the immune system is one characteristic pathological feature of the syndrome and likely contributes to increased susceptibility to viral or bacterial infections, autoimmune diseases, and haematologic malignancies. Chromosome 21 contains the interferon cytokine receptors cluster of genes that are structurally and functionally related. Interferon has pleiotropic effects that manifest mainly on immune system but even in the brain, as shown in DS and in its animal model, the trisomy 16 mouse. Interferon-γ plays a pivotal role in the polarization of immunity towards Th1mediated responses, which are mainly involved in protection from virus infection and in

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autoimmunity. It could also cause neurodegeneration and β-amyloid production in DS, thus accounting for cognitive impairment. Notwithstanding these recent discoveries, most of the studies on immunological aspects in DS are old. Investigation with upgraded technologies is needed to improve knowledge in this field. In particular, studies on the expression of proteins, whose genes are encoded on chromosome 21 and that are directly or indirectly involved in immunity, may provide a better understanding of genotypephenotype correlation in DS and, possibly, a rationale for therapeutic strategies aimed at contrasting the immune derangement and neurodegeneration that are typical of this syndrome.

Keywords: Down Syndrome, development, aging.

INTRODUCTION Down syndrome (DS) is a common genetic disorder affecting around 1 in 800 live births in the human population. It is caused by a complete, or occasionally partial, triplication of chromosome 21 resulting in a complex and variable phenotype. It was originally described by John Langdon H Down (1866) as “Mongolian type of idiocy” as the peculiar face seems to suggest the mental retardation that remains the invariable hallmark of this disorder. The causes of mental retardation in DS remain elusive, although certain neuroanatomical changes found in DS individuals may be involved in mental retardation.

Brain in DS 1) Neuropathology The neuropathology of DS is complex; DS individuals have decreased brain weight, decreased neuronal number, and abnormal neuronal differentiation (Wisniewski et al., 1985), however they do not usually present any macroscopic brain malformation. Individuals with trisomy have smaller brains overall with a small cerebellum, frontal and temporal lobes, a simplified appearance of the sulci, and a narrow superior temporal gyrus (Pinter, 2001). This reduction is accompanied by regional shape changes that include an anteroposteriorly shorter cerebrum, reduced frontal lobes and compressed occipital lobes that are steeply sloped in height. Numerous studies have reported reduced volume of the cerebellum in humans with DS as well as underdeveloped cerebellar folia. The small size of the cerebellum is correlated with significantly reduced density of granule cell neurons. A number of early studies point to the already noted conclusion that the brain of an individual with DS at or shortly before birth is in many respects macroscopically indistinguishable from the brain of a normal newborn. (Nadel, 2003) Microscopically some changes begin to emerge as early as 22 weeks gestational age and it is clear that by 6 months of age, a number of important differences are already obvious (Nadel, 2003). In fact, DS fetuses (17–21 weeks of gestation) exhibit reduction in total cell number in the dentate gyrus, hippocampus and parahippocampal gyrus (Guidi, 2008). Hypocellularity has been found in

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all structures forming the fetal hippocampal region; this defect is caused by neurogenesis disruption during early phases of brain development (ibidem). Altered levels of brain amino acids or monoamines could account for the altered neurodevelopmental process in brains with DS. Whittle (2007) observed reductions in serotonin and its metabolite 5-hydroxyindol-3-acetic acid in DS fetal frontal cortex tissue versus control subjects. A delay in myelinization (more evident in nerve tracts that are myelinated late in development), was observed in about 25% of infants with Down’s syndrome who came to post-mortem analysis between the ages of 2 months and 6 years (Wisniewski, 1990). Delayed myelination has also been observed in a study employing magnetic resonance imaging on a single infant (18 months of age) with Down’s syndrome (Koo et al., 1992). For Nadel (2003) investigations of neural function, as opposed to structure, in early infancy suggest some abnormalities: there is evidence of either delayed or aberrant auditory system development (Jiang et al., 1990) that might contribute to the widespread hearing disorders observed in Down’s syndrome (Vicari, 2004). This disorder, if organic, could be related to many of the subsequent difficulties seen in the learning of language. Karrer et al. (1998) have reported delayed development of cerebral inhibition using visual event related potentials (ERP) in a visual recognition memory paradigm. There is also evidence of a more widespread abnormality in EEG coherence that seems to reflect the generally impoverished dendritic environment (Nadel, 2003). This difference, like many of the others, emerges only sometime after birth. It appears that this effect is predominant in posterior, rather than anterior, brain regions, and in the left, more than the right, hemisphere. The evidence of neuropathological sequelae in Down’s syndrome is more extensive for the middle stage of life. Data from both post-mortem studies and from studies of brain function in selected populations indicate that the changes beginning to emerge early in life and become more prominent and prevalent by early adolescence. There have been relatively few studies of brain functions in adolescents and young adults with Down’s syndrome, and the existing data are somewhat equivocal. Devinsky et al. (1990) reported relatively normal EEG alpha activity in young adults (<40 years of age), while Schapiro et al., (1992) using positron emission tomography (PET) reported relatively normal brain metabolism in a similar group. They did report some disruption of normal neuronal interactions between the frontal and parietal lobes, possibly including the language area of Broca. The superior temporal gyrus, a language-related structure, is often singled out as one of the most severely affected temporal regions. Most of the auditory association cortex lies on the superior temporal gyrus and particularly on the planum temporale, a triangular plane at the posterior end of the superior surface of the superior temporal gyrus (Frangou, 1997). Neurogenesis impairment seems to be a generalized feature of the DS brain and to underlie the widespread brain hypotrophy that characterizes DS subjects starting from infancy (Guidi, 2008). This author also found enhanced apoptotic cell death, suggesting that this may be an additional cause of brain hypotrophy. Thus, disruption of two fundamental processes underlying brain building appears to be a crucial determinant of microencephaly and mental retardation in DS (ibidem). This knowledge is of obvious importance because it might open the way to future studies aimed at identifying the molecular mechanisms of

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altered neuron production. In cell culture, the DS cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in DS (OMIM #190685) DS brain phenotype is not the result of three copies of the genes in the supposed DS critical region in isolation. Instead, it is the combination of the specific genes at dosage imbalance and variation in modifier genes (likely located on other chromosomes) that are key to the production of brain phenotypes in DS (Aldridge, 2007). 2) Intellectual Disability (ID) Cognitive disability of varying degrees is the most consistent feature of DS and contributes to about 30% of all moderate -to-severe cases of mental retardation. Most children and adults with DS function in the mild or moderate range of intellectual disability. About 10% have a low average-borderline degree of intellectual disability (cognitive impairments that are not so severe as to be classifiable as a learning disability). A minority have a severe or profound cognitive impairment. In DS patients, the average IQ score is around 50, with individual values ranging from 30 to 70 (Rachidi, 2007). Cognitive dysfunction is manifested as deficits in specific tasks requiring a functional hippocampus, specific strengths and weaknesses in language skills, implicating regions of the prefrontal and temporal cortices and the cerebellum, and additional deficits suggesting impaired prefrontal cortex function (Ma’ayan, 2006). Patients with Down’s syndrome show smaller volumes of temporolimbic structures, suggesting that these abnormalities may underlie the language impairment observed in this syndrome (Frangou, 1997).

Figure 1. Mean and observed range of IQ of children with DS as a function of age (data from Morgan, 1976).

The early infancy is characterized by a delayed cognitive development, leading to mildto-moderate intellectual disability. The IQ declines rapidly from early in the first year to late childhood (Figure 1) and the decline in cognitive performance that occurs in the adult DS patients has been considered as the consequence of accelerated aging. Rates of cognitive

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development, as measured by Piagetian sensorimotor tasks, decrease after the first two years of life and appear correlated in infancy with rates of delayed myelination (Chapman, 2000). Almost all children with DS have a relatively specific expressive language impairment. Expressive language deficit in syntax is greater than expressive language deficit in the lexicon. Comprehension of words typically more advanced than nonverbal cognition (Abbeduto, 2006). The pragmatics of language tend to be good, however, grammatical abilities are impaired (Harris, 2005). Expressive language delay is usually obvious by the toddler period. It begins in expressive phonology and nonverbal requests, then later progresses to slower expressive vocabulary accumulation (Mervis, 2000). Children with trisomy 21 also have deficits in the development of variability in number of different words, intelligibility, and mean length of utterance compared with mental age-matched controls. (Visootsak, 2007) Developmental progress from birth to 11 years is characterized by greater variability, including failures to exercise and maintain existing skills and by persistent use of old, counter-productive strategies on new problems (Chapman, 2000) ID in DS is characterized by major neurological dysfunctions in the short- and long-term memory. Cognition deficits in verbal working-memory and delayed recall has been described. It is of interest that, compared to the dramatic impairment in these areas, visuospatial processing skills appear to be relatively preserved in individuals with Down’s syndrome (Pinter, 2001). It has been also demonstrated a decline with age on measures of long-term memory, providing behavioral evidence of hippocampal dysfunction by adolescence, consistent with the structural magnetic resonance imaging (MRI) finding of reduced hippocampal volumes in adolescents with DS (Pinter, 2001). There is also evidence for impairment of prefrontal cortex and cerebellar function and speech and articulation are also particularly affected (Pinter, 2001). 3) Early onset Dementia Early cognitive impairment and cognitive decline with aging due to an early onset of Alzheimer’s disease-like symptoms have been described in DS. Dementia associated with Alzheimer's disease (AD) is defined in the Diagnostic and Statistical Manual of the American Psychiatric Association - DSM-IV (1994) as the development of multiple cognitive deficits that include memory impairment and at least one of the following: aphasia, apraxia, agnosia, or a disturbance in executive functioning. The cognitive deficits must be sufficiently severe to cause impairment in occupational or social functioning.. Adults with DS are much more likely to develop dementia of Alzheimer type than the general population. On post-mortem examination, almost all adults with DS over the age of 35 have the brain changes characteristic of AD but prevalence rate of clinical dementia in DS is age dependent: 9% between 40-49 years, 36% between 50-59 years, 55% between 60-69 years (Prasher, 1995; Deb & Braganza, 1999; Roizen & Patterson, 2003). AD is the most common form of senile dementia and affects approximately 50% of persons over 85 years of age. Age is the biggest risk factor for AD and over 95% of cases have no known cause. However, approximately 5% of AD cases result from mutations within

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genes that produce a peptide known as amyloid beta-peptide (Abeta), which accumulates as amyloid in the parenchyma and cerebral blood vessels in the AD brain and serves as one the major neuropathological hall marks of AD (Tansley, 2007). AD is characterized by 2 neuropathological hallmarks: extracellular formations defined neuritic or senile plaques and intracellular silver stained formation called neurofibrillar tangles, the consequences of which are neuronal loss and cerebral atrophy: AD is genetically heterogeneous and four different chromosomal loci that confer inherited susceptibility to this disease have been identified (Del Bo, 1997): 1. 2. 3. 4.

AD1 on chromosome 21 (APP gene) AD2 on chromosome 19 (APOE gene) AD3 on chromosome 14 (S182 gene) E5-1 on chromosome 1

DS subjects suffer of AD with a much higher prevalence and amyloid plaques as well as AD appear very precociously in DS persons. The gene for APP is located on chromosome 21 and this observation did stimulate the research on DS as a model for AD and precocious ageing. Similar to patients with sporadic AD, elderly DS subjects show cerebral atrophy, deposition of a protein in extracellular senile plaques and perivascular amyloid (amyloid angiopathy) (Teipel, 2006) intra-neuronal neurofibrillary tangles (NFT) and extracellular neuritic plaques and neuropil threads (Jellinger and Bancher, 1998; Teipel, 2006). Neurofibrillary degeneration of abnormally hyperphosphorylated tau are seen as intraneuronal neurofibrillary tangles. Amyloid beta protein (Abeta) derives from atypical splicing of an ubiquitous transmembrane protein, the amyloid precursor protein, which is coded on chromosome 21 (Vassar, 2007). The deposition of beta A4 amyloid protein in the brain of persons with DS begins 50 years earlier than it does in normal brains, possibly as the result of overexpression of the amyloid precursor protein (APP) gene (Rumble, 1989; Epstein, 2001). However, ubiquitinimmunoreactive dystrophic neurites have been observed in the gray matter of brain of DS persons as young as 6 years of age, prior to the time of amyloid deposition, as compared with 29 years of age in control brains (Mattiace, 1991). The human APP gene maps to chromosome 21q21.3, and two seminal observation demonstrate the pivotal role of APP gene dose in determining the age of onset of AD (Tansley et al., 2007). First, excess APP is required for the accelerated onset of AD in DS (Prasher, 1998). This was shown by the identificaytion of a 78-year ol DS subject who exhibited no amyloid deposition upon autopsy and who had partial trisomy 21 in which the chromosomal breakpoint excluded APP. More recently, five independent kindreds have been identified that contain a duplication of the APP locus in the absence of mental retardation and other aspects of DS (Rovelet-Lecrux, 2006). These families all exhibit aytosomal dominant early-onset AD with an average clinical age of onset of 52 years, and who exhibit abundant amyloid deposition in the parenchyma and cerebrovasculature. Taken together, these studies conclusively demonstrate that APP gene dose critically regulates the age of onset. However,

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these studies do not rule out the possibility that other genes on chromosome 21 may also contribute to the decreased age of onset of AD neuropathology in DS (Myers, 2002). IT is possible that inheritance of extra copies of genes near this region may functionally synergize with excess APP and provide a better explanation for the greatly accelerated onset of AD neuropathology in DS than APP gene dose alone. This overexpression of APP (and consequently of Abeta) is thought to be responsible for the early onset of AD-like dementia in DS. Furthermore, phenotypes such as increased bamyloid deposition, oxidative stress, and astrocytic hypertrophy may occur, in part, due to the constitutively increased expression of genes that encode the amyloid precursor protein (APP) (Head and Lott 2004), superoxide dismutase-1 (SOD-1) (Brooksbank and Balazs 1984), and the calcium binding-protein S-100b (Allore et al. 1988), all of which map near chromosome 21q22 in the Down Syndrome Critical Region. Adults with DS have both an increased neural beta A load and onset of dementia that is 20-30 years earlier than seen in general population. Age of onset varies widely, and Apolipoprotein E (APOE) phenotype, age at menopause, total cholesterol level as well as BMI are known to influence the development of AD (Wark, 1983). ApoE is a polymorphic protein encoded by a gene located on human chromosome 19q13.2; it has a role in plasma lipoprotein metabolism and cholesterol homeostasis for its ability to interact with the LDL receptor and the LDL receptor-related protein. ApoE is the major apolipoprotein in brain, its production and accumulation are increased in CNS disorders and in peripheral nerve injury. There are three common alleles of the APOE gene, indicated as ApoE epsilon 2, 3 and 4. ApoE epsilon4 has an increased frequency in late-onset familial and in sporadic AD; yet ApoE epsilon4 should be considered a susceptibility gene or risk factor for earlier onset AD. ApoE immunoreactivity has been shown within senile plaques, suggesting the possible role of ApoE as a pathological “chaperon protein” involved in insoluble amyloid formation (Lai et al, 1999). In a group of 100 DS patients (age range 3579 years), 57 with AD, that underwent APOE genotyping, was found that APOE epsilon 2 alleles conferred a protective effect whereas epsilon 4 allele did not confer a significantly increased risk for AD as observed in the general population. Women were 1.77 times as likely to dement as man at any given time (Van Gool WA, 1995). APOE4 protein which is considered a risk factor for AD in the general population, displays a significant lower incidence in DS when compared to AD patients. These observations indicate that the early, selective accumulation of beta amyloid peptide is independent from APOE genotype. The progressive reduction of this phenotype in older DS patients suggests that APOE4 allele predisposes to various causes of early death. (Folin et al., 2003) In the general population cholesterol levels as well as APOE4 are recognized as risk factors for AD. Many groups have reported that high intracellular cholesterol levels result in enhanced release of A-beta in vitro and in vivo (Refolo, 2000; Shie, 2002; Wahrle et al., 2002; Burns, 2003), whereas low intracellular cholesterol levels decrease A-beta production. However, the relationship between cholesterol and A-beta metabolism is considerably more complex than simply correlating the absolute level of total cholesterol with APP metabolism. The physiological regulation of intracellular cholesterol levels is mediated by a network of genes involved in sterol homeostasis. For example, members of the ABCA and ABCG

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classes of ATP-binding cassette transporters are believed to act as critical gate keepers of cholesterol homeostasis. ABCA1 is essential for the efflux of excess intracellular cholesterol onto lipid-free or lipid-poor apolipoproteins and is a key regulator of APOE levels and lipidation in the brain and influences amyloid burden but not amyloid production in vivo. The human ABCG1 gene resides on chromosome 21.q22.3 suggesting that it may be of interest for some of the clinical phenotypes associated with DS. ABCG1 maps within the DS critical region and near the linkage peak that may affect onset and risk in sporadic AD. Evidences have been provided of elevated ABCG1 expression and increased proteolytic products of APP in DS cortex compared to normal controls. Neuritic changes arise from the formation of paired helical filaments (PHF) containing polymerized hyperphosphorylated tau protein triplets and cause disruption of the neuronal cytoskeleton with loss of synapses and neurons and altered cortico-cortical connectivity, leading to disconnection of the cerebral cortex (Teipel, 2006).A clinical and neuropathological association between dementia of the Alzheimer type and Down’s syndrome has been well established (Oliver & Holland 1986; Prasher & Krishnan 1993) because of the presence of the specific amyloid beta -protein in the brain of DS patients. The beta -amyloid peptide (Abeta) is involved in the etiology of Alzheimer disease (AD). The most common Alzheimer’s symptoms in DS patients are epilepsy crisis (58%), change in personality (46%), focal neurological signs (46%), apathy (36%) and loss of conversational skills (36%). Seizures are much more frequent in DS with dementia in comparison with Alzheimer’s disease in general population. There are different types of symptoms of dementia in DS. Cognitive symptoms are characterized by forgetfulness of recent events (progressively long-term), geografical disorientation, loss of previously learned skills, confusion. Affective symptoms are more frequently: low mood, insomnia/hypersomnia, decreased concentration, aggression and irritability, anxiety and fearfulness, loss of interest and anergia. Behavioural symptoms are characterized by increased dependence, social isolation, excessive overactivity or restlessness, excessive uncooperativeness, personality change (Stanton,2004). Individuals with DS are at risk for developing AD. However, dementia does not appear inevitable even at older ages. DS provides a link between development and aging in that amyloid accumulates in the brain across the lifespan (Zigman, 2007).

Down Syndrome: Beyond the Brain 140 years after its initial description by John Langdon H. Down (1866-67), today one can say that Down Syndrome (DS) consists of a classic phenotype, which has been known for a very long time, but also of additional disease traits which have become known more or less recently. We note this because until about 50 years ago, the significant associations of DS (which became trisomy 21 in 1959) did not include atlantoaxial instability, antithyroid autoimmunity (with the other dysfunctions of this gland), celiac disease or a rather particular (cytokine-related) proinflammatory tendency. One can say, instead, that the association of congenital cardiopathies (Cronk, 1993) with the classic Down phenotype, which is recognizable at first sight and at first visit, had long been acknowledged to be highly

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prevalent. Undoubtedly, the anatomical-malformative anomalies frequently associated with DS (cardiopathies, esophago-gastroenteric stenoses, Hirschsprung’s disease) require more or less urgent surgical corrections which allow survival. However, particular immunoreactive, endocrine or hematological disorders also affect the quality and span of the life of Down individuals. Therefore, it is not difficult to acknowledge that two distinct paradigms of associations characterize the Down phenotype considered in its essential aspects: an anatomicalmalformative one and a biological-functional one. Accordingly – and now routinely – a child with DS must be investigated with several screenings. The pediatrician must therefore check the child with a promptly planned multidisciplinary approach. Proposals have been made to perform: a. cardiological screening, precociously after birth, within the second month of life. b. thyroid function screening, repeated annually c. celiac disease screening: anti-endomysial antibodies and total IgA levels at 2 years of age: DSMIG US, 1999 (as also discussed later) d. atlantoaxial screening (questionable, not accepted uniformly as being indispensable). A) Considering anatomical Defects. Malformations 1. Congenital Heart Disease Generally speaking, the prevalence of congenital cardiopathies associated with DS (Epstein, 2001) is approximately 40%, 44% in Freeman’s case histories (Freeman, 1998). It is an established opinion that in DS the most frequent congenital heart defect is atrioventricular septal defect (atrioventricular canal), on average 39% of all DS-associated congenital cardiopathies (Epstein, 2001) or 45% (Freeman, 1998) (followed by ventricular septal defect (31%; 35%) (Epstein, 2001; Freeman, 1998). A significant difference in terms of lifespan of DS patients depending on association with cardiopathy or not (Table 1) had already been demonstrated (Baird, 1987) and then confirmed repeatedly. 20 years after these conclusions, there is little doubt that it is convenient to subject Down children to heart defect correction precociously: “Surgical correction for cardiac defects inherited as a part of Down Syndrome significantly improves survival, and it has been reported that when cardiac anomalies are successfully treated in the early years of life, the mortality risk is decreased to that of affected individuals without cardiac defects” (Bittles, 2004). Table 1. Survival of Patients with Down Syndrome (%) to age (Baird, 1987) (years) A) with congenital heart anomalies (%) B) without

1 76.3 90.7

5 61.8 87.2

10 57.1 84.9

20 53.1 81.9

30 49.9 79.2

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2. Other Malformations (and possible indications) Falling within Surgical Competence Stenoses-atresias of the digestive tract, esophagus, small intestine (5% of total malformations occurring in DS) are certainly surgical urgencies and so is Hirschsprung’s disease (Epstein, 2001). Corrective indications for facial plastic surgery proposed by Hohler (1977) to correct the most typical (“mongolian like”) features are instead questionable. At first sight, it might be suggestive to remove important facial markers of DS from a young Down person. In this regard, a quote from Aristotle has been cited: “Beauty is a greater recommendation than any letter of introduction” (Rozner, 1983). However, this would also trivialize (depersonalize) the features of the “Down patient”, depriving the patient of the simplest explanation of his or her mental disability, probably harming his or her social and relational life. The limiting burden of atlantoaxial instability on the quality of life has been observed for approximately 40 years (Dzenitis, 1966; Gerard, 1971). A distance between the odontoid process of the axis and the anterior arch of the atlas of more than 4.5 mm defines the condition of atlantoaxial instability. It is a risk condition for the neuraxis and is therefore a selective indication to neurosurgery for cervical spine fusion. The extent of the problem, however, is judged variably (Cohen, 2006). Any sport that exposes the head and cervical vertebral column to traumas must be considered at risk. B) The Biological Profile of DS (hematopoietic, endocrine-metabolic, immunological, and inflammatory features) 1. Although a significant “leukemia risk” has long been known in DS patients, its nature and scope have become progressively more clear. A high risk of contracting lymphatic neoplasms had been recognized as particularly typical of DS in the 20- to 34-year-old adult already about thirty years ago (Epstein, 2001). More generally, malignancies have been one of the main causes of death. Down children and young patients were also found to be particularly exposed to the relevant risk of leukemia and testicular neoplasms, with an incidence approximately 20 times higher than in elderly adults of the general population (Miller, 1970, Roizen, Patterson, 2003, Yang et al 2002, Goldacre 2004) Recently a research in DS mice have found an explanation for why having three, rather than the normal two, copies of chromosome 21, the hallmark of DS in humans, provide some protection from solid tumors. These Authors have demonstrated that the overexpresssion of Ets” gene located on chromosome 21, promotes tumor resistance with a different mechanism as compared to tumor suppression (Threadgill , 2008, Sussan , 2008). “Acute megakaryoblastic leukemia” is significantly important among Down patients (200-400 times more frequent than in non-trisomic population) (Zipursky, 1987) and “leukemoid reactions” or “transient acute leukemia” are very frequent in DS infants (approximately 10%). Studies of transient myeloprolipherative disorders in DS patients have shown that 20 to 30% will develop acute megakaryocytic leukaemia by age 3 years, with a mean age of appearance of 16 month. (Crispino JD, 2005) A mutation of GATA1, an essential transcriptional regulator of megakaryocytic differentiation, is commonly found in the leukemic clones at birth (Hitzler, 2006).

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Regarding “transient acute leukemia”, usually interpreted not as leukemia but as an “ineffective regulation of granulopoiesis masquerading as congenital leukemia” (occurring <1 year of age), there are instead a few isolated voices (Rogers, 1978) who interpret it as a peculiar possible true leukemia, although usually it can regress spontaneously. The “leukemic clone” is in any case always trisomic, according to observations made in (mosaic) trisomy 21/2n patients. In 25% of cases of these leukemoid reaction, one observes subsequently, over a period of 3 years, the onset of megakaryoblastic leukaemia (Zipursky, 1987; Rogers, 1978). Most leukemias had in the past a more unfavorable course in Down patients than in nontrisomic individuals (Robison, 1987) (due both to intervening infectious diseases (Robison, 1987) and to severe methotrexate toxicity for forms of ALL and those diagnosed as such), (Peeters, 1987). ALL and AML are now thought to develop with equal frequency (1 in 300). Patients with DS given standard treatment for ALL now have 5-year survival outcomes similar to patients without DS, although they tolerate treatment poorly. (Roizen et al 2003) while Down children with AML have a very high rate of event-free survival after chemotherapy (1-β-D-arabinofuranosylcytosine) (Taub, 1996). The favourable response of AML in DS is at least in part attributable to the increased sensitivity of myeloid leukemic blasts in DS to cytotoxic agents such as cytarabine (Hitzler, 2007). 2) Down Syndrome and Thyroid Disorders While significant impairment of certain immune parameters had been known for a long time, a prevalence of antithyroid autoimmunity, already demonstrated at the time in Down children (Burgio 1965), received the incisive addition of a progressively better documented thyroid pathology. Thyroid disorders have been reported to have a prevalence rate of 3-54% in persons with DS: this large range depends primary on the age of the population tested (frequency increases with the age), secondary from the clinical and laboratory criteria used for defining hypo- or hyper-thyroidal a DS person. In 1903, Bournville reported a pathological association between DS and thyroid disorders. The acquired hypothyroidism (AH) is the condition most frequently diagnosed in DS and its prevalence increases with the age of the population tested. The congenital hypothyroidism (CH) is also increased in DS newborns. Hyperthyroidism has been also reported in DS children. (Gilchrist, 1946) A peculiar condition associated with 21 trisomy is the isolated raised TSH (IR-TSH), or compensated hypothyroidism, which resolves quite often spontaneously. Maranon et al. in 1951 described the first DS person with hypothyroidism. Acquired hypothyroidism (AH) has been ascribed mostly to the higher prevalence of autoimmune disorders in DS but in pre-school and elementary school age AH is usually not associated with autoantibodies (Karlsson 1998). It is still debated whether the CH incidence as diagnosed on the screening measurement of TSH and T4, is really increased in DS newborn as most of the TSH increases will return to normality by the end of the first year of life. Some authors suggest that reference values specific for DS should be created for DS subjects since TSH and T4 values are shifted to the right and to the left respectively when compared to the general population. (Prasher V, 2005). Despite this uncertitude, most of the publications of the last 40-50 years, have repeatedly shown a definite association between DS and thyroid disorders. At present three different thyroid disorders can be reported (Table 2).

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Hypothyroidism: Maranon et al. in 1951 described the first DS person with hypothyroidism. A lifetime prevalence of approximately 25-30% could be suggested (Prasher 1999).Two type of hypothyroidism should be considered: congenital (CH) and acquired (AH). Congenital hypothyroidism (CH), or primary hypothyroidism, is more common in DS patients than in general population. Forth et al in 1984 reported a prevalence of CH in DS neonates as high as 0.12% (28 times higher than for general population). In a population based observational study on Dutch newborns, Van Trotsenburg et al (2003) found a sevenfold increase in the prevalence of CH as diagnosed by the T4 value on the newborn blood spot screening (3.5% vs 0.5%). At the follow-up only 2 had the diagnosis of true CH. In 2001 Tüysüz on a population of Turkish children found a prevalence of 1.8% in DS newborns while 25.3% of them had compensated hypothyroidism. Table 2. Thyroid disorders in DS (modified from Prasher, 1994)

HYPOTHYROIDISM ISOLATED RAISED-TSH (IR-TSH) (subclinical/compensated hypothyroidism) HYPERTHYROIDISM

FREE T4 Low (< 9 pmol/L) Normal (9-24 pmol/L)

TSH High (> 5mU/L) High (> 5mU/L)

High (> 9 pmol/L)

Low (<0.5 mU/L)

Definition of CH has been subjected to continuous re-evaluation since most of these newborns when tested few weeks later showed a normal thyroid function. It is therefore questionable according the majority of the AA to label this condition as true congenital hypothyroidism whereas it seems more appropriate to consider this condition as an isolated increase of TSH (see the following paragraph). We will therefore consider only the congenital persistent hypothyroidism. At variance from the condition present in general population, the thyroidal dysgenesis (ectopy or agenesis) is not more frequent in DS. The coexistence of DS with severe persistent primary congenital hypothyroidism with a normally located gland of normal or increased size, reported in a few cases, may represent a chance association (Van Vliet G, 2005). The acquired hypothyroidism (AH), mostly from autoimmune thyroid diseases (Hashimoto thyroiditis), is much more common in DS. Its prevalence is better established as compared to the congenital form (Goldacre et al 2004). It increases with age up to 25-30 % of DS adults (Prasher 1999). The prevalence of autoimmune thyroid disease is at least fourfold higher in DS children than in general population. Other autoimmune diseases such as celiac disease and type 1 diabetes are also more common among DS people (10-40 times for celiac disease and 4 times for diabetes). DS therefore appears to confer susceptibility to multiple forms of autoimmunity, although no mechanism has been proposed to explain this phenomenon. Some specific genes linked to different autoimmune disorders (celiac disease, type 1 diabetes, thyroid disease) such as DR4-DQ8 and DR3-DQ2 are not overrepresented in DS. The excess susceptibility to autoimmunity is therefore not attributable to differences in HLA (Gillespie KM, 2006). The possibility still exists that genes, such as AIRE gene located at 21q22.3, on chromosome 21 may increase the entrance of these autoimmune disorders (Aaltonen et al, 1999, Gillespie, 2006).

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We should also take in account the existence of an altered immune system in DS which mainly affects the cellular compartment, T cell-dependent, leading to a precocious ageing of the most important immune functions as the immune surveillance (Nespoli, 1993). Thyroid autoantibodies are found in 13-34% of patients with DS (Burgio, 1965). The role of thyroid autoimmunity as causative event in AH has been extensively assessed in a group of 93 DS persons from the Uppsala county in Sweden followed up for several years from entering the school to the age of 25 with very interesting results: AH, raised serum concentration of TSH and either low serum concentration of T4 or marginally low concentration of T4 associated with symptoms of hypothyroidism, was diagnosed in 28 of the 85 Ds people that were regularly submitted to the follow-up. Half of the AH cases acquired the disorders by the age of 8 years, the remaining half appeared between 9 and 25 years of age. A significant difference was observed between the 2 groups as far as autoantibodies against thyroid peroxidase or thyroglobulin are concerned: only 1of the younger AH subjects was positive for autoantibodies, whereas ~ 80% of those older than 8 years were positive (Karlsson 1998). Among the euthyroid DS the prevalence of autoantibodies was ~15%. These data suggest that the insufficient thyroid size might cause AH before 8 years of age whereas autoimmunity has a pathogenetic role after that age. Thyroid autoantibodies are repeatedly found in 29-40% of DS persons, suggesting an autoimmune basis for the different thyroid abnormalities. Another group of researchers have tested the thyroid function in 122 DS children (age 1-14 years) and then repeated the tests 4-6 later in 103 adolescents (age 10-20 years) (85% of 122 initial group). At the second test 2 were hypothyroid and 2 were receiving thyroxin because of isolate raise of TSH. They found that the likelihood ratio for a positive result at second testing when raised TSH and positive autoantibody status on first testing are combined, is 20. The association between positive autoantibodies on first testing and a second abnormal test (combining hypothyroidism, IR-TSH, and positive antibodies) was significant, but not with hypothyroidism on its own (Noble et al, 2000). Therefore they suggested that, at variance with the AAP statement, annual screening for thyroid functions should be limited to the high risk group after the childhood (A.A.P., 2001; Gibson 2005). The regular, repeated testing during adolescence may not be accepted because it require a venipuncture causing that the correct diagnosis and the required treatment are missed with negative consequences on the health status of these subjects. It is well known how DS and AH have common features (constipation, dry skin, slow growth velocity, hair loss, overweight, learning difficulties) which render the clinical diagnosis very difficult and delayed. Recently a group from Scotland has shown the feasibility and reliability of a dried blood spot TSH screening by capillary testing on a group of 204 DS persons, aged 4-19 years. Those scoring positive for high TSH were assessed for T4 and autoantibodies. Hashimoto thyroiditis was diagnosed in 7/15 while 8/15 has an isolated raised TSH (IRTSH). The screening allowed a prompt treatment that would have not been possible only on the clinical ground assessment: symptoms of AH were very few and the reduced height was non-contributory, with 10 of the 15 children on or above the 50th percentile on Down’s specific height percentile charts. The AH should be promptly treated with substitute therapy to avoid the negative effects on the brain development, on the growth and on the final height (Gibson, 2005).

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Isolated raised TSH (IR-TSH) or subclinical hypo-thyroidism: IR-TSH is variably present in DS neonates (19-60%).The cause of the IR-TSH has not been elucidated. It might indicate a predisposition in young people with DS to a self-limiting autoimmune process without clinical symptoms. After the neonatal period autoantibodies did correlate with IRTSH but not with hypothyroidism. The presence of anti-TPO autoantibodies may be a marker for a potential risk of developing AH. (Dias VMA et al, 2005). Other possible mechanisms are: (A) an inappropriate release of TSH related to a central disorder which can persist up to the age of three years (Oliveira ATA, 2002); (B) the production of less active TSH (Konings, 2001); (C) TSH insensitivity of the thyroid gland. (Tonacchera et al 2003). Konings et al 2001 did show a normal TSH bioactivity in DS children, indicating that increased TSH in these patients is of thyroidal origin. They suggested that “the thyroid gland in these children needs an elevated TSH pressure to produce sufficient thyroid hormones”. A delay in the maturation of the hypothalamic-pituitary-thyroid axis is hypothesized as the probable cause and TSH response to TRH was shown to be more exaggerated in these patients (Tuysuz, 2001). Although an autoimmune mechanism underlying IR-TSH is accepted by many AA, this condition should be distinguished from reduced biological activity of TSH as investigated by Konings and from the rare inherited condition of thyroid resistance to TSH. Tonacchera et al (2003) have carried on the genetic analysis of TSH receptor and GS (alpha) genes (two proteins known to be involved in mild TSH resistance) and excluded the role of TSH receptor or Gs(alpha) gene mutations in the pathogenesis of the non-autoimmune IR-TSH, sub-clinical hypothyroidism. Most authors agree that this condition should not be treated. Van Vliet (2005) says that “it is questionable to label as hypothyroidism this shift of thyroid function values of the whole population with DS, especially in view of the fact that they do not seem to be associated with abnormal myocardial structure and function”. Discussion exists also on the opportunity to treat with thyroxine these children: some AA agree that treatment should be offered but others strongly disagree and ask for a randomized, double blind controlled study. Several research groups have challenged the assumption that IR-TSH is a benign condition. Van Trostsenburg, (2005) treated in a placebo-controlled trial a group of newborns with IR-TSH, with thyroxine and was able to show that the treated group had 0.7-month smaller motor delay as well as greater gains in length and height. Tuyusuz (2001) treated the DS patients with TSH ≥11 and ≤ 20 mU/L and felt that they prevented frank hypothyroidism in children whose thyroid function was not stable. Further studies will clarify the opportunity to treat these subjects. Hyperthyroidism (HT): The first case of a DS person and clinical hyperthyroidism was reported in 1946 (Gilchrist). This disorder is the last common among DS people. The incidence of hyperthyroidism is higher in children with DS than in normal population (Pozzan, 1990; Pueschel, Pezzullo, 1985). Few patients with elevated anti-TPO levels developed HT, probably due to Graves’ disease (Dias VMS, 2005) Occurrence of asymptomatic transient HT has been reported in DS patients without detectable antibodies. The mechanisms of this thyroid dysfunction have not been clarified yet.

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3. Less than 20 years ago, the substantial prevalence of celiac disease (CD) in DS was added to these first scenarios of substantial autoimmune pathology. Today it is acknowledged that the prevalence of celiac disease in the general Caucasian population is 1/1331 (Fasano, 2003) and that for Down subjects it is on the order of 5-15% (Cohen, 2006). In contrast with 69% of classic forms of CD in Down patients, 11% atypical ones are reported; latent forms constitute approximately 20% (Bonamico, 2001); likewise, the prevalence of silent forms in the general population of the United States is reported to be of this extent (Zachor, 2000). The first reports of significant prevalence of CD in trisomy 21 are dated 1990 (Dias, 1990). The following factors of the celiac way of reacting are known: the causal “environmental” factor which determines it (gluten) and the “genetic” factor which predisposes for it, which is identified as the DQ2 heterodimer of the HLA-MHC system and, with lower prevalence, as the DQ8 heterodimer. Intestinal tissue stress (essentially hypertrophy of the crypts and atrophy of the villi) also includes a certain increase in intercellular spaces [which is zonulin-dependent (Fasano, 2000)] which in turn facilitates a less selective absorption of gluten peptides and possibly of other derived molecules released by the digestive process. We are, therefore, faced with a sort of “reverse malabsorption”23 which actually adds itself to the typical malabsorption of nutrients which is typical and fundamental of celiac disease, caused by atrophy of the intestinal villi and responsible for malnutrition, poor stature increase, hypochromic or macrocytic anemia. An excessive absorption of antigens by the celiac intestine and, therefore, a facilitated immune-autoimmune stimulation can indeed be attributed to a reverse malabsorption (Burgio, 1991). The diagnostic procedure for CD in DS is not different from the one usually used when CD is suspected in non-trisomic subjects (Naspghan, 2005). Early recognition of CD in a Down patient will prevent, with an appropriate diet, celiac damage from adding itself to the biological-physiopathological profile of trisomy 21 (Cohen,2006). It has been debated whether it is appropriate to investigate extensively in Down patients the occurrence of other autoimmune disorders (type 1 diabetes and autoimmune thyroiditis) (Cohen, 2006). The appropriateness of applying CD screening extensively in these children also is considered uncertain, (Cohen, 2006) although the 1999 Health Care Guidelines DSMIG US recommended an initial screen at age 2 years and NASPGHAN (2005) recommends an initial screen at 3 years. Nevertheless there is no evidence of morbidity associated with the failure to detect silent or asymptomatic CD in children with DS (Catassi, 2002). In the absence of proven benefit, making recommendations to treat these “CDasymptomatic” children with a gluten-free diet may impose an unnecessary burden (Cohen, 2006). Established knowledge that those who have neither DQ2 nor DQ8 are at minimal risk of CD justifies their exclusion from repeated tests. 4. The prevalence of a certain overweight has long been acknowledged as typical of the somatic profile of DS in addition to a certain reduction in height. But today it is obesity that has attracted considerable interest in metabolism together with some correlations between type 2 (insulin-resistent) diabetes mellitus and DS and with some cutaneous expressions typically acanthosis nigricans (Munoz-Perez, 2001). Reduction in body length at birth in DS

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is a prelude to slower stature increase and to an ultimately low adult height. The “stature growth model” that has been found to be characteristic for DS has long justified the use of specific “charts” (Rarick, 1974; Cronk, 1988). Trisomy 21 individuals lack the doubling of plasma values of IGF-I that normally occurs between early childhood and adult life (Epstein, 2001). However, plasma values of GH in children with DS are not reduced. In them, however, treatment with this hormone between 3.5 and 6.5 years of age resulted in increases in the levels of both immunoreactive IGF1 and IGF2, and 50 to 200 percent increases in growth velocity (Annerén, 1986). Down children and adults tend to be overweight (Cronk, 1988; Bronks, 1985). Although in itself the stature reduction affects the duration (and quality) of life scarcely or not at all, the opposite must be said for obesity, in view of its easy association with (predisposition to) “metabolic syndrome” (resistance to insulin, hypertension, atherosclerotic and cardiovascular damage), (Eckel, 2005) which may affect with increasing frequency the Down population, which is reaching a progressively older age. Unsurprisingly, it has been observed that obesity, hypothyroidism, epilepsy, dementia, and Alzheimer’s disease are known to become increasingly prevalent in DS in later life (Rubin, 1998; Glasson, 2002). 5) Down Syndrome and Immunity Dysregulation of the immune system is one characteristic pathological feature of DS, and accounts for increased susceptibility to viral and bacterial infections and, possibly, to childhood leukemia (Fong, et al., 1987). DS has been associated with decreased phagocytic activity of neutrophils, decreased microbicidal activity, deficient chemotaxis as well as accelerated apoptosis of neutrophils (Yasui et al, 1999, Garrison et al, 2005). The high mortality from bacterial infections, the significantly elevated risk of mortality and the high frequency of HBsAg carriers among instituzionalized DS persons are interpreted as supportive for an abnormal immune response (Hawkes et al., 1980; Garrison, 2005). Similarly to other aspects, such as Alzheimer-like brain lesions and neurodegeneration, a precocious senescence of the immune system has been hypothesized as a co-factor at least (Cuadrado et al., 1996; Novo et al., 1993). The DS has been proposed as a model of precocious ageing by Burgio (1974). It has indeed been shown that both thymus dependent and thymus independent functions start deteriorate early, during the initial phases of the development of the immune system, and of worsening progressively with ageing (Lockitch et al., 1987). Recently De Hingh has confirmed studying the peripheral blood nucleated cells in DS children the absence of the expansion of lymphocytes in the first years of life (2005). At birth, the thymus gland in DS subjects is smaller than in age-matched normal controls. Marked thymocyte depletion and poor corticomedullary demarcation are evident together with a thin cortex, and an increased number of Hassall corpuscles (Levin et al., 1979). DS thymocytes express low levels of the CD3 antigen as well as of the alpha-beta chains of the T-cell receptor (Murphy, Epstein, 1990; Murphy et al., 1993). The integrin, lymphocyte function associated antigen-1 (LFA-1) whose -chain (CD18) of LFA-1 is encoded on chromosome 21, is upregulated in lymphocytes of DS patients (Taylor et al., 1988). According to the Murphy hypothesis (1993), the overexpression of LFA-1 could be responsible for the increased adhesiveness of DS lymphocytes that would result in abnormalities in their development and function (Murphy et al., 1993). Abnormalities of

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LFA-1 usually impair the lymphocyte maturation and activation (Larson, Springer, 1990). These findings suggest a reduced expansion of T-cell precursors and possibly an incomplete cell repertoire (Musiani et al, 1990; Ugazio et al., 1990). Mice with a null mutation in the gene that code for LFA-1 show defects in immune function: impairment in the cytotoxic activity towards allogenic spleen cells and cell line targets, in tumor rejection, despite a normal in vitro NK cell activity (Shier et al., 1996). Moreover, the increased expression of intercellular adhesion molecule (ICAM)-1, which is the counter-receptor of LFA-1, on thymic epithelium fits with the theory that the immunodeficiency in DS individuals is likely due to excessive thymic deletion caused by overexpression of LFA-1 (Murphy et al., 1993). The theory that lymphocyte hyperadhesiveness could be one of the factor that contribute to immunodeficiency in DS has not been supported by the data by Lin et al who failed in confirming an age-associated LFA-1 up-regulation and impaired ICAM-1 binding in lymphocytes from DS individuals (Lin et al., 2001). They also found that DS children less than 2 years of age expressed a higher level of LFA-1 when compared with age-matched controls, but the difference in LFA-1 expression was much less significant in older DS individuals, when compared with age-matched children. These authors conclude that a generalized pathological process, such as early senescence of the immune system and ineffectiveness in activating lymphocytes, rather than pure lymphocyte hyper-adhesiveness, may underlie the immune function defects in older DS individuals (Lin et al., 2001). Another gene, named AIRE (autoimmune regulator), has been identified on chromosome 21q22.3 by positional cloning (Aaltonen et al., 1999). This gene codes for a protein that contains DNA-binding domains and is located in both the nucleus and cytoplasm (Aaltonen et al., 1999). Nonsense or missense mutations of AIRE gene has been identified as the cause of a familial immunodeficiency and autoimmune endocrinopathy (Bjorses et al., 2000). The role for this gene, which is likely to be up-regulated in DS individuals, could be detrimental, especially in a condition characterized by the LFA-1 upregulation and activation of integrinmediated adhesion. Significant differences in the lymphocyte subpopulations in DS children and adults, when compared with age-matched normal subjects, have also been reported (Maccario et al., 1984; Barena et al., 1993; De Hinch et al., 2005). The number of CD8+ T cells was increased in DS individuals, whereas that of CD4+ T cells was decreased; this decrease in the CD4+ subset subpopulation was due to the low proportion of CD4+ CD45RA+ naive lymphocytes (Barena et al., 1993). The elevated number of circulating CD8+ lymphocytes is related to the high percentage of cells with NK phenotype (CD57+CD16+), only some of which express CD3 antigen (Maccario et al., 1984). These data further support the hypothesis that abnormalities in the development of the lymphocytes occur in DS. Others researchers found that peripheral CD4+ T-cells were decreased in children with DS, but in their series mean values of cytotoxic CD8+ T-cells were comparable with those from healthy children (Corsi et al., 2003). They also reported an increase in circulating activated (CD3/HLA-DR positive) Tcells, and in purified T-cells that were positive for APO-I/Fas (CD95) antigen (Corsi et al., 2003). However, these data on CD4+ T cell decrease in DS have not been confirmed in a study by Lin et al. (2001), whereas proportions of memory lymphocytes expressing the CD45RO isoform were found to be higher in both younger and older DS individuals, when compared with age-matched control groups (Lin et al., 2001). More recently De Hinch et al.

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(2005) have numbered the lymphocyte subpopulations in a group of DS subjects from infancy to complete adolescence and found very similar results (Figure 2).

Figure 2. The median absolute size (x109/L) of the main lymphocyte subpopulations in pheripheral blood. Values of the children without DS are shown as light-gray bars; those of children with DS (n=96) as dark-gray bars. The age ranges of the different groups are indicated: A total lymphocytes; B T lymphocytes; C B lymphocytes; D NK cells; E helper T lymphocytes; F cytotoxic T lymphocytes. Statistical significance: *p<.05 and **p<.01 NS, not statistically significant (modified from De Hingh et al, 2005).

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The most striking feature of DS children was the absence of expansion of lymphocytes that occurs in control children during the first years of life. In the 9- to 15-month age group, DS children had median total lymphocyte counts below those of the controls. This pattern is reflected in the absolute counts of T and B lymphocytes. T-lymphocyte subpopulations gradually reached normal values (Figure 2). B cells remained low throughout childhood, however, and were the most severely decreased population in all age groups. Eighty eight percent of the DS children had a value below the 10th percentile. These observations point to the fact that in DS children the massive activation, proliferation, and maturation of T and B lymphocytes that occurs in karyotypically normal children is lacking. Of special interest is the observation that the occurrence of infections, as well as of autoimmune phenomena does not correlate with the variations in the lymphocytes subpopulations (De Hinch et al., 2005). The in vitro proliferative response to the T-cell mitogens PHA and ConA has been reported in the normal range during the first decade, but decreased thereafter progressively (Burgio et al., 1974; Burgio et al., 1975) (Figure 3). By using a novel animal model of DS (Tc1 mouse), O’Doherty and Colleagues studied the T cell receptor (TCR)–induced activation of T lymphocytes (O'Doherty et al, 2005), which has been reported to be defective in DS (Scotese et al., 1998). The Authors consistently found that both CD4+ and CD8+ T cells from both spleen and lymph nodes of Tc1 mice upregulated CD25 (a marker of regulatory T cells) and CD69 (a marker of T cell activation) to a lesser extent than wild-type cells, in response to stimulation either through the TCR alone with antibodies to CD3 or in combination with antibodies to the costimulatory receptor CD28 (O'Doherty et al., 2005). In humans, it has been demonstrated a reduced response to anti-CD3 in DS. (Bertotto et al., 1987) The production of IL-2 is also reduced in cultures stimulated with PHA (Ugazio et al., 1990). Scotese and Colleagues also reported that a T cell activation defect seems to particularly depend on a partial impairment of signal transduction after TCR/CD3 complex engagement (Scotese et al., 1998). This defect did not prevent phorbol ester and ionomycin from inducing proliferative responses of DS lymphocytes. Cumulatively, these data suggest that regulatory circuitries, which involves specific T cell subsets, and defects in T cell activation could contribute to the generation of abnormal immune responses in DS. NK activity is abnormally low in the majority of DS subjects as well as the antibody-dependent cellular cytotoxicity and lectindependent cellular cytotoxicity. Consistent data indicate that DS individuals have also abnormalities in the humoral immunity. Before 6 years of age, serum immunoglobulin concentration did not differ between DS children and age-matched healthy controls, whereas, after that age, considerable hyper-IgG and hyper-IgA were found. DS was also characterized by high concentrations of IgG1 and IgG3 subclasses, which are involved in IgM switch and are related to IFN-gamma stimulation and Th1 activation, and a progressive age-dependent decline of IgG2 and IgG4 subclasses, which are mostly related to Th2 activation and allergy. Response to vaccination was shown to be impaired, as the presence of a protective antibody titres in DS children vaccinated for hepatitis B virus was 17%, in comparison with 75% detected in healthy controls (Nespoli et al., 1993). The immunodeficiency also affects the lower response rate to vaccination in DS children and adults, in comparison with agematched subjects (Ahman et al., 1993).

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Figure 3. PHA responsiveness of peripheral blood lymphocytes from DS patients of different ages ages (—–) as compared with karyotypically normal controls (- - - -). Data re expressed as mean ± SD. The number of subjects in each age group is given in parentheses (from Burgio GR et al 1975).

In contrast, natural antibodies against intestinal antigens are low, while in the presence of cow’s milk, abnormally high titres against casein and beta-lactoglobulin were present. High levels of IgG antibodies against gliadin, and autoantibodies against various thyroid antigens are found with a higher frequency in serum of DS individuals (Nespoli et al., 1993). Recently, Chaushu et al found that the concentration of parotid salivary IgG and IgA was decreased (IgG by 83%, and IgA by 75%) in DS individuals in comparison with age- and sex-matched healthy controls (Chaushu et al., 2002). These data would be in line with the observed high prevalence, extent and severity of periodontitis in DS persons (Zigmond et al., 2006). Data in the literature suggest that molecules and receptors usually operating in adaptive immunity may also be implicated in neurodevelopmental abnormalities and neurodegeneration in DS and trisomy 16 mice (Tan et al., 1974, Tan, 1976; Lin et al., 1980; Epstein, Epstein, 1983). In addition to the brain abnormalities that are detectable both in DS and Alzheimer dementia (Wisniewski et al., 1985), other neuropathological features shared by DS and trisomy 16 mice include decreased brain weight and decreased neuron number and density (Coyle et al., 1986; Lacey-Casem, 1994). The chromosome 21 complete DNA sequencing shows that several structurally and functionally related genes form clusters, for examples the keratin-associated proteins, the trefoil peptides, and, interestingly, the interferon cytokine receptors (Hattori et al., 2004). Table 3 shows the genes that are located on chromosome 21 and involved in immunity. The two genes IFNAR1 and IFNAR2 code for IFN-alfa -beta-and -omega receptor 1 and receptor 2, the IFNGR2 codes for IFN-gamma receptor 2. Other genes on chromosome 21 that are

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linked to the IFN system are MX1 and MX2 that code for IFN inducible proteins involved in responses to virus infections (Table 3) (Franciotta et al., 2007). Table 3. Genes mapped to human chromosome 21 that are specifically involved in immunity (Franciotta, 2007) Gene CRFB4 IFNAR1

IFNAR2 IFNGR2 ITGB2

MX1

MX2

Protein CRF2-4 Cytokine receptor family II, member 4 IFRC IFNAR Interferon (alfa, beta, omega) receptor 1 IFNABR Interferon (alfa, beta, omega) receptor 2 IFNGT1 Interferon gamma receptor 2 (interferon gamma transducer 1) MF17 CD18 LFA-1 Integrin, beta2 [macrophage antigen 1 (mac-1)beta subunit; antigen CD18 (p95), lymphocyte function-associated antigen 1] IFI-72K MxA myxovirus (influenza) resistance 1 myxovirus (influenza) resistance 2

Gene location 21q22.1 21Q22.2 21q22.121q22.1 21q22.121q22.1 21pter 21qter 21q22.321q22.3

21q22.321q22.3 21q22.1 21q22.3121q22.3

Knock out mice that lack IFNAR1 demonstrated a compromised ability to withstand viral infections. Mutant mice that do not produce MX proteins show increased susceptibility to influenza virus infection (Staeheli et al., 1988). An additional gene on chromosome 21, namely CRFB4, is a member of the class II cytokine receptor family, which includes the IFN receptors (Lutfalla et al., 1995). Therefore, many genes that function in the IFN signalling pathways, or that are structurally related to IFN receptors, localize to human chromosome 21. In a group of adult subjects with DS or mental retardation we found that the percentages of IFN-gamma-producing CD4+ and CD8+ T cells, namely Th1 and Tc1 cells, and the Th1/Th2 ratio in DS were significantly higher in DS subjects (Figure 4, Franciotta et al., 2006). Interestingly, nearly all the DS subjects with high Th1 or Tc1 cell percentages were also seropositive for anti-transglutaminase IgA, a biomarker of celiac disease. No correlation between high Th1 or Tc1 cell percentages and sex, age, APOE genotypes, coexisting autoimmune diseases, susceptibility to infections, or cognitive impairment was found. Therefore, it is likely that the substantial up-modulation of IFN-gamma-producing CD4+ and CD8+ T cells that we found in our DS series could be among the many factors involved in DS-correlated immune dysregulation.

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% IFN-γ-producing T cells

54

75

Down's syndrome Mental retardation Healthy controls

50

25

0 Figure 4. Percentage of CD3+ IFN gamma producing cells from peripheral blood of patients with Down’s syndrome (DS), individuals with mental retardation (MR) and healthy controls (HCs). Dotted bar, reference value; horizontal bars, mean value; vertical bars, S.E.M (from Franciotta, 2006).

REFERENCES Aaltonen, J., Bjorses P. (1999) Cloning of the APECED gene provides new insight into human autoimmunity. Ann Med, 31, 111-6. Abbeduto, L., Murphy, M.M., Richmond, E.K., Amman, A., Beth, P., Weissman, M.D., Kim, J.S., Cawtho, S.W. & Karadottir, S. (2006) Collaboration in refential communication: Comparison of youth with Down syndrome or fragile X syndrome. Am J Ment Retard, 111, 170-183. Ahman, L., Back, E., Bensch, K. & Olcen, P. (1993) Non-efficiency of low-dose intradermal vaccination against hepatitis B in Down's syndrome. Scand Infect Dis, 25, 16-23. Aldridge, K.; Reeves, R.H.; Olson, L.E. & Richtsmeier, J.T. (2007) Differential effects of trisomy on brain shape and volume in related aneuploid mouse models. Am J Med Genet, 143(A), 1060–1070. Allore, R., O’Hanlon, D., Price, R., Neilson, K., Willard, H.F., Cox, D.R., Marks, A. & Dunn, R.J., (1988) Gene encoding the beta subunit of S100 protein is on chromosome 21: implications for Down syndrome. Science, 239(4845), 1311-3. American Academy of Pediatrics, Committee of Genetics (2001) Health supervision for children with Down syndrome. Pediatrics, 107, 442-449. American Psychiatric Associations. (1994) Diagnostic and Sratistical Manual of Mental Disorders DSM-IV-TR Fourth edition (text revision), APA Annerén, G., Sara, V.R., Hall, K. & Tuvemo, T. (1986) Growth and somatomedin responses to growth hormone in Down's syndrome. Arch Dis Child, 61, 48. Baird, P.A., Sadovnick, A.D. (1987) Life expectancy in Down Syndrome. J Pediatr, 110, 849-54.

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Wahrle, S., Das, P., Nyborg, A.C., McLedon, C. et al. (2002) Cholesterol-dependentsecretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis, 9, 11-23. Wark, H.J., Overton, J.H. & Marian, P. (1983) The safety of atropine premedication in children with Down’s syndrome. Anesthesia, 38, 871. Whittle, N., Sartori, S.B., Dierssen, M., Lubec, G. & Singewald, N. (2007) Fetal Down syndrome brains exhibit aberrant levels of neurotransmitters critical for normal brain development. Pediatrics, 120(6), 1465-71. Wisniewski, K.E. (1990) Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet Suppl, 7, 274-81. Wisniewski, K.E., Wisniewski, H.M. & Wen, G.Y. (1985) Occurrence of neuropathological changes in dementia of Alzheimer’s disease in Down syndrome. Ann Neurol, 17(3), 278282. Yang, Q., Rasmussen, S.A. & Friedman, J.M. (2002) Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet, 359, 101925. Yasui, K., Shinozaki, K., Nakazawa, T., Agematsu, K. & Komiyama, A. (1999) Presenility of granulocytes in Down syndrome individuals. Am J Med Genet, 84, 406-412. Zachor, D.A., Mroczek-Musulman, E. & Brown, P. (2000) Prevalence of celiac disease in Down syndrome in the United States. J Pediatr Gastroenterol Nutr, 31, 275-9. Zigman, W.B., Lott, I.T. (2007) Alzheimer's disease in Down syndrome: neurobiology and risk. Ment Retard Dev Disabil Res Rev, 13(3), 237-46. Zigmond, M., Stabholz, A., Shapira, J., Bachrach, G., Chaushu, G., Becker, A., Yefenof, E., Merrik, J. & Chaushu, S. (2006) The outcome of a preventive dental care programme on the prevalence of localized aggressive periodontitis in Down’s syndrome individuals. J Intellect Dis Res, 50(7), 49. Zipursky, A., Peeters, M. & Poon, A. (1987) Megakaryoblastic leukemia and Down's syndrome: a review. In E.E. McCoy, C.J. Epstein (Eds.), The Oncology and Immunology of Down Syndrome. New York. Liss.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter III

LIFE SPAN DEVELOPMENT IN TURNER SYNDROME (TS) Annapia Verri1,∗, Valeria Destefani2, Anna Cremante3 , Carla Uggetti4 and Daniela Larizza5 1

Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, Pavia, Italy; 2 Laboratory of Cognitive-behavioral Psychology, Neurological Institute C. Mondino Foundation, Pavia, Italy; 3 Paediatric Clinic, University of Insubria, Varese, Italy; 4 Neurological Institute C. Mondino Foundation, Service of Neuroradiology, Pavia, Italy; 5 Paediatric Department, University of Pavia, Italy.

ABSTRACT Turner Syndrome (TS) has been associated with different psychiatric conditions: social anxiety is considered a characteristic trait of the syndrome and clinical associations with psychotic disorder are also well known in literature. Recently we diagnosed TS in two patients in different life stage: adolescence and adulthood. The first case deals with a 15 years old girl who came to observation for the recent onset of a school refusal behavior while attending the first class at the socio-psychopedagogical lyceum. The second case deals with a 51 years old woman affected by TS and Psychotic Disorder, with a prevalent somatic and sexual focus. Aim of the present study is to describe the relationship between clinical and genetic phenotype and its role in the development of the psychopathologic condition.

∗

Correspondence concerning this article should be addressed to: Dr. Annapia Verri, Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, via Mondino, 2 – 27100 Pavia, Italy. e-mail: [email protected].

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Annapia Verri, Valeria Destefani, Anna Cremante et al. Both patients underwent a complete cognitive and behavioral assessment supported by psychometric and diagnostic instruments (WISC-R, Colored Progressive Matrices, Token Test, Rey Figure, Stroop Test, BSRI) and a clinical and neuroradiological evaluation (MRI). Peculiarities of their cognitive-behavioral phenotype, including visual-spatial ability, attention, working memory, and spatially dependent executive function, are presented and discussed. In conclusion, both our cases underline the importance of investigating psychiatric comorbidities (school refusal and separation anxiety, psychosis) in TS.

Keywords: Turner syndrome, school phobia, psychosis.

INTRODUCTION Turner syndrome (TS) is one of the most common chromosome abnormalities with an estimated frequency of 1%-2% among the recognised pregnancies (Jacobs 1997). 70-80% of the 45,X subjects retain the maternal X chromosome and the other 20-30% retain the paternal X (Martins, 1999). TS is also a developmental disorder associated with neuropsychological and behavioral deficits (Lesniak-Karpiak et al., 2003). The clinical phenotype is characterized by short stature, ovarian failure, webbed neck (50%), wide carrying angle (50%), broad chest with widely spaced nipples (60%), low posterior hairline (75%) associated with well described neurocognitive dysfunction (Ross et al., 2000). Short stature is not due to growth hormone deficiency as such, but is associated with the deletion of the distal portion of the short arm of the X-chromosome, which contains genes that are important for normal growth. Short stature reflects a generalised growth defect that manifests in utero, and not simply the absence of the pubertal growth spurt. Growth hormone treatment (not replacement therapy), usually started in early childhood may be associated with an increase in adult height of 8-10 cm at best. Moreover, there is a failure of secondary sexual characteristics development in most cases, and oestrogen replacement therapy is now given routinely in adolescence. The ovaries fail to develop, and the uterus and vagina are often small and immature. Other physical features are much more variable. Most investigators believe that the phenotype in TS is the result of a deficiency of specific genes, most of which are as yet unidentified, rather than to the consequence of the presence of a single X chromosome (45,X) per se. Cytogenetically, there is great variability within the Turner population in terms of chromosomal constitution. Approximately 50% of patients have a single X-chromosome in all cells examined, of which most (70%) are maternal in origin. The great majority of the other 50% are mosaics, possessing at least two cell lines, one of which is 45,X. A small proportion has an additional normal 46,XX cell line (5%). In the remainder (40%) there is a second X which is structurally abnormal. In a few cases (6%), there is a structurally abnormal Y. The presence of a partial Y chromosome increases the risk of gonadoblastoma in situ, but how risk relates to the structure of that partial Y, or to specific Ylinked genes, is as yet uncertain. There is a significantly increased risk of global learning difficulties and behavioral maladjustment in nearly 30% of mosaic Turner subjects with a ring-X chromosome.

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Most TS present normal verbal IQ; on the other hand they exibit impaired visuo-spatial, spatial perceptual, motor and attentional abilities and executive functions (McCauley 1987; Romans, 1998). The cognitive phenotype generally includes normal verbal function with relatively impaired visual-spatial ability, attention, working memory, and spatially dependent executive function. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies (Skuse et al., 1997). Furthermore, other determinants, including an additional genetic mechanism, imprinting, may also contribute to cognitive deficits associated with monosomy X (Ross et al, 2006). Recently discalculation associated with structural and functional alteration in right intraparietal sulcus has been described (Molkov, 2003; Bruandet, 2004) so that TS has been indicated as a potential etiology of nonverbal learning disability (Lesniak-Karpiak et al., 2003). The hypothesis of defective right hemisphere specialization has been proposed to explain the visuospatial deficits in TS. In contrast, an alternative explanation proposes a more uniform dysfunction of the left and right hemispheres, based on findings of symmetrical abnormalities (Ganou & Grouios, 2007; Rae et al., 2004). Behavior difficulties in TS subjects are characterized by immature social relationships, poor scholar performance and low self-esteem in early adolescence (Romans, 1998). Obsessive-compulsive symptoms are also common throughout childhood and adolescence, and clinical experience suggests they become more disabling in early adulthood (El Abd et al., 1995). Gender role development in TS has been studied with the aim to establish the importance of the second X chromosome and of the phoetal ovary in determinating behavior characteristics of the female population (Downey, 1987) that is the parent-of origin effect of the X chromosome (Donnelly, 2000). Results suggested that feminine gender identity and role behavior depend neither on the second X chromosome nor on the phoetal ovary. Identity development in TS has been considered always true feminine. Women with Turner syndrome report lower self-concept and show a tendency to exhibit more conservative sexual attitudes and a more negative body image, being less likely to have sexual activity (Pavlidis et al., 1995; Sutton et al., 2005). Turner Syndrome (TS) constitutes a chronic medical condition, with possible physical, social and psychological complications. Most girls with TS are intensively followed by paediatricians, but are lost to follow-up when they reach adulthood (Verlinde et al., 2004). Patients with TS drift away from medical care as they achieve adulthood, despite the need for regular surveillance and management of associated conditions, which would reduce morbidity and prevent complications. Adult care for adults with TS is suboptimal and assessment of comorbidities remains sporadic. Adequate transition guidelines and patient education are needed for long-term management of women with TS, to impact on quality of life and longevity (Pedreira et al., 2006). A specialized multidisciplinary approach for adults with TS is needed in order to optimize health and psychosocial status in these women. Recently we diagnosed TS in two patients observed in two different life stages: adolescence and adulthood.

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The first case deals with a 15 years oldgirl who came to observation for the recent onset of a school refusal behavior, that required an urgent consultation, while attending the first class at the socio-psycho- pedagogical lyceum (Verri et al., 2006). School refusal behavior refers to a child-motivated refusal to attend school or difficulty remaining in classes for an entire day (Kearney, 2002); the behavior includes complete or partial absence from school, severe morning misbehaviors to miss school and final school non-attendance. It represents a complex and heterogeneous phenomenon that consists of numerous symptoms and is commonly marked by various degrees of general and social anxiety, somatic complaints, depression, fatigue, fear, non-compliance, defiance, tantrums, running away, aggression and other misbehavior (Kearney, 2004). School refusal can be classified according to the function of the behavior itself: (1) to avoid school related stimuli that provoke a sense of general negative affectivity; (2) to escape from aversive social and/or evaluative situations at school; (3) to pursue attention from significant others; (4) to pursue tangible reinforcement outside the school setting. The initial two conditions refer to youth who refuse school for negative reinforcement, or to terminate an aversive situation at school. The latter two conditions refer to youth who refuse school for positive reinforcement, or to pursue rewarding situations more palatable than school. Many youth also refuse school for a combination of these reasons (Kearney, 2002). The behavior is often seen as either a primary problem or one embedded in an array of problems. We discuss the case of a school refusal behavior in a Turner syndrome adolescent, considering the relationship between clinical and genetic phenotype and its role in the development of the pathologic condition. The second case deals with a 51 years old woman affected by TS and Psychotic Disorder, with a prevalent somatic and sexual symptoms.

CASE REPORT 1 A..E. is a 15years old girl living in Pavia district (Figure 1). She lives with her parents and a 3years old brother. Her mother is a school caretaker and suffers for recurrent depressive episodes. A.E. thinks look like her mother, that is anxious and apprehensive and suffers from irritable colon. The father is a farmer. He noticed A.E. temperamental immaturity; her excessive shyness and insecurity and her lack of initiatives. She frequently fights with the 3 years old brother. She came to our attention because of a school refusal behavior, while attending the first class at the socio-psycho-pedagogical liceum. The parents appeared really worried about her school refusal. After the beginning of lessons she started to refuse going to school. Every morning, at the time to go out for taking the school-bus, she began to cry and was frightened to go to school. Several times she left the class and phoned to her mother to take her home At home she refuses food, she often cried, she couldn’t sleep alone and she was strangely silent and lonely. At primary school she didn’t present learning disabilities. During the first weeks at the new school she didn’t obtain bad results at class-works or interrogations. She doesn’t remember negative episodes in classroom with classmates or teachers, that she finds friendly and nice. The only problem is the strong suffering she feels,

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especially during the teaching hours. She feels “bored”, she counts the hours missing to get back home, then the heart starts beating too fast, she can’t breath, she sweats and would run away from the class. She prefers to stay at home with her grandmother, watching TV, reading her favourite magazines and copying part of books at the computer. When she is at home, she feels safe and she does the homework, always watching TV. She isn’t worried about a possible school failure; “If I don’t attend lessons, of course I’ll be stopped!” she says.

Figure 1. A.E. 11 years old.

Developmental History A.E. was born from non consanguineous parents after a normal pregnancy. Weight at birth was 3300 g. She received bottle feeding. At 6 months she developed intolerance to milk. Developmental milestones: upright station at one year, first steps without help at 16 months, first words at 1 year. Until 3 years of age she had problems to get asleep. During childhood she was often ill, with frequent parotities and stomach-ache crisis. She attended nursery school with some resistances, she was often at home with her grandmother. At the Primary School she wasn’t signalled for learning disabilities. She could write her name and read some easy words before starting school. Teachers said that she was very obedient and quiet. Her school results were normal. She was the tallest in her classroom. At Secondary School she found difficulties in the initial adaptation and socialization. She has a few reliable friends.

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Objective Evaluation At clinical examination she presented dysmorphic features (ogival palate and oblique-cut palpebral rhymes) in an average weight and height figure (60 Kg,162 cm) associated with primary amenorrhea. Pubertal stages according to Tanner were Breast 2 and Pubic Hair 2. Pediatric endocrinological evaluation confirmed the presence of an endocrine disorder characterized by gonadal failure. Pelvic ultrasound evidenced prepubertal uterus and small ovaries with homogeneous structure. An estrogen replacement therapy was administered. Genetic counselling (karyotype: 45, X) confirmed the diagnosis of TS. Dermatologic consultation detected a generalized spinulosism and presence of an angioma on the right subscapular region. X-rays of pelvis, thorax and spine visualized a dorsal scoliosis, an asymmetry of hips and valgoid femurs. Bone age corresponded to 12yrs 6 months. Physiatric consultation confirmed the right dorsal deviation and dissymmetry of lower limbs. Hand and wrist X- rays revealed a malformation of trapezoid and capitate bone and a dymorphism of radial epiphysis and uncinatus. Echocardiography revealed a minimal ectasia of aorta.

Neurophysiological and Neuroradiological Findings EEG was normal for the age. At MRI (Magnetic Resonance Imaging) altered activation in right frontal anterior region was evidenced for the presence of an arachnoid cyst with enlargement, not consistent for the age, of subarachnoidal spaces, more apparent in the left parietal region. Enlargement of cerebellar sulci (vermian in particular) (Figures 2,3)

Figure 2. MRI Axial image: right frontal arachnoid cyst with enlargement, not consistent for the age, of subarachnoidal spaces, more evident in the left parietal region.

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Figure 3. MRI Sagittal image: enlargement of cerebellar sulci (vermian in particular).

Cognitive-Behavioral Assessment The girl underwent a complete cognitive and behavioral assessment supported by psychometric and diagnostic instruments (Table 1). At the psychological observation she appeared sociable and collaborating even if she never began the interaction. Cognitive Profile The intellectual functioning was measured with Wechsler Intelligent Scale for Children Revised (WISC-R; Wechsler, D. 1991) and documented a low average IQ level (Full IQ =81; Verbal IQ=87; Performance IQ =78). A discrepancy between the performance and verbal abilities emerged. In particular some difficulties in the logical-mathematician reasoning were evidenced while the space and temporal organization of objects and events resulted good. She completed the following psychometric tests: Token Test; Coloured Progressive Matrices (CPM); Rey Figure Drawing Test; Stroop Color and Word Test (Golden, 1978); Minnesota Multiphasic Personality Inventory (MMPI-A); BEM Sex Role Inventory (BSRI). Cognitive psychometric evaluation scores are reported in Table 1 At Token Test she showed good language comprehension and normal process of succession and discrimination.; also the performance at Coloured Progressive Matrices (CPM) revealed normal analogical-deductive reasoning and abstraction. Visual-spatial organizational skills as assessed by the Rey Complex Figure Copy resulted slightly compromised. A.E. completed the drawing rather quickly (approximately 2 minutes), but she copied the elements of the figure, placing them in wide of the mark position, losing the proportions between the various parts. Even visual-spatial memory resulted severely impaired: at the Rey Complex Figure Memory she only reproduced the outline of the figure and little elements to its inside, but not correctly placed. At the Stroop Test she showed normal selective attention and good inhibition of authomatic responses.

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Annapia Verri, Valeria Destefani, Anna Cremante et al. Table 1. Psychometric assessment of A.E.

INSTRUMENTS Wechsler Intelligent Scale For Children Revised (WISC-R)

Mmpi-A

Colored Progressive Matrices Token Test

SCALES Full IQ Verbal IQ Performance IQ Information Similarities Arithmetic Vocabulary Comprehension Picture completion Picture arrangement Block design Object assembly Digit Span ValidityClinical Scales F - Infrequency L - Lie K - Correction Clinical Scales (Hs) Hypochondriasis (D) Depression (Hy) Hysteria (Pd) Psychopathic Deviate (Mf) Masculinity– Femininity (Pa) Paranoia (Pt) Psychasthenia (Sc) Schizophrenia (Ma) Hypomania (Si) Social Introversion PM38 (Raven, 1938)

Rey Figure

(De Renzi & Vignolo, 1962) Rey copy: type 3

Stroop Test

Congruent

Stroop Test

Incongruent

Bem (BSRI)

Standard diff.

SCORE 81 87 78 10 9 8 9 4 7 6 9 7 5 42 80 87 0 40 56 40 70 46 30 32 42 32 36/36

COMMENTS Low average IQ level

Discrepancy between performance and verbal scales. Poor practical information and social knowledge. Difficulties in the logical-mathematician reasoning. Low efficacy of short-term memory recall. Difficulties in nonverbal reasoning and planning. Sufficient attention to detail and visual recognition of objects.

Tendency to show a conformist self-image. L, K and Mf scales are elevated and the global profile results invalid for incomprehension, severity and anxiety. In particular the Lie scale, a measure of the individual’s tendency to respond in a socially acceptable manner, thus minimizing symptoms, is significantly elevated. According to Reynolds and Richmond (1997), cited in McCauley (2001) the Lie Scale is a useful predictor of emotional, peer, academic and family stress-related problems. In particular, failure to self-report emotional distress observed in Turner adolescents can reflect a coping or adaptive response style to health problems. Normal analogical-deductive reasoning and abstraction.

34/36

Normal process of succession and discrimination.

Copy: 90” Recall: 45” Completion time: 60’’ Number incorrect:0 Completion time: 75’’ Number incorrect:0 66

Discreet abilities of visuo-spatial organization but difficulties in the recall performance. Normal selective attention.

Good inhibition of authomatic responses.

Sex-role identity is undifferentiated.

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Clinical Interview According to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV; American Psychiatric Association - Text Revision [APA] 2002) AE. presented a separation anxiety disorder associated with a secondary-school refusal behavior. Personality Profile MMPI-A Personality profile illustrates a tendency to show a conformist self-image. L, K and Mf scales are elevated and the global profile results invalid for incomprehension, severity and anxiety. In particular the Lie scale, a measure of the individual’s tendency to respond in a socially acceptable manner, thus minimizing symptoms, was significantly elevated. Sexual role identity resulted undifferentiated at BEM Sex Role Inventory. Two projective test were finally proposed: 1) DPT (Draw a Person Test): Self-representation was still not deeply differentiated from the environment. The drawing of the person was produced in a simplified and schematic way, with highlights only on the essential parts of the human figure. This may indicate the presence of an emotional constriction in the subject, whose social participation and whose affective communication is blocked by the intense consciousness of her own needs. What emerges in particular is the need of support from the environment and the sense of impotence in the active manipulation of reality, that is accompanied by feelings of inadequacy and lack of self esteem. There is tendency to self-enclosure and an emotional control system associated to repression and denegation of the emotional states. Moreover a marked sensibility toward social criticism was found. The DPT finally expressed the presence of sexual worries in relation to the acceptance of the feminine role and difficulty in acquiring knowledge of her own body. 2) DFT (Drawing Family Test): A marked attachment to the parental figures emerged that is expressed by the constant search of physical contact and maternal reassurance. The parental relationship is perceived like stable and supporting and seems to influence in a meaningful way the emotional equilibrium of the subject, characterized by insecurity and affective dependency. The search for attention and support is expressed in infantile attitudes. Finally the fear of failing to meet parental expectations emerged. In conclusion the psychometric evaluation revealed a low average intellectual functioning in patient with good ability of analogical-deductive reasoning, of discrimination and some difficulties in the recall performance. The cognitive-behavioral assessment pointed out a form of “social anxiety” characterized by fear of social or performance situations in the school context, with a strong avoidant behavior that could resemble a real “school phobia”.

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DISCUSSION We studied the cognitive and behavioral profile of a patient with an atypical presentation of TS. School refusal behavior and social impairments were the presenting clinical signs. School refusal behavior is a typical feature of Scholar Phobia, a complex psychiatric disorder which may be associated to different DSM IV condition range (from anxiety spectrum disorders to borderline personality disorder). On the other hand, TS has been associated to different psychiatric conditions and social anxiety is considered a characteristic trait of the syndrome (Lesniak-Karpiak et al., 2003). Our patient showed anxiety traits, stable over time and settings, which were already evident during early childhood, (such as quiet exploration of object/solitary passive play and social approach-avoidance behaviors that are supposed to reflect enduring temperamental characteristics of anxiety in preschool age) but she came to our attention because of an anxiety transitory state which emerged in the specific school context. She also showed a limited repertoire of social behavior and expression, problems during peer interactions and in understanding social clues, but these problems were not specifically related to elevated levels of social anxiety. Another interesting feature is the undifferentiated gender identity, as manifested from the behavior (which appear immature) as well as from the psychological evaluation (no difference between the two persons at the DPT (Drawing Person Test). Moreover, evaluation of the masculinity-femminility scale of MMPI revealed a tendency to show a conformist self-image. Gender identity has been always considered to be female in TS (see Dowrart, 1999). In addiction, although physical appearance may be related to greater social/emotional disturbance in females with TS, A.E. psychosocial adjustment was not negatively influenced by short stature. Finally, according to Ganou & Grouios (2007) the impact of the genetic and hormonal mechanisms on the neurocognitive profile of TS should be considered. A recent study in experimental animals has shown that gender identity is due to genes which directly induce sexually dimorphic pattern of neural development, influence the sexual difference between male and female brain at the beginning of the embriogenic life, prior to the gonadal differentiation. Up to date the sexual dimorphism of somatic tissue was considered only due to gonadal secretion from the developing foetus (Dewing, 2003). As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic and hormonal factors that influence female cognitive development. TS is an excellent model for such studies because of its prevalence, the wellcharacterized phenotype, and the wealth of molecular resources available for the X chromosome (Ross et al., 2006) In this study we stress the importance of a deep clinical assessment including laboratory and psychological investigations in order to perform a correct diagnosis and to better understand the different aetiologies of behavioral symptoms. In our case School Phobia represented a symptomatic manifestation of a multi-determined psychological sufferance, linked in particular to the difficulty to face physical and sexual development with insufficient coping skills and to accept and overcome the overall sense of inadequacy arisen from the non

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verbal learning disability. Furthermore, lack of estrogens, due to gonadal dysgenesis, might have negatively influenced our patient’s behavior, since it has been suggested that estrogens improve motor speed and nonverbal processing time in the estrogen-treated TS girls compared to that in the placebo-treated TS girls (Ross, 1996). In conclusion we suggest attention to the diagnosis of psychiatric conditions during adolescence, and in association with school refusal in particular, because of their different potential functional profiles. The case of A.E. underlines the importance to study disorders in early infancy, and longitudinally, to understand how alternative developmental pathways might lead to different phenotypical outcomes, stressing the importance of developmental history and behavioral phenotype in the diagnosis of TS.

CASE REPORT 2 Developmental History M.T. is a 51years old woman living in Pavia district (Figure 4). When she came to observation her mother was 82 years old, she had been a shopkeeper and was still active in family. The patient’s father was 86 years old, he also had been a shopkeeper. The patient had four sisters and two brothers, in good health. M.T. was born full term as the last daughter with a normal delivery. Her linguistic and motor development were reported to be normal. She attended regular school. The interpersonal relationships with her peers were reported to be satisfactory. Her teachers’ training school certificate was achieved with full marks. At the end of the secondary upper Institute the patient attended for two years the Faculty of Psychology then she left her studies to work as a teacher. She worked for about 20 years as a primary school teacher, but she left the school to devote completely herself to the adoptive daughter. At the age of 14 years, following primary amenorrhea, Turner syndrome was diagnosed (karyotype 45, X). She started an hormone replacement therapy followed with some regularity until 2000. At the age of 18 years, the patient presented a first psychotic breakdown. Subsequently, she showed perceptive hallucinations in which M.T. heard voices, the sound of bells and she often appeared very confused to family members. She was hospitalized for 40 days in a Psychiatric Department. At the end of the hospitalization she returned at home unable to eat and move independently; her siblings claimed that several years were necessary to regain the previous level of independence. M.T. got married in 1982. Her husband was 58 years old and affected by severe obesity. They adopted a daughter in 1986 with an international adoption from Brazil, the baby was only 40 days old at the adoption time. The conjugal relationship, once peaceful, became more difficult after the adoption. The couple breakdown was triggered by discordant views regarding the child’s education. The girl development became very soon problematic. When the daughter manifested learning difficulties and school refusal, M.T. chose to devote herself full time to the family, with excessive fatigue and stress.

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In 2000, when M.T. was 49 years old, she presented persistent alteration of the sleepwaking pattern. In this period increased drowsiness, rough speech and marked dependence from her mother began to emerge. The patient gradually wasn’t able to manage herself and to take care of her family. She then decided to move to her mother and to leave her own family. Following a further worsening, antidepressive medications were started; but then the patient manifested hyperactivity, restlessness and disorientation in space and time. In a second time, haloperidol was administered, with some benefits. Although with continuous support from her sisters with regard to household and personal care, the patient was able to return home to her husband and daughter. In the same period (2000-2005) M.T. has also started several cycles of psychotherapy without being able however to complete anyone of them. Since the early 2006 she complained motor difficulties, especially with regard to normal every day activities, so she went back to live with her parents who assisted her all the time. She claimed to feel pain in different body parts, which seemed not justified by the medical objective evaluation. She presented also many phobies and restriction of the social relationships, limited to close members of the family. She claimed to see objects and hear voices that others did not perceive. Within the last 15 days before hospitalization, in addition to the persistence of anxious-depressive symptoms, ideas of reference and bizarre sexual behaviors were also present. Autoeroticism behaviors were frequent, but she lived with deep sensation of guilt. Sisters referred the recent worsening of behavioral disorders and increased difficulty in every day life activities. Trend of suspiciousness and irritability became more evident. M.T. slept only about 3-4 hours at every night. She reported difficulties to fall asleep and frequent night-time awakenings for which she required her mother to sleep beside her.

Figure 4. M.T. 51 years old.

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Clinical Evaluation, Neurophysiological and Neuroradiological Findings Patient is 1.47 m in height and 40 kgs in weight. The general objective evaluation was normal. Neurological evaluation documented bradikinesia, ataxia and global motor clumsiness. Normal electroencephalogram. Pattern of reversal visual evoked potentials were bilaterally abnormal. Auditory evoked potentials were bilaterally altered: peak I and peak III were absent, whereas peak V was delayed. Audiometric evaluation documented severe neuro-sensory hypocusia and keratoconus. Normal Brain CT. MRI showed minimum enlargement for the age of the ventricular system, of the scissure of Silvio and of the grooves of the cerebellar vermis.

Cognitive-behavioral Assesment During the hospitalization, the patient required constant supervision; traits of dependence on the familiar figures, on the roommate and on the operators emerged, to which she asked their support for just simple and ordinary activities. There were bizarre and inappropriate behaviors related to poor impulse control (compulsive onanism) and disinhibition with consequent emergence of sensations of guilt and pronounced anxiety. Self-neglect in hygiene also emerged. The patient often left her room forgetting to wear shoes and appropriate clothing. During the hospitalization frequent critic episodes characterized by a deep sense of confusion, emotional flattening, spontaneous tears and search of familiar figures occurred. She alternated periods of delusion and lucid intervals in which, upon request, she talked about her profession and the city where she lived with many details. She reported a difficult relationship with the adoptive daughter, now twenty years old, due to her decision to leave the school to start working. M.T., however, didn’t show to know her daughter’s job, documented a mnestic deficit. The married life appeared conflictual: the husband did not seem to be interested in his wife’s pathology and the sexual intercourses were reported to be interrupted for years. She feared to suffer from loneliness and expressed recurrent thoughts about health, she feared to feel unwell, to "fail" and to be "punished". During the psychological evaluation, the patient joined the conversation, merely answering questions in a limited way, without bringing spontaneously personal contributions in the interaction. Movements and speech appeared considerably slowed and reduced, and poverty in ideation emerged. She also had poor ability to express her emotions. Tendency to be easily distracted emerged at times. She reported the worsening of symptoms related to family problems concern the relationship with her daughter and her health. Memory difficulties emerged. The psycho-diagnostic evaluation was completed with the administration of tests, to describe cognitive and emotional state besides personality structure.

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Cognitive and Behavioral Profile During the hospitalization, M.T. underwent a complete cognitive and behavioral assessment supported by psychometric and diagnostic instruments (see Table 2). • Cognitive Profile At the Wechsler Adult Intelligence Scales (WAIS) the patient reported: QItot = 96; QIv = 110; QIp = 78. This result documented the presence of a standard intellectual level. She willingly cooperated to the administration of the test, maintaining appropriate levels of attention and concentration. There were significant differences in performance between verbal and non-verbal subtests. In the first one the patient showed good ability of understanding and expression; the wealth of information gained through experience, as well as the ability to abstract reasoning, seem appropriate. From no-verbal trials, however, reduced ability of planning sequences, random events, perception and visual-motor coordination emerged. There was, finally, during the execution of non-verbal subtests, a marked motor slowdown. Table 2. Psychometric assessment of M.T. INSTRUMENTS Wechsler Assessment Intelligence Scale (WAIS)

SCALES Full IQ Verbal IQ Performance IQ

SCORE 96 110 78

Information Comprehension Arithmetics Similarities Digit span Vocabulary

13 10 8 12 10 13

Digit Symbol Picture completion Block design Picture arrangement Object assembly

4 5 5 2 4

Coloured Progressive Matrices (CPM) Token Test

24/36 34/36

Rey-Osterreith Complex Figure

Copy 28/36 Recall 6,5/36

COMMENTS standard intellectual level

There were significant differences in performance between verbal and performance subtests. In the first one the patient showed good ability of understanding and expression; the wealth of information gained through experience, as well as the ability to abstract reasoning, seem appropriate. From no-verbal trials, however, reduced ability of planning sequences, random events, perception and visual-motor coordination emerged. There was a marked motor slowdown. deductive analogical reasoning and abstraction skills below the norm seriation and discrimination skills in the norm presence of deficits about visual-spatial memory.

The assessment by Token Test documented the presence of normal seriation and discrimination skills. The scoring of Coloured Progressive Matrices (CPM) detected low deductive analogical reasoning and abstraction skills.

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Rey-Osterrieth complex figure documented the presence of deficits of the visual-spatial memory. • Adaptive Behavior The etero-compilation questionnaire Behavior Rating Scale (Aman-Singh) was drawn up by using information and observations recorded during the hospitalization. She alternated among apathy, laziness, inactivity and hyperactivity. In the first case, M.T. appeared indifferent to the activities of the department and required constant reminders to move and to carry out normal daily activities, her gaze was fixed (and often absorbed in a vacuum). The facial expressions were fixed, there was no emotional reactivity and flattening affectivity emerged. Little interest in interpersonal contacts emerged. There were motor and verbal stereotypies. During periods of restlessness, however, the patient showed hyperactivity, and proved unable to maintain a firm position and to conform to the instructions given by others. She behaved so impulsive and exhibited bizarre, repetitive and ritualized behaviors. She talked alone in a loud voice, repeating hardly understandable expressions. • Psychiatric Evaluation The patient participated to the Brief Psichiatric Rating Scales (BPRS, version 4.0) interview showing discrete levels of cooperation. She appeared sometimes confused and disorientation in space and time emerged: she showed difficulty in realizing properly her actual physical location and identifying the time of important events in her life. The ideation was characterized by the presence of somatic concerns. She seemed to be unable of distractions causing considerable compromise in the normal operation: she feared, in fact, that her body can meet fragmentation/disintegration and losing of the genitals; she described, about this constant fear, the presence of hallucinations of tactile nature. There were also hallucinations of auditory nature. Ideas of reference emerged: the patient described the conviction that people could harm and punish her because of her sexual behaviors that she considered inappropriate and lived with extreme guilt.

DISCUSSION We reported the case of a woman affected by Turner Syndrome and psychotic disorder with a normal intellectual level, however with a deep discrepancy between verbal and performance scores. The cognitive phenotype of Turner Syndrome generally includes normal verbal function with relatively impaired visual-spatial ability, attention, working memory, and spatially dependent executive function. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies (Ross et al., 2006). Clinical associations between Turner Syndrome and psychotic disorder, are well known in literature. It has been hypothesized that loss of balance of gene products from sex chromosomes may increase susceptibility to external insults, thereby facilitating the development of psychotic disorders

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(Kumra et al., 1998). Much writing about the psychological aspects of TS has focused on the influence of the physical stigma of TS on psychological development in young womanhood. A “TS personality” characterized by excessive dependence, immaturity, passivity, distractibility, and docility was suggested by Nielsen and Thomsen (1968), although no rigorous scientific study has examined these claims. Some of these traits can be underlined also in the personological structure of our patient. For example, the nursing staff reported that the patient was more peaceful and collaborating when the roommate or relatives were present. She was constantly anxious and worried to be abandoned by the sisters. In effect, quite often, parents overprotect children affected by Turner Syndrome, treating them according to their height and not according to their age, thus increasing their dependence and immaturity (Nielsen & Sillesen, 1981; Nielsen, 1993). In comparison with the population at large, women with TS usually have their first sexual experience much later, are sexually less active and tend not to get married (McCauley et al., 1986; Aran et al., 1992). A failure to live a mature womanhood is evident in our patient, who was unable to deal with her daughter problems and to carry on her home duties without the help of her family. Studies attempting to correlate TS with psychiatric illness statistically have admixed results. Prior et al. (2000) surveyed 10 cytogenetic studies of chronically psychotic patients, and in a total of 6,483 patients found 11 cases of TS, or three times the expected number if the diseases were to occur simultaneously randomly. In evaluating case studies, Moore suggests a psychological “fragilité” in TS that confers a vulnerability to psychiatric syndromes. Mellbin (1965) briefly describes four TS women; two suffered from psychoses: one had “attacks of laughing or weeping” and the other, who also suffered from epilepsy, slowly became withdrawn and psychotic at age 23, “began feeling that her end was near, refused to eat,” yet recovered within a few weeks of her hospitalization and never had another episode. In another report, Nielsen (1970) describes two cases who had psychotic reactions to life stressors, and another one had a psychiatric syndrome that was questionably organic. One of the women with psychosis was first hospitalized at 53 years, following her mother’s definitive diagnosis of dementia. The other psychosis patient presented with psychiatric symptoms at the age of 42 after hospitalization related to diabetes. Prior et al. (2000) also described two cases. His first patient presented with a psychotic episode at 28. Trapet et al. (1981) described a case who was hospitalized in her 20s, with depression, euphoria, erotomania, and sometimes a mute dissociative state. Her syndrome included agitated depression, bizarre behaviors, and a psychosis with somatic themes. The psychosis overcame with antipsychotic treatment, to be replaced by apathy. Recently, numerous substance have been identified as so-called “endocrine disruptors” because exposure to them results in disruption of normal endocrine function (Brown,2008). Other indications that estrogen may be involved in schizophrenia have been found in genetic conditions that cause abnormal estrogenic function. Turner (XO) and Klinefelter's syndromes (XXY) are possible genetic models of endocrine disruption although not directly comparable to chemical exposures as entire chromosomes are involved in these syndromes(Brown,2008). Turner syndrome, in which there is a missing X gene causing an absence of estrogen during prenatal/perinatal life, is associated with cognitive problems and psychosis (Kawanishi,

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199(7; Everhart, 2004). One study found Turner syndrome patients have 3 times the risk for schizophrenia as normal controls (Prior, 2000). Klinefelter's syndrome, which often presents with hypogonadism, has been proposed as a genetic model of psychotic disorders (Delisi, 2005). If TS is a unique syndrome, it is important to identify it in order to avoid labeling patients with a more severe diagnosis, to determine its frequency and epidemiology, to understand its biological basis, and most importantly, to identify optimal treatment strategies. Psychological support for TS individuals and families is important throughout life and should ideally be provided by both health professionals and TS support groups. Despite the prevalence of this chromosomal condition, the challenges these women face throughout their lives are not fully understood. A specialized multidisciplinary approach for adults with TS is needed in order to optimize health and psychosocial status in these women.

REFERENCES Aran, O., Galatzer, A., Kauli, R., Nagelberg, N., Robicsek, Y., & Laron, Z. (1992) Social, educational and vocational status of 48 young adult females with gonodal dysgenesis. Clin Endocrinol (Oxf), 36:405-10. Batch, J. (2002) Turner syndrome in childhood and adolescence. Best Pract Res Clin Endocrinol Metab.; 16(3):465-82. Bondy, CA. (2005) New issues in the diagnosis and management of turner syndrome. Rev Endocr Metab Disord., 6(4), 269-80. Brown,JS (2008) Effects of Bisphenol-A and Other Endocrine Disruptors Compared With Abnormalities of Schizophrenia: An Endocrine-Disruption Theory of Schizophrenia. Schizophrenia Bulletin, Jan 31. [Epub ahead of print] Bruandet, M., Molko, N., Cohen, L., & Dehaene, S. (2004) A cognitive characterization of dyscalculia in Turner Syndrome. Neuropsychologia, 42, 3, 288-298. Catinari, S., Vass, A., & Heresco-Levy, U. (2006) Psychiatric manifestations in Turner Syndrome: a brief survey. Isr J Psychiatry Relat Sci., 43(4), 293-5. Delisi LE, Maurizio AM, Svetina C. (2005) Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Genet B Neuropsychiatr Genet, 135, 15–23. Dewing, P., Shi, T., Horvath, S., & Vilain, E. (2003) Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation. Mol Brain Res., Oct 21, 118(1-2), 82-90. Donnelly, S.L., Wolpert, C.M., Menold, M.M., Bass, M.P., Gilbert, J.R., Cuccaro, M.L., Delong, G.R. & Pericak-Vance, M.A. (2000) Female with autistic disorder and monosomy X (Turner Syndrome): parent-of origin effect of the X chromosome. American Journal of Medical Genetics, 96, 3, 312-316. Downey, J., Ehrhardt, A.A., Morishima, A., Bell, J.J. & Gruen R. (1987) Gender role development in two clinical syndromes: Turner Syndrome versus constitutional short stature. J Amer Acad Child Adol Psychiat, 26, 4, 566-573. El Abd, S., Turk, J. & Hill, P. (1995) Annotation: Psychological characteristics of Turner Syndrome. J Child Psychol Psychiat, 36, 7, 1109-1125.

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Everhart DE, Shucard JL, Quatrin T, Shucard DW. (2004) Tone probe event-related potential differences during a face recognition task in prepubertal children and Turner syndrome girls. Psychoneuroendocrinology, 29, 1260–1271. Ganou, M., Grouios, G. (2007) Cerebral Laterality in Turner Syndrome: A Critical Review of the Literature. Child Neuropsychol. 16, 1-13. Jacobs, P., Dalton, P., James, R., Mosse, K., Power, M., Robinson, D. & Skuse, D. (1997) Turner syndrome: a cytogenetic and molecular study. Ann Hum Genet. 61, 471-483. Kawanishi C, Kono M, Onishi H, Ishii N, Ishii K. (1997) A case of Turner syndrome with schizophrenia: genetic relationship between Turner syndrome and psychosis. Psychiatry Clin Neurosci, 51, 83–85. Kearney, C.A., Albano, A.M. (2004) The Functional Profiles of School Refusal Behavior. Behavior Modification, 28, 1, 147-161. Kearney, C.A. (2002). Identifying the Function of School Refusal Behavior: A Revision Of The School Refusal Assessment Scale. Journal of Psychopathology and Behavioral Assessment. 24, 4, 235-245. Kumra, S., Wiggs, E., Krasnewich, D., Meck, J., Smith, A.C., Bedwell, J., Fernandez, T., Jacobsen, L.K., Lenane, M. & Rapoport, J.L. (1998) Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders. J Am Acad Child Adolesc Psychiatry, 37, 292-296 Lesniak-Karpiak, K., Mazzocco, M.M. & Ross, J.L. (2003) Behavioral Assessment of social Anxiety in females with Turner or Fragile X Syndrome. Journal of Autism and developmental disorders, 33, 1, 55-67. Martins, A.M. (1999) Inborn errors of metabolism: a clinical overview. Sao Paulo Med J, 4;117(6), 251-65. McCauley, E., Feuillan, P., Kushner, H. & Ross, J.L. (2001). Psychosocial Development in adolescents with Turner Syndrome. Developmental and Behavioral Pediatrics, 22(6), 360-365. McCauley, E., Kay, T., Ito, J., Treder, R. (1987). The Turner syndrome: cognitive deficits, affective discrimination, and behavior problems. Child Dev, 58(2), 464-73. McCauley, E., Sybert, V. & Ehrhardt, A.A. (1986) Psychosocial adjustment of adult women with Turner syndrome. Clin Genet, 29, 284-90. Melbin, G. (1965) Neuropsychiatric Disorders in sex chromatin negative woman. Br I Psychiatry, 112, 145-148 Nielsen, J. (1993) What more can be done for girls and women with Turner syndrome? In: I. Hibi, K. Takano (Ed), Basical and clinical approach to Turner syndrome (pp.169-76) Amsterdam: Excerpta Medica. Nielsen, J., Sillesen, I. (1981) Turner syndrome in 115 Danish girls born between 1955 and 1966. Acta Jutlandica LIV Medicine Series, 22. Nielsen, J., Thomsen, N.(1968) A psychiatric-cytogenetic study of a female patient with 45/46/47 chromosomes and sex chromosomes XO/XX/XXX. Acta Psychiatr Scand; 44, 141–155. Nielsen, J(1970) Turner’s syndrome in medical, neurological and psychiatric wards. A psychiatric cytogenetic and clinical study. Acta Psychiatr Scand, 46, 286-310.

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Pavlidis, K., McCauley E. & Sybert V.P. (1995). Psychosocial and Sexual functioning in women with Turner Syndrome. Clinical Genetics, 47, 85-89. Pedreira, C.C., Hameed, R., Kanumakala, S.& Zacharin, M. (2006). Health-care problems of Turner syndrome in the adult woman: a cross sectional study of a Victorian cohort and a case for transition. Intern Med J., 36(1), 54-7. Prior, T.I., Chue, P.S. & Tibbo P.(2000) Investigation of Turner Syndrome in schizophrenia. Am J Med Genetics (Neuropsychiatruic Genetic), 96, 373-378. Rae, C., Joy, P., Harasty, J., Kemp, A., Kuan, S., Christodoulou, J., Cowell, C.T., & Coltheart, M. (2004). Enlarged temporal lobes in Turner syndrome. An X-chromosome effect? Cerebral Cortex, 14, 156-164. Romans, S.M., Stefanatos, G., Roeltgeten, D.P., Kushner, H. & Ross, J.L. (1998) Transition to Young Adulthood in Ulrich-Turner Syndrome: Neurodevelopmental changes. American Journal of Medical Genetics, 79, 140-147. Ross, J., Roeltgen, D., Zinn, A. (2006) Cognition and the sex chromosomes: studies in Turner syndrome. Horm Res, 2006, 65(1), 47-56. Ross, J., Zinn, A.& McCauley, E. (2000) Neurodevelopmental and Psychosocial aspects of Turner Syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 135-141. Ross, J.L., Mccauley, E., Roeltgen, D., Long, L., Kushner, H., Feuillan, P. & Cutler, G.B. (1996) Self-Concept and Behavior in Adolescent Girls with Turner Syndrome: Potential Estrogen Effects. Journal of Clinical Endocrinology and Metabolism, 81, 926-931. Skuse, D.H., James, R.S., Bishop, D.V.M., Coppin, B., Dalton, P., Aamodt.Leeper, G., Bacarese-Hamilton, M., Creswell, C., McGurk, R.& Jacobs, P.A. (1997) Evidence from Turner Syndrome of an imprinted X-linked locus affecting cognitive function. Nature, 387, 705-708. Sutton, E.J., McInerney-Leo, A., Bondy, C.A., Gollust, S.E., King, D. & Biesecker, B. (2005) Turner syndrome: Four challenges across the lifespan. Am J Med Genet A, 1, 139(2), 5766. Sybert, V.P., McCauley, E. (2004) Turner Syndrome. The New England Journal of Medicine, 315, 1227-38. Trapet, P., Brenot, M., Gisselmann, A., Guillermet, A.M.& Marin, A. (1981) Syndrome de Turner, gémellité monozygote et psychose ou l’oeuf indivisible. Annales medicopsychologiques. Ann Med Psychol (Paris), 139, 581–585 Verlinde, F., Massa, G., Lagrou, K., Froidecoeur, C., Bourguignon, J.P., Craen, M., De Schepper, J., Du Caju M., Heinrichs, C., François, I., Maes, M., Belgian Study Group of Paediatric Endocrinology. (2004). Health and Psychosocial Status of Patients with Turner Syndrome after Transition to Adulthood: The Belgian Experience. Horm Res, 62(4), 1617. Verri, A.P., Destefani, V., Larizza, D. (2006). Rifiuto scolastico in un'adolescente con sindrome di Turner (TS). Giornale Italiano della Disabilità, 3, 68-81. Wechsler, D. (1991). Wechsler Intelligence Scale for Children–Revised. San Antonio, TX: The Psychological Corporation.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter IV

LIFE SPAN DEVELOPMENT IN KLINEFELTER SYNDROME Luigi Tarani∗ Clinical Genetics Unit, Pediatric Departement of “La Sapienza” University Hospital of Rome, Italy.

ABSTRACT Klinefelter Syndrome, is characterized by hypogonadism (small testes, azoospermia/ oligospermia), infertility, gynecomastia in late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules and elevated urinary gonadotropin levels. The incidence is about 1 in 600 males. The extra sex chromosome, acquired through an error of nondisjunction during parental gametogenesis, determines hypogonadism, gynecomastia, and psychosocial problems. Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland. Androgen deficiency may cause eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, which is presumably the hormone regulator of the follicle-stimulating hormone (FSH) level. The AR gene of SK patients contains a highly polymorphic trinucleotide (CAG) repeat sequence in exon 1, whose length is inversely correlated with the functional response of the androgen receptor to androgens and directly with the severity of the phenotype, determining a modulation in the phenptype. Most males with the 47,XXY karyotype have normal intelligence. Diagnosis is made with prenatal and postnatal karyotype, hormone testing (hypergonadotropic hypogonadism), spermiogram

∗

Correspondence concerning this article should be addressed to: Dr. Luigi Tarani, MD, Assistant professor of Pediatrics, Clinical Genetics Unit, Pediatric Departement of “La Sapienza” University Hospital of Rome. e-mail: [email protected]

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Luigi Tarani (azoospermia). Treatment consists of androgen sobstitutive therapy, mastecomia in case of gynecomastia, psychosocial approach and terapy of infertlity (TESE, ICSI).

INTRODUCTION Klinefelter syndrome, was clinically described in 1942 and is the most common male chromosomal disorder. It is defined since 1959 by a 47,XXY karyotype that has variants with additional X and Y chromosomes. The syndrome is characterized by hypogonadism (small testes, azoospermia/oligospermia), infertility, gynecomastia in late puberty, psychosocial problems, hyalinization and fibrosis of the seminiferous tubules and elevated urinary gonadotropin levels. The incidence is about 1 in 600 males. The mortality rate is not significantly higher than in healthy individuals (Nielsen & Wohlert, 1991). The presence of more than one extra X chromosome to a male karyotype results in variable physical and cognitive abnormalities. In general, the extent of phenotypic abnormalities, including mental retardation, is directly related to the number of supernumerary X chromosomes. As the number of X chromosomes increases, somatic and cognitive development are more likely to be affected. The intelligence quotient (IQ) score is reduced by approximately 15 points for each supernumerary X chromosome, but conclusions about reduced mental capacity must be drawn cautiously. All major areas of development, including expressive and receptive language and coordination, are affected by extra X chromosome material. In fact mental retardation and hypogonadism are more severe in patients with 49,XXXXY than in those with 48,XXXY (Chen, 2004). The extra sex chromosome, acquired through an error of nondisjunction during parental gametogenesis, determines hypogonadism, gynecomastia, and psychosocial problems. Klinefelter syndrome is a form of primary testicular failure, with elevated gonadotropin levels due to lack of feedback inhibition by the pituitary gland. Androgen deficiency may cause eunuchoid body proportions; sparse or absent facial, axillary, pubic, or body hair; decreased muscle mass and strength; feminine distribution of adipose tissue; gynecomastia; small testes and penis; diminished libido; decreased physical endurance; and osteoporosis. The loss of functional seminiferous tubules and Sertoli cells results in a marked decrease in inhibin B levels, which is presumably the hormone regulator of the follicle-stimulating hormone (FSH) level. The hypothalamic-pituitary-gonadal axis may be altered in pubertal patients with Klinefelter syndrome. An increased incidence of autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, has been reported in persons with Klinefelter syndrome. This may be due to lower testosterone and higher estrogen levels because androgens may protect against autoimmunity, while estrogens can promote. The genetic cause of Klinefelter syndrome is meiotic nondisjunction. Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases, while paternal errors in autosomal trisomies contribute for only about 10%. The errors by which maternal and paternal XXYs arise differ substantially in nature. In fact maternal nondisjunction cases are caused by meiosis I and II errors, which are associated with increased maternal age. By contrast XXY of paternal origin can arise only by a meiosis I

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error not related with age, but with a precedent child with a trisomy. The most common karyotype is 47,XXY, which accounts for 80-90% of all cases. Mosaicism (46,XY/47,XXY) is observed in about 10% of cases. Other variant karyotypes, including 48,XXYY; 48,XXXY; 49,XXXYY; and 49,XXXXY, are rare. The mosaic forms of Klinefelter syndrome are due to mitotic nondisjunction after fertilization of the zygote. These forms can arise from a 46,XY zygote or a 47,XXY zygote. Variant forms of Klinefelter syndrome include 48,XXXY; 49,XXXXY; 48,XXYY; and 49,XXXYY (Thomas & Hassold, 2003). In the modulation of the phenotype is invoved also the Androgen Receptor (AR) gene, wich is located on the X chromosome and encodes the androgen receptor. The AR gene contains a highly polymorphic trinucleotide (CAG) repeat sequence in exon 1, and the length of this CAG repeat is inversely correlated with the functional response of the androgen receptor to androgens and directly with the severity of the phenotype. Thus, a short AR CAG repeat sequence correlates with a marked effect of androgens. In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation. Individuals with short AR CAG repeats have been found to respond better to androgen therapy, to form more stable partnerships, and to achieve a higher level of education compared with individuals with long CAG repeats. Conversely, long AR CAG repeat lengths are associated with increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia. Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the differences of phenotype observed in affected individuals. In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis (Zitzmann & Nieschlag, 2003). Infants and children achieve normal height, weight, and head circumference. Height velocity increases by age 5 years, and adults with Klinefelter syndrome are usually taller than adults who do not have the syndrome. Affected individuals also may have disproportionately long arms and legs. Most males with the 47,XXY karyotype have normal intelligence. Family background influences IQ score. Mental retardation may be associated with the presence of a higher number of X chromosomes. A large group of patients have minor developmental and learning disabilities. These may include academic difficulties, delayed speech and language acquisition, diminished short-term memory, decreased data-retrieval skills, reading difficulties, dyslexia, and attention deficit disorder. Patients may exhibit behavioral problems and psychological distress. This may be due to poor self-esteem and psychosocial development or a decreased ability to deal with stress. Psychiatric disorders involving anxiety, depression, neurosis, and psychosis are more common in this group than in the general population. Dental: about 40% of patients have taurodontism (1% in general population), which is characterized by enlargement of the molar teeth by an extension of the pulp. Patients may lack secondary sexual characteristics because of a decrease in androgen production. This results in sparse facial, body, or sexual hair, a high-pitched voice, and fat distribution as is observed in females. By late puberty, 30-50% of boys with Klinefelter

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syndrome present with gynecomastia, which is secondary to elevated estradiol levels and an increased estradiol-to-testosterone ratio. The risk of developing breast carcinoma is at least 20 times higher than in healthy individuals. Postpubertal patients may have testicular dysgenesis (small firm testis, with size <10 mL). Infertility, azoospermia, or both may result from atrophy of the seminiferous tubules. Practically all individuals with a 47,XXY karyotype are infertile, while patients with Klinefelter syndrome mosaicism (46,XY/47,XXY) can be fertile. Few patients with 46,XY/47,XXY mosaicism are known to have fathered a child, which is associated with a risk of having an offspring with the 47,XXY form (Tarani & Verri, 2007). Patients may have an increased frequency of extragonadal germ cell tumors such as embryonal carcinoma, teratoma, and primary mediastinal germ cell tumor. Cardiac and circulatory problems: Mitral valve prolapse occurs in 55% of patients. Varicose veins occur in 20-40% of patients. The prevalence of venous ulcers is 10-20 times higher than in healthy individuals, and the risk of deep vein thrombosis and pulmonary embolism is increased.

Klinefelter Variants o

o

o

o

48,XXYY variant: Patients typically have mild mental retardation; tall stature; eunuchoid body habitus; sparse body hair; gynecomastia; long, thin legs; hypergonadotropic hypogonadism; and small testes. 48,XXXY variant: Patients typically have mild-to-moderate mental retardation, speech delay, slow motor development, poor coordination, immature behavior, normal or tall stature, abnormal face (epicanthal folds, hypertelorism, protruding lips), hypogonadism, gynecomastia (33-50%), hypoplastic penis, infertility, clinodactyly, and radioulnar synostosis and benefit from testosterone therapy. 49,XXXYY: Patients typically have moderate-to-severe mental retardation, passive but occasionally aggressive behavior and temper tantrums, tall stature, dysmorphic facial features, gynecomastia, and hypogonadism. 49,XXXXY variant: The classic triad is mild-to-moderate mental retardation, radioulnar synostosis, and hypergonadotropic hypogonadism. Other clinical features include severely impaired language, behavioral problems, low birthweight, short stature in some individuals, abnormal face (round face in infancy, coarse features in older age, hypertelorism, epicanthal folds, prognathism), short or broad neck, gynecomastia (rare), congenital heart defects (patent ductus arteriosus is most common), skeletal anomalies (genu valgus, pes cavus, fifth finger clinodactyly), muscular hypotonia, hyperextensible joints, hypoplastic genitalia, and cryptorchidism. Pea-sized testes, micropenis, and infantile secondary sex characteristics are characteristic in patients with 49,XXXXY, whereas patients with 48,XXXY exhibit milder hypogonadism similar to that found in patients with 47,XXY (Thomas & Hassold, 2003).

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DIAGNOSIS Klinefelter syndrome can be detected prenatally with amniocentesis and cytogenetic analysis of amniotic fluid. This presents a dilemma for parents because prognosis is good, but phenotypic abnormalities are possible. But, it also represents the opportunity to prevent clinical manifestations such as speech disturbances or puberty abnormalities. Klinefelter syndrome goes undiagnosed in most affected males (calculated 64% of patients) (Abramsky & Chapple, 1997), among males with known Klinefelter syndrome, many do not receive the diagnosis until they are adults. The most common indications for karyotyping are hypogonadism and infertility. In infancy diagnosis is made because the presence of hypospadias, small phallus or cryptorchidism. In the toddler years, boys may present with developmental delay, expecially with expressive language skills. The schoolaged child may present with language delay, learning disabilities, or behavioral or social problems. The older child or the adolescent may be discovered during an endocrine evaluation for delayed or incomplete pubertal development with eunuchoid body habitus, gynecomastia, and small testes. Infertility, breast cancer and gynecomastia are the 3 symptoms that lead to diagnosis in the adult age. Other symptoms include fatigue, weakness, erectile dysfunction, osteoporosis, language impairment, academic difficulty, subnormal libido, poor self-esteem, and behavioral problems (Visootsak & Graham, 2006). Hormone testing: Before puberty plasma gonadotropin concentrations and the response to gonadotropin-releasing hormone do not differ from those in unaffected boys, but by the time of expected puberty, plasma FSH and LH and the response to Gn-RH hormone are higher than normal. Patients aged 12-14 years may have high plasma FSH, luteinizing hormone (LH), and oestrogens. Testosterone levels increase during early adolescence in some patients, then begin to decrease by 15 years of age, being lower than normal in 80% of adult patients with 47,XXY karyotype. The exact mechanism of androgen deficiency is unknown, and the degree of Leydig-cell disfunction is variable. On average the oestradiol concentration is higher than in normal men. Serum concentrations of sex-hormone-binding globulin (SHBG) are high, causing a further decrease in biologically active free testosterone. Concentrations of LH and FSH are high in most cases. Concentrations of inhibin B are generally within the normal range in prepubertal boys with Klinefelter syndrome, but decrease significantly during late puberty, because virtually all germ cells and the majority of Sertoli cells disappear. In response to administration of human chorionic gonadotropin (hCG), the increase in testosterone levels in patients with Klinefelter syndrome is diminished compared with in the general population. Urinary gonadotropin levels are increased because of abnormal Leydig cell function. Serum osteocalcin levels are decreased and the hydroxylproline–to-creatinine ratio is increased, reflecting decreased bone formation and increased bone resorption (Lanfranco et al., 2004). Ejaculates from patients with 47.XXY karyotype show azoospermia. The high proportion of patients able to ejaculate allows speculation on patients capacity to carry out reasonably successful sexual relations. Sperm are observed only rarely, and exceptional cases of spontaneous paternity have been reported. Echocardiography is performed in adult age to assess for mitral valve prolapse.

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Radiography is performed to assess for radioulnar synostosis, and taurodontism. Bone densitometry for lower bone mineral density. Histologic Findings may include small, firm testes with seminiferous tubular hyalinization; sclerosis and atrophy with focal hyperplasia of mostly degenerated Leydig cells. Germ cells are markedly deficient or absent. Spermatogenesis is absent or rarely are present tubules with residual foci of spermatogenesis, with meiotic arrest at primary spermatocyte or spermatide stages. In patients with mosaicism, progressive degeneration and hyalinization of seminiferous tubules take place after puberty despite the presence of normalsized testes and spermatogenesis at puberty. Histology of gynecomastic breasts shows hyperplasia of interductal tissue.

TREATMENT Early identification and anticipatory guidance are extremely helpful, although the syndrome is rarely diagnosed in prepubertal males. Treatment should address 4 major facets of the disease: hypogonadism, gynecomastia, psychosocial problems, and infertility. Androgen therapy: is the most important aspect of treatment. Testosterone replacement should begin at puberty, around age 11-12 years, and the dose should increase until it is sufficient to reduce gonadotropin levels and gradually induce virilization, maintaining ageappropriate serum concentrations of testosterone, estradiol, FSH, and LH. Starting dose of Testosterone enanthate or cypionate at age 11-12 years is 50 mg IM qmo; increasing dosage 50 mg qmo annually in accord with the patient's state of well-being, degree of virilization, growth, and serum gonadotropins levels, eventually reaching the adult dose of 200-300 mg IM q2-3wk. Actually is possible to use a daily administration of gel Testosterone that reduce the disconfort of injections and maintains a more physiologic level of serum androgens. Androgen therapy is used to correct androgen deficiency, to provide appropriate virilization, and to improve psychosocial status. Regular testosterone administrations can promote strength and facial hair growth; build a more muscular body type; increase sexual desire; enlarge the testes; improve mood, self-image, and behavior; and protect against precocious osteoporosis (Thomas & Hassold, 2003; Tarani & Verri, 2007). Mastectomy may be indicated in post-pubertal age for gynecomastia, that is not generally influenced by hormon therapy, and places considerable psychological strain on the patient and increases the risk of breast cancer. A multidisciplinary team approach can assist in improving speech impairments, academic difficulties, and other psychosocial and behavioral problems. In children, early speech and language therapy is particularly helpful in developing skills in the understanding and production of more complex language. Physical therapy should be recommended in boys with hypotonia or delayed gross motor skills that may affect muscle tone, balance, and coordination. Occupational therapy is advised in boys with motor dyspraxia. Males with Klinefelter syndrome should receive a comprehensive psychoeducational evaluation to assess their areas of strengths and weaknesses. The information obtained from these evaluations may be helpful in planning appropriate resources and classroom placement.

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Treatment for infertility: spermatogenesis is present at a very low rate in occasional patients with Klinefelter’s syndrome and very rare cases of spontaneous paternity have been reported. However, before the introduction of TESE and ICSI (testicular sperm extraction and intracytoplasmic sperm injection) in 1996, these patients were considered infertile. With these techniques, viable spermatozoa can now be extracted from the testes via surgical biopsy, and a spermatozoon can be injected directly into an ovum. More than 60 children have been born worldwide after successful ICSI in couples in which the male partner has Klinefelter syndrome. Moreover testicular tissue can be successfully cryopreserved in patients with non mosaic Klinefelter’s syndrome without significant compromise of fertilization. Germ-cell depletion is evident even in the testes of 47,XXY infants and it progresses rapidly. Otherwise a minority of young men with Klinefelter syndrome have viable sperm in their ejaculate and are able to provide sperm for cryopreservation in early puberty for future pregnancies (Lanfranco et al., 2004).

COMPLICATIONS The risk of breast carcinoma in men with the XXY variant may approach 20 times that of healthy men. Other types of neoplasia occur in 1.6% of patients and include acute leukemia, Hodgkin and non-Hodgkin lymphomas, chronic myelogenous leukemia, and other myeloproliferative diseases. Gonadal and extragonadal germ cell tumors (mediastinal germ cell tumors, teratoma, teratocarcinoma, choriocarcinoma) may also occur (Swerdlow et al., 2005). Psychologic and psychiatric complications may occur in individuals with lower-thanaverage intelligence, hypogonadism, or impotence. Vertebral collapse may result from osteoporosis. Development of varicose veins and leg ulcers may result from venous stasis. Associated endocrine diseases include diabetes mellitus, hypothyroidism, empty sella syndrome, hypoparathyroidism, and precocious puberty in association with hCG-producing germ cell tumors. Benign prostatic hyperplasia may result from testosterone supplementation. Adults undergoing such therapy should be screened for prostatic enlargement starting at age 30 years. In males with polysomic X Klinefelter syndrome, the mortality rate due to cerebrovascular diseases such as aortic valvular disease and berry aneurysm rupture is more than 6 times that in healthy males aged 25-84 years. Enhanced platelet aggregation, thrombotic disease, and hypercoagulability have been demonstrated and may be related to increased estrogen levels (Swerdlow et al., 2005).

PROGNOSIS Early studies of men with XXY Klinefelter syndrome produced disturbing findings of an increased risk of psychiatric disturbance, criminality, and mental retardation. These results are considered highly questionable because of selection bias from institutionalized populations.

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Babies with the XXY form differ little from healthy children. Although boys with the 47,XXY karyotype may struggle through adolescence with limited academic success, many frustrations, and, in a few instances, serious emotional or behavioral difficulties, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning.

GENETIC COUNSELING The recurrence risk is not increased above that in the general population, but the diffusion of TESE and ICSI techniques revealed that a higher risk of fathering a child with sex-chromosome and autosome abnormalities (47,XXY or 47,XXX or a 13, 18, 21 trisomy) after successful fertilisation treatment has to be taken in account. Preimplantation genetic diagnosis by embryo biopsy offers efficient tool for embryo selection. The best time to reveal the condition to an affected male is probably late adolescence or later, when his sexual activity has begun and some self-exsteem has been acquired and when he is old enough to understand his condition (Tarani & Verri, 2007).

REFERENCES Abramsky, L., Chapple, J. (1997) 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of an indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn, 17, 363-8. Chen, H. (2004) Klinefelter Syndrome. eMedicine , December 17. Lanfranco, F., Kamischke, A., Zitzmann, M & Nieschlag, E. (2004) Klinefelter’s syndrome. Lancet, 364, 273-83. Nielsen, J., Wohlert, M. (1991) Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet, 70, 813. Swerdlow, A.J., Schoemaker, M.J., Higgins, C.D., Wright, A.F. & Jacobs, P.A. (2005) Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst, 97, 1204-10. Tarani, L., Verri, A.P. (2007) Sindrome di Klinefelter. http://www.ambulatorio.com/ site/malattie/view.xpd?mode=read&info_key=1&id_malattia=901 Thomas, N.S., Hassold, T.J. (2003) Aberrant recombination and the origin of Klinefelter syndrome. Hum Reprod Update, 9, 309-17. Visootsak, J., Graham, J.M. (2006) Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orph J Rare Dis, 1, 42. Zitzmann, M., Nieschlag, E. (2003) The GAG repeatpolymorphism within the androgen receptor gene and maleness. Int J Androl, 26, 76-83.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter V

LIFE SPAN DEVELOPMENT IN XYY Mirta Vernice1,∗ Anna Cremante2 1 2

Department of Psychology, University of Pavia, Italy. Paediatric Clinic, University of Insubria, Varese, Italy.

ABSTRACT In the present chapter we describe an overview on the developmental history of a 34 years old left-handed male, with normal intelligence and XYY syndrome, focusing on the major variations of development occurring across neurological, cognitive and psychiatric domains. The patient was followed-up for over 30 years. He was first referred to a neuropsychiatric service for a delayed motor and language development and an immunodeficiency syndrome at the age of 2. Then he was diagnosed with XYY syndrome. At 8 years he developed a refractory focal epilepsy. Since adolescence the patient started to exhibit increasingly prominent obsessive thoughts, paranoid ideation, and aggressive sexual fantasies and behaviour. Functional MRI performed confirmed an atypical lateralization of language functions. The present case suggests a pathophysiological link between XYY chromosome abnormality, characteristic psychiatric symptoms and epilepsy disorder. The relationship between XYY chromosomal abnormality, psychiatric disorders and epilepsy will be discussed in light of previous research and hypothesis proposed by the literature.

Keywords: XYY syndrome; lateralization; epilepsy; psychosis.

∗

Correspondence concerning this article should be addressed to: Dr. Mirta Vernice, Department of Psychology, University of Pavia, Italy. e-mail: [email protected].

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INTRODUCTION XYY syndrome is a genetic condition caused by the presence of an extra Y chromosome, with karyotype 47, XYY. This syndrome represents one of the most frequent sex chromosome anomalies at birth, with an incidence of 1 in 1000 live born (Robinson & Jacobs, 1999). First described in 1961 by Sandberg and colleagues (Sandberg et al., 1961), this aneuploidy is found in approximately 80% of males with double Y and in 10% of males with chromosome constitution 48, XXYY. The last 10% have a mosaic chromosome constitution; that is, some of their cells are 46, XY and the others are 47, XYY (Abramsky & Chapple, 1997). Despite of the high rate of incidence of XYY syndrome, little is known about this syndrome and most of the patients go undiagnosed. Only approximately 10% are identified, a third prenatally, two thirds postnatally. These patients are usually diagnosed because of a developmental delay (Davey & Vance, 2007).

Clinical Description Clinical descriptions of males with XYY syndrome suggest the presence of a specific phenotype. Patients are usually normally developed at birth with normal birth weight, length and head circumference without any physical abnormalities. Between the age of 4 and 9 years they exhibit a rapid increase in body and leg length, usually averaging the 75th percentile among males of their same age. The average final height is approximately 10-12 cm above the expected; body build is normal and weight is comparatively low in relation to stature (Ratcliffe et al., 1992). The physical sexual development for XYY males is reported to be normal. Development of sex organs and secondary sex characteristics is typical. Puberty appears at the expected time. XYY males are fertile, with testes of normal size, and normal sexual libido and potency (Ratcliffe, 1999). Though chromosome aberrations do not represent per se a cause of epilepsy (Jennings & Bird, 1981; Holmes, 1987; Battaglia & Guerrini, 2005), XYY syndrome can be associated with a variety of seizure type (Benezech & Noel, 1975). Pathological electroencephalogram patterns have been reported in several cases (Ruud et al., 2005). Tremor and involuntary movements are very common in this syndrome so that it has been suggested that unexplained tremor should be regarded as a symptom for chromosome aberrations in males (Daly & Matthews, 1974).

Cognitive and Social Abilities A broad understanding of cognitive development in XYY patients has to be combined with knowledge of the developmental discrepancies and discontinuities associated with this syndrome. XYY patients show an IQ ranging from the mild mental retardation level to the normal intelligence (Fryns et al., 1995). Most studies report a mean total IQ of approximately

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90, and a consistent discrepancy between verbal and performance IQ, with the verbal IQ being higher than the performance IQ (Firth et al., 2005). In general, sex chromosome aberrations are reported in concomitance with reduced abilities in verbal fluency and general learning disabilities (Pennington et al., 1982; Bender et al., 1993). Limitations in verbal abilities might result in mild form of speech dysfluency. In the pre-school years, patients may experience slight difficulties in a variety of components of expressive language, including grammatical and syntactic development, semantic development and phonological development (e.g., phonological awareness), that together may constitute a general impairment in narrative formulation. To a lesser extent these patients may manifest receptive difficulties, specifically in understanding complex sentence structure. Though these impairments might not be severe and consistent as in other pervasive developmental disorders, previous research suggests that the common trend of language skills development in XYY patients is slower and more problematic in comparison with an unaffected control group (Bender et al., 1983). Socialization is not separated from communication. These are overlapping areas of development, dependent on cognition (Volkmar et al., 2005). It is probably this overlap that is at the root of social adjustment problems of patients with XYY syndrome. Crucially, this syndrome appears to be associated with serious social-behavioural disturbance (Geerts et al., 2003). Most studies describe the general phenomena of tempertantrums, aggressiveness and hyperactivity. Indeed, the hyperactivity and impulsiveness traits appear to be often surmounted by additional phenomena suggestive of mood and arousal dysregulation (Burgio & Notarangelo, 2002). For these reasons, the XYY syndrome has been regarded for decades as the "supermale" syndrome, since men with this condition were thought to be overly aggressive and more likely to become criminals. Jacobs (1965) claimed that XYY men displayed the tendency to commit criminal acts more frequently than expected in the general population. The occurrence of criminal offenses and anti-social behaviour in males with XYY chromosomal abnormality has been reported in a number of further studies (Berner et al., 1977; Schroeder et al., 1981; Freyne & O’Connor, 1992). However, as pointed out by more recent research, a population-based investigation revealed this aggressive behaviour to be related more to lower intelligence level than to the chromosomal aberration (Goetz et al., 1999).

Psychiatric Comorbidity in XYY Syndrome Since the past decades a number of studies claimed that XYY patients are at an increased risk of psychiatric disturbances (DeLisi et al., 1994) and abnormal sexual conduct (Klein, 1971; Fryns et al., 1995). Importantly, there are evidence that individuals with additional Y chromosome material are overrepresented in population with psychosis (Abdullah et al., 1969; Baker et al., 1970; Sorenson & Nielsen, 1977). Some case reports add support for the hypothesis that a loss of balance of gene products on the sex chromosomes may predispose these individuals to susceptibility to additional genetic and environmental insults resulting in childhood-onset psychotic disorders (Kumra et

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al., 1998, Jacobsen et al., 1998). Although the causal mechanisms for the chromosomal disorder are unknown, there is evidence that neuropsychiatric disorders might result from overexpression of genes involved in functional differentiation between hemispheres (DeLisi et al., 2005). Though cerebral asymmetries are not confined to language function, cerebral dominance is generally characterized by a left over right hemisphere specialization for language function observed in most individuals (Smalley et al., 2005). A long-lasting debate has emerged in order to shed light on the complex correlation of atypical brain lateralization and the occurrence of psychiatric disorders. Originally Flor Henry explored the relationship between psychopathology and cerebral lateralization (1969; 1979). Subsequently Crow expanded this concept, hypothesizing that schizophrenia involves dysfunction of genetic mechanisms that control the development of cerebral asymmetry (Crow, 1990; 2004; Klar, 1999). Crucially, schizophrenia might be caused by a disruption in the normal process of hemispheric specialization, resulting in a more bilateral distribution of language components normally localized on the left hemisphere (Savitz et al., 2007). In the following section, we will describe the co-occurrence of psychotic disorder, focal epilepsy and XYY chromosome abnormality in a 34-year-old left handed man (Verri et al., in press). The alteration in the typical pattern of cerebral dominance, such as a loss of temporal leftward asymmetry, detected in our patient, might provide evidence in order to better investigate the association of psychiatric disorder with XYY chromosomal aneuploidy.

CLINICAL REPORT: THE CASE OF P.G. P.G. (Figure 1) was born full term with normal birth weight, length and head circumference. The course of the gestation was unremarkable, ending with a normal delivery. Family history was negative for epilepsy and psychiatric disturbances. Early motor and language development were delayed, with first words at 20 months, and first sentences at 30 months. At 18 months he presented an isolated febrile seizure. At 2 years he was diagnosed with an IgA deficit and a T-lymphocyte deficiency which was diagnosed as idiopathic; his karyotype resulted 47, XYY (Verri et al., 1989).

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Figure 1. The 32 years old patient (frontal view).

At the age of 8 years, he developed focal motor seizures, mostly nocturnal, without secondary generalization. Seizures persisted with varying frequency (from weekly seizures to seizure-free intervals up to 18 months) despite subsequent treatments with phenobarbital (up to 150 mg/day), carbamazepine (up to 800 mg/day) and, currently, oxcarbazepine (900 mg/day). Spontaneous unprovoked epileptic seizures firstly presented when the patient was 8 years /6 months. Seizures were strictly focal. Patient reported seizure onset as the arising of paresthesia (tingling and feeling of numbness) involving the tongue and the left side of lips and chin; somatosensory phenomena were rapidly followed by left clonic deviation of the mouth and hypersalivation; clonic jerks of the left shoulder were possible. Seizure duration was 20-40 seconds. During the attacks the child showed difficulty in speech articulation, but consciousness was always preserved. At the onset such as during the follow up, seizures mainly occurred when the patient was falling asleep, during sleep (ictal symptoms woke the patient) or in coincidence with the awakening. Since the seizure onset, the patient started antiepileptic drug treatment, initially with phenobarbitone (PB, up to 150 mg / day). Rare sensory-motor seizures persisted in developmental age, with a frequency ranging from > 1 seizure weekly to less than 1 seizure monthly and recurring seizure-free intervals of 12-18 months. With subsequent antiepileptic drugs and with plasma levels within the therapeutic range (carbamazepine CBZ alone or associated with PB; CBZ controlled release on monotherapy; eventually oxcarbazepine OXC, 600 mg / b.i.d.) a complete, long term seizure remission was never obtained. A 5 years seizure-free period was achieved on CBZ-CR when the patient was 23 years old, but seizures recurred when drug discontinuation was tried. Sporadic attacks are now persisting, usually limited to somatosensory symptoms reported above and with very short duration.

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Neurological examinations show a final height above average (185 cm), normal body build, weight comparatively low in relation to stature (about 75 Kg), normal head circumference, larger craniofacial dimensions, normal motor and sensory status, normal level of consciousness, a global and persistent clumsiness associated with ligamentous hyperlaxity and bilateral scapular winging. Dominant laterality is left for hand and foot but right for eye.

Neurophysiological Evaluation The EEG recordings periodically performed show a posterior alpha activity normally reacting to eye opening and closure; a variable quota of slow abnormalities, usually with right predominance, and more prominent on frontal-temporal regions was constantly found. Interictal epileptiform abnormalities (intermittent or repetitive focal spikes, sharp-waves and spike-and waves) were inconstantly detectable on the right frontal-temporal areas. Sleep EEG recordings document a moderate activation of interictal epileptiform abnormalities during light sleep (stages I-II). Three 24 hour Ambulatory EEG recordings performed at differing times during the follow up, never detected ictal epileptiform patterns. Recent standard recordings (the last one at the age of 32 years) show occipital alpha rhythm around 9 Hz, and the persistence of mild slow and epileptiform focal abnormalities, with slow abnormalities and, at times, intermittent or repetitive focal spikes, sharp-waves and spikeand-waves predominant over the right frontal-temporal regions.

Neuroradiological Findings The brain MRI at the age of 30 shows some punctiform areas in the extension time of resonance in the cerebellar white matter in the right hemisphere and a mild asymmetry of the lateral ventricles (right larger than left). Functional MRI (fMRI) showed a right temporal and frontal activation during the execution of a verb generation task

Cognitive and Behavioural Assessment Since early infancy the patient was hyperactive and started to display some signs of conduct disturbance even in the pre-school years. The patients was segregated from peers whilst at school because of his immunodeficiency. The isolation affected his social style, impoverishing personal social skills and social responsiveness. At school he presented learning problems such as dysgraphia, dyslexia and language difficulties. Impairments in expressive language were mainly related to words finding and narrative formulation. Consistently with the diagnosis of learning disability, at 10 years his IQ was normal (total IQ=101). For these reasons the patient needed special education support at school and was followed at a Mental Hygiene Centre for some years during infancy. Later, he attended a special adjustment school. Since early adulthood the patient has been employed in a factory as milling machine operator.

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During adolescence, his immunodeficiency disappeared but he remained socially isolated. Sexual development, while physically normal, was characterized by striking isolation and traits of withdrawal. At 17 years he started to exhibit obsessive thoughts with aggressive sexual fantasies. Since then P.G. started to have obsessive thoughts regarding sex crimes, aggressive sexual fantasies or abuses, auditory hallucinations and delusions of homicide. He reported distress and guilt over such sexual thoughts and anxiety in relation to his aggressive obsessions. At the same age, a structured interview with DSM-IV criteria, revealed a generalized anxiety and obsessive compulsive disorder, associated with dystimia. Since then he is on charge at the laboratory of Cognitive Behavioural Psychology, at the Neurological Institute “Casimiro Mondino” of Pavia, for both medical examination and cure (Risperidone, 1 mg daily) and for psychological evaluation and support. The Minnesota Multiphasic Personality Inventory (MMPI), first performed when he was 17 years old and further at 30 years, documented the progressive worsening of his psychotic traits (Figure 2).

Figure 2. The elevation of the profile from 17 to 30 years shows significant differences in scores for Hysteria and Psychopathic Deviate scales. Elevated scores were also obtained in the MasculinityFemininity scale. High scores in Schizophrenia scale document a significant worsening of the profile, with anxious and depressive traits, difficulties in the social area, paranoid ideation, and suspicious behaviour.

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At the age of 17 the MMPI-1 profile showed elevated scores in the psychotic area. MMPI-2 was repeated at the age of 30, revealing a progressive worsening of his profile. Importantly, the last profile exhibited at the MMPI-2 revealed severe anxious (“Very often I’m anxious for anybody and anything”) and depressive traits, psychotic traits (“When I stay with other persons I’m annoyed to hear things that the others don’t hear”; “Usually I hear voices without knowing where they come from”, “I’m afraid to become mad”), social hostility (“Sometimes I feel as I should harm myself or others”), difficulties in the social and interpersonal areas, the tendency to be isolated and withdrawn, the presence of obsessive thoughts (“I’m afraid to use knifes or other sharp things”), paranoiac and bizarre ideas (“I believe the others are plotting against me”, “I believe to be persecuted by the destiny”, “Somebody tried to influence my thought”), suspicious behavior and withdrawn in the sexual area (“I’m worried by sexual problems” “I’m afraid to seem homosexual”). At the age of 32 years, a psychological assessment showed a total IQ of 115 (verbal 112, performance 116), good reasoning skills (score 36/36 at the Coloured Progressive Matrices, CPM), adequate comprehension and discrimination abilities (Token test score, 36/36), normal visuospatial organization skills and adequate short term visual memory, although some slowdown were reported in semantic and phonetic word rehearsal at the Verbal Fluency Test. At the Wisconsin Card Sorting Test (WCTS) for executive skills, the score was in the normal range. A structured interview was performed using the Structured Clinical Interview For DSMIV Axis I Disorders (SCID) at 32 years. The interview revealed the presence of suspiciousness and paranoid ideation such as severe psychotic symptoms associated with an anxiety and mood disorder. The Cognitive Behavioural Assessment (CBA 2.0) displayed features of agoraphobia and claustrophobia, low level of autonomy, fear for repellent animals and dark and dirty places, social phobia and feelings of inadequacy. The Personality Diagnostic Questionnaire-Revised (PDQ-R) showed a personality disorder of the third cluster. P.G. was given a diagnosis of paranoid psychosis, since features of delusion appeared to be incongruent with his cognitive organization. In a recent clinical interview, at the age of 33, P.G. reported that he had been experiencing intrusive fantasies about killing someone, and confirmed that aggressive behaviour towards women would excite him sexually. He appears to be constantly obsessed by the thought of having killed someone without any reason. He told he recently went to the police office because he had murdered someone near his home (he didn’t know exactly who was victim) asking the police to find the body, which was not found, because no murder has been done. He further indicated having fear of harming himself and other person. He explained he fears contracting AIDS (even though he has never had any sexual intercourse nor sentimental relationship), and to be considered homosexual by women soon after even a prostitute had refused him for his violent touch. In the last year his anxious and depressive state worsened and his parents reported the occurrence of some motor stereotyped actions and new compulsions (washing, checking).

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DISCUSSION The present chapter describes the atypical development of a patient with XYY syndrome. In accordance with previous research, our patient presented the main signs of the syndrome, including tall stature, minor neuromotor deficits, normal cognitive abilities and retarded speech development (Harrison et al., 2001). P.G. additionally exhibited prominent psychopathology and epilepsy. Importantly, our patient showed psychiatric disorders and behavioural problems. The concomitance of these disturbances with his chromosomal aberration appears to be critical according with studies from the literature (DeLisi et al., 2005). Although he did not have a history of violent behaviour, he revealed delusions of a paranoid nature, whose content was homicide. His pathological ideation led him to report a crime that he had not committed. Furthermore P.G. presented aggressive sexual fantasies leading to sexual arousal. Research offered divergent evidence about the relation between this chromosomal anomaly and criminal behaviour. Schroeder et al. suggested that individuals with karyotype XYY are believed to be at an increased risk of impulsive offenses and anti-social behaviour (1981). A recent retrospective investigation of psychiatric court reports documented a higher than expected frequency of XYY chromosomal abnormality among sexual homicide perpetrators (Bricken et al., 2006). A number of studies have made contributions to the understanding of the relationships between hormones and criminal behaviour in sexual chromosome aneuploidy, such as XYY syndrome (Schiavi et al., 1988). Despite findings of increased serum levels of testosterone, luteinizing hormone and follicle-stimulating hormone in XYY men, evidence from this study do not support the hypothesis that sex hormones mediated anti-social and criminal behaviour in these individuals. Recently, Verri (in press) proposed that delusions and hallucinations observed in XYY individuals may lead to behavioural problems, including anti-social conduct, sexual offenses and violent crimes. This explanation could be extended to previous cases described in literature, in which delusion and hallucinations might have been underestimated in favour of other theories, such as hormonal factor and lower intelligence. Moreover, we observed in our patient the patho-physiological co-occurence of focal epilepsy with the XYY genotype. Indeed, according to previous studies, epilepsy is among the most common findings associated with chromosome aberrations (Battaglia & Guerrini, 2005; Armfield et al., 1999). The immunodeficiency syndrome which the patient suffered from during infancy, supports the association between immune system disorders and epilepsy that has already been described in many studies (Aarli, 1993; Vezzani & Granata, 2005). In particular, the present case report accounts for the hypothesis that immune factors play a role in the epileptogenic process (Steinman, 2004; Mueller et al, 2005). Findings of the neuro-radiological investigation, exhibiting an altered cerebral lateralization, appear to be remarkably consistent with the literature. Though, it is not yet fully explained whether alterations in brain function in patients with XYY syndrome depend directly on their chromosomal aberration, recent studies suggest that an extra Y chromosome may trigger over-expression of genes located in this chromosome which influences brain growth and functional differentiation among hemispheres (DeLisi et al., 2005). Indeed,

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functional asymmetries documented in the adult human cerebral cortex are linked to asymmetric gene expression (Sean Hill & Walsh, 2005). It is known that handedness influences cerebral organization affecting the representation of language. Left hemisphere however presents a specialization for language both in rightand left-handed people, even though in left-handers the left hemisphere dominance for language appears to be less consistent (Pujol et al., 1999). In the Right shift theory, Annett (1999) states that the typical pattern of human cerebral asymmetries depends on a single gene which impairs the speech related cortex of the right hemisphere. Cerebral dominance is therefore determined by an X-Y homologous set of genes that is also present in schizophrenia (Leask & Crow, 1997). Mitchell and Crow emphasize the role of the sapiens-specific cerebral torque in determining the four-chambered nature of the human brain in relation to the origins of language and the symptoms of schizophrenia (2005). Then, it may be speculated that the language deficits observed in XYY individuals, including our patient, may be caused by an abnormal lateralization of the left hemisphere language functions, and that psychotic symptoms could similarly be attributed to a failure of segregation of right from left hemisphere functions (Mitchell & Crow, 2005). Developmental aspects of the syndrome have been discussed to characterize the neurodevelopmental, affective and behavioral profile of patients with XYY sex chromosome aneuploidy, which is highly underdiagnosed. The profile described was evaluated with the purpose of presenting elements for a precocious diagnosis of this syndrome. The clinical spectrum of anomalies associated with XYY will be better investigated with the evolution of clinical research. In particular the connection between XYY genotype and psychiatric disorders has to be clarified. To this extent more precise investigations are needed in order to study the expression of genes on the X&Y chromosomes that may be related to medical and neurodevelopmental problems in patients with XYY syndrome.

REFERENCES Aarli, J.A. (1993) Immunological aspects of epilepsy. Brain Dev, 15, 41-49. Abdullah, S., Jarvik, L.F., Kato, T., Johnson, W.C. & Lanzkron, J. (1969) Extra Y chromosome and its psychiatric implications. Arch Gen Psychiatr, 21, 497-501. Abramsky, L., Chapple, J. (1997) 47, XXY (Klinefelter syndrome) and 47, XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn, 17, 363-368. Annett, M. (1999) The theory of an agnosic right shift gene in schizophrenia and autism. Schizophr Res, 39, 177-182. Armfield, K., Nelson, R., Lubs, H.A., Hane, B., Schroer, R.J., Arena, F., Schwartz, C.E. & Stevenson, R.E. (1999) X-linked mental retardation syndrome with short stature, small hands and feet, seizures, cleft palate, and glaucoma is linked to Xq28. Am J Med Genet, 85, 236-242. Baker, D., Telfer, M.A., Richardson, C.E. & Clark, G.R. (1970) Chromosomal errors in men with antisocial behaviour. JAMA, 214, 869-878.

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Battaglia, A., Guerrini, R. (2005) Chromosomal disorders associated with epilepsy. Epileptic Disord, 7, 181–192. Bender, B., Fry, E., Pennington, B., Puck, M., Salbenblatt, J. & Robinson, A. (1983) Speech and language development in 41 children with sex chromosome anomalies. Pediatrics, 71, 262-267. Bender, B.G., Linden, M.G. & Robinson, A. (1993) Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am J Med Gen, 48, 169-173. Benezech, M., Noel, B. (1975) Neurological disorders in 47, XYY men. Lancet, 27, 617. Berner, W., Grunberger, J., Sluga, W., Schnedl, W., Wagenbichler, P. & Herbich, J. (1977) Catamneses of YY carriers in prison. Fortschr Neurol Psychiatr Grenzgeb, 45, 194-205. Bricken, P., Habermann, N., Berner, W. & Hill, A. (2006) XYY chromosome abnormality in sexual homicide perpetrators. Am J Med Genet B Neuropsychiatr Genet, 141, 198-200. Burgio, G.R., Notarangelo, L.D. (2002) Malattie maestre:una storia di grandi malattie dei piccoli. Torino: UTET. Crow, T.J. (1990) The continuum of psychosis and its genetic origins. Br J Psychiatry, 156, 788–797. Crow, T.J. (2004) Directional asymmetry is the key to the Origin of Modern Homo sapiens (the Broca-Annett axiom). Response to Lesley Rogers. Laterality, 9, 233-242. Daly, I.F., Matthews, C.G. (1974) Impaired motor function in XYY males. Neurology, 24, 655–658. Davey, C., Vance, A. (2007) A possible behavioural and cognitive phenotype for the 47, XYY karyotype in a pre-pubertal child. Australas Psychiatr, 15, 72-74 DeLisi, L.E., Friedrich, U., Wahlstrom, J., Boccio-Smith, A., Forsman, A., Eklund, K. & Crow, T.J., (1994) Schizophrenia and sex chromosome anomalies. Schizophr Bull, 20, 495-505. DeLisi, L.E., Maurizio, A.M., Svetina, C., Ardekani, B., Szulc, K., Nierenberg, J., Leonard, J. & Harvey, P.D. (2005) Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders. Am J Med Gen, 135, 15-23. Firth, H.V., Hurst, J.A. & Hall, J.G. (2005) Oxford Desk Reference: clinical genetics. Oxford: Oxford University Press. Flor-Henry, P. (1969) Psychosis and temporal lobe epilepsy: a controlled investigation. Epilepsia, 10, 363–395. Flor-Henry, P. (1979) On certain aspects of the localization of the cerebral systems regulating and determining emotion. Biol Psychiatry, 14, 677–698. Freyne, A., O’Connor, A. (1992) XYY genotype and crime: two cases. Medicine, Science and the Law, 32, 261-263. Fryns, J.P., Kleczkowska, A., Kubien, E., & Van den Berghe, H. (1995) XYY syndrome and other Y chromosome polysomies: mental status and psychosocial functioning. Genetic Couns, 6, 197-206. Geerts, M., Steyaert, J. & Fryns, J.P. (2003) The XYY syndrome: a follow-up study on 38 boys. Genetic Couns, 14, 267-279. Goetz, M.J., Johnstone, E.C. & Ratcliffe S.G. (1999) Criminality and antisocial behaviour in unselected men with chromosome abnormalities. Psychological Medicine, 29, 953-962.

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Harrison, L.E., Clayton-Smith, J. & Bayley, S. (2001) Exploring the complex relationship between adolescent sexual offending and sex chromosome abnormality. Psychiatr Genet, 11, 5-10. Hathaway, S.R.; McKinley, J.C. (1997) MMPI-2 – Minnesota Multiphasic Personality Inventory–2. Firenze: O.S. Organizzazioni Speciali. Heaton, R.K., Chelune, G.J., Talley, J.L., Kay, G.G. & Curtiss, G. (1993) Wisconsin Card Sorting Test manual. Italian version. Firenze: O.S. Organizzazioni Speciali. Holmes, G.L. (1987) Genetics of epilepsy. In G.L. Holmes (Ed.) Diagnosis and management of seizures in children. (pp. 56-71) Philadelphia: Saunders Company. Hyler, S.E., Rieder, R.O. (1987) Personality Diagnostic Questionnaire-Revised (PDQ-R). New York: New York State Psychiatric Institute. Jacobs, P.A., Brunton, M., Melville, M.M., Brittain, R.P. & McClemont, W.F. (1965) Aggressive behavior, mental sub-normality and the XYY male. Nature, 208, 1351-962. Jennings, M.T., Bird, T.D. (1981) Genetic influences in the epilepsies. Am J Dis Child, 135, 450-457. Klar, A.J.S. (1999) Genetic models for handedness, brain lateralization, schizophrenia, and manic-depression. Schizophrenia Res, 39, 207–218. Klein, D. (1971) Aspect génétique des déviations sexuelles. J Gén Hum, 19, 317-336. Kumra, S., Wiggs, E., Krasnewich, D., Meck, J., Smith, A.C., Bedwell, J., Fernandez, T., Jacobsen, L.K., Lenane, M. & Rapoport, J.L. (1998) Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders. J Am Acad Child Adolesc Psychiatr, 37, 292-296. Leask, S.J., Crow, T.J. (1997) How far does the brain lateralize?: an unbiased method for determining the optimum degree of hemispheric specialization. Neuropsychologia, 35, 1381-1387. Mazzi, F., Morosini, P., De Girolamo, G., Bussetti, M. & Guaraldi, G.P. (2000) SCID-I. Interviste Cliniche Strutturate per il DSM-IV. Italian version. Firenze: O.S. Organizzazioni Speciali. Mitchell, R.L., Crow, T.J. (2005) Right hemisphere language functions and schizophrenia: the forgotten hemisphere? Brain, 128, 963-978. Mueller, F.J., McKercher, S.R., Imitola, J., Loring, J.F., Yip, S., Khoury, S.J. & Snyder, E.Y. (2005) At the interface of the immune system and the nervous system: how neuroinflammation modulates the fate of neural progenitors in vivo. Ernst Schering Res Found Workshop, 53, 83-114. Pennington, B.F., Bender, B., Puck, M., Salbenblatt, J. & Robinson, A. (1982) Learning Disabilities in Children with Sex Chromosome Anomalies. Child Development, 53, 1182-1192. Pujol, J., Deus, J., Losilla, J.M. & Capdevila, A. (1999) Cerebral lateralization of language in normal left-handed people studied by functional MRI. Neurology, 52, 1038-1043. Ratcliffe, S.G. (1999) Long-term outcome in children of sex chromosome abnormalities. Arch Dis Child, 80, 192–195. Ratcliffe, S.G., Pan, H., McKie, M. (1992) Growth during puberty in the XYY boy. Ann Hum Biol, 19, 579–587.

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Raven, J.C., Court, J.H. & Raven, J. (1977) Manual for Raven’s Progressive Matrices and Vocabulary Scales. London: HK Lewis and Co. Renzi, E., Vignolo, L.A. (1962) Token test o test dei gettoni. Firenze: O.S. Organizzazioni Speciali. Robinson, D.O., Jacobs, P.A. (1999) The origin of the extra Y chromosome in males with a 47, XYY karyotype. Hum Mol Gen, 8, 2205 – 2209. Ruud, A., Arnesen, P., Larsen Stray, L., Vildalen, S. & Vesterhus, P. (2005) Stimulant medication in 47, XYY syndrome: a report of two cases. Dev Med Child Neurol, 47, 559562. Sanavio, E., Bertolotti, G. & Michielin, P. (1986) CBA-2.0 Scale Primarie. Firenze: O.S. Organizzazioni Speciali. Sandberg, A.A., Koepf, G.F., Ishihara, T. & Hauschka, T.S. (1961) An XYY human male. Lancet, 2, 488-489. Savitz, J., Van Der Merwe, L., Solms, M. & Ramesar, R. (2007) Lateralization Of Hand skill in bipolar affective disorder. Genes Brain Behav, 13, 1-7. Schiavi, R.C., Theilgaard, A., Owen, D.R. & White, D. (1988) Sex chromosome anomalies, hormones and sexuality. Arch Gen Psychiatry, 45, 19-24. Schroeder, J., De la Chapelle, A., Hakola, P. & Virkkunen, M. (1981) The frequency of XYY and XXY men among criminal offenders. Acta Psychiatr Scand, 63, 272-276. Sean Hill, R., Walsh, C. (2005) Molecular insights into human brain evolution. Nature, 437, 64-67. Smalley, S.L., Loo, S.K., Yang, M.H. & Cantor, R.M. (2005) Toward localizing genes underlying cerebral asymmetry and mental health. Am J Med Genet B Neuropsychiatr Genet, 135, 79-84. Sorenson, K., Nielsen, J. (1977) Reactive paranoid psychosis in a 47, XYY. male. Acta Psychiatr Scand, 55, 233–236. Steinman, L. (2004) Elaborate interactions between the immune and nervous systems. Nat Immunol, 5, 575-581. Verri, A.P., Monaco, V., Galimberti, A., Mauri, M., Ronchi, G. & Ruiz, L. (1989). Sindrome XYY: associazione con epilessia parziale, transitoria immunodeficienza cellulare e deficit IgA. In A. Forabosco, G. Andria, G. Neri & F. Sereni (Ed), Genetica e ritardo mentale. (pp.183-187) Bologna: Monduzzi Editore. Verri, A.P., Galimberti, C.A., Perucca, P., Cremante, A., Uggetti, A. & Vernice, M. (in press). Psychotic disorder and focal epilepsy in a left handed patient with chromosome XYY abnormality. Genet Counseling Vezzani, A., Granata, T. (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia, 46, 1724-1743. Volkmar, F.R., Klin, A. & Cohen, D.J. (2005) Handbook of Autism and Pervasive Developmental Disorders. New Jersey, USA: Wiley & Sons. Wechsler, D. (2003) Wechsler Adult Intelligence Scale. Italian version. Firenze: O.S. Organizzazioni Speciali.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter VI

NEUROBIOLOGICAL ADVANCES IN THE FRAGILE X FAMILY OF DISORDERS AND TARGETED TREATMENT Randi Hagerman1,2 and Michele Ono1,2 1

M.I.N.D. Institute, University of California, Davis, School of Medicine, Sacramento, CA; 2 Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, CA.

ABSTRACT Fragile X mutations cause a family of disorders that affect multiple members in a family tree throughout the generations. The full mutation can cause intellectual disability in addition to autism. However, many individuals affected by fragile X syndrome, especially females, present with learning disabilities or emotional problems without significant intellectual deficits or mental retardation. In the carrier state or premutation (55 to 200 CGG repeats), premature ovarian insufficiency occurs in approximately 20 %. Approximately 40% of male carriers and 4 to 8% of female carriers develop the fragile X-associated tremor ataxia syndrome (FXTAS) that consists of intention tremor, ataxia, neuropathy and eventual cognitive decline. Individuals with the premutation usually have normal cognitive abilities but males often demonstrate attention deficits in addition to shyness or social anxiety. Autism spectrum disorders can also occur in some individuals with the premutation. Adult females with the premutation often experience hypothyroidism and fibromyalgia suggesting autoimmune dysfunction as they age. The premutation is common in the general population and approximately 1 in 130 females and 1 in 250 to 800 males has the premutation. Advances in the neurobiology of fragile X syndrome have lead to new targeted treatments including mGluR5 antagonists that hold promise from animal studies for improving the behavioral problems, seizures and cognitive deficits in fragile X syndrome.

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INTRODUCTION Significant neurobiological advances have occurred within the last decade regarding our understanding of those who are affected with fragile X syndrome and those who carry the premutation. Fragile X syndrome is typically associated with individuals with a full mutation in their fragile X mental retardation 1 (FMR1) gene. The full mutation involves >200 CGG repeats in the front end of this gene. Usually the full mutation is completely methylated, such that little FMR1 messenger RNA (mRNA) is produced and therefore little or no fragile X protein (FMRP) is made. It is the lack or deficiency of FMRP which leads to the clinical features of fragile X syndrome including characteristic physical features, behavioral features, and cognitive deficits described below (Loesch, Huggins, & Hagerman, 2004). Individuals who carry the premutation in the FMR1 gene have between 55-200 CGG repeats (Maddalena et al., 2001). These individuals are usually unaffected cognitively during most of their life, although an occasional patient with the premutation may have autism or mental retardation (Farzin et al., 2006; Goodlin-Jones, Tassone, Gane, & Hagerman, 2004; Tassone, Hagerman, Taylor, Mills et al., 2000). However, individuals who have the premutation make excessive levels of mRNA ranging from 2 to 8 times normal (Allen, He, Yadav-Shah, & Sherman, 2004; Tassone, Hagerman, Taylor, Gane et al., 2000). The increased level of mRNA can lead to toxicity in the neurons associated with dysregulation of a number proteins and an enhanced vulnerability to oxidative stress (Arocena et al., 2005; Iwahashi et al., 2006; Usdin & Woodford, 1995). Approximately 40% of older males with the premutation and up to 8% of older females with the premutation may develop neurological problems in aging including tremor and ataxia which is part of a syndrome called the fragile X-associated tremor/ataxia syndrome (FXTAS) (Berry-Kravis, Goetz et al., 2007; Coffey et al., 2008; R. J. Hagerman et al., 2001; Jacquemont, Hagerman, Hagerman, & Leehey, 2007). Premutation carriers may also experience an increased incidence of depression or anxiety in addition to mood instability during childhood or in their adult life prior to the aging process (Farzin et al., 2006; Franke et al., 1998; Hessl et al., 2005; Sobesky et al., 1996). These problems may represent a developmental effect of the premutation or RNA toxicity which impacts the limbic system during adult life (Hessl et al., 2007; Hessl et al., 2005; Koldewyn et al., in press). Additional neurological or endocrine problems which can occur in carriers without FXTAS include neuropathy (Berry-Kravis, Goetz et al., 2007; R. J. Hagerman et al., 2007), hypothyroidism and fibromyalgia, particularly in women (Coffey et al., 2008) and premature ovarian insufficiency (POI) (Wittenberger et al., 2007).

PREVALENCE The prevalence of fragile X syndrome in the general population depends on how it is defined. The majority of males with the full mutation have significant mental retardation usually in the mild to moderate range, however 15% are high functioning with an IQ of 70 or greater (R. J. Hagerman, 2006; R. J. Hagerman et al., 1994). In females with the full mutation, approximately 25% have mental retardation although up to 70% can have a

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cognitive impairment that includes a borderline IQ (de Vries et al., 1996). The prevalence figures for fragile X syndrome have focused on those with significant cognitive impairment by screening special education programs or individuals with either autism or mental retardation (Crawford, Zhang, Wilson, Warren, & Sherman, 2000; Sherman, 2002; Turner, Webb, Wake, & Robinson, 1996). Such studies have led to a prevalence of fragile X syndrome with significant cognitive impairment of approximately 1 in 3600 to 1 in 4000. The prevalence of the premutation has focused on studies which include population screening and the allele frequency of the premutation is approximately 1 in 130 females (P. J. Hagerman, 2008; Pesso et al., 2000; Toledano-Alhadef et al., 2001) in the general population. In Canada, the prevalence of the premutation was approximately 1 in 250 in females and 1 in 800 in males in the general population (Dombrowski et al., 2002; Rousseau, Rouillard, Morel, Khandjian, & Morgan, 1995).

CLINICAL FEATURES OF FRAGILE X SYNDROME Individuals who are affected with the full mutation typically present in early childhood with hypotonia, developmental delay particularly in language,, hyperactivity, a short attention span, poor eye contact and stereotypic features of the hands including hand flapping or hand biting (R. J. Hagerman, 2002b). Most individuals with fragile X have a short attention span and approximately 80% of the boys have significant hyperactivity (Cornish, Sudhalter, & Turk, 2004; Cornish, Turk et al., 2004; Turk, 1998). Approximately 30% of the girls with the full mutation are diagnosed with ADHD but attention problems appear to be far more prevalent (R. J. Hagerman, 2002b; R. J. Hagerman et al., 1992). Physical features of fragile X syndrome include hyperextensible finger joints, double jointed thumbs, flat feet, a long face and prominent ears. However, about 30% of individuals with fragile X do not have prominent ears or obvious physical features of fragile X. In adolescence macroorchidism or large testicles become apparent, although on careful examination this begins at about 8 years old even before development of pubic hair (Lachiewicz & Dawson, 1994). A high arched palate can sometimes lead to dental crowding or maloccclusion later in life. Eye problems, including strabismus, may occur in 8-30% (R. J. Hagerman, 2002b; D.D. Hatton, Buckley, Lachiewicz, & Roberts, 1998) and nystagmus or ptosis in less than 5%. The loose connective tissue in fragile X syndrome can occasionally lead to a hernia or joint dislocation but this is seen in less than 10% of patients (R. J. Hagerman, 2002b). Recurrent otitis media occurs in the majority of patients and this may also be related to collapse or dysfunction of the Eustacian tube so that drainage of the middle ear is impaired. Placement of PE tubes are typically needed to ensure normal hearing in a child who has recurrent otitis media (R. J. Hagerman, Altshul-Stark, & McBogg, 1987). On occasion the airway may obstruct while sleeping leading to sleep apnea in childhood or adulthood. Surgery to remove the adenoids and sometimes the tonsils usually alleviates the sleep apnea (R. J. Hagerman, 2002a).

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Approximately 20% of individuals with fragile X syndrome experience seizures and these may be petit mal, absence seizures, or grand mal episodes (Berry-Kravis, 2002; Musumeci et al., 1999). Usually individuals with fragile X syndrome and seizures respond well to anticonvulsant medication such as valproate or leviteracetam. However, a subgroup of children may continue to have seizures that have never been recognized or have been difficult to control with medication. Recent research suggests that those with seizures have a higher rate of autism in follow-up (Garcia-Nonell et al., in press). Rigorous treatment of seizures is recommended so that there is not a negative effect on future development or a kindling of further seizures (R. J. Hagerman, 2002a). The behavioral features of fragile X syndrome include poor eye contact, hyperactivity, attentional problems, tactile defensiveness, anxiety, hyperarousal to sensory stimuli, hand flapping with excitement and hand biting. These problems create a behavioral phenotype that is often more helpful in suggesting the diagnosis of fragile X than the physical features. Tantrums are common in childhood and typically relate to hyperarousal with sensory stimuli or anxiety in a new situation. Children with fragile X syndrome demonstrate an enhanced sympathetic response to sensory stimuli with decreased vagal tone and a lack of habituation to repetitive stimuli (Miller et al., 1999; Roberts, Boccia, Hatton, Skinner, & Sideris, 2006). The enhanced sympathetic response may facilitate outbursts, either verbal or physical. Significant aggression is more common in adolescence and it occurs in approximately 30% (R. J. Hagerman, 2002b). The stress hormone, cortisol, is elevated in individuals with fragile X syndrome compared to controls after stressful social stimuli (Hessl et al., 2002; Hessl, Glaser, Dyer-Friedman, & Reiss, 2006). On a cellular level, oxidative stress is increased in the absence of FMRP with higher levels of reactive oxygen species and altered levels of components of the glutathione system in the FMR1 knock out mouse compared to controls (el Bekay et al., 2007). Speech is typically perseverative and cluttered, although approximately 10% of the children are non verbal. Children with fragile X syndrome and autism have the lower verbal abilities with greater deficits in expressive language than receptive language compared to those with fragile X syndrome without autism (Philofsky, Hepburn, Hayes, Hagerman, & Rogers, 2004; Roberts, Hennon et al., 2007; Roberts, Price et al., 2007; Rogers, Wehner, & Hagerman, 2001). Perseverative speech can worsen in anxiety provoking situations as can aggression, so calming routines are useful. Sometimes the anxiety can be so severe that selective mutism, the lack of speaking in some environments, such as school, can occur. Selective mutism is more common in females with the full mutation compared to males, particularly in those individuals without significant hyperactivity or impulsivity (R. J. Hagerman, Hills, Scharfenaker, & Lewis, 1999).

AUTISM AND FRAGILE X SYNDROME There is a strong association between fragile X syndrome and autism. Approximately 30% of individuals with fragile X syndrome have full autism and an additional 20-30% have PDD-NOS (Harris et al., in press; D. D. Hatton et al., 2006; Kaufmann et al., 2004; Rogers et al., 2001). The association between fragile X and autism is likely related to the fact that

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FMRP is a regulator of translation for many other genes. Therefore, when FMRP is absent there is an up regulation of translation of other genes since FMRP is usually an inhibitor of the translation of mRNAs into protein. It is likely that some of these messages from other genes are also associated with autism (R. J. Hagerman, Rivera, & Hagerman, 2008). For those individuals with fragile X syndrome who are not on the autism spectrum, they still may have difficulties with poor eye contact, anxiety, unusual stereotypic features with the hands and obsessive compulsive behavior. Those with autism and fragile X syndrome have a lower IQ than those with fragile X alone (Bailey, Hatton, Skinner, & Mesibov, 2001; Rogers et al., 2001). However, the level of FMRP does not correlate with the presence of autism once the IQ is controlled (Loesch et al., 2007). Therefore it is likely that background genetic factors or environmental factors are related to the presence of autism in those with fragile X. If a second medical condition, such as birth trauma, cerebral palsy, or poorly controlled seizures occur, it is much more likely that the individual will have autism (Garcia-Nonell et al., in press). The Prader-Willi phenotype (PWP) in fragile X syndrome which represents obesity, hyperphagia, a lack of satiation and small genitalia occasionally occurs in individuals with fragile X syndrome (Nowicki et al., 2007). Recently, this subphenotype of fragile X syndrome has also been associated with a higher rate of autism and lower expression of cytoplasmic interacting FMR1 protein (CYFIP) (Nowicki et al., 2007). CYFIP is a sister protein to FMRP and it resides at 15q in the Prader-Willi/Angelman syndrome critical region. FMRP controls the expression of CYFIP and when FMRP is absent CYFIP levels are usually up regulated. However, in the Prader-Willi phenotype of fragile X CYFIP levels are down regulated. Lowered CYFIP levels may cause more significant problems in synaptic plasticity since CYFIP interacts with Rac 1, an important regulator of synaptic plasticity (Nowicki et al., 2007). It is unknown why CYFIP is down regulated in the Prader-Willi phenotype of fragile X syndrome. Very little information is known regarding aging in fragile X syndrome, although this is an area of more intensified interest after the discovery of FXTAS. There is some evidence that autistic features may increase as individuals with fragile X syndrome age (D. D. Hatton et al., 2006). FMRP also regulates the Amyloid Precursor Protein (APP) so levels are increased in individuals with fragile X syndrome and there may be a higher rate of dementia in this disorder (Westermark et al., 2007). Further study of this possibility is warranted.

CLINICAL FEATURES IN PREMUTATION CARRIERS INCLUDING FXTAS Most individuals with the premutation are normal cognitively during their lives but a significant number of males (40% overall) and limited number of females (4 to 8%) with the premutation develop FXTAS (Coffey et al., 2008; Jacquemont et al., 2004). FXTAS is completely different than fragile X syndrome including the clinical features and the molecular etiology. The core features of FXTAS include intention or action tremor and ataxia with tremor more common initially; average age of onset of approximately 60 years (Leehey et al., 2007). The age of onset of tremor and ataxia correlates significantly with elevation in

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the CGG repeat within the premutation range, therefore the higher the repeat number, the earlier the onset of FXTAS (Tassone et al., 2007). Additional clinical features associated with FXTAS include neuropathy (Berry-Kravis, Goetz et al., 2007; R. J. Hagerman et al., 2007) which can often occur before the onset of tremor and ataxia. Impotence is also very common and typically occurs as the first symptom well before tremor or ataxia (Greco et al., 2007). FXTAS also involves other autonomic problems including hypertension, orthostatic hypotension, incontinence, and swallowing problems (Jacquemont et al., 2007; Jacquemont et al., 2003). Psychiatric problems that are common in premutation carriers, such as depression and anxiety, can worsen significantly after the onset of FXTAS. Additional psychiatric problems with FXTAS include apathy, irritability and increased mood instability (Bacalman et al., 2006). Late features of FXTAS include bowel and bladder incontinence, increased falling associated with the ataxia leading to use of a cane or walker and eventually a bedridden state (Berry-Kravis, Abrams et al., 2007; R. J. Hagerman et al., 2001). Neuropathological findings in FXTAS include the presence of inclusions in the nucleus of both neurons and astrocytes (Greco et al., 2006; Greco et al., 2002). These inclusions occur throughout the brain but they are most dense in the limbic system including the hippocampus and the amygdala. The inclusions are synuclean and tau negative but they are eosinophilic and ubiquitin positive. The molecular findings within the inclusions include a number of proteins including hnRaPA2, muscleblind protein, myelin basic protein (MBP), Lamin A/C and αB crystallin (Iwahashi et al., 2006). The presence of a premutation in a neuron leads to up regulation of heat shock proteins in addition to αB crystallin and this may relate to a cascade of reactions leading to significant neurotoxicity (P. J. Hagerman & Hagerman, 2004; Iwahashi et al., 2006). Significant dysregulation of lamin A/C occurs in the neurons with the premutation (Arocena et al., 2005) and it is likely that the neuropathy associated with FXTAS is a functional laminopathy related to lamin A/C disruption (R. J. Hagerman et al., 2007). Neuroimaging features of FXTAS include global brain atrophy, diffuse white matter disease which typically is periventricular, subcortical and involving the middle cerebellar peduncles (MCP sign) (Cohen et al., 2006; Jacquemont et al., 2003). The MCP sign is relatively unique to FXTAS and it is seen in 60% of males with FXTAS but only 13% of females with FXTAS (Adams et al., 2007). The diagnostic criteria for definite FXTAS includes the presence of tremor and ataxia in addition to the MCP sign on MRI, however probable FXTAS does not require the MCP sign (Jacquemont et al., 2003). Cardiovascular features that are common in premutation carriers include hypertension and this is significantly different than controls (Berry-Kravis, Abrams et al., 2007; Coffey et al., 2008; Jacquemont et al., 2003). A relatively frequent number of individuals with the premutation also may experience arrhythmias which often can lead to placement of a pacemaker. This finding may also relate to disruption of lamin A/C within the nucleus in neurons, fibroblasts and perhaps other cell lines involving heart (Arocena et al., 2005). Cognitive deficits are common in FXTAS and by the time an individual presents with tremor and ataxia, executive function (EF) deficits are seen in almost all males but in a minority of the women (Grigsby et al., 2008; Grigsby et al., 2007; R. J. Hagerman et al., 2004). Approximately 50% of men with FXTAS eventually develop dementia (Bourgeois et al., 2006). The dementia is described as a frontal subcortical dementia because verbal

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abilities are relatively spared at first and the EF deficits are the presenting sign (Bacalman et al., 2006). Individuals with FXTAS should receive treatment for medical problems when they occur including hypertension, psychiatric problems, painful neuropathy, hypothyroidism in addition to their primary symptoms of tremor and ataxia. A review of treatment options for FXTAS is summarized in a recent consensus paper (R. J. Hagerman, Hall et al., 2008). Potential prophylactic treatment that may be neuroprotective to prevent the onset of FXTAS is currently being studied. Candidates for neuroprotective agents include lithium. Since the neurons with the premutation are sensitive to oxidative stress (Arocena et al., 2005), avoidance of elective surgery and smoking which can lead to significant oxidative stress is important (R. J. Hagerman, Hall et al., 2008). Future molecular interventions that can knock down excessive levels of mRNA are currently being studied but access across the blood brain barrier for such agents is still problematic. Treatment of FXTAS includes the use of medications to improve tremors such as primidone or beta blockers (R. J. Hagerman, Hall et al., 2008; Hall et al., 2006). Significant neuropathic pain is common and typically responds well to gabapentin or pregabalin. Psychiatric features typically respond well to SSRIs such as sertraline or SNRIs such as venlafaxine or duloxetine. Duloxetine (Cymbalta) may be particularly helpful for fibromyalgia because it decreases pain symptoms (R. J. Hagerman, Hall et al., 2008). Another disorder that is unique to premutation carriers is premature ovarian insufficiency (POI). The premutation is the most common single gene cause of early ovarian failure. Approximately 4 to 14% of woman with POI will turn out to have the premutation (Sullivan et al., 2006; Wittenberger et al., 2007). Approximately 20% of women with the premutation will have POI meaning ovarian insufficiency before age 40 and an additional 20% will have it before age 45. POI correlates with the size of the premutation and it is thought to also be cause by RNA toxicity (P. J. Hagerman & Hagerman, 2004).

TARGETED TREATMENT FOR FRAGILE X SYNDROME Neurobiological studies of animal models of fragile X including the knockout mouse have led to the discovery of an enhancement of the metabotropic glutamate 5 pathway (mGluR5) in the absence of FMRP leading to long term depression (LTD) or weakening of synaptic connections (Bear, 2005; Huber, Gallagher, Warren, & Bear, 2002). Further support of this up regulation of the mGluR5 system has been demonstrated by using agents that directly lower FMRP levels in hippocampal slices leading to internalization of AMPA receptors and LTD at the synapse (Nakamoto et al., 2007). These findings have reinforced the mGluR5 theory of mental retardation in fragile X (Bear, 2005; Bear, Huber, & Warren, 2004). A genetic proof of this theory includes experiments carried out by Dolen et al. (2007), where the fragile X knockout mouse is crossed with an mGluR5 deficient mouse leading to rescue of the dendritic spine abnormalities, the behavioral problems, the cognitive deficits and the growth abnormalities in fragile X in the offspring of this crossing. The macroorchidism was not rescued so macroorchidism does not appear to be related to the enhancement of mGluR5 pathways. This advance in our understanding of the neurobiological

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underpinnings of fragile X syndrome has led to targeted treatments for this disorder specifically the use of mGluR5 antagonists to reverse the LTD in fragile X syndrome. Studies of the nGluR5 antagonist MPEP in the knockout mouse have led to rescue of the seizures and improvement in cognition and behavior (Bauchwitz, 2006; Yan, Rammal, Tranfaglia, & Bauchwitz, 2005). Studies in the drosophila model of fragile X have demonstrated that MPEP treatment or lithium treatment can rescue the structural abnormalities in the brain in addition to learning deficits and LTD (McBride et al., 2005). These studies in the animal models have paved the way to human trials of an mGluR5 antagonist, specifically fenobam. Fenobam was studied as an anxiolytic agent in the 1980s in FDA approved research trials, but in 2005 it was discovered to be an mGluR5 antagonist by Porter et al. (2005). Human trials have been initiated with fenobam but the results are not yet available. Other mGluR5 antagonists are being developed for human use and the future looks bright for development of new psychotherapeutic agents that will improve both the cognitive and the behavioral problems associated with fragile X.

SCREENING FOR FRAGILE X A new blood spot technique for screening newborns or individuals at high risk for fragile X including those with autism or cognitive deficits has now been developed (Tassone, Pan, Amiri, Taylor, & Hagerman, 2008). This new screening methodology will facilitate the identification of individuals who are at high risk for fragile X or extended family members of a proband who has already been identified. Population screening either through newborn screening or through prenatal screening will also lead to improved prevalence figures for both the premutation and the full mutation. The benefits of identifying infants early include the ability to provide early intervention for the child and genetic counseling for the family so that informed decisions can be made for subsequent children (Bailey, Beskow, Davis, & Skinner, 2006; Bailey, Skinner, Davis, Whitmarsh, & Powell, 2008; McConkie-Rosell et al., 2007). Early speech and language therapy and occupational therapy in addition to educational intervention are helpful for the child with fragile X syndrome (Braden, 2002; Scharfenaker, O'Connor, Stackhouse, & Noble, 2002). A variety of medications are currently available to treat fragile X syndrome even before the mGluR5 antagonists become generally available. Use of alpha agonists, such as clonidine or guanfacine are commonly used in preschoolers to treat anxiety, hyperarousal and ADHD (R. J. Hagerman, 2002a). Stimulant medications are used to treat ADHD symptoms from 5 years of age and older and non stimulants such as atomoxetine may also be helpful for treatment of ADHD (Berry-Kravis & Potanos, 2004). Use of an SSRI in preschoolers can also be helpful to treat anxiety and autism (R. J. Hagerman, 2002a). Most recently aripiprazole (Abilify), an atypical antipsychotic which does not cause as much weight gain as risperidone, has become a popular and commonly used in treatment in fragile X syndrome. Its popularity is related to aripiprazole’s ability to improve attention, anxiety and mood stabilization (R. J. Hagerman, 2006). The future looks bright regarding both the wider identification of those with fragile X and improvements in treatment. The use of targeted treatments holds the hope of improving not only behavior but also cognition in those affected by fragile X. It is possible that mGluR5

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antagonists may also be helpful for other subgroups of autism so controlled trials are planned for both autism and fragile X syndrome.

ACKNOWLEDGEMENTS This work was supported by the NIH grants HD 036071, HD02274, UL1 RR024922, RL1 AG032115, RL1 AG032119, Health and Human Services Administration on Developmental Disabilities (90DD0596), Autism Speaks, and the M.I.N.D. Institute.

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In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter VII

LIFE SPAN DEVELOPMENT IN NANCE-HORAN SYNDROME (NHS) Silvia Russo1, Annapia Verri2,∗, Valeria Destefani3, Francesca Cogliati1 and Maria Teresa Dotti4 1

Laboratorio di Citogenetica e Genetica Molecolare, Istituto Auxologico Italiano, Milano, Italy; 2 Fondazione Istituto Neurologico C. Mondino, Dipartimento di neurologia del comportamento, Pavia, Italy; 3 Laboratorio di Psicologia Cognitivo-comportamentale, Fondazione Istituto Neurologico C. Mondino, Pavia, Italy; 4 Dipartimento Scienze Neurologiche e del Comportamento, Università di Siena, Italy.

1. ABSTRACT Nance-Horan Syndrome (NHS; OMIM 302350) is a rare X-linked condition characterized by severe congenital cataract with microcornea, distinctive dental findings, evocative facial features, mental disability and autistic traits. In this chapter we present a clinical study focused on psychomotor development, intellectual abilities, and behavior in DA, a 27 years old affected male. Our intent is describing the life span development, the cognitive and behavioral profile in a case of NHS. Psychological evaluation was performed using neuropsychological and psychiatric instruments (the Wechsler Adult Intelligence Scale, the Token Test and the Colored Progressive Matrices; the Autism Behavior Checklist and the Adaptive Behavior Inventory). Results of the clinical longitudinal observation are reported. Neurological evaluation shows a global clumsiness. An initial cerebellar atrophy was found in D.A. MRI. Genetic counseling for NHS gene identification in D.A. identified a nonsense mutation in exon 6. This mutation ∗

Correspondence concerning this article should be addressed to: Dr. Annapia Verri, Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, via Mondino, 2 – 27100 Pavia, Italy. e-mail: [email protected].

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Silvia Russo, Annapia Verri, Valeria Destefani et al. was also found in his mother and in his sister but not in his maternal uncle, confirming the clinical data and the results of haplotype analysis. A mild mental disability is present (global IQ = 62 verbal IQ = 74, performance QI = 52), characterized by a marked discrepancy among the verbal and performance subtests. At the Colored Progressive Matrices D.A. performed 23/36 (reasoning skill). At the Token Test, D.A. shows a good level of comprehension (31/36). At the Autism Behavior Checklist (Krug, 1980) D.A. he showed isolation features, with impaired relationships and limited autonomy skills. At the Adaptive Behavior Inventory D.A. shows difficulties in communication and social areas. D.A. received a late diagnosis of NHS in adulthood. Mild mental disability, behavioral and social impairments were the first signs that suggested us to investigate his clinical condition. This highlights the necessity to conduct a deep assessment along all the aspects of NH syndrome.

2. INTRODUCTION Nance-Horan syndrome (NHS; OMIM 302350) is a rare X-linked condition often associated with mental retardation and autistic traits (Toutain et al., 1997); it is also known as: Brachymetarcarpia-cataract-mesiodens syndrome, cataract-dental syndrome, mesiodenscataract syndrome, X-linked cataract-dental syndrome, X-linked cataract with hutchinsonian teeth, X-linked congenital cataracts-microcornea syndrome. It was first described by Horan and Nance as a congenital syndrome affecting both sexes characterized by cataracts, impaired vision, supernumerary central incisor (mesiodens), incisor diastemas, narrowed incisal edges, anteverted pinnae and short fourth metacarpals (Nance et al., 1974; Horan & Billson, 1974). In some patients developmental delay and mental retardation (MR) are present, in most cases, MR is mild or moderate (80%) and not associated with motor delay. Conversely, a severe mental handicap associated with autistic traits may be observed. The disease is diagnosed on the basis of the clinical symptoms (Table 1). Ocular abnormalities usually require surgery for cataract extraction although the results are poor. Complications are treated medically or surgically depending on the type and severity. The ocular problem requires education appropriate for the degree of visual handicap and often necessitates education in special school for the visually impaired. Dental anomalies may require orthodontic treatment when there are supernumerary teeth or for aesthetic reasons. Intellectual impairment requires special education. NHS is a rare disorder, whose incidence is probably underdiagnosed. Fewer than 20 families have been reported in literature. The diagnosis is made early, generally in the first year of life, and most often at birth, particularly in cases where there is a known family history. Regarding differential diagnosis, McKusick’s catalogue on hereditary disorders distinguishes NHS from two forms of isolated X linked congenital cataract: 1) X linked congenital cataract with posterior sutural opacities in heterozygotes (OMIM 300200); 2) X linked congenital cataract with microphthalmia (OMIM 302300). It is possible that these three group correspond to a single condition with variable expression (Goldberg & Hardy, 1971). It is still unknown whether the interfamilial phenotypic variability of NHS and the putative existence of isolated X-linked congenital cataracts are the result of allelic mutations

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in a single gene or whether NHS is a contiguous gene syndrome (Franco et al., 1995; Ramprasad et al., 2005). Similarly, the nosologic relationships with X-linked microphthalamias and Lenz Syndrome (colobomatous microphthalmia with various visceral and skeletal malformations) are not clear at the moment (Figure 1). Table 1. Clinical features in NHS male patients Ocular findings Severe visual impairment Congenital cataract Microcornea Nystagmus Strabismus Glaucoma * Retinal detachment* Cornea lesions* Eyeball atrophy* Dental abnormalities involving permanent and deciduous teeth Crown shape anomalies Number anomalies Position and impantation anomalies Other anomalies (late persistence of deciduous teeth, pulp chamber anomalies) Dysmorphic features A long narrow rectangular face Marked long sometimes vertical chin and prognathism in all cases A large nose with a high narrow nasal bridge Large often protruding ears Mental retardation Mild/Moderate Profoun with autistic features

100% 100% 96% 93% 43% 28% 14% 14% 12% 100%

100%

30% 80% 20%

*Post-operative complications after surgery (Hibbert, 2005).

The report by Francis et al., of a first locus for isolated X-linked cataract on Xp22 in a region overlapping the NHS genetic interval strongly support this hypothesis (Francis et al., 2002); more recently another family segregating both the phenotype Nance-Horan and X linked cataract in two first cousins was reported (Florijn et al., 2006). NHS is a genetic condition of X-linked dominant transmission with a variable penetrance and results preferentially from mutations occurring in male gametes (inserire REF). Several linkage studies mapped the NHS gene firstly to Xp22 (Lewis et al., 1990); subsequently the interval was refined to 1,3 Mb in Xp22.13, between DXS1195 and DXS999, by the study of 13 independent multiplex families with classical NHS (Toutain et al., 2002). Burdon et al. (2003) studying a large Australian pedigree, confirmed the mapping and found the first truncating mutation within a novel gene, which was called NHS gene.

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Figure 1. Schematic representation of the human NHS gene structure. The V lines indicate the alternative splicing. NHS-A skips exon 1a and codes for the longest protein (1652 aminoacids), NHS-A does not use exon 1 and codes for a transcript of 1474 aa. The shortest protein is that coded by NHS-B (1335 aa) ( Sharma, 2006).

The gene NHS (MIM300457) produces three different, N-terminal alternatively spliced transcripts resulting in NHS-A protein (1652 aa), NHS-1A (1474 aa) and NHS-B (1335 aa). These isoforms show differences in tissutal and cellular compartment localization, suggesting their ability to perform diverse functions. In fact it has been demonstrated that NHS-B is expressed in human brain (Burdon et al., 2003), NHS-1A in fibroblast cells and NHS-A in epitelia and neural tessues of brain and retina, lens cells, olphactory epithelium, teeth primordia and whiskers follicles (Burdon et al., 2003; Sharma et al., 2006). Moreover it has been demonstrated that NHS-1A isoform is present in cytoplasm, while NHS-A localizes in the cell periphery at the sites of contact between adjoining cells. Finding of NHS-A expression in human lens and throughout mammalian embryonic development of lens ephitelium suggests that the lack of a wild type NHS-A leads to cataract formation in human and mice. Mutational studies of NHS gene identified the occurrence of truncating mutations in Nance-Horan patients confirming their pathogenetic role in the syndrome (Burdon et al., 2003; Huang et al., 2007). Aim of the present paper is to study the developmental history and evolution of a patients recently observed at the Neurological Institute “Casimiro Mondino” of Pavia affected by NH syndrome and to describe the life span development in NHS.

3. CASE REPORT D.A. is a 32 years-old Italian male. He lives with both parents. The father, 66 years old, is affected by insulin-dependent diabetes in treatment. The mother, 67 years old, is medicated for recurrent anxiety disorders. Patient is the secondborn. He has a 8 years elder sister with mild cataract, who is married and lives outside the family. D.A. works as a mechanical assembly worker and recently he presents discomfort in working context as indicated by frequent absences, fear for responsibilities and a growing tension with collegues. He came to observation for maladaptive behaviour. Parents report the observation of signs of disadaptation to the working context. In addiction, D.A. shows an anxiety disorder characterised by recurrent, persistent obsessions and compulsions involving

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contamination and self doubt. His mood is often depressed and characterised by feelings of sadness, despair and discouragement alternated to nervosism and episodes of anger. He shows a loss of interest in activities and complain a sense of fatigue associated to a change in eating and sleeping habits. Recurrent somatic complains are characterised by dizziness, tremors, toothache, digestive system diseases, nocturnal bruxism, excessive perspiration and allergic reactions to pollen. A detailed family history and a pedigree were obtained through personal interviews and corroborated by medical examination (Figure 2). The responsible adult signed a Consent for participation approved by the Institutional Review Board.

D. A.:FAMILY TREE I 2

1

3

II 1

2

Figure 2. Family tree.

Developmental History D.A. was born after an uncomplicated 9 months pregnancy. Neonatal weight was 3,650 kg. During the neonatal period D.A. showed a cephalo-hematomas, reabsorbed within the second month. Motor developmental was normal, while the language appeared delayed, with first words only after the age of two. He attended special schools for eleven years, getting a professional degree. A sheltered work in order to help his socialization was required by the family with the support of National Association of Families with Disability (ANFFAS Associazione Nazionale Famiglie di Persone con Disabilità Intellettiva e/o Relazionale). His physical appearance is quite normal, but he shows some characteristic of NanceHoran syndrome like a bilateral cataract with rotatory nystagmus, a long narrow face and a marked chin and large anteverted ears. The objective evaluation documented the presence of some dysmorphic features: a long narrow rectangular face, narrow mandibole and a narrow basal bridge and dental anomalies (Figures 3,4). His speech and voice are monotonous. His non verbal communication is poor and the expression of his emotions is almost absent. He shows no interest in understanding other people and so he lacks the ability for normal social interaction and has no close friends at school or at home.

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His gross motor movements are quite clumsy and ill coordinated. Neurological evaluation showed a global clumsiness.

Figure 3. D.A. 32 yrs old patient (lateral view): See distintive facial features: a long face with a narrow mandibole and a narrow basal bridge.

Figure 4. The 32 yrs old patient (frontal view). See dental anomalies which include serrated incisal edges and barrel-shaped teeth in which the incisal edge and the gingival margin are narrower than the cervix of the tooth.

Neurophysiological and Neuroradiological Findings Electromyographic (EMG) study showed no signals of abnormal neurogenic activity. Electroencephalography (EEG) showed a mild inter-hemisferic asimmetry of brain waves.

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Electrophysiological tests such as visual evoked potentials recorded in basal conditions were normal. Brain MRI documented enlargement of cerebellar sulci and no associated supratentorial anomalies were demonstrated (Figure 5).

Figure 5. Sagittal T1-IR weighted image shows the enlargement of cerebellar sulci.

Linkage analysis using polymorphic markers spanning the whole X chromosome mapped the disease locus to Xp22.12-p21.33 interval and confirmed the clinical diagnosis of NanceHoran Syndrome. Genetic counseling for NHS gene identification in D.A. identified a nonsense mutation in exon 6 (Glu1281X) (Toutain, 2005 personal communication). According to the rules of non-mediated-decay (NMD), aberrant transcript should be degradated and aberrant protein not to be coded. This mutation was also found in his mother and in his sister but not in his maternal uncle, confirming the clinical data and the results of haplotype analysis.

Cognitive-Behavioural Assessment The evaluation with DSM-IV criteria documented an obsessive-compulsive disorder associated with emotional instability. During the various sessions of assessment D.A. was scarcely collaborating and answered to the proposed questions showing distraibility and low motivation. Eye contact was often missing. Personal contributions to the interaction were generally a small amount of the conversation and almost not pertinent. He showed a mental introversion in which the attention and interest appeared fastened upon his own ego. His behaviour was characterized by a lack of responsiveness to the examiner, and bizarre responses to the environment. The language was stereotyped and characterized by monotone repetitions; in several occasions D.A. enunciated phrases without a communicative finality, as absorbed in a self centered

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state from which reality tends to be excluded. He revealed a gross impairment in verbal and nonverbal communication. In any case he showed good understanding of the instructions and he was able to remember them throughout the tasks. Feelings of inadequacy arise from difficulties, when he performed the more complex tasks. The following instruments were administered: Wechsler Adult Intelligence Scale (WAIS), Token Test; Coloured Progressive Matrices (CPM); Rey Figure Drawing Test; Adaptive Behaviour Inventory (Brown & Leigh, 1987); Autism Behavior Checklist (Krug Autism Scale – Krug et al., 1980). Cognitive psychometric evaluation scores are reported in Table 2. Table 2. Cognitive psychometric evaluation TEST WAIS Full Scale IQ Verbal IQ Performance IQ Token Test CPM

SCORE

NORMATIVE DATA MEAN ± D.S.

62 64 52 31 23

100 ±15 100 ±15 100 ±15 34.45 ±1.58 36.18 ±7.43

In the Wechsler Adult Intelligence Scale (WAIS), D.A. obtained a Full Scale IQ = 62 (mild mental retardation score) with a marked discrepancy among the verbal subtests (Verbal IQ = 74, low average score) and the performance subtests (Performance I.Q. = 52, mild to moderate mental retardation score). Verbal subtests showed good knowledge and padronance of verbal competences and verbal language and sufficient comprehension and analogical thinking. Performance subtests revealed impairments in nonverbal reasoning and logical sequencing associated to deficits in organization of the perception and reconstruction of concrete shapes (“object assembly”). He maintained a low speed of execution during all the tasks. In the Token Test he showed good understanding of spoken language, while the performance in Coloured Progressive Matrices (CPM) revealed reduced efficiency in the logical-deductive and abstract reasoning. Visual-spatial organizational skills as assessed by the Rey Complex Figure Copy results were compromised. D.A. completed the design rather quickly (approximately 2 minutes), but he copied only few elements of the figure, placing them in wrong position, losing the proportions between the various parts. Also visual-spatial memory results were severely impaired: in the Rey Complex Figure Memory he only reproduced the outline of the figure and little elements to its inside, but not correctly placed. The patient was sufficiently autonomous and able to work: Adaptive Behaviour Inventory (Brown & Leigh, 1987) pointed out a good level of autonomy associated to difficulties in social and communication areas. Finally in the Autism Behavior Checklist (Krug Autism Scale – Krug et al., 1980) he showed isolation features, with impaired relationships and limited autonomy skills. The most evident impairments were found in the general skills and autonomy areas, and finally in the relationships area. The final score fell in autism range.

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Discussion We studied the cognitive and behavioral profile of a patients with a developmental syndrome compelling autistic traits in which the diagnosis was performed only in the adulthood. Mental retardation, behavioral and social impairments were the main clinical signs. In this case we found an interesting association between mild intellectual disability and peculiar autistic traits, as evidenced by the comparison of DA profile at Autism Behavior Checklist with the profile of a patient affected by Asperger Syndrome (Figure 6).

20 15 10 5 0

Sensory area

Relational area

Body and objective use

Linguistic area

General abilities and autonomy 11

F.A.

6

13

10

12

D.A.

4

19

2

3

9

0,65

0,96

0,53

0,55

1,21

Normal

Figure 6. Comparison of D.A. profile at Autism Behavior Checklist with the profile of a patient (F.A.) affected by Asperger Syndrome.

DA profile was characterized by more compromised abilities in relational area associated to good competence in body and objects using and in linguistic area, while FA profile resulted more homogeneus. According to the literature, the compresence of a mild intellectual disability and autistic traits represent an atypical finding. In this study we stress the importance of a deep clinical assessment including laboratory and psychological investigations in order to perform a correct diagnosis and to better understand the different behavioral profile of the different autistic syndromes. Because both normal and abnormal development is progressive, a change of focus is essential in future research. Rather than concentrate on the study of disorders solely at their end state in school aged children and adults, which is most commonly the case, it becomes essential to study disorders in early infancy, and longitudinally, to understand how alternative developmental pathways might lead to different phenotypical outcomes. We stress the importance of Developmental history and Behavioral Phenotype in the diagnosis of autistic spectrum disorders particularly in adult age.

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As most of NHS mutations reported up to day, the Glu1281X found in our patient is a truncating mutation which probably is undergone to NMD. This observation confirms the pathological role caused by the absence of the NHS protein in the Nance-Horan syndrome. It is interesting to note that any missense mutation has been reported. It will be necessary to collect a wider cohort of patients in order to evaluate the occurrence of a correlation between the mutation type and the severity of the clinical presentation.

REFERENCES Associazione per lo sviluppo delle ricerche neuopsicologiche. (1985) Test dei gettoni. Manuale. Firenze: Organizzazioni Speciali. Bergen, A.A., ten Brink, J., Schuurman, E.J. & Bleeker-Wagemakers, E.M. (1994) NanceHoran syndrome: linkage analysis in a family from The Netherlands. Genomics, 1, 21(1), 238-40. Bixler, D., Higgins, M. & Hartsfield, J. (1984) The Nance-Horan syndrome: A rare X-linked oculodental trait with expression in heterozygous families. Clinical Genetics, 26: 30-35. Brooks, S., Ebenezer, N., Poopalasundaram, S., Maher, E., Francis, P., Moore, A. & Hardcastle, A. (2004) Refinement of the X-linked cataract locus (CXN) and gene analysis for CXN and Nance-Horan syndrome (NHS). Ophthalmic Genet, 25(2), 121-31. Brooks, S.P., Ebenezer, N.D., Poopalasundaram, S., Lehmann, O.J., Moore, A.T. & Hardcastle, A.J. (2004). Identification of the gene for Nance-Horan syndrome (NHS). J Med Genet, 41(10), 768-71. Brown, L., Leigh, J.E. (1987) Adaptive Behavior Inventory. Test di valutazione del comportamento adattivo. Trento, Ed. Centro Studi Handicap Erickson. Burdon, K.P., McKay, J.D., Sale, M.M., Russell-Eggitt, I.M., Mackey, D.A., Wirth, M.G., Elder, J.E., Nicoll, A., Clarke, M.P., FitzGerald, L.M., Stankovich, J.M., Shaw, M.A., Sharma, S., Gajovic, S., Gruss, P., Ross, S., Thomas, P., Voss, A.K., Thomas, T., Gecz, J. & Craig, J.E. (2003) Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet, 73(5), 1120-30. Florijn, R.J., Loves, W., Maillette de Buy Wenniger-Prick, L.J., Mannens, M.M., Tijmes, N., Brooks, S.P., Hardcastle, A.J. & Bergen, A.A. (2006) New mutations in the NHS gene in Nance-Horan Syndrome families from the Netherlands. Eur J Hum Genet, 14(9), 986-90. Francis, P.J., Berry, V., Hardcastle, A.J., Maher, E.R., Moore, A.T. & Bhattacharya, S.S. (2002) A locus for isolated cataract on human Xp. J Med Genet , 39, 105–109. Franco, E., Hodgson, S., Lench, N. & Roberts, G.J. (1995) Nance-Horan syndrome: a contiguous gene syndrome involving deletion of the amelogenin gene? A case report and molecular analysis. Oral Dis, 1(1), 8-11. Goldberg, M.F. & Hardy, J.E. (1971) X-linked cataract: Two pedigrees. Birth Defects Original Article Series, 7(3),164-165. Hibbert, S. (2005) A previously unreported association between Nance-Horan syndrome and spontaneous dental abscesses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 99(2), 207-11

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Horan, M.B., Billson, F.A. (1974) X-linked cataract and hutchinsonian teeth. Australian Paediatric Journal, 10, 98-102. Huang, K.M., Wu, J., Brooks, S.P., Hardcastle, A.J., Lewis, R.A. & Stambolian, D. (2007) Identification of three novel NHS mutations in families with Nance-Horan syndrome. Mol Vis, 27, 13, 470-4. Krug, D., Arik, J. & Almond, P. (1980) Autism Behavior checklist. J Child Psych Psychiatr, 21, 223-225. Lewis, R.A., Nussbaum, R.L. & Stambolian, D. (1990) Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3. Ophthalmology, 97:110-120. Nance, W.E., Warburg, M., Bixler, D. & Helveston, E.M.(1974) Congenital X-linked cataract, dental anomalies, and brachymetacarpalia. Birth Defects Original Article Series, New York, Ser X, 10(4), 285-291. Ramprasad, V.L., Thool, A., Murugan, S., Nancarrow, D., Vyas, P., Rao, S.K., Vidhya, A., Ravishankar, K., & Kumaramanickavel, G. (2005) Truncating mutation in the NHS gene: phenotypic heterogeneity of Nance-Horan syndrome in an Asian Indian family. Invest Ophthalmol Vis Sci, 46(1), 17-23. Raven, J.C. (1985) Coloured Progressive Matrices. Firenze: Organizzazioni Speciali,. Reches, A., Yaron, Y., Burdon, K., Crystal-Shalit, O., Kidron, D., Malcov, M. & Tepper, R. (2007) Prenatal detection of congenital bilateral cataract leading to the diagnosis of Nance-Horan syndrome in the extended family. Prenat Diagn, 27(7), 662-4. Seow, W.K., Brown, J.P. & Romaniuk, K. (1985) The Nance-Horan syndrome of dental anomalies, congenital cataracts, microphthalmia, and anteverted pinna: case report. Pediatr Dent., 7(4), 307-11. Sharma, S., Ang, L.S., Shaw, M., Mackey, D.A., Gecz, J., McAvoy, J.W. & Craig, J.E. (2006) Nance-Horan syndrome protein, NHS, associates with epithelial cell junctions. Hum Mol Gen, 15(12), 1972-1983. Stambolian, D., Lewis, R.A., Buetow, K., Bond, A. & Nussbaum, R. (1990) Nance-Horan syndrome: localization within the region Xp21.1-Xp22.3 by linkage analysis. Am J Hum Genet, 47(1), 13-9. Toutain, A., Ayrault, A.D., Moraine, C. (1997) Mental retardation in Nance-Horan Syndrome: clinical and neuropsychological assessment in four families. Am J Med Genetics, 71, 305-314. Toutain, A., Dessay, B., Ronce, N., Ferrante, M.I., Tranchemontagne, J., Newbury-Ecob, R., Wallgren-Pettersson, C., Burn. J., Kaplan, J., Rossi, A., Russo, S., Walpole, I., Hartsfield, J.K., Oyen, N., Nemeth, A., Bitoun, P., Trump, D., Moraine, C., & Franco, B. (2002) Refinement of the NHS locus on chromosome Xp22.13 and analysis of five candidate genes. Eur J Hum Genet, 10(9), 516-20 Toutain, A., Ronce, N., Dessay, B., Robb, L., Francannet, C., Le Merrer, M., Briard, M.L., Kaplan, J. & Moraine, C. (1997) Nance-Horan syndrome: linkage analysis in 4 families refines localization in Xp22.31-p22.13 region. Hum Genet, 99(2), 256-61. Walpole, R., Hockey, A.& Nicoll, A. (1990) The Nance-Horan syndrome. Journal of Medical Genetics, 27(10), 632-634.

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Walpole, S.M., Ronce, N., Grayson, C., Dessay, B., Yates, J.R., Trump, D. & Toutain, A. (1999) Exclusion of RAI2 as the causative gene for Nance-Horan syndrome. Hum Genet, 104(5), 410-1. Walsh, F.B. & Wegman, M.E. (1937) Pedigree of hereditary cataract, illustrating sex-limited type. Bulletin of the Johns Hopkins Hospital, Baltimore, 61, 125-135. Wechsler, D. (1981) Wechsler Adult Intelligence Scale Revised (WAIS-R) Manual. New York: the Psychological Corporation. Zhu, D., Alcorn, D.M., Antonarakis, S.E., Levin, L.S., Huang, P.C., Mitchell, T.N., Warren, A.C., & Maumenee, I.H. (1990) Assignment of the Nance-Horan syndrome to the distal short arm of the X chromosome. Hum Genet, 86(1), 54-8.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter VIII

IDIOPATHIC HYPOPARATHYROIDISM AND CHROMOSOME 10P DELETION Annapia Verri1,∗ and Paola Maraschio2 1

Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, Pavia, Italy; 2 Institute of Biology and Medical Genetics, University of Pavia, Italy.

ABSTRACT Chromosome 10p terminal deletions have been associated with a DiGeorge like phenotype. Haploinsufficiency of the region 10p14-pter, results in hypoparathyroidism, sensorineural deafness, renal anomaly: the triad that features the HDR syndrome. Van Esch et al. (2000) identified in a HDR patient, within a 200 kb critical region, the GATA3 gene, a transcription factor involved in the embryonic development of the parathyroids, auditory system and kidney. We describe a male patient, 26 yrs old, with a 10p partial deletion affected with hypocalcemia, basal ganglia calcifications and a severe autistic syndrome associated with mental retardation. Neurologically he presented with severe impairment of language, hypotonia, clumsiness and a postural dystonic attitude. A peripheral involvement of auditory pathways was documented by auditory evoked potentials alterations. CT scan documented basal ganglia calcifications. Hyperintensity of the lentiform nuclei was evident at the MRI examination. Renal ecography showed hypoplasia of the left kidney. Haploinsufficiency for GATA 3 gene was documented by Fish analysis using cosmid clone 1.2.

∗

Correspondence concerning this article should be addressed to: Dr. Annapia Verri, Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, via Mondino, 2 – 27100 Pavia, Italy. e-mail: [email protected].

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Annapia Verri and Paola Maraschio Phenotypic spectrum observed in del (10p) is more severe than the classical DGS spectrum. The GATA3 gene has been found to regulate the development of serotoninergic neurons. A serotoninergic dysfunction may be linked with autism in this patient.

Keywords: 10p deletion, HDR, mental retardation, autism.

INTRODUCTION Idiopathic hypoparathyroidism has been defined as a deficiency of parathyroid hormone (PTH) secretion without any definite causes, such as post-thymectomy and hypomagnesemia (Ishida et al., 2001). PTH is an 84 aminoacid polypeptide hormone functioning as a major mediator of bone remodelling and as an essential regulator of calcium homeostasis (Swarthout et al., 2002). The autoimmune and genetic etiologies of idiopathic hypoparathyroidism have been suggested (but the definite pathophysiology remains unclear). Inherited forms of hypoparathyroidism may occur as either isolated endocrinopathies with autosomal dominant, autosomal recessive or X-linked recessive transmission, or as part of complex congenital anomalies such as the DiGeorge (MIM 188400), Kenny-Caffey (MIM 244460) and hypoparathyroidism-deafness-renal dysplasia (HDR) (MIM 146255) syndromes (Ali et al., 2007). The DiGeorge syndrome, characterized by parathyroid hypoplasia, thymic hypoplasia, Tcell mediated immunodeficiency, and cardiac defects, is due to deletions of chromosome 22q11.2 that encompass abnormalities of the T-box transcription factor-1 (TBX1) gene (Ali et al., 2007). The Kenny-Caffey syndrome, characterized by hypoparathyroidism, short stature, osteosclerosis, cortical thickening of long bones and eye abnormalities, is associated with mutations of the Tubulin binding chaperone- E (TBCE) gene that is located on chromosome 1q42.3 (Ali et al., 2007). The HDR syndrome, an autosomal dominant disorder, is caused by mutations of the GATA3 gene that is located on chromosome 10p15 (Bileous et al., 1992). Partial monosomy 10p is a rare chromosomal aberration, characterized by a quite heterogeneous phenotype: most frequently, severe mental retardation, hypoparathyroidism, heart malformations, perceptive deafness, renal anomalies, facial dysmorphism and growth retardation have been described (Sunada et al., 1998; Van Doorninck et al., 1999). Patients often show symptoms of the DiGeorge/velocardiofacial syndrome spectrum. Karyotype-phenotype correlation in patients with different deletions of chromosome 10 short arm prompted to the definition of two distinct critical regions. Hemizigosity of the more proximal one, located on 10p13-14 and termed DiGeorge critical region II (DGCR2), accounts for heart defects and T cell deficiency. Haploinsufficiency of the region 10p14-pter, distal to DGCR2, results in hypoparathyroidism, sensorineural deafness, renal anomaly: the triad that features the HDR syndrome (Lichtner et al., 2000). This clinical condition, was first recognised by Barakat et al. (1977) and later by Bilous et al. (1992) (MIM 146225). Barakat reported steroid-resistant nephrosis with progressive renal failure and death at ages 5 and 8 years in 2 brothers who also had nerve deafness and hypoparathyroidism. At autopsy, the

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parathyroid glands were absent in one child and hypoplastic in the other. Barakat et al. (1977,2006) also described two male twins from another family with similar findings and died between the ages of 3 and 8 years. At autopsy, their parathyroid glands were fibrotic and glomerular basement membranes were thickened. The same syndrome may have been present in the families reported by Yumita et al. (1986) and Shaw et al. (1991) (OMIM 146255). Subsequently the clinical condition was associated with 10p deletion by Hasegawa et al. (1997) who proposed the acronym HDR. Other synonyms for Barakat syndrome include “Hypoparathyroidism, sensorineural deafness and renal dysplasia”, “HDR syndrome”, and “Nephrosis, nerve deafness and hypoparathyroidism” (Muroya et al., 2001). The syndrome should then consist of hypoparathyroidism, sensorineural deafness and renal disease, since various renal abnormalities have been described including nephrotic syndrome, renal dysplasia, hypoplasia and unilateral renal agenesis, vesicoureteral reflux, pelvicalyceal deformity, hydronephrosis, and chronic renal failure. Van Esch et al. (2000) identified in a HDR patient, within a 200 kb critical region, the GATA3 gene, that codes for transcription factor involved in the embryonic development of the parathyroids, auditory system and kidney. Chromosome deletions including the GATA3 gene in HDR patients, and particularly missense, truncating and nonsense mutations found in families with HDR syndrome, but without cytogenetic abnormalities, confirmed that haploinsufficiency for this gene is the underlying defect in the HDR syndrome (Van Esch & Devriend, 2001; Muroya et al., 2001). Transcription factors in the GATA family are so-called because they bind to the consensus DNA sequence (A/T) GATA (A/G). GATA factors contain either one or two distinctive zinc-finger domains that, with an adjacent conserved highly basic region, constitute the DNA-binding domain. They have been found throughout eukaryotes, from fungi to plants and from invertebrates to vertebrates (Patient & McGhee, 2002). GATA factors have been shown to play critical roles in development, including cell-fate specification, regulation of differentiation and cell proliferation and movement. Expression of GATA3 and repression of the T-box transcription factor T-bet are required for T helper (Th)2 cell commitment. By contrast, for Th-1 cells, T-bet expression and GATA3 repression are required. Recent evidence from bipotent Th cells in culture indicates that although induction of GATA3 and T-bet expression is cell-cycle-independent, their reciprocal silencing, as well as the induction of lineage-restricted gene expression, requires cell-cycle progression. Thus, GATA3 requires cell division to secure stable commitment and terminal differentiation of Th-2 cells (Patient & McGhee, 2002). The importance of the dual functions of the two zinc fingers has been well illustrated by studies of GATA3 mutations associated with the HDR syndrome. Thus, of the 25 HDR causing GATA3 mutations reported to date, 6 are whole gene losses, 10 are mutations that disrupt ZnF2 and lead to a loss of DNA binding, 2 are mutations that disrupt ZnF1and destabilize DNA binding and/or its interaction with FOG2, and 7 are deletions/insertions that disrupt both ZnF1 and ZnF2 (Ali et al., 2007). The triad of HDR syndrome was inconstantly manifested by patients with GATA3 haploinsufficiency. In particular penetrance of renal malformation seems to be variable, some HDR patients lacking kidney abnormalities.

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A severely mentally retarded patient with an interstitial deletion of chromosome 10 short arm (10p14 - 10p15.3) had been studied since many years, presenting with dysmorphic features, hypoparathyrodism, and autistic behaviour (Verri et al., 2004).

CASE REPORT The 33 yrs old patient was born from non-consanguineous parents after a 36 week gestation. His father -72 years old-, the mother -60 years old- and a sister, -24 years old- deny clinical problems. The parents were respectively 39 (father) and 27 (mother) years old when the child was born. The father who accepted only recently to be evaluated resulted to be affected with bilateral perceptive hypoacusia and non symptomatic hypocalcemia. Neonatal weight was 3550 gr. At two months of age the child was submitted for a surgical correction of an inguinal hernia. During the first months of life the child had frequent crying and sleep disturbances. Since the age of two months he presented with hypocalcemic seizures; for this reason he was hospitalized at the age of 3 yrs and at the age of 9 yrs. He was treated daily with calcium supplementation and 1,25 cholecalciferol. Developmental milestones were delayed: first steps without help at 24 months; language development was severely impaired. He never obtained sphincter control. He attended a special school until the age of 12, and since then lived at home with his parents, becoming more and more isolated. At the age of 26, he was examined by the neurologist, during a screening program for mentally retarded patients. At the age of 30 years, was observed in the patient a rise of blood creatinine that was submitted again to renal ecography.

Figure 1. The 30 yrs old patient.

The patient presented with dysmorphic features (large low set ears, short palpebral fissures, facial asymmetry, bristly hair), pectus excavatum, dorsal right convex scoliosis (Figure 1). At neurological evaluation bilateral complete cataract, hypotonia, clumsiness, extrapiramidal features (bradikinesia and dystonic posture) were noted. The patient had

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severe language impairment, being only able to pronounce monosyllabic words, without any relational intent. He presented with many motor stereotypies and ritualistic behaviours; he also was very oppositive and instable: he refused to sit down and usually stayed standing up during the night time as well. When he was evaluated at 26, laboratory investigations documented hypocalcemia (Ca=8 mEg/l; range 8.80-10.20 mEg/l) with a low serum parathyroid hormone level (PTH=11pg/ml; range 12-72 pg/ml ). High levels of homocystinemia were present (77,8 moli Ln; normal values below 15 moli Ln); vitamin B12 levels and pholic acid were in the normal range (vitamin B12 303 pgr/ml; pholic acid 5,0 ng/ml). Serum creatinine was normal (1.10 mg/dL; range 0.70-1.50mg/dL). IgG, IgA and IgM concentrations, the absolute number as well as the percentage of T-cell subpopulations (CD3,CD4,CD8) were within the normal range. The in vitro mitogenic response to PHA-Con A and the in vitro cytotoxicity against K-562 cells were normal. Homozigosity for a point mutation (C to T in position 677) in the MTHFR gene was also documented. EKG was normal; it was not possible to perform echocardiography because of the lack of cooperation. The patient had a bilateral complete cataract. Auditory evoked potentials were altered: when the left ear was examined, peak I was absent whereas peaks III and V were normal; when the right ear was stimulated peak I was absent, whereas peaks III and IV were delayed, and III-V interval was normal. Audiometric evaluation was not performed. Renal ecography at the age of 26 resulted normal and renal biopsy was therefore not performed. In a further renal ecography at the age of 30 yrs hypoplasia of the left kidney image was documented. Brain CT scan showed basal ganglia calcifications. Hyperintensity of the lentiform nuclei (T1 weighted image) was evident at MRI examination (Figure 2).

Figure 2. CT Basal ganglia calcifications.

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Psychological Evalution The patient had a severe mental retardation with IQ below 35. Checklist for autistic behaviour (Krug et al., 1980) documented high levels of autistic behaviour (total score of 113 - autistic score > = 78). Autistic behaviour was documented in all the symptom areas related to sensory, relation, body and object use, language and social behaviour. The Aberrant Behaviour Checklist (Aman et al., 1985) also documented autistic behaviour and many motor stereotypies and ritualistic attitudes.

Cytogenetic Results Chromosome analysis was performed on PHA stimulated lymphocytes of the proband, his parents and his healthy sister with standard and high resolution G banding. For FISH analysis lymphocyte metaphases spreads of the proband were hybridised with the cosmid 2189b6, located in the subtelomeric 10p region. Fish analysis using cosmid clone 1.2 (Labastie et al., 1994), which contains the entire GATA3 gene, was carried out on metaphases from lymphoblastoid cell lines of the proband. Routine and high-resolution chromosome studies revealed a partial deletion of the short arm of one chromosome 10. FISH analysis carried out with the cosmid 2189b6, located in the subtelomeric 10p region, showed the presence of hybridization signals both on the distal region of the normal chromosome 10 and on the deleted one. This result indicates that the deletion is interstitial, with breakpoints in p14 and p15.3. Hybridization analysis performed with the cosmid called cos1-2 (Labastie et al., 1994) demonstrated that GATA3 was present on the normal chromosome 10, but absent on the abnormal one. The chromosome structural anomaly resulted de novo.

DISCUSSION The clinical phenotype of HDR syndrome is quite different in comparison with 22q11 deletion syndrome: severe mental retardation has been found in most del 10 patients, while only 30-40% of DiGeorge patients have mental retardation (usually borderline to mild). More than 80% of HDR syndrome patients have renal and urinary tract abnormalities, while these abnormalities have been found only in 39% of del 22q11 (Van Esch et al., 1999), hypoparathyroidism is present in 56% of 10p deletion and 60% of 22 q del (Van Esch et al., 1999); heart malformations are more frequent in del 22 q11, particularly in the Takao phenotype (80% have conotruncal heart defects, tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, vascular rings) while they are rarer in HDR Syndrome. Perceptive deafness is described in about 50% of HDR, while 40% in del 22q11 have hearing loss or abnormal ear exams. 2% of del 22 q11 patients have severe immunologic dysfunction, while this is rarer in del 10p patients.

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This patient with an interstitial 10p deletion presents with craniofacial anomalies, bilateral cataract, hypoparatyroidism, basal ganglia calcifications, severe intellectual disability and autistic behaviour. The phenotipic spectrum observed in the 10p deletion is more severe than the classical DiGeorge spectrum associated with del 22q11: the10ppatients are affected with severe mental retardation, whereas this condition is rarely seen in patients with a del 22q11 (Van Esch et al., 2000). A peripheral involvement of auditory pathways was documented by auditory evoked potentials alterations. Perceptive deafness is common in 10p deletion [ibidem]. The association of hypoparathyroidism and deafness with renal anomalies is considered typical for the HDR syndrome, however some HDR patients lack renal abnormalities (Van Esch & Devriend, 2001). In the present patient renal function and renal ultrasound were reported normal at the age of 26, while a rise in creatinine and a left renal hypoplasia was documented at 30 yrs. A familial association of hypoparathyroidism and sensorineural deafness without renal dysplasia, has also been described (Watanabe et al., 1998; Van Esch et al., 1999). In addition our patient showed cataracts and calcifications of basal ganglia, as reported in Dasouki (1997), and in Fujimoto (1999) cases. We did not find any reduction of the white matter volume in this patient, in contrast to a previously reported patient (Sunada et al., 1998). Basal ganglia calcification is reported in hypoparathyroidism. This condition may also be present in Fahr disease, in some mitochondrial diseases and may not be associated with clinical signs of extrapyramidal system involvement. We reported in our patient a high homocysteine level associated with homozigosity for a point mutation in the MTHFR gene. The HDR patient reported by Fujimoto (Fujimoto et al., 1999) showed recurrent cerebral infarctions; we do not know if the patient was also affected by hyperomocysteinemia, however we know that this can be a risk factor for occlusive vascular diseases.

Figure 3. Family picture (3 years old).

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In this patient progressive increase of isolation and decrease of spontaneous motor activity could be observed by the parents and documented through family pictures (Figures 3,4).

Figure 4. Family picture (11 years old).

A progression of basal ganglia calcifications can be observed in successive CT scans. A link might be postulated between the progressive isolation of the patient and the increase of basal ganglia calcifications. Affective disorders and organic brain syndromes with affective or paranoid symptoms are increased in patients with bilateral basal ganglia mineralization of different aetiology (Forstl et al., 1991). A subcortical pattern of neuropsychological dysfunction and behavioural changes which are known to be associated with alterations of the frontal limbic basal ganglia circuits have been observed in patients with bilateral ganglia calcifications (Lopez-Villegas et al., 1996). Extensive basal ganglia calcifications due to parathyroid hormone deficiency secondary to thyroidectomy may lead to mental deterioration and psychopathological alterations (Konig, 1989). Even though GATA 3 is known to play an essential role in T cell development (Van Esch & Devriend, 2001), immunological function was normal in this patient. Thus far, no immunological deficiency has been signalled in GATA 3 haploinsufficiency (ibidem). As known, autism is a behavioural syndrome of multiple biological aetiologies (Gillberg, 1998). GATA3 has been shown to play a critical role in the development of different neural populations within the CNS in mammals (Karunaratne et al., 2002): in the embryonic midbrain, expression of GATA3 correlates with the development of the optic tectum and in the developing hindbrain, loss of GATA3 affects differentiation of the vestibuloacoustic efferent neurons; furthermore, in adult caudal raphe nuclei, GATA3 has been found to regulate the development of serotoninergic neurons (Van Doorninck et al., 1999). In 30% of people with autism the most frequent dysfunction is the increase of serotonine (Baghdadli et al., 2002). This led to the serotoninergic hypothesis in autism and to the use of active drugs in

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the serotonine system (Cook & Leventhal, 1996). A serotoninergic dysfunction might be associated also to GATA3 deletion in our patient.

REFERENCES Ali, A., Christie, P.T., Grigorieva, I.V., Harding, B., Van Esch, H., Ahmed, S.F., BitnerGlindzicz, M., Blind, E., Bloch, C., Christin, P., Clayton, P., Gecz, J., Gilbert-Dussardier, B., Guillen-Navarro, E., Hackett, A., Halac, I., Hendy, G.N., Lalloo, F., Mache, C.J., Mugha, Z., Ong, A.C.M., Rinat, C., Shaw, N., Smithson, S.F., Tolmie, J., Weill, J., Nesbit, M.A. & Thakker, R.V. (2007) Functional Characterisation of GATA3 Mutations causing the Hypoparathyroidism-Deafness-Renal Dysplasia (HDR) Syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Human Molecular Genetics , 3, 265-275 . Aman, M.G., Singh, N.N., Stewart, A.W. & Field, C.J. (1985) Psychometric characteristics of the aberrant behavior checklist. Am J Ment Defic, 89(5), 492-502. Baghdadli, A., Gonnier, V. & Aussilloux, C. (2002) Review of psychopharmacological treatments in adolescents and adults with autistic disorders. Encephale, 28(3Pt 1), 24854. Barakat AY, D'Albora JB, Martin MM, Jose PA. (1977) Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr. 91(1), 61-4. Barakat AY (2006). Hypoparathyroidism, sensorineural deafness and renal disease. Orphanet Encyclopedia, March 2006. Bileous, R.W., Murty, G. & Thakker, R.V. (1992) Autosomal dominant familial hypoparathyroidism, sensorineural deafness, and renal dysplasia. N Engl J Med, 357, 1069-74. Cook, E.H., Leventhal, B.L. (1996) The Serotonin System in Autism. Current Opinion in Pediatrics, 8(4), 348-354. Dasouki, M., Jurecic, V., Phillips, J.A., Whitlock, J.A. & Baldini, A. (1997) DiGeorge anomaly and chromosome 10p deletions: one or two loci? Am J Med Genet, 73, 72-75. Daw, S.C.M., Taylor, C., Kraman, M., Call, K., Mao, J., Schuffenhauer, S., Meitinger, T., Lipson, T., Goodship, J. & Scambler, P.J. (1996) A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet, 13, 458-460. Forstl, H., Krumm, B., Eden, S. & Kohlmeyer, K. (1991) What is the psychiatric significance of bilateral basal ganglia mineralization? Biol Psychiatry, 29(8), 827-833. Fujimoto, S., Yokochi, K., Morikawa, H., Nakano, M., Shibata, H., Togari, H. & Wada, Y. (1999) Recurrent cerebral infarctions and del (10) (p14 p15.1) de novo in HDR (hypoparathyroidism, sensorineural deafness, renal dysplasia) syndrome. Am J Med Genet, 86(6), 427-429. Gillberg, C. (1998) Chromosomal Disorders and Autism. J Autism Dev Disord, 28(5), 415425.

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Hasegawa, T., Hasegawa, Y., Aso, T., Koto, S., Nagai, T., Tsuchiya, Y., Kim, K.C., Ohashi, H., Wakui, K. & Fukushima, Y. (1997) HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10) (p13). Am J Med Genet, 73(4), 416-8. Ishida, S., Isotani, H., Kameoka, K. & Kishi, T. (2001) Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia. Intern Med, 40, 110113. Karunaratne, A., Hargrave, M., Poh, A. & Yamada, T. (2002) GATA protein identify a novel ventral interneuron subclass in the developing chick spinal cord. Developmental Biology, 249, 30-43. Konig, P. (1989) Psychopathological alterations in cases of symmetrical basal ganglia sclerosis. Biol Psychiatry, 25(4), 459-468. Krug, D., Arick, J. & Almond, P. (1980) Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. J Child Psychol Psychiatry, 21(3), 221-229. (Italian version Erickson -Trento 1994). Labastie, M.C., Bories, D., Chabret, C., Gregorie, J.M., Chretien, S. & Romeo, P.H. (1994) Structure and expression of the human GATA3 gene. Genomics, 21, 1-6. Lichtner, P., Konig, R., Hasegawa, T., Van Esch, H., Meitinger, T. & Schuffenhauer, S. (2000) An HDR (hypoparathyrodism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14. J Med Genet, 37, 33-37. Lopez-Villegas, D., Kulisevsky, J., Deus, J., Junque, C., Pujol, J., Guardia, E. & Grau, J.M. (1996) Neuropsychological alterations in patients with computed tomography-detected basal ganglia calcification. Arch Neurol, 53(3), 251-256. Muroya, K., Hasenegawa, T., Ito, Y., Nagai, T., Isotani, H., Iwata, Y., Yamamoto, K., Fujimoto, S., Seishu, S., Fukushima, Y., Hasegawa, Y. & Ogara, T. (2001) GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet, 38, 374-80. Patient, R.K., McGhee, J.D. (2002) The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev, 12, 416–422. Shaw, N. J.; Haigh, D.; Lealmann, G. T.; Karbani, G.; Brocklebank, J. T.; Dillon, M. J. : Autosomal recessive hypoparathyroidism with renal insufficiency and developmental delay. Arch. Dis. Child. 66: 1191-1194, 1991 Sunada, F., Rash, F. & Tam, D. (1998) MRI findings in a patient with partial monosomy 10p., J Med Genet, 35, 159-161. Swarthout, J.T., D'Alonzo, R.C., Selvamurugan, N. & Partridge, N.C. (2002) Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene, 282(1-2), 1-17. Van Doorninck, J.H., Van Der Wees, J., Karis, A., Goedknegt, E., Engel, J.D., Coesmans, M., Rutteman, M., Grosveld, F. & De Zeeuw, C.I. (1999) GATA-3 is involved in the development of serotoninergic neurons in the caudal raphe nuclei. J Neurosi, 19(12), RC12. Van Esch, H., Devriend, K. (2001) Human Genome and Disease: Review. Transcription factor GATA3 and the human HDR syndrome. Cell Mol Life Sci, 58, 1296-1300.

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Van Esch, H., Groenen, P., Fryns, J.P., Van de Ven, W. & Devriendt, K. (1999) The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet Couns, 10(1), 59-65. Van Esch, H., Groenen, P., Nesbit, M.A., Schuffenhauer, S., Lichtner, P., Vanderlinden, G., Harding, B., Betzrbijaus, R., Holaway, I., Shaw, N., Fryns, J., Van de Ven, W., Thakker, R. & Devriendt, K. (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature, 406, 419-422. Verri, A., Maraschio, P., Devriendt, K., Uggetti, C., Spadoni, E., Haeusler, E. & Federico, A. (2004) Chromosome 10p deletion in a patient with hypoparathyroidism, severe mental retardation, autism and basal ganglia calcifications. Ann Genet, 47(3), 281-7. Watanabe, T., Mochizuki, H., Kohda, N., Minamitami, K., Minagawa, M., Yasuda, T. & Niimi, H. (1998) Autosomal dominant familiar hypoparathyroidism and sensorineural deafness without renal dysplasia. Eur J Endocrinol, 139, 631-634. Yumita, S., Furukawa, Y., Sohn, H.E., Unakami, H., Miura, R. & Yoshinaga, K. (1986) Familial idiopathic hypoparathyroidism and progressive sensorineural deafness. Tohoku J Exp Med, 148, 125-141.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter IX

LIFE SPAN DEVELOPMENT IN INTERSTITIAL DELETION CHROMOSOME 21 Annapia Verri1∗, Anna Cremante2, Biancardi Caterina1, Federica Clerici1, Maria Grazia Egitto 1 and Enrico Alfonsi1 1

Neurological Institute C. Mondino Foundation, Pavia, Italy; 2 Paediatric Clinic, University of Insubria, Varese, Italy.

ABSTRACT Rearrangements involving chromosome 21 are relatively common but interstitial deletions are rare. Human chromosome 21 has been of interest and major focus of scientific investigation mainly for two reasons. It is the smallest human chromosome containing only about 1.7% of the human genome (Korenberg, 1978) and its role in Down Syndrome and familial Alzheimer Disease (St. George-Hyslop, 1987) is well documented. In this chapter we describe a patient with dismorphic features, borderline IQ and vulnerability to psychotic disorder. Our patient was evaluated with clinical, neurophysiological, neuroradiological instruments. He underwent a complete cognitive and behavioral assessment supported by psychometric and diagnostic instruments. Affective state and executive functions were also evaluated. Array-CGH demonstrated an interstitial deletion of ~10Mb at 21q with the proximal breakpoint within 21.89 and 22,15Mb and the distal one within 32,59 and 32,68 Mb. The same association between a chromosomal deletion of 21q21.1-21q22.11 and psychotic disorder has been described in literature (Murtagh et al., 2005; Demihran & Tastemire, 2003). Identification of susceptibility genes will greatly facilitate investigation of factors that contribute to the disease process and may lead to early intervention and prevention. An interstitial deletion of the long arm of chromosome 21 in specific chromosome regions may be useful in the ∗

Correspondence concerning this article should be addressed to: Dr. Annapia Verri, Neurological Institute C. Mondino Foundation, Department of Behavioral Neurology, via Mondino, 2 – 27100 Pavia, Italy. e-mail: [email protected].

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INTRODUCTION Cases of del(21q) are usually due to maternal translocation. Because of the difficulty in differentiating chromosomes 21 and 22 prior to chromosomes banding, critical analysis of cases published since 1973 was reported by Gorlin, Cohen and Hennekam (2001). A good review of 25 cases is that of Huret et al. (1995). Infant affected by del(21q) is small at birth and fails to thrive, often succumbing within the first year of life. Head circumference measures between the 3rd and 10th centiles. The occiput is prominent and the hairline is low. The facies is characterized by down-slanting small palpebral fissures, thick eyebrows, hypertelorism, broad nasal base with large tip, no alar furrows, anteverted nostrils, low-set large pinnae with prominent anthelix and large lobes, large carp mouth, long philtrum, thin vermilion, micrognathia, and short neck (Gorlin, Cohen & Hennekam; 2001). Most have cleft lip and/or cleft palate (Davis et al., 1976; Fryins et al., 1977; Herva et al., 1983). Skeletal anomalies include overlapping and/or flexed fingers and toes, kyphoscoliosis, pseudoarthrosis of clavicles, short thorax, and narrow pelvis (Azouz, 1999; Houston & Chudley, 1981; Wang & Aftimos, 1999). Inconstant features include wide-set nipples, ambiguous genitalia or micropenis, cryptorchidism, and imperforate anus (Philip et al., 1984). Cardiac anomalies have included preductal coarctation and patent ductus arteriosus. Thrombocytopenia has been described in about 20% of cases, most of which were hypertonic. Pure proximal monosomy for 21q is very rarely observed in humans, but a few cases have been reported to date (Wulfsberg et al 1983; Reynolds & Engels 1985; Roland et al., 1990; Korenberg et al., 1978; Ahlbom et al., 1996). Mild to moderate intellectual disability is a common symptom in almost all the reported monosomy 21q21 cases, but other clinical features were not consistent (Wakui et al., 1999). Vulnerability to psychosis disorders has been described in interstitial 21q-21-q22. Stedman's Medical Dictionary (2006) defines psychosis as "a severe mental disorder, with or without organic damage, characterized by derangement of personality and loss of contact with reality and causing deterioration of normal social functioning.” The term “psychotic” describes a broad range of behaviors marked by loss of ego boundaries or gross impairment in reality testing (Rapaport & Ismond, 1996). When this condition exists, the individual is unable to correctly evaluate the accuracy of his/her perceptions and thoughts and therefore makes incorrect assumptions about external reality. More narrowly defined, the term describes symtoms and behaviors involving delusions, any prominent hallucinations, grossly disorganized or catatonic behavior, or incoherent speech.

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Interestingly, in literature there are some contributions of an association between a chromosomal deletion of 21q-21-q22 and schizophrenia. Takhar et al. (2002) reported a case of an interstitial deletion (21) (q21; q22.1) in a 16-years-old student originally from Somalia with learning disability, schizophrenia and dysmorphic features. More recently, Demirhan and Tastemire (2003) described 4 individuals with deletion 21q22 in a sample of 134 individuals with schizophrenia. Murtagh et al. (2005) identify an interstitial deletion of chromosome 21q, del (21) (q21.2;q22.1) in a man with learning disability, dysmorphic features and schizophrenia. Our patient was evaluated with clinical, neurophysiological, neuroradiological instruments (Verri,Zuffardi, work in progress). Written, informed consent for the study was provided by the patient.

CASE REPORT Clinical and Developmental History Male, 53 years old. Since 2002 we have followed CC, for behavioral problems. Patient’s mother was 79 years old and she was affected by heart disease caused by hypertension. His father was 80 years old and presented insulin-dependent diabetes mellitus and stroke outcome. The patient had poor relationship with his brother, a 55 years old electrician, affected by diabetes as their mother. The patient was born full-term. We have poor information about his developmental history. CC achieved middle school graduation and then changed jobs several times (for example: gardener, bricklayer). He was working the last 30 years as crane worker. He married in 1980 and had two children. He was first evaluated at the age of 53 years, when he came to the observation for behavioral problems. He appeared scarcely collaborative and showed negative attitudes toward the examinations.

Neurological Evaluation Neuroradiological Findings The patient was 160 cm tall and weight was 72 Kg. The occipito-cranial circumference was 57 cm. The objective evaluation documented mild facial dysmorphysm: deep set eyes, large ears, prominent nose. At neurological evaluation he presented a mild head tremor and hands postural tremor. Horizontal nystagmus was documented. The patient was submitted to an electromyographic (EMG) study that showed bilateral entrapment of median nerve at wrist. Nuclear Magnetic Risonance (NMR), performed by a Philips "Gyroscan T5" 0,5 Jesk tool documented periventricular white matter hyperintensity and wide cisterna magna.

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Cognitive Behavioral Assesment CC underwent a complete cognitive and behavioral assessment supported by psychometric and diagnostic instruments. Affective state and executive functions were also evaluated. The term “executive functions” describes a set of cognitive abilities that control and regulate other abilities and behaviors. They are high-level abilities that influence more basic abilities like attention, memory and motor skills. They include the ability to initiate and stop actions, to monitor and change behavior as needed, and to plan future behavior when faced with novel tasks and situations. Executive functions allow us to anticipate outcomes and adapt to changing situations. They are necessary for goal-directed behavior. The ability to form concepts and think abstractly are often considered components of executive functions. During the several sessions of assessment, the patient was generally scarcely collaborating: he participated to the talks, limiting the profusion of the informations about his person and his life conditions. He appeared quite anxious but executed the proposed tasks with adequate levels of attention and concentration. The language was rather simple, and he uses the language to give pertinent answers to the questions. He was well oriented in space. He frequently showed the tendency to give a distorted imagine of his person, describing himself as a positive person. The evaluation with DSM-IV criteria using Brief Psichiatric Rating Scale (BPRS 4.0) documented a psychotic disorder with persecutory delusion. Persecutory delusion is a a fixed false belief in which the central theme is that one (or someone to whom one is close) is being attacked, harassed, cheated, persecuted, or conspired against (DSM-IV-TR). The family had noted increasing fearfulness secondary to delusions of persecution, disorganized thinking, displaying anxious affect/mood and oppositional behavior. An overall deterioration in functioning in most areas of life was noted by his family. The administration of the Barratt Impulsivity Scale (BIS-11, 1995), which measures levels of impulsivity, documented high levels of attentional impulsiveness, motor impulsiveness (two of the three second order factors of the factor structure of this questionnaire, Patton et al, 1995). In fact, the psychological assessment documented alcohol abuse. The evaluation using the Diagnostic Assessment for the Severly Handicapped-II (DASH-II), a rating scale which contains purely behavioral criteria that are essential features of various DSM-IV disorders, documented high levels of aggressivity and impairment in behavioral control. Cognitive evaluation was performed using the following instruments: Wechsler Adult Intelligence Scale (WAIS), Token Test; Coloured Progressive Matrices (CPM); Ray Taylor Complex Figure Test; Rey Auditory Verbal Learning Test (RAVLT); Verbal Fluency; Stroop Test; Trail Making Test. Full IQ was 87, without an important discrepancy among verbal subtest (Verbal IQ= 88,) and the performance subtests (Performance IQ = 88). The Wechsler Adult Intelligence Scale-Revised (WAIS-R) is a general test of intelligence, which Wechsler defined as "the global capacity of the individual to act purposefully, to think rationally and to deal effectively with his environment." In keeping with this definition of intelligence as an aggregate of mental aptitudes or abilities, the WAISR consists of 11 subtests divided into two parts, verbal and performance. Poor attentive skills

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and short-term memory associated with a limited knowledge acquired through school and cultural experience (“information”) were documented by verbal subtests. Abstract thinking and understanding, as tested by “similarities” and “comprehension” respectively, were simple, with limited ability to synthesize verbal relationships and restricted practical information and social knowledge. The patient had limited computational skills: at the “arithmetic scale” he was able to solve only those tasks requiring the use of one single of the four fundamental arithmetical operations (addition, subtraction, multiplication and division). He appeared more anxious when he executed performance tests. Performance subtests revealed scarce accuracy and speed of visual motor coordination and some difficulties in scanning ability (“coding”), in nonverbal reasoning and logical sequencing, (“picture arrangement”), in visual-spatial organization (“block design”) and, above all, in the organization of the perception and the reconstruction of concrete shapes (“object assembly”). Colour Progressive Matrices (CPM) showed impairments in understanding of spoken language, reduced efficiency in the logical-deductive and abstract reasoning. Visual-spatial organizational skills as assessed by the Rey Complex Figure Copy seemed severely limited. His spatial memory seemed to be severely impaired. The Rey-15 Item Memory Test documented a low immediate recall accuracy score, while the delayed recall appeared normal. Selective and focused attention, mental control and response flexibility as assessed by the Stroop Test seemed to be fairly good. The Trail Making Test task A showed average attention and visual-motor tracking skills, while the task B revealed difficulties efficiency in divided attention and ability to shift.

DISCUSSION In this chapter we describe a patient affected by a microdeletion 21q21.1-21q22.11. Our patient shows not only a typical facial dymorphisms but mostly overlapping behavioral abnormalities, consisting in impulsive-obsessive behavioral disorder and vulnerability to psychosis. The patient, now 53 years old, was affected by paranoid psychosis and behavior disorders since the age of 40 years. The concept of impulsivity covers a wide range of ”actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes” (Evenden, 1999). As such it plays an important role in normal behavior, as well as, in a pathological form, in many kinds of mental illness such as mania, personality disorders, substance abuse disorders and attention deficit/hyperactivity disorder. In particular, CC presented a maladaptive pattern of alcohol abuse. High levels of impulsivity emerged by the scoring of the Barratt Impulsivity Scale (BIS-11, 1995). This aspect appears very important if we consider that the BIS-11 total score was correlated significantly with aggression and also significantly differentiated between high and low levels of binge eating, alcohol consumption, and cigarette smoking (Fossati et al, 2001). In this case IQ was in the borderline range. Mental retardation appeared to be linked with 21q22.2/22.3 delection syndrome, while seemed to be associated with cortical dysplasia and severe mental retardation (Yao et al., 2006). Cortical dysgenesia was not detected in our

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patient, who presented no brain malformations and a borderline IQ, not achieving the mental retardation range1. Duplication of the region 21q.22.2-22.3 (also called the Down Syndrome critical region) has been shown to contribute to the cognitive defect of Down Syndrome. This report confirmed a possible association between 21q21.1-21q22.11 del and psychosis. The identification of genes involved in common disorders have proven much more difficult than anticipated around 15 years ago when molecular genetic studies were inititated. Despite considerable effort no DNA sequence variation of relevance has yet been found with certainty. However, hopes are high that the identification of some of the genes involved in susceptibility to the most severe psychiatric disorders will be made soon. This will make further research into the etiology and pathophysiology possible. Molecular studies of structural chromosomal abnormalities even in single patients have proven to be of significant importance. Such molecular cytogenetic studies have identified possible risk genes for a severe speech and language disorder, panic disorder and joint hypermobility and possibly for a subform of schizophrenia. Furthermore the identification of the molecular basis of the 22q deletion syndrome, of which perhaps one-third of the cases are schizophrenic, is now progressing. In fact, this is not the first report of an association between a chromosomal deletion of 21q21.1-21q22.11 and psychotic disorder: the same association has been described in literature (Murtagh 2005; Demihran & Tastemire 2003). Moreover, evidence for linkage to this region in schizophrenia is not compelling, although suggestive evidence has been reported from a Canadian study (Maziade et al., 2001). This chromosomal region has also been linked to Bipolar Affective Disorder in a subset of families across a number of studies (Saito et al 2001). This locus has previous been implicated as part of the Down Syndrome Critical Region. Although psychiatric disorders are known to be more frequent in Down Syndrome than in the general population, a lower prevalence of schizophrenia has been reported (Collacott et al., 1992). Amyloid precursor protein (APP) maps to chromosome 21q21 an when present in triplicate is known to be caused of presenile dementia associated with Down Syndrome (trisomy 21). Mutations with APP may confer increased risk for early onset of Alzheimer disease and late onset of Alzheimer disease. We agree with Takhar (2002) that the haploinsufficiency may confere susceptibility to psychosis. This suggests that loss of function of genes at this locus may contribute to schizophrenia susceptibility (Murtagh, 2005). The findings clearly indicate that haploinsufficiency for one or more genes at the delected region is responsible for their behavioral phenotype. The 11 Mb 1

The DSM-IV diagnosis of mental retardation is further specified with a code or grouping label that indicates the diagnosing clinician's impression of the severity of the presenting retardation. This grouping label is linked to IQ. Mild Mental Retardation affects 85 percent of the mentally retarded population. Their IQ score ranges from 5075. Many individuals can become self-sufficient and in some cases, live independently with community and social support. Moderate Mental Retardation affects around 10 percent of the individuals under the classification of mental retardation. This group score between 35 and 55 on IQ tests and has adequate communication skills. Many of these individuals function very well in group homes and in the community. Many are employed and can take care of themselves with minimal supervision. Severe Mental Retardation describes 3 - 4 percent of the population within this classification. IQ scores range from 20 to 40. Communication skills and self-help skills are very basic and many individuals require supervision and assistance. Many of these individuals reside in group homes with assistance. Profound Mental Retardation describes a very small portion of the mentally retarded population, about 1 - 2 percent of those affected. These individuals score under 25 on IQ tests and require around-the-clock care and support. Their communication skills are limited and they require assistance for selfcare. People with profound mental retardation usually have neurological disorders as well.

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deletion region contains several genes, some of them expressed also in brain, whose function has not been fully characterized. Identification of susceptibility genes will greatly facilitate investigation of factors that contribute to the disease process and may lead to early intervention and prevention. An interstitial deletion of the long arm of chromosome 21 deletions in specific chromosome regions may be useful in the further mapping of chromosome 21 and others that have been implicated in schizophrenia. The possibility that loci predisposing to schizophrenia exist on chromosome 21 needs to be considered and revisited.

REFERENCES Ahlbom, B.E., Sidenvall, R. & Annerén G. (1996) Deletion of chromosome 21 in a girl with congenital hypothyroidism and mild mental retardation. Am J Med Genet, 23, 64(3), 5015. American Psychiatric Associations. (1994) Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR Fourth Edition (Text Revision), APA. Azouz, E.M. (1999) Abnormal clavicles in a neonate with partial monosomy 21 by Wang and Aftimos, Pediatr Radiol, 29, 720. Collacott, R.A., Cooper, S.A.& McGrother, C. (1992) Differential rates of psychiatric disorders in adults with Down’s syndrome compared with other mentally handicapped adults. Br J Psychiatry, 161, 671– 674. Davis, J.G., Jenkins, E.C., Klinger, H.P., Weed, R.G. (1976) A child with presumptive monosomy 21 (45,XY,—21) in a family in which some members are Gq. Cytogenet Cell Genet, 17, 65—77. De Renzi, E., Vignolo L. A. (1962) The Token Test: A sensitive test to detect receptive. disturbances in aphasics. Brain, 85, 665-678. Demirhan, O., Taştemire, D. (2003) Chromosome aberrations in a schizophrenia population. Schizophr Res, 1, 65(1),1-7. Evenden, L.J. (1999) Varieties of impulsivity, Psychofarmacology, 146, 348-361. Fossati, A., Di Ceglie, A., Acquarini, E. & Barratt, E.S. (2001) Psychometric properties of an Italian version of the Barratt Impulsiveness Scale-11 (BIS-11) in nonclinical subjects. J Clin Psychol, 57(6), 815-28. Fryns, J.P., D'Hondt, F., Goddeeris, P.& van den. Berghe, H. (1977) Full monosomy 21: A clinically recognized syndrome? Hum Genet, 37,155—159. Gorlin, R.J., Cohen, M.M. & Hennekam, R.C.M. (2001) Syndromes of the head and neck, Oxford: University Press. Herva, R., Koivisto, M. & Seppänen U. (1983) 21-Monosomy in a liveborn male infant. Eur J Pediatr, 140, 57—59. Houston, C.S., Chudley, A.E. (1981) Separating monosomy 21 from the “arthrogryposis basket.” J Can Assoc Radiol, 32, 220—223. Huret, J.L., Leonard, C., Chery, M., Philippe, C., Schafei-Benaissa, E., Lefaure,G., Labrune, B.& Gilgenkrantz, S. (1995) Monosomy 21q : two cases of del(21q) and review of the literature; Clinical genetics, 48, 3,140-147.

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Korenberg, J.R., Engels, W.R. (1978) Base ratio, DNA content, and quinacrine brightness of human chromosome. Proc Natl Acad Sci USA, 75, 3382–3386. Lezak, MD. (1995) Neuropsychological Assessment. 3rd edition. New York: Oxford University Press. Maziade, M.A. Roy, E. Rouillard, L. Bissonnette, J.P. Fournier, A. Roy, Y. Garneau, N. Montgrain, A. Potvin, D. Cliché, C. Dion, H. Wallot, A. Fournier, L. Nicole, J.C. Lavallee & C. Merette, (2001) A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes, Mol. Psychiatry, 6(6), 684–693. Murtagh, A., McTigue, O., Ramsay, L., Hegarty, A.M., Green, A.J., Stallings & R.L., Corvin, A. (2005) Interstitial deletion of chromosome 21q and schizophrenia susceptibility. Schizophr Res, 15, 78(2-3), 353-6. Patton, J.H., Stanford, M.S. & Barratt, E.S. (1995) Factor structure of the Barratt Impulsiveness Scale. Journal of Clinical Psychology, 51, 768-774. Philip, N., Baeteman, M.A., Mattei, M.G. & Mattei, J.F. (1984) Three new cases of partial monosomy 21 resulting from one ring 21 chromosome and two unbalanced reciprocal translocations. Eur J Pediatr, 142, 61—64. Rapaport, M.D., Ismond, M.A. (1996) Dsm-IV Training Guide for Diagnosis of Childhood Disorders, Taylor & Francis; 2 edition. Reynolds, J.F., Wyandt H.E. & Kelly, T.E., (1985) De novo 21q interstitial deletion in a retarded boy with ulno-fibular dysostosis. Am J Med Genet, 20, 173-180. Roland, B., Cox, D.M., Hoar, D.I., Fowlow, S.B. & Robertson, A.S. (1990) A familial interstitial deletion of the long arm of chromosome 21, Clin Genet, 37, 423-428. Saito, F., Guan, D.F., Papolos, S., Lau, M., Klein, C.S., Fann & Lachman HM. (2001) Mutation analysis of SYNJ1: a possible candidate gene for chromosome 21q22-linked bipolar disorder, Mol. Psychiatry, 6(4), 387–395. Stedman J. (2006) Stedman’s Medical Dictionary, 28th . St. George-Hyslop, P.H., Tanzi, R.E., Polinski, R.J.(1987) The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science, 235, 885–890. Takhar, J., Malla, A.K., Siu, V., MacPherson, C., Fan, Y.S., Townsend, L. (2002) An interstitial deletion of the long arm of chromosome 21 in a case of a first episode of psychosis. Acta Psychiatr Scand, 106(1), 71-4. Wakui, K., Tanemura, M., Suzumori, K., Hidaka, E., Ishikawa, M., Kubota, T. & Fukushima, Y. (1999) Clinical applications of two-color telomeric fluorescence in situ hybridization for prenatal diagnosis: Identification of chromosomal translocation in five families with recurrent miscarriages or a child with multiple congenital anomalies. J Hum Genet, 44, 85-90. Wang, S.H., Aftimos, S. (1999) Abnormal clavicles in a neonate with partial monosomy 21, Pediatr Radiol, 29, 221—222. Wechsler, D. (1991) Wechsler Intelligence Scale for Children–Revised. San Antonio: The Psychological Corporation. Wulfsberg, E.A., Carrel, R.E., Klisak, I.J., O'Brien, T.J., Sykes, J.A.& Sparkes, R.S.(1983) Normal superoxide dismutase-1 (SOD-1) activity with deletion of chromosome band 21q21 supports localization of SOD-1 locus to 21q22. Hum Genet, 64(3), 271-2.

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Yao, G., Chen, X.N., Flores-Sarnat, L., Barlow, G.M., Palka, G., Moeschler J,B., McGillivray, B., Morse, R.P., Korenberg, J.R. (2006) Deletion of chromosome 21 disturbs human brain morphogenesis.Genet Med, 2006, 8(1), 1-7.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter X

COGNITIVE ENRICHMENT ISSUE Valeria Destefani∗ Laboratory of Cognitive Behavioral Psychology, Neurological Institute C. Mondino Foundation, Pavia, Italy.

ABSTRACT There is much evidence of a limitation in interventional strategies dealing with the implementation of cognitive deficiency in deprived subject. The disbelief in the capacity of the individual to become modified has its conterpart in the lack of interventional strategies proposed to deprived subjects. Feuerstein and his new paradigm of learning focuses on the possibility of Cognitive Enrichment. The Feuerstein’s Instrumental Enrichment program is an intervention strategy developed with the aim of modifying the cognitive structures of retarded, disadvantaged subjects. IE focuses on the acquisition of general learning strategies which are the core prerequisite for any formal learning. The program seeks to sharpen critical thinking with concepts, skills, strategies, operations, and techniques necessary for independent learning. FIE and the early subjecthood version (FIE-BASIC) are used as a remediation program and as a tool of cognitive enrichment for individuals with special needs. The general goals of the FIE-B are to provide acceleration of cognitive development, the prevention of cognitive dysfunctions, or the remediation of dysfunctions or gaps in skill and cognitive development and it is best indicated in the case of genetic synromes with ID. Strong evidence for specific cognitive and other developmental profiles to be associated with some genetic disorders is well known so that it can be hypothesized that genetic syndromes with intellectual and learning disabilities “share” some of their cognitive and behavioural effects. In this perspective, it seems possible to attempt etiology-related cognitive interventions for subjects with genetic syndromes with Intellectual disability. Common weakness areas in their intellectual functioning could be addressed by the proposal of specific instruments for cognitive enrichment. ∗

Correspondence concerning this article should be addressed to: Dr. Valeria Destefani, Laboratory of Cognitive Behavioral Psychology, Neurological Institute C. Mondino Foundation, via Mondino, 2 – 27100 Pavia, Italy.

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Keywords: cognitive enrichment, genetic syndromes with intellectual disability.

INTRODUCTION “Can the cognitive processes and structures of Intellectual Disability (ID) subjects be changed so that their behaviour can improve?” (Brooks & McCauley, 1984). This core question expresses the ongoing interest for cognitive modifiability of individuals with ID. A good model of cognitive processes is an essential prerequisite to develop efficient and focused interventions. In 1972, Feuerstein & Krasilowsky addressed the problem of the limitation in interventional strategies dealing with the implementation of cognitive deficiency in deprived subject identifying some theoretical assumptions, underlying these limitations, that expressed the dibelief in the capacity of the individual to become modified (Feuerstein & Krasilowsky, 1972). Uncontested limits to the capacity of the organism to recover at a later stage from the damage produced by the deprivation of perceptual stimuli during early childhood are assumed by the critical age hypotesis and by Piagetian model, which both reconduct to a deficiency in the neurophysiological substratum of the organism the irreversible damage affecting the capacity to elaborate adequately the stimoli. Actually, the issue of cognitive modifiability is not a question of whether it can be done, but what can be modified, how much can it be modified, and how can it be modified (what does it take to change a cognitive process), according to Feuerstein and his assumption about the reversibility of the negative effects of cultural deprivation at critical age (Forsyth et al., 2004). Core concept of Professor Reuven Feuerstein’s Theory of Structural Cognitive Modifiability (The International Center for the Enhancement of Learning Potential Basic Theory, 2008) is the fundamental belief that there is a possibility to bring about significant change, which in turn leads to a more optimistic future. Feuerstein’s theory views the human organism as open, adaptive and amenable for change. The aim of this approach is to modify the individual, emphasizing autonomous and self-regulated change. Intelligence is viewed as a propensity of the organism to modify itself when confronted with the need to do so. It involves the capacity of the individual to be modified by learning and the ability to use whatever modification has occurred for future adjustments. Intelligence is defined as a changeable state rather than an immutable trait. Cognition thus plays a central role in human modifiability. An increased disposition to use, in a mode adequate way, stimuli offered to the subject in his own environment, thus enabling him to become enrriched by direct exposure to reality and the world in general. This is what is meant for “Cognitive enrichment” in Feuerstein pespective of cognitive modifiability. Feuerstein leading principles are realized in applied systems as the Learning Potential Assessment Device, a viable alternative to static IQ type of tests which focuses on the learners’ dynamic potential or propensity (rather than their current performance level) and the Instrumental Enrichment cognitive intervention program.

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COGNITIVE ENRICHMENT ISSUE Feuerstein's Instrumental Enrichment Program (FIE – Feuerstein, et al., 1980) is a cognitive intervention program that has been successfully used all over the world as a tool for the enhancement of learning potential and cognitive functioning of children and adults (Feuerstein, Rand et al., 1979). The program seeks to sharpen critical thinking with concepts, skills, strategies, operations, and techniques necessary for independent learning. The early subjecthood version (FIE-BASIC) is used as a remediation program and as a tool of cognitive enrichment for individuals with special needs. The FIE-B program is directed toward the younger child, from approximately three to seven years of age, and the very low functioning older individual, who are a special risk for their development, or who have not acquired basic foundational knowledge and skills, to respond to the direct world of stimuli and develop the pre-requisite cognitive functions. The general goals of the FIE-B are to provide acceleration of cognitive development, the prevention of cognitive dysfunctions, or the remediation of dysfunctions or gaps in skill and cognitive development. The fundamental assumption of the program, based on Feuerstein’s theory of Structural Cognitive Modifiability and Mediated Learning Experience, is that intelligence is dynamic and modifiable, not static or fixed (Feuerstein, 1990). In looking for the etiology of this type of deficient functioning Feuerstein distinguish between distal and proximal factors, that account for the specific outcome of cognitive deficiency in a more dynamic way. Genetic, organic, experiential and socio-cultural factors constitute only distal determinants of the cognitive development. Any of the distal conditions may trigger the proximal etiology that is a lack of or reduced exposure to mediated learning experience (MLE), a particular kind of interaction between a learner and a mediator. The mediator’s implicit or explicit intention to mediate the world transmits to the learner new modalities of interacting with and exploring the world. The type and amount of mediated learning experiences constitute the proximal determinant that can substantially moderate the impact of proximal factors. The absence of the necessary type or/and amount of MLE leads to the underdevelopment of the child’s cognitive functions and direct learning strategies. Massive infusion of mediated learning may improve the situation of cognitive deficiency and turn the child into an independent and selfregulating learner. The locus of the deficiencies reflects attitudinal and motivational deficiencies, lack of working habits and learning sets rather than structural and elaborational incapacities. Evidence of the reversibility of the phenomena has been provided by clinical and experimental work – especially through dynamic assessment (Learning Potential Assessment Device -LPAD). The LPAD has also enabled cognitive researchers to establish an inventory of cognitive functions that are undeveloped, poorly developed, arrested and/or impaired. Impaired cognitive functions are a useful instrument to describe the typical functioning of subjects with intellectual disability. For example, impaired cognitive functions affecting the Input Level of mental act include those impairments concerning the quantity and quality of data gathered by the individual as he is confronted by a given problem, object, or experience. They include: blurred and sweeping perception; unplanned, impulsive, and unsystematic exploratory behavior; lack of, or impaired, receptive verbal tools which affect discrimination (e.g. objects, events, relationships, etc. do not have appropriate labels); lack

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of, or impaired, spatial orientation; the lack of stable systems of reference impairs the establishment of topological and euclidean organization of space; lack of, or impaired, temporal concepts; lack of, or impaired, conservation of constancies (size, shape, quantity, orientation) across variation in these factors; lack of, or deficient, need for precision and accuracy in data gathering; lack of capacity for considering two or more sources of information at once; this is reflected in dealing with data in a piecemeal fashion, rather than as a unit of organized facts. The severity of impairment at the Input level may also affect ability to function at levels of elaboration and output, but not necessarily so. Impaired cognitive functions affecting the Elaboration level include those factors which impede the efficient use of available data and existing cues, such as inadequacy in the perception of the existence and definition of an actual problem; inability to select relevant vs. non-relevant cues in defining a problem; lack of spontaneous comparative behavior or limitation of its application by a restricted need system; narrowness of the psychic field; episodic grasp of reality; lack of, or impaired, need for pursuing logical evidence; lack of, or impaired, interiorization; lack of, or impaired, inferential-hypothetical, “iffy” thinking; lack of, or impaired, strategies for hypothesis testing; lack of, or impaired, ability to define the framework necessary for problem-solving behavior; lack of, or impaired, planning behavior; non-elaboration of certain cognitive categories because the verbal concepts are not a part of the individual’s verbal inventory on a receptive level, or they are not mobilized at the expressive level. “Thinking” usually refers to the elaboration of cues. There may well be highly original, creative, and correct elaboration which yields wrong responses, because it is based on inappropriate or inadequate data on the Input level. Finally, impaired cognitive functions on the Output level include those factors that lead to an inadequate communication of final solutions. They are: egocentric communicational modalities; difficulties in projecting virtual relationships; blocking; trial and error responses; lack of, or impaired, tools for communicating adequately elaborated responses; lack of, or impaired, need for precision and accuracy in communicating one’s responses; deficiency of visual transport; impulsive, acting-out behavior. It should be noted that even adequately perceived data and appropriate elaboration can be expressed as an incorrect or haphazard solution if difficulties exist at this level. There is interaction occurring between and among the input, elaboration and output levels, which is of vital significance in understanding the extent and pervasiveness of cognitive impairment. The FIE program seeks to correct deficiencies in fundamental thinking skills, provides individuals with the concepts, skills, strategies, operations and techniques necessary to function as independent learners, increases their motivation, and help low-performing subjects to prevent learning problems through early, developmentally appropriate, intervention. In a word it helps subjects learn how to learn. These goals are achieved through an emphasis on a systematic exposure to information and specific skills that are transformed into working concepts that build toward subsequent learning and development, and the process of how to think. FIE and FIE-B materials are organized into a set of playful learning activities that comprise paper-and- pencil tasks aimed at such specific cognitive domains.

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The FIE-B instruments, aimed to provide acceleration of cognitive development, the prevention of cognitive dysfunctions, or the remediation of dysfunctions or gaps in skill and cognitive development, are best suited for subjects with genetic syndromes with Intellectual disability and can be grouped according to their contribution to the development of the cognitive structure (Table 1): Table 1. Classification of IE instruments according to their contribution to the development of the cognitive structure FOCUS Non-verbal instruments

Instruments requiring limited vocabulary and reading skills Instruments requiring good verbal fluency

Instruments requiring independent reading and comprehension skills

Other instruments

perceptual-motor development, oriented toward learning processes, attention, and planning behavior. spatial orientation, emphasizing receptivity to instructions, systematic searching, and crystallization of spatial relationships. decoding emotional expression, understanding their social/behavioral correlates, and searching for factors that generate them. abstractive/integrative thinking

Critical thinking

14 STANDARD INSTRUMENTS Organization of Dots Analytic Perception Illustrations (cartoons)

10 BASIC INSTRUMENTS Organization of Dots-Basic Tri-Channel Attentional Learning

Orientation in Space (I,II,III) Family Relations Comparisons Classification Numerical Progression Stencil Design

Orientation in Space-Basic

-

Identifying Emotions From Empathy to Action

Categorization Instructions Temporal Relations Transitive Relations Syllogisms

From Unit to Group Knowledge; Compare and Discover the Absurd Thinking to Learn to Prevent Violence Learning to Question for Reading Comprehension -

Absurdities Convergent and Divergent Thinking Illusions

1. Instruments that focus on perceptual-motor development, oriented toward learning processes, attention, and planning behavior: Organization of DotsBasic, Tri-Channel Attentional Learning;

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Organization of Dots: Provides practice in projecting virtual relationships through tasks that require identification and outline of a given figure within a cloud of dots. Builds task intrinsic motivation and feelings of competence. Orientation in Space I: Develops ability to perceive differing points of reference with concrete objects before developing ability to consider different points of view in abstract. Mediates goal-achieving behavior. Comparisons: Increases the ability to differentiate between similar items and events. Develops concepts, labels and operations to describe similarities and differences. Enriches organization and integration of discrete information into systemic whole. Builds self-regulation of behavior (impulse control). Analytic Perceptions: Develops ability to divide a whole into parts (differentiate) and join parts into a whole (integrate). Mediates intentionality, reciprocity, meaning and transcendence in confronting tasks. Numerical Progressions: Introduces induction and deduction or relationships among objects and events. Mediates precision, discrimination and willingness to defer judgment. Illustrations: Develops ability to perceive details with precision, use multiple sources of information, and development of vocabulary. Mediates regulation of impulsivity and task-intrinsic motivation. Temporal Relations: Develops ability to use temporal concepts to describe and order experiences. Without an awareness of the continuity of time, individuals find it difficult to make use of past experience to predict future events and plan. Instructions: Focuses on encoding and decoding verbal and written information in order to deciphar implications of words in context. Enables learners to become generators of information able and willing to interpret complex instructions. Family Relationships: Uses a system of relationships to link separate beings and categories and emphasizes identification of necessary and sufficient conditions for inclusion in a category. Mediates sharing behavior and goal-seeking behavior. Catagorizations: Develops flexibility in divergent thinking necessary for re-categorizing items and groups to meet changed conditions. Forms the basis for logical and verbal operations. Syllogisms: Develops formal, propositional logic promoting discrimination between valid and invalid conclusions and fostering inferential and abstract thinking. Mediates transcendence through insight and generalization. Orientation in Space II: Introduces external, stable and absolute systems of reference and enables linking of internal systems with the external. Mediates deferring of responses until all data studied. Transitive Relations: Helps recognition of the conditions that permit inductive and deductive reasoning and engages learners in inferential thinking based on logical implication and relational thinking. Representational Design: Requires the construction of a design through a complex series of tasks which require active, mental construction via inferential thinking and an anticipation of the outcome. Mediates challenge, competence and optimism.

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COGNITIVE ENRICHMENT IN GENETIC SYNDROMES WITH INTELLECTUAL DISABILITY Strong evidence for specific cognitive and other developmental profiles to be associated with some genetic disorders, most notably fragile X syndrome (Mazzocco, 2000; Turk & Graham, 1997) and Turner’s syndrome (Bishop et al., 2000; Ross, Zinn & McCauley, 2000), is well known (Cornish, 2004) so that it can be hypothesized that genetic syndromes with intellectual and learning disabilities “share” some of their cognitive and behavioural effects (Dykens, Hodapp & Finucane, 2003). In this perspective, it seems possible to attempt etiology-related cognitive interventions for subjects with genetic syndromes with Intellectual disability. Powerful Feuerstein's Instrumental Enrichment Program - FIE (Table 2), and FIEBasic version in particular, are indicated to provide acceleration of cognitive development, and to tempt the remediation of dysfunctions or gaps in skill and cognitive development of these subjects. In our opinion, common weakness areas in their intellectual functioning could be addressed by the proposal of specific instruments for cognitive enrichment (Table 3). The combination of reading problems and frontal-executive/attentional dysfunction represents one of the most common comorbidities observed among subjects with ID. Recent neuropsychological studies show that Fragile X Syndrome (FXS) is associated specifically with visual-motor and visuo-constructive deficits, i.e., impairment in the ability to manipulate objects in space and the capacity to construct concrete and abstract designs, respectively. Together, these results suggest a syndrome-specific visual impairment in fragile X syndrome, with visuo-constructive and visuo-motor tasks being most vulnerable. Turner syndrome (TS) subjects also present selective deficits in spatially dependent executive function in their neurocognitive phenotype (Ross et al., 2006). Verbal abilities are usually normal; however, 45,X subjects have impaired visual-spatial and visual-perceptual abilities, motor function, nonverbal memory, executive function and attentional abilities compared to normal females matched for age, height, IQ, and socioeconomic status (Waber, 1979). The neurocognitive phenotype in TS resembles Harnadek and Rourke’s characterization of nonverbal learning disability (NLD), a disorder characterized by academic deficits in arithmetic, mathematics and science, impaired adaptation to novel situations, impaired social competence and internalized forms of psychopathology (anxiety and depression). NLD arises from impaired nonverbal memory, attention, concept formation, and problem solving. The persistent cognitive phenotype includes a typical pattern of impaired performance in related areas: visual-motor tasks that have a spatial component; tasks that involve manipulation of spatial-relational information; attention tasks requiring control of impulsivity and selfmonitoring. In the range of instrumental enrichment tools that focus on perceptual-motor development, oriented toward learning processes, attention, and planning behavior, “Organization of Dots” is a task that engages subjecs in projecting virtual relationships in an amorphous cloud of dots to form specific geometrical forms. The resulting products must conform to given forms and sizes in changing spatial orientation. The exercises become progressively complex as the subject gradually overcomes the challenges of conservation, representation, and precision. This instruments is particularly indicated in subjects presenting

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non verbal learning disabilities caratherized by impaired attention, working memory, discalculation and spatially dependent executive function. Table 3. Hypothesis of application of IE in genetic syndromes with ID GENETIC SYNDROMES WITH ID Down Syndrome

Turner syndrome

Klinefelter Syndrome

WEAKNESS AREAS IN COGNITIVE PHENOTYPE Expressive language impairment Verbal working memory deficits Precox cognitive decline (dementia-type) Nonverbal learning disability (Impaired attention, working memory, discalculation and spatially dependent executive function) Social cognition

Language based learning disability (dyslexia/dysphasia)

Frontal executive dysfunction

Social cognition

GOALS FOR COGNITIVE ENRICHMENT Emphasizing verbal expression, receptivity to instructions and independent reading and comprehension skills

Perceptual-motor development, oriented toward learning processes, attention, and planning behavior

Decoding emotional expression, understanding their social/behavioral correlates, and searching for factors that generate them Language and abstractive/integrative thinking

Perceptual-motor development, oriented toward learning processes, attention, and planning behavior. Decoding and modulating emotional expression, understanding their social/behavioral correlates

INSTRUMENTS

Auditory and Haptic Discrimination Language and Symbolic Comprehension Learning to Question for Reading Comprehension Organization of Dots Analytic Perception Illustrations (cartoons) Tri-Channel Attentional Learning

Identifying Emotions From Empathy to Action

Auditory and Haptic Discrimination Language and Symbolic Comprehension Categorization Instructions Temporal Relations Transitive Relations Syllogisms Organization of Dots Analytic Perception Illustrations (cartoons) Tri-Channel Attentional Learning Identifying Emotions From Empathy to Action Prevent Violence

Cognitive Enrichment Issue GENETIC SYNDROMES WITH ID XYY syndrome

WEAKNESS AREAS IN COGNITIVE PHENOTYPE Language based learning disability

GOALS FOR COGNITIVE ENRICHMENT Language and abstractive/integrative thinking

Social cognition

Decoding and modulating emotional expression, understanding their social/behavioral correlates Attention and planning behavior. Spatial orientation, emphasizing receptivity to instructions, systematic searching, and crystallization of spatial relationships.

Ditractibility/hyperactivity Fragile X Syndrome

Nonverbal learning disability (numerical and visuospatial skills)

165 INSTRUMENTS

Auditory and Haptic Discrimination Language and Symbolic Comprehension Instructions Categorization Temporal Relations Transitive Relations Syllogisms Convergent and Divergent Thinking Compare and Discover the Absurd Identifying Emotions From Empathy to Action Prevent Violence

Tri-Channel Attentional Learning Orientation in Space (I,II,III) Numerical Progression Comparisons Classification Stencil Design

“Orientation in Space (two levels)” is also an indicated tool for subjects that need help for spatial orientation and crystallization of spatial relationships. It develops an operational vocabulary that is related to orientation in space. Tasks present familiar but increasingly complex scenes, and the learner is asked to identify positions in the space and talk about them using specific vocabulary, including: up/down, above/below, inside/outside, in front of/behind, above/below, and ultimately right/left. Second level introduces external, stable and absolute systems of reference and enables linking of internal systems with the external. Mediates deferring of responses until all data studied. Also “Tri-Channel Attentional Learning” involves subjects in exploring the characteristics of geometric shapes (squares, circles, triangles, various polygons, segmented irregular forms with elements to be counted, sequenced, etc.) first through the tactile modality, then through drawing, and ultimately visually. The tasks are presented in sequential order from simple to complex. This task is conceived as a way to prevent and remediate a variety of difficulties underlying learning disabilities and attention deficits. Particular difficulties with numeracy and visuospatial skills are common in Fragile X Syndrome (Cornish, 2004), in which intellectual impairment is very variable, is associated with spatial deficits, impairments in the processing of visual spatial information to

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discriminate and manipulate figures and objects, as well as attentional and inhibitory impairment (Loesch et al., 1987; Theobald et al., 1987) and verbal intelligence often exceeds performance abilities. The behavioural difficulties are generally not consistent with their cognitive level (Berry-Kravis & Potanos, 2004). Fragile X Syndrome is associated with a particular profile of attention deficit at higher levels of attention and executive functioning (Turk, 2004; Koukoui & Chaudhuri, 2007). Attention and concentration difficulties may be disproportionate to the degree of learning difficulty (Turk & Graham, 1997) while inattention and hyperactivity disorders are the most salient and recurrent traits found in children with FXS (Backes et al., 2000; Baumgardner et al., 1995). FX subjects are impaired for inhibition (the ability to suppress a prepotent response), selective attention (the capacity to attend to relevant visual information and ignore irrelevant stimuli), divided attention (the ability to shift attention from one stimulus or concept to another), and sustained attention (the ability to attend to task-relevant information for a given time period). Higher levels of executive and attention deficits in FXS are witnessed by impairments at switching visual attention and inhibiting repetitive behavior (Wilding et al., 2002). In the range of instruments aimed to foster abstractive/integrative thinking, “From Unit to Group” facilitates the development of the cardinal concept of numbers. In this set of activities the subject must divide a cloud of dots into equal-size groups. The concept of group gradually takes on variations of form, color, heterogeneity, and configuration. The variations encourages the emergence and flexible applications of the concept of number as group. In this context the subject also constructs the operations of addition and multiplication with complete understanding of the commutative and associative properties. Also “Know, use and classify” focuses on a task of categorization (“What do they have in common?”), working with positive/negative attribution, concepts, deduction and functional connections. Moreover, the instrument “Compare and Discover the Absurd A & B” facilitates comparative behavior as it requires that subjects identify what is unusual or unreasonable. The motivation to compare is generated by the presentation of incongruity and humour. The relevant determinants of the absurd are initially limited to size, shape, direction and quantity. The more progressive tasks involve also the consideration of weight, age, and function. Several genetic syndromes with ID lack of emotional competence ed social cognition. Specific tools for decoding emotional expression, understanding their social/behavioral correlates, and searching for factors that generate them should be widely considered. Disturbances in perception, experience and expression of social cognitive information in Klinefelter syndrome (Van Rijn et al., 2006). Various studies have revealed significant relationships between facial affect recognition performance and social functioning (Hooker & Park, 2002). Klinefelter men seem less accurate in perception of social– emotional cues, experience increased levels of emotional arousal, but are less able to identify and verbalize the emotions they experience, in comparison to the general population. These deficits in social cognition may explain, in part, the social difficulties that have been described in Klinefelter syndrome (Geschwind, Boone, Miller, & Swerdloff, 2000). As in Klinefelter syndrome, individuals with Turner syndrome have social adjustment problems and poor social skills (Lesniak-Karpiak et al., 2003; Mazzocco et al., 1998).

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The tool “Identifying Emotions” capitalizes upon the relationship between emotional and cognitive states. The subject is asked to recognize emotions from pictures of facial expressions and connect them with illustrated scenes that are likely to cause them. The exercises are made increasingly difficult by the gradation of possible causes among given scenes (finer distinctions must be made between situations as to the likelihood of their match with the given emotional expression). One choice is always irrelevant, but the others vary in terms of emotional intensity (deemed inappropriate, irrelevant, poor (intensity), or appropriate). Thus, the challenge for the subject is to reason about their chosen link between cause and emotional consequence. The tool “From Empathy to Action” involves the subject in reflecting upon empathic reactions to given situations where a person (or animal) is in trouble: "What should one do to help in such situation?" “Preventing Violence” builds on what the subject has learned in the earlier instruments to develop self control and regulation of behavior, search for meaning (understanding the nature of a conflict between two subjectren), and planning behavior. In the range of IE instruments that focus on verbal expression, receptivity to instructions and independent reading and comprehension skills, “Illustrations” develops ability to perceive details with precision, use multiple sources of information, and development of vocabulary. The instrument is used also to mediate the regulation of impulsivity and taskintrinsic motivation. It is indicated for subjects with Down Syndrome, typically showing an expressive language impairment (syntax more than lexicon) and loss of conversational skills in adult age, generally correlated to clinical signs of precox cognitive decline (dementia-type) as weakness areas in their cognitive profile. Speech and language development is almost always delayed with disfluent conversation, incomplete sentences, echolalia and verbal perseverations also in Fragile X Syndrome (Mazzocco, 2000). The instrument “Instructions” could be proposed because it focuses on encoding and decoding verbal and written information in order to deciphar implications of words in context, thus enabling the learners to become generators of information able and willing to interpret complex instructions. In general, sex chromosome aberrations are reported in concomitance with reduced abilities in verbal fluency and general learning disabilities (Pennington et al., 1982; Bender et al., 1993). The common trend of language skills development in XYY patients is slower and more problematic in comparison with an unaffected control group (Bender et al., 1993). XYY patients may experience slight expressive language problems, including grammatical, syntactic, semantic and phonological development associated to less manifest receptive difficulties, specifically in understanding complex sentence structure. Specific impairments in language, arithmetic, and frontal-executive domains, as well as anomalies of gross and fine motor coordination are reported in Klinefelter syndrome (KS) patients (Geschwind, Boone, Miller, & Swerdloff, 2000). These deficits are especially striking among KS cases with average or above-average IQ scores. Although the behavioral and neurologic difficulties that have been identified in Klinefelter syndrome (KS) are in most cases milder than the consequences of many other genetic syndromes, the deficits in KS cause significant morbidity, representing a more common, but poorly understood, subtype of those with learning disabilities.

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Children with fragile X syndrome have both delayed speech and language abilities, with language delays congruent with nonverbal cognitive delays (Abbeduto, Hagerman, 1997). Strengths of the children with fragile X syndrome included appropriate switching from indefinite to definite object descriptions during the conversation and the use of referential frames. The use of unique object mappings, the use of consistent descriptions for recurring shapes, and the signalling of comprehension to the other communication partner are weakness areas (Rice, Warren & Betz, 2005). Down syndrome subjects are not as robust at accounting for the informational needs of their listener but do understand the increase in shared knowledge that occurs during the course of a conversation (Rice, Warren & Betz, 2005). Children with Down syndrome display relative strengths in visual versus auditory short memory skills (Marcel & Armstrong, 1982). In contrast, most DS subjects display weak language expressive skills. In comparison to nonverbal cognitive skills, subjects with Down syndrome show an incongruence with language performance, such that they have a slower acquisition of overall language than expected for the level of nonlinguistic development (Chapman & Hesketh, 2000). However, this discrepancy between linguistic and non-linguistic skills differs for different domains of language. Vocabulary skills are often at or above nonverbal levels but syntactic development is at lower levels than nonverbal abilities (Chapman, Schwartz & Kay–Raining Bird, 1991). Therefore, children with Down syndrome show an incongruence between nonverbal cognition and grammatical development but a congruence between vocabulary and nonverbal cognitive skills (Rice, Warren & Betz, 2005). In particular, the pragmatic abilities of children with Down syndrome are impaired with some areas of strength. They show appropriate switching from indefinite to definite object descriptions over time and the use of consistent object descriptions for recurring shapes, while the use of unique mappings for objects, the use of referential frames, and the signalling of comprehension to the other speaker is more compromised (Abbeduto & Murphy, 2004). The instrument “Learning to Question for Reading Comprehension”, designed to prepare the subject for reading comprehension by mediating the development of the question asking skills, could be indicated at higher levels of acquisition, because it develops the cognitive functions of comparing, analyzing, summarizing and hypothesis making. Mediation with this instrument emphasizes impulse control, precision, and the feeling of competence. This contribution underlines the need for future research oriented to the systematic application of FIE-B instruments to groups of subjects affected by different genetic conditions. In our opinion, the prevailing tendency to interpret developmental disorders in terms of fixed damage to distinct modular functions needs to be reconsidered (Cornish, 2004). The perspective of Cognitive Enrichment best fit an alternative life span approach, attempting to identify an initial deficit and its consequences for the course of development, at the same time contributing to a better definition of the cognitive and behavioural phenotype of genetic syndromes with ID.

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REFERENCES Abbeduto, L., Hagerman, R. (1997) Language and communication in fragile X syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 7, 45–55. Abbeduto, L., Murphy, M. M. (2004) Language, social cognition, maladaptive behavior, and communication in Down syndrome and fragileXsyndrome. In M. L. Rice & S. F.Warren (Ed.), Developmental language disorders: From phenotypes to etiologies. Mahwah NJ: Erlbaum. Backes, M., Genc, B., Schreck, J., Doerfler, W. & Lehmkuhl, G. (2000) Cognitive and behavioral profile of fragile X boys: correlations to molecular data. Am J Med Genet 95, 150–156. Baumgardner, T.L., Reiss, A.L., Freund, L.S. & Abrams, M.T. (1995) Specification of the neurobehavioral phenotype in males with fragile X syndrome. Pediatrics 95, 744–752. Bender, B.G., Linden, M.G., Robinson, A. (1993) Neuropsychological impairment in 42 adolescents with sex chromosome abnormalities. Am J Med Gen, 48, 169-173. Berry-Kravis, E., Potanos, K. (2004) Psychopharmacology in fragile X syndrome--present and future. Ment Retard Dev Disabil Res Rev, 10(1):42-8. Bishop, D.V., Canning, E., Elgar, K., Morris, E., Jacobs, P.A. & Skuse, D.H. (2000) Distinctive patterns of memory function in subgroups of females with Turner syndrome: Evidence for imprinted loci on the X-chromosome affecting neurodevelopment. Neuropsychologia, 38, 712–721. Brooks, P.H., McCauley C. (1984) Cognitive research in mental retardation. Am J Ment Defic, Mar, 88(5): 479-86 Chapman, R. S., Hesketh, L. J. (2000) Behavioral phenotype of individuals with Down syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 84– 95. Chapman, R. S., Schwartz, S. E. & Kay–Raining Bird, E. (1991) Language skills of children and adolescents with Down syndrome I. Comprehension. Journal of Speech and Hearing Research, 34, 1106–1120. Cornish, K., Sudhalter, V. & Turk, J. (2004) Attention and language in Fragile X. Ment Retard Dev Disab Res Rev 10, 11-16. Dykens, E. M., Hodapp, R. M. & Finucane, B. M. (2000) Genetics and Mental Retardation Syndromes. A New Look at Behavior and Intervention. Paul Brookes Publishing. (Tr. 2003. Ritardo mentale: sindromi a base genetica. Nuove prospettive nella comprensione del comportamento e nell’intervento. Bergamo: Edizioni Junior). Feuerstein R., Rand Y., Hoffman M., Hoffman M. & Miller R. (1979) Cognitive modifiability in Retarded adolescents: effects of instrumental enrichment. Am J Ment Defic, 83(6):539-50. Feuerstein, R. (1980) Instrumental Enrichment. An Intervention Program for Cognitive Modifiability. Baltimore: University Park Press. Feuerstein, R. (1990) The theory of structural cognitive modifiability. In B. Presseisen (Ed.), Learning and thinking stiles: classroom interaction. Washington, DC: National Education Association.

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Feuerstein, R., Krasilowsky D. (1972) Interventional strategies for the significant modification of cognitive functioning in the disadvantaged adolescent. J Am Acad Child Psychiatry, 11(3):572-82. Forsyth, RJ., Feuerstein, R., Rand, Y. & Hoffman, M. (2004) Cognitive modifiability in retarded adolescents: effects of Instrumental Enrichment. American Journal of Mental Deficiency 83:539-550, 1979. Pediatr Rehabil, Jan-Mar; 7(1):20-9. Geschwind, D.H., Boone, K.B., Miller, B.L. & Swerdloff, R.S (2000) Neurobehavioral phenotype of Klinefelter syndrome. Mental Retardation and Developmental Disabilities Research Reviews 6:107-116. Hooker, C., Park, S. (2002) Emotion processing and its relationship to social functioning in schizophrenia patients. Psychiatry Res 112, 41– 50. Koukoui, S.D., Chaudhuri, A. (2007) Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome. Brain Research Reviews, 53, 27-38. Lesniak-Karpiak, K., Mazzocco, M.M., Ross, J.L. (2003) Behavioral assessment of social anxiety in females with Turner or fragile X syndrome. J Autism Dev Disord, Feb;33 Loesch, D.Z., Hay, D.A., Sutherland, G.R., Halliday, J., Judge, C. & Webb, G.C. (1987) Phenotypic variation in male-transmitted fragile X: genetic inferences. Am J Med Genet 27, 401–417. Marcell, M.M., Armstrong,, J. (1982) Auditory and visual sequential memory of Down syndrome and non-retarded children. American Journal of Mental Deficiency, 87, 86-95. Mazzocco, M. (2000) Advances in research on the fragile X syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 96–106. McGivern, RF., Andersen, J., Byrd, D., Mutter, KL. & Reilly, J. (2002) Cognitive efficiency on a match to sample task decreases at the onset of puberty in children. Brain and Cognition, 50, 73-89. Pennington, B.F., Bender, B., Puck, M., Salbenblatt, J. & Robinson, A. (1982) Learning Disabilities in Children with Sex Chromosome Anomalies. Child Development, 53, 1182-1192. Rand, Y., Tannenbaum, A.J. & Feuerstein, R. (1979) Effects of instrumental enrichment on the psychoeducational development of low-functioning adolescents. J Educ Psychol, 71(6):751-63. Rice, M.L., Warren, S.F. & Betz, S.K. (2005) Language symptoms of developmental language disorders: An overview of autism, Down syndrome, fragile X, specific language impairment, and Williams sindrome. Applied Psycholinguistics, 26 7–27. Ross, J., Roeltgen, D. & Zinn A. (2006) Cognition and the sex chromosomes: studies in Turner syndrome. Horm Re, 65(1), 47-56. Ross, J., Zinn, A. & McCauley, E. (2000) Neurodevelopmental and psychosocial aspects of Turner syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 135–114. The International Center for the Enhancement of Learning Potential. Research. Basic Theory. Febbraio 2008. Online at: http://www.icelp.org Theobald, T.M., Hay, D.A. & Judge, C. (1987) Individual variation and specific cognitive deficits in the fra (X) syndrome. Am J Med Genet 28, 1–11.

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Turk, J. (2004) Fragile X syndrome and attentional deficits. J of Applied Research in Int Disab 11, 175-191. Turk, J., Graham, P. (1997) Fragile X syndrome, autism and autistic features. Autism, 1, 175– 197. Van Rijn, S., Swaab, H., Aleman A. & Kahn RS. (2006) X Chromosomal effects on social cognitive processing and emotion regulation: A study with Klinefelter men (47,XXY). Schizophrenia Research 84 194–203. Waber, D. (1979) Neuropsychological aspects of Turner syndrome. Dev Med Child Neurol; 21: Wilding, J., Cornish, K. & Munir, F. (2002) Further delineation of the executive deficit in males with fragile-X syndrome. Neuropsychologia 40, 1343–1349. Mazzocco, M.M., Pulsifer, M., Fiumara, A., Cocuzza, M., Nigro, F., Inc, orpora G,, Barone, R. (1998) Brief report: autistic behaviors among children with fragile X or Rett syndrome: implications for the classification of pervasive developmental disorder. J Autism Dev Disord., Aug; 28(4):321-8.

In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter XI

REHABILITATION ISSUES Michelangelo Bartolo1,2∗, Monica Dulio1,3, Ennio Pucci1,2 and Giorgio Sandrini1,2 1

Neurorehabilitation Unit, IRCCS Casimiro Mondino Institute of Neurology Foundation, Pavia, Italy; 2 Department of Neurology, Faculty of Medicine, University of Pavia, Italy; 3 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, University of Pavia, Italy.

ABSTRACT A genetic disorder is a medical condition caused by mutations in a single gene or in an entire set of genes. These mutations can manifest themselves at any point in life, from the gamete stage through to the cessation of an organism’s biological functioning. There exist different categories of genetic disorders, such as chromosomal abnormalities, single-gene disorders, mitochondrial disorders, and multifactorial disorders (in the latter, multiple genes are affected and environmental factors often play a role, too). The effects of genetic disorders vary greatly in severity: some have little or no effect on an individual’s physical and mental development, while others can be fatal within hours of birth. It is not known why these errors occur. Some common genetic disorders occur when an individual has either three or four copies of a chromosome, instead of the usual two. Other types can occur when an individual has the appropriate number of chromosomes, but small pieces of them are inverted, duplicated, deleted, misplaced, or exchanged with another parts of the chromosome. All these disorders can result in childhood disability and affected children need active rehabilitation, in order to increase their life expectancy and improve their quality of life.

∗

Correspondence concerning this article should be addressed to: Michelangelo Bartolo, MD, Neurorehabilitation Unit, IRCCS Casimiro Mondino Institute of Neurology Foundation, Pavia, Italy. e-mail: [email protected].

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Michelangelo Bartolo, Monica Dulio, Ennio Pucci and Giorgio Sandrini Epidemiologically, childhood disability is a changing and complex area. We are seeing a substantial increase in major disabling conditions and children with disabilities, despite frequently presenting comorbidities, are surviving longer. Measuring disability and progress in childhood is complex. It is difficult to know which measurement tools/scales to apply and what outcomes to measure. The International Classification of Functioning (ICF) seems to be emerging as a useful tool for evaluating and monitoring impairment and functioning in children with disabilities, who need a plan of intervention that takes into account their need to acquire new skills and maximise their potential. The transition from adolescence to adulthood is a complex stage that needs to be addressed through a holistic approach (taking into account a range of aspects: physical, mental, family, socialisation). It is obviously difficult for paediatricians, physiatrists and healthcare workers to have in-depth experience of every single disease. Furthermore, little is done to favour the development planned healthcare programmes, tailored to specific diseases or groups of diseases. There is also a lack of coordination within and between health services and social services, and too little attention is focused on empowering patients’ families. This chapter reviews the genetic disorders most frequently encountered in paediatric neurorehabilitation, looking at how to approach rehabilitation in these children from the life span development perspective.

1. INTRODUCTION A genetic disorder is a medical condition caused by mutations in a single gene or in an entire set of genes. These mutations can manifest themselves at any point in life, from the gamete stage through to the cessation of an organism’s biological functioning. Genetic disorders fall into four categories: in chromosomal abnormalities, a large segment or entire chromosome in the DNA is missing, duplicated, or otherwise altered; single-gene disorders are due to a mutation that results in the alteration or absence of the protein product of a solitary gene; multifactorial disorders occur when mutations affect multiple genes (in these cases, environmental factors can also play a role); finally, mitochondrial disorders are due to mutations in the non-chromosomal DNA of mitochondria. The effects of chromosomal abnormalities vary greatly in severity: some have little or no effect on an individual’s physical and mental development while others can be fatal within hours of birth. In the most common type, an individual has either three (trisomy) or four (tetrasomy) copies of a chromosome, instead of the usual two. In other types, an individual has the appropriate number of chromosomes, but small pieces of them are inverted, duplicated, deleted, misplaced, or exchanged with another parts of the chromosome. Several genetic diseases, because of their low frequency of occurrence, are recognised as rare diseases. There is no established definition of a rare disease, although it is often defined as follows: an affection with an incidence ranging from 1/20,000 to 1/200,000, defining an absolute number of about 5,000 diseases, corresponding to 10% of the total diseases (I Quaderni di Orphanet, 2007). This low incidence explains the particular difficulties associated with these diseases from the perspective of diagnosis, treatment and rehabilitation. First of all, it is difficult to detect these conditions early and accurately. The very low number of patients affected also makes it difficult to conduct research into these conditions and to set up clinical trials.

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Awareness of rare diseases is, in a geographical sense, patchy; added to this, there are for historical, social, and cultural reasons, disparities in the development and application of healthcare programmes specifically targeting rare diseases (I Quaderni di Orphanet, 2007). Because of this difficulty gathering enough patients to allow statistical evaluations, there has been a tendency to develop diagnostic and therapeutic courses and, in particular, rehabilitation programmes on an individual basis. This has not encouraged a standardisation of approaches, or allowed generalisation of the results obtained. It is also important to bear in mind that children are changing all the time and that their rehabilitation programmes need to be constantly updated and adapted. The concept of life span development encompasses all developmental changes, both the ones generally associated with childhood and adolescence, and those that take place with aging. Because functional demands are different at different ages, an individual’s functional status changes in the course of his or her development. The authors briefly review some genetic disorders focusing on the most important issues concerning the rehabilitation of affected individuals.

2. DOWN SYNDROME Down’s syndrome is the most common autosomal trisomy syndrome. Its incidence, which increases with increasing maternal age, is nearly 1 in 700 live births (Hook & Cross, 1989; Epstein, 1995). Regular trisomy 21, accounting for 95% of cases (Mutton et al., 1996), is the result of a nondisjunction process in the first division of maternal meiosis (Antonarakis & Down Syndrome Collaborative Group, 1991). In nearly 4% cases there are Robertsonian translocations between chromosome 21 and other acrocentric chromosomes, like chromosome 14. A mosaic karyotype accounts for the remaining 1% of individuals affected by the syndrome (Antonarakis, 1998). The gene overexpression on chromosome 21, leading to a dysregulation in the development of several neuronal genes, seems to be closely linked to the pathogenesis of Down’s syndrome (Bahn et al., 2002 ). The characteristic features of individuals with Down’s syndrome include short stature, brachycephaly, and mild microcephaly. Craniofacial features include upslanted palpebral fissures, epicanthal folds, flat facial profile, small and low-set ears, with narrow ear canals (Jackson et al., 1976; Preus, 1977; Cooley & Graham, 1991). White speckles may be present on the iris. The presence of redundant folds of nuchal skin is one of the markers used in ultrasound maternal screening for prenatal diagnosis (Gray & Crane, 1994). Two typical features of hands and fingers (both short) are a single transverse palmar crease and incurving fifth finger (clinodactyly). A wide space between first and second toes is also frequent. There are various expressions of impaired brain (Lott & Richardson, 1981; Lott, 1986) and neurological (central nervous system, CNS) development (Pueschel et al., 1987). Microscopic analysis has revealed impaired myelinisation, reduced density of neurons, malformed dendritic trees and spines, defective lamination of the cortex and abnormal synaptic density (Wisniewski, 1990; Golden & Hyman, 1994). From a clinical point of view, the predominant neurological feature of Down’s syndrome is hypotonia. An increased frequency of psychiatric problems, such as depression and behavioural problems including hyperactivity, disruptive behaviours and

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repetitive behaviours, has been reported (Gath & Gumley, 1986; Myers & Pueschel, 1991; Pueschel et al., 1991). Linguistic ability may be impaired, because of or within a picture of cognitive impairment (Kernan & Sabsay, 1996; Kernan, 1990). Seizures, including infantile spasms, are frequently expressions of medical complications or their treatment (Pueschel et al., 1991; Stafstrom et al., 1991). An increased frequency of dementia, associated with the same pathological changes seen in Alzheimer’s disease, has been described in patients affected by Down’s syndrome (Lai & Williams, 1989; Iwatsubo et al., 1995; Johannsen et al, 1996; Schupf et al, 1996). This might be partially due to overexpression of the amyloid precursor protein, whose locus is on chromosome 21 (Teller, 1996; Cataldo et al., 2003). Down’s syndrome subjects commonly have congenital heart defects (atrioventricular canal defect in particular) and gastrointestinal malformations (duodenal atresia and Hirschsprung’s disease). The life expectancy of people with Down’s syndrome has increased in recent decades, due to advances in surgery and in the medical/clinical treatment of the complications of the disorder. Today survival into the seventh decade is not unusual (Baird & Sadovnick, 1989). In 2001, the American Academy of Pediatrics published treatment guidelines for children with Down’s syndrome (American Academy of Pediatrics Committee on Genetics, 2001). An important role is attributed to the surgery that is often necessary to correct congenital malformations commonly found in the syndrome, such as heart defects and gastrointestinal malformations. Affected children need careful clinical management, given their considerably increased risk of respiratory infections and increased frequency of leukaemia and transient leukaemoid reactions. Moreover, nutritional supplementation has been recommended, although the benefits of this intervention are not clearly documented. Some clinical trials reported positive results using the anticholinesterase inhibitor (donepezil) to prevent/treat dementia in patients affected by Down’s syndrome (Lott et al., 2002). Children with Down’s syndrome are susceptible to atlantoaxial dislocation, and neurological signs of cervical cord compression should be looked for. The American Academy of Pediatrics recommends radiographic monitoring for cervical cord compression throughout the preschool years; moreover, these patients should be screened before beginning sports activities (Cremers et al., 1993; American Academy of Pediatrics Committee on Sports Medicine and Fitness, 1995; Morton et al., 1995; Risser et al., 1995). It is very helpful to set up an adequate programme of counselling for the parents of children with Down’s syndrome to familiarize them with natural history of the disorder, and also to inform them about opportunities for intervention and genetic recurrence risks; emotional and psychological support is also needed to help families to cope with this condition. In general, children affected by Down’s syndrome will benefit from early intervention, physical therapy and being reared in a family setting (Gath & Gumley, 1984; Gath, 1990; Whitt-Glover, 2006).

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3. SEX CHROMOSOME ABNORMALITIES: ANEUPLOIDIES [TURNER SYNDROME; KLINEFELTER SYNDROME] Turner’s Syndrome Turner’s syndrome is the clinical expression of a 45,X0 karyotype (one X chromosome is missing) . Mosaic karyotypes may be also present (Hassold et al., 1988; Jackobs et al., 1990; Crocker, 1992; Kuznetzova et al., 1995). The incidence of this aneuploidy syndrome does not increase with increasing maternal age (Warburton et al., 1997). Individuals affected by Turner’s syndrome have a female phenotype; in mosaic forms, including a cell line containing a Y chromosome, there may be a degree of virilization, with ambiguous genitalia. Newborns may show pedal oedema or diffuse oedema. A small mandible, narrow maxilla and epicanthal folds are frequent facial characteristics. In adults, short stature and webbing of the neck are common. The thorax is broad, with an increased distance between the nipples. Features of hands and feet include cubitus valgus, short fourth metacarpal and metatarsal bones, narrow or hyperconvex nails. Multiple pigmented naevi are present on the skin. The following congenital anomalies and malformations are typically found in individuals with Turner’s syndrome: lymphatic system abnormalities, cardiac defects (coarctation of the aorta and of the aortic valve) and renal malformations, such as horseshoe kidney. Mental retardation is rare, although both gross and fine motor development present delays (Salbenblatt et al., 1989; Bender et al., 1993; Nijhuis-Van der Sanden et al. 2003 ). Alterations of the visuo-spatial perception is the predominant cognitive problem (Pennington et al., 1982; Bender et al., 1984). Children with Turner’s syndrome should be screened for hearing deficits, which are common in this condition, to prevent progression of the impairment. Recommendations for diagnosis and management of Turner’s syndrome have been published (Saenger, Wikland, Conwai, et al., 2001; Frias, Davemport, 2003). Newborns should be screened for cardiac and renal defects and monitored over time if these are found. Thyroid function should be monitored too, because of cases of thyroid autoimmunity among patients with this syndrome. Serial growth hormone (GH) measurements, over time, can help to establish whether GH therapy is warranted, to stimulate growth (Cianfarani et al., 1994; Ranke, 1995; Rocchiccioli et al., 1995). The presence of a streak gonad, lack of secondary sexual development and infertility are typical findings in Turner’s syndrome; puberty can be induced in these patients by hormone replacement therapy, at an appropriate age (Hanton et al., 2003). Patients with a mosaic karyotype, including a cell line containing a Y chromosome, should be screened for the presence of intrabdominal gonads which, if detected, should be removed because of the risk of transformation into gonadoblastoma (Saenger, Wikland, Conwai, et al., 2001).

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Klinefelter’s Syndrome Klinefelter’s syndrome is associated with a 47, XXY karyotype and occurs in nearly 1 in 3000 male births. Its incidence increases with increasing maternal age (Carothers et al., 1988). Rarely, there are cases of patients with multiple X chromosomes (48, XXXY; 49, XXXXY), a finding usually associated with more severe cognitive impairment. The diagnosis of Klinefelter’s syndrome is generally not suspected at birth. Affected males are usually tall and long-limbed. They show hypogonadism, with partial/incomplete virilization at puberty; some patients develop gynaecomastia. Azoospermia and infertility are typical features (Yoshida et al, 1997). Testosterone administration, beginning in adolescence, improves secondary sexual development. Children affected by Klinefelter’s syndrome present neuromotor developmental delay, learning disabilities and behavioural problems (Salbenblatt et al., 1981; Salbenblatt et al., 1987). In the literature, there are reports of problems in receptive and expressive language (Pennington et al., 1982; Bender et al., 1983). Because of their learning and behavioural problems, these patients require special support at home and at school.

4. MICRODELETION SYNDROMES: 10Q- SYNDROME, NANCE-HORAN SYNDROME Microdeletion Syndromes (Chromosome 10q Deletion Syndrome) Chromosome 10q deletion syndrome, which is associated with delayed physical and mental development and variable, relatively non-specific abnormalities (Table 1), is caused by a deletion of the long arm of chromosome 10. The most frequent type of microdeletion is a terminal deletion of the long and short arm, with the formation of a ring chromosome (Sparkes et al., 1978; Tsukino et al., 1980). Next in frequency are terminal deletions (Gorinati et al., 1989; Tanabe et al., 1999), while interstitial deletions are the least common (Glover et al., 1987; Mori et al., 1988; Lobo et al., 1992). The phenotype of affected individuals varies accordingly to the type of deletion. The most frequent abnormalities, which are common to all the types, include microcephaly, congenital heart defects, and hypotonia. The first descriptions of different kinds of chromosome 10q deletions appeared in the literature at the end of 1970s (Lansky, 1977; Fryns et al., 1978; Lewandowski et al., 1978). From the 1980s on, several cases of terminal-subterminal 10q deletions were reported; these cases showed similar clinical findings, supporting the hypothesis that there exist distinct 10q deletion syndromes, with characteristic phenoytpes, related to selective involvement of specific genetic sites (Tsukino et al., 1980; Serville et al., 1982; Wulfsberg et al., 1989; Schrander-Stumpel et al., 1981; Irving et al., 2003). Patients with ring chromosome 10 usually have hydronephrosis, bladder obstruction, cryptorchidism and hypoplastic scrotum (Lansky, 1977; Fryns et al., 1978; Simoni et al., 1979; Nakai et al., 1983; Kondo et al., 1984).

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Table 1. Predominant clinical features in chromosome 10q microdeletion syndromes

Head and neck

Ears Eyes

Nose

Mouth and oral structures Thorax Hand, foot and extremities

Spine Muscles Skin Skin appendages Cardiovascular system

Respiratory system

chromosome 10q deletion syndrome Microcephaly, brachycephaly, plagiocephaly, micrognathia, triangular facies with broad forehead, midfacial hypoplasia, and facial asymmetry, short and webbed neck Low-set deformed ears Deep-set eyes, hypertelorism, strabismus, cataracts, upward/downward slanting palpebral fissures Stubby nose, broad bridge, broad philtrum, and epicanthal folds Cleft lip and/or palate, highly arched palate, and cupid-bow mouth Pectus excavatum and widely spaced nipples Occasional syndactyly, cubitus valgus, knee dimples, and limited joint movement

ring chromosome 10

Malformed ears Hypertelorism, strabism

Prominent nose

Small penis and cryptorchidism

Growth and development

Growth, motor, and mental retardation

non-distal monosomy 10q Sinophris, narrow forehead [occasional sign]

Squint/paresis of ocular muscles, epicanthic folds [very frequent], upslanted fissures [frequent], ptosis [occasional] Broad nasal root [occasional]

Simian crease [very frequent], abnormal sole/deep creases [frequent], clinodactyly of fingers, brachydactyly [occasional]

Lordosis, kyphosis, and scoliosis Hypotonia Dry skin and café-au-lait spots Hypoplastic nails and fine sparse hair Patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot, and truncus arteriosus Respiratory distress at birth

Urogenital system

terminal deletion 10q Short, webbed neck

Hypotonia [very frequent]

Anoxia and respiratory distress at birth Hydronephrosis, bladder obstruction, cryptorchidism, hypoplastic scrotum Frequent prematurity at birth

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Behaviour and performance

chromosome 10q deletion syndrome Deafness in some cases and occasional movement disorders with difficulty in raising hands above the head

ring chromosome 10

terminal deletion 10q

non-distal monosomy 10q Abnormal gait, ataxia/incoordination [very frequent], mental retardation [degree not assessed]

Terminal deletion is usually characterized by anoxia and respiratory distress at birth, frequent prematurity, malformed ears, prominent nose, hypertelorism, strabismus, and short or webbed neck (Gorinati et al., 1989; Tanabe et al., 1999). Studies conducted in informative families led to further phenotypical descriptions in relation to specific microdeletion sites, but also highlighted the extreme variability of the clinical features of affected patients (Wagner et al., 1981; Larson et al., 1982; Van de Vooren et al., 1984; Doheny et al., 1997). What these studies tried to do, however, was to establish the presence of common features. Irving and colleagues (Irving et al., 2003) reported eight familial and four de novo cases of terminal 10q deletion syndrome, and three cases with interstitial deletion of 10q25.2-q26.3. Common features included facial asymmetry, prominent nose, thin upper lip, strabismus, low birth weight, short stature and fifth finger clinodactyly. Variable degrees of learning difficulty were found in 11 patients, and four had seizures. Four patients had violent mood swings and aggression, whereas two displayed affectionate behaviour. Visceral abnormalities were uncommon: renal anomalies, vescicoureteral reflux and acute renal failure of unknown aetiology, and atrial septal defect were reported. Moreover, cryptorchidism was described in the two male patients. More recently, Courtens and collaborators (Courtens et al., 2006) described a 13-year-old girl with a de novo subterminal 10q26.2 deletion with typical clinical findings of monosomy 10qter syndrome, including mental retardation, pre- and postnatal growth retardation, microcephaly at birth, and strabismus.

Nance-Horan Syndrome Nance-Horan syndrome (NHS, also called cataract-dental syndrome; cataract, X-linked, with Hutchinsonian teeth syndrome; mesiodens-cataract syndrome) is a rare, hereditary disorder, whose incidence is not yet clear; however, it is probably underdiagnosed. NHS shows X-linked semi-dominant transmission, with high penetrance in heterozygotes, resulting from mutations in male gametes, on locus Xp22.2 (Lewis, 1989; Stambolian et al., 1990; Zhu et al., 1990; Francis et al., 2002; Toutain et al., 2002), even though the exact gene remains to be identified. The pathogenesis of NHS is unknown. This syndrome is clinically characterized, in males, by the association of congenital cataracts with microcornea or microphthalmia (Walsh & Wegman, 1937; Goldberg & Hardy, 1971), causing severe visual impairment that is reflected in the presence of nystagmus, sometimes associated with strabismus. Abnormalities in the number, position and implantation of the teeth as well as in

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the crown shape – these dental abnormalities include supernumerary central incisor or mesiodens, incisor diastemas, narrowed incisal edges (Horan & Billson, 1974; Nance et al., 1974) – are typically found in NHS, but generally don’t require intensive orthodontic treatment. They are therefore of high diagnostic value. Facial dysmorphisms can include: a long, narrow, rectangular face; marked, long, vertical chin and prognathism; a large nose, with a high, narrow nasal bridge; large, anteverted pinnae; and short fourth metacarpals in the hands (Seow et al., 1985). These clinical manifestations are associated, in 30% of cases, with mild or moderate mental retardation (Toutain et al., 1997). In rare cases, there may be severe retardation with autistic features. Interfamilial phenotypic variability is observed, correlations being found in the severity of ocular, dental and dysmorphic features, but not in the degree of mental impairment. Heterozygous females with NHS present with similar, but less severe symptoms and seem to be free from cognitive impairment (Bixler et al., 1984; Walpole et al., 1990). The presence of clinical signs in heterozygotes is unrelated to X chromosome inactivation. Ocular signs include bilateral, often asymmetrical, posterior lens opacities, while microcornea, like low visual acuity and strabismus, is rarely described. Dental abnormalities are always present; dysmorphic features are not a constant finding. Diagnosis is generally made on the basis of clinical features. Genetic counselling and prenatal diagnosis are based on linkage analysis with polymorphic markers in informative families (Toutain et al., 1997; Bergen et al., 1994). The congenital cataract and the other ocular anomalies in males generally require surgical treatment. Postoperative visual prognosis, however, remains poor, due to the high frequency of complications: glaucoma, retinal detachment, corneal lesions and, sometimes, eyeball atrophy. In the worst cases, enucleation may be necessary. The most severely visually impaired subjects need tailored educational programmes at special schools for the visually impaired. In heterozygous females, on the other hand, surgery is necessary only in cases of progressive lesions with advancing age or in the presence of extensive congenital cataract. The postoperative prognosis is good overall, with complete visual recovery in the majority of cases. Orthodontic treatment is needed in case of supernumerary teeth and for aesthetic reasons. Intellectual impairment calls for an appropriate educational programme.

5. REHABILITATION The above-mentioned diseases are associated with lifelong disability, but they can be treated through a variety of appropriate educational and behavioural interventions, in addition to physical and occupational therapies, speech and language interventions, behaviour modification, and parental training. To understand the best approach to adopt in these young patients we can draw on the general concepts of paediatric rehabilitation (American Academy of Pediatrics, 2004). In general, it must be appreciated that every individual has a unique timetable for the acquisition and development of different abilities (Gallahue & Ozmun, 2002).

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Development is an ongoing process which Keogh and Sugden (1985) have called “adaptive change towards competence”. This definition encapsulates the idea that development is a lifelong process in which not only children and adolescents but also adults are engaged. It is important that therapists and other healthcare assistants understand the developmental changes of the nervous system, as this will allow them to view their patients/clients in the context of their developmental timeline. Rehabilitation professionals must also appreciate the significance of the patient’s/client’s age at the time of neurological damage as it is known that the effect of damage is closely related to the functional maturity of the damaged area. as well as to the individual’s psychophysical conditions. For example, if the area was mature at the time of the insult, its consequences will remain stable over time, regardless of the patient’s age. On the other hand, if the damaged area was not mature at the time of the insult, it could be that no deficit will initially be apparent. In this situation there are several possibilities: another region could assume the functional responsibilities of the damaged area, or the deficits may become apparent at the time when the damaged area would normally have matured (Cohen, 1999). Recovery or even maintenance of a function appears to depend on the stage of development of the damaged pathway, but also on the stage of development of the undamaged pathways. There is wide acceptance of the concept of critical periods (periods of time when axons are competing for synaptic sites and pathways are becoming organized). It is also widely accepted that damage to various parts of the CNS will have different behavioural effects depending on whether the damage occurs before or after the relevant critical period (Leonard, 1994). The concept of critical periods has important clinical implications. For example, if the input from an area or a sensory receptor is dysfunctional during that region or structure’s critical period, the axons are at a disadvantage as they compete for synaptic space). Permanent neural change will result. Various CNS structures have different critical periods of different durations (Haines, 1997). It is necessary to plan the rehabilitation intervention considering the single patient’s own critical period, and adapting the plan to his/her developmental timeline. It is important to remember, when treating genetic and developmental diseases, that these patients have multiple functional deficiencies, and therefore need to be managed by a range of medical and psycho-social healthcare specialists. This multi-disciplinary approach will combine the efforts of several specialized health centres and/or leading universities with social and healthcare resources available locally. Rehabilitation specialists are thus important members of an interdisciplinary team that may include medical professionals such as physical and occupational therapists, speech pathologists, vocational counsellors, psychologists, and social workers.

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The Neurorehabilitation Team The neurorehabilitation team incorporates professionals from different areas who work together in the management of the individual rehabilitation plan. The team includes: Rehabilitation Physicians Rehabilitation physicians, such as physiatrists or neurologists with specific neurorehabilitation training and experience, play an important role in the evaluation and management of children with disabilities (DeLisa & Gans, 2005). The problems of these young patients, particularly those affected by genetic disorders, range from physical mobility issues to complex cognitive involvement. Child Neurologists The child neurologist is actively involved in the care of children affected by disabilities and needing rehabilitation. Child neurologists usually assist the patient and his or her family when they are first confronted with the disease, and are the ones who first refer the patient for rehabilitation. They also manage some of the complications presented by infants and children with rehabilitation needs (Tilton & Weimer, 2006). Physical Therapists Physical therapists, who are specialised in the selection and application of orthotics and mobility devices, play a central role in the care of children with developmental problems and gross motor delays (Campbell et al., 2000). Moreover, physical therapists provide caregivers and patients with emotional support and education, emphasizing in particular, the importance of regular stretching to maintain full range of motion and prevent contractures. Occupational Therapists Occupational therapists can help to improve functional deficits related to personal activities, activities of daily living (dressing, eating) and upper extremity function. They can also offer their support in the selection and modification of devices and equipment intended to improve patients’ access to the environment (Neistadt & Crepeau, 1998; Pedretti & Early, 2001). It is very important to note that the role of occupational therapists complements that of physical therapists in the care of children under the age of 3 years, when the focus must be on supporting the family and encouraging the child’s development of appropriate postural control and patterns of movement. Speech Therapists and Audiologists Speech therapists and audiologists, by developing the child’s ability to communicate (both verbally and through alternative channels), are instrumental in helping him or her to become as independent as possible (Owens et al., 2003). In many cases, a child’s cognitive abilities are underestimated simply because he cannot be assessed using traditional testing techniques. Communication boards, sign language, and computer modifications may offer new ways of communicating. Audiological screening is important in order to establish whether a hearing impairment is contributing to a child’s language delay (Tilton et al., 2006).

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Other Health Figures In the context of a multidisciplinary approach to rehabilitation, there are also other professionals who can offer valuable support. Psychologists can indicate what kind of educational setting a child needs and can provide the child and his or her family with counselling. The issues psychologists may address include the impact of the diagnosis on the family and the various transitions that the children will experience as they become teenagers and then young adults. Social workers can help to identify resources in the community (therapy, equipment and funding). Other special therapists use music or recreational activities, for example, to help patients achieve the therapeutic targets set for them by the rehabilitation team (Tilton et al., 2006). More recently, with the expansion of instrumental evaluation techniques (such as gait analysis, 3D movement analysis), technicians, like bioengineers, have also started to make a contribution. Caregivers Caregivers play a central role in the day-to-day management of children with motor impairment and should be involved in every stage of the rehabilitation process: goal setting, treatment planning, and plan modification. Various considerations should be taken into account when establishing the best therapeutic approach: the age of the child, any coexisting condition, such as seizures or cognitive impairment, and the ability of the family to implement treatments at home, to cope with the demands of ongoing outpatient care, and to manage the financial costs of care (Tilton et al., 2006).

The “Health Care Complexity” The rehabilitation in children with genetic disorders raises a series of problems, mainly organizational, that, taken together, show why we can talk about the “complexity” of healthcare in these cases. Various factors contribute to this “healthcare complexity”: 1) each single disease is rare, but there are very many (some thousands) of these recognized genetic diseases; 2) previous drugs and therapies may have not been effect; 3) these conditions demand a highly articulated approach (multidisciplinary, multi-sectorial, with integration of social-health aspects and involvement of the family) in which the primary objective is the wellbeing of the child and his or her family. There are several crucial pointers that must be borne in mind in the provision of this kind of multidisciplinary healthcare for children affected by complex genetic diseases and developmental disorders. First of all, the developed healthcare system will need to exploit environmental resources; second, hospital care/visits to hospital must be reduced to a minimum; third, the healthcare model must be based on full involvement of the family; and fourth, the healthcare programme must be managed by one or two “patient managers”, one in the referring centre and another who will be the family’s local point of reference. This organizational model is intended to promote the global health of the child and his/her family and to help him or her lay the foundations for the greatest possible level of autonomy in adulthood (depending, of course, on his or her particular medical problems).

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The construction of this kind of healthcare model could, conceivably, be initiated by the referring centres (e.g. leading clinical and research centres) that are equipped to diagnose these diseases and to organize follow up programmes. These centres, which ideally should be linked in a network, can support local services. In short, optimal healthcare intervention should be based on professional expertise (provided by leading medical centres), and on the creation of extensive healthcare networks that reach patients in their own local areas. These medical centres of excellence must be able to respond adequately to the needs of patients affected by a wide range of different, rare syndromes. Their tasks include: developing individual healthcare plans in collaboration with health centres and hospitals in the child’s local area; putting the patient’s family in touch with a local patient manager; identifying a patient manager within their own organization; keeping the patient’s medical records updated; developing and disseminating guidelines for integrated multidisciplinary healthcare; identifying and establishing minimum healthcare levels; conducting clinical or social research into these rare diseases; and compiling disease registers for evaluation or clinical purposes. These specialized health centres should also do all they can to encourage the empowerment of families through local support organizations and groups. In the approach to more complex diseases, then, local healthcare networks should collaborate with health centres of excellence and both should be guided by the importance of establishing individual healthcare plans, from assessment of need, through the problem definition, to the sharing of the plan of action with the rehabilitation team, the patients themselves, and their families.

Measurement of Childhood Disability In the field of childhood disability, one of the most interesting issues is the reliability and validity of disability measurement. Although disability measurement problems generally are not unique to child health, there has been a failure to develop specific measures for childhood. Child health measures, most of which are modelled on adult measures, have not been previously seen as a priority area, because children’s health has a relatively small impact on the economy, has a lower frequency of individual conditions, and is very challenging in comparison with the measurement of adult health. Adult measures should not be downsized for application to children because adult health measures focus on the presence or absence of certain functions, which may not be relevant in children. Whereas adult measures do not focus on habilitation (the modification and acquisition of skills), child health measures should consider this aspect, because childhood is best understood through instruments that measure the acquisition of new skills. Child health measures must also take into account the inherent developmental potential of children. The main task of childhood is development. Child health measures should be designed to assess whether an individual child’s potential is being maximised. A child’s potential is dynamic, and the range of what might be considered “normal” is very wide; therefore, a single measure is not reliable. Since,

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in children, it is not possible to refer to a baseline function, in the same way one can not consider the presence or absence of disease at the starting point (Stein, 2005).

The International Classification of Functioning (ICF) The International Classification of Functioning, Disability and Health (ICF) (World Health Organization, 2001), aims to provide a common interdisciplinary and consumer language with which to communicate and understand health, health-related outcomes and health determinants. It is also a classification tool used to describe and measure functioning. The ICF makes possible the development of a model showing how the complex and dynamic relationships among the various/different elements of an individual’s life contribute to the determining of health and health outcomes, and this is one of its main advantages (Imms, 2006). The ICF was designed to be used (1) as a conceptual framework in advocacy, teaching, planning or education; (2) as a classification system, to capture national data on disability or services; (3) to provide detailed codes in specific service, clinical or therapeutic settings; or (4) as a classification framework for designing new outcome measures or for relating measures to each other. The ICF contains a set of specific codes that classify functioning. Use of the ICF codes related to impairment, activity, participation or environment is more likely to result in meaningful data collection, thus helping the allied health professions in the clear identification of where and why they provide services. The first domain of the ICF is body functions and structures, which are defined as follows: in the context of health experience, body functions are the physiological functions of body systems (including psychological functions). Body structures are anatomical parts of the body such as organs, limbs, and their components. Impairments are problems in body function or structure such as a significant deviation or loss. Impairments in the ICF include deviations from generally accepted population standards in the biomedical status of the body and its function and can be temporary or permanent. The ICF defines the activity and participation domains as follows: in the context of health experience, Activity is the execution of a task or action by an individual. Activity limitations are defined as difficulties an individual may have in executing activities. Participation is involvement in a life situation, while participation restrictions are problems an individual may experience in involvement in life situations. The ICF organizes the domains of activity and participation into subdomains. The subdomains are the same for both domains and include the following: 1) learning and applying knowledge; 2) general tasks and demands; 3) communication; 4) mobility; 5) selfcare; 6) domestic life; 7) interpersonal interactions and relationships; 8) major life areas; and 9) community, social and civic life. A five-point scale is used to record the severity of impairment as: no impairment, mild, moderate, severe, and complete impairment) (the scale includes a code 8 “not specified”, and a code 9 “not applicable”).

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In the activity and performances domains, the ICF advocates the use of qualifiers to rate performance or capacity. A performance qualifier should be used to describe what a person does in his/her current environment, including whether assistive devices or other accommodations are needed to perform actions or tasks and whether there are barriers or obstacles in the person’s current environment. Capacity qualifiers, on the other hand, should be used to describe a person’s inherent ability to execute a task or an action in a specified context at a given moment. The capacity qualifier identifies the highest probable level of functioning of a person in a given ICF domain in a standardized environment without the use of specific assistance or accommodations. In essence, the performance qualifiers specify what people actually do in their normal environments, whereas the capacity qualifiers describe the person’s inherent ability to function without considering specific environmental impact. The gap between capacity and performance reflects the difference between the impacts of current and uniform environments as well as personal factors, covered in the second part of the ICF. The ICF framework includes contextual factors of two types: environmental and personal. Environmental factors are defined as the physical, social, and attitudinal environment in which people live and conduct their lives. The subdomains included within the domain of environment include: products and technology; natural environment and human-made changes to the environment; support and relationships; attitudes; and services, systems, and policies. The environmental factors classification, once operationally defined, can be used to identify specific features of the person’s actual environment that act to facilitate or hinder his or her level of function and disability. It can be also used to standardize specific testing environments where capacity in activity and participation can be assessed. Personal factors describe an individual’s particular background, life and living, and are composed of features of the individual that are not part of a health condition or health status. Personal factors can include sex, race, age, lifestyle, habits, upbringing, coping styles, social background, past and current experience, personality style, as well as other psychological assets. The ICF was initially designed for adults; because of its emphasis on assessing functional status in individuals, the ICF is currently being expanded to include children and adolescents and to take into account changes associated with growth and development. The challenge faced by the WHO working group, developing the ICF for Children and Youth (ICF-CY) has been to ensure that the paediatric ICF adequately addressed the dynamics and uniqueness of childhood development. The domains of the ICF-CY should be identical to those included in the ICF. Age-appropriate measurements, taking into account changing body morphology and major childhood activities (play) should be incorporated into its structure. Correctly developed, the ICF-CY should provide a valid, new instrument for documenting childhood disability and aid the tracking of the developmental aspects of disability. Application of the ICF, in the context of healthcare systems, will provide better indicators of treatment needs than diagnosis alone (Placek, 2005).

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6. CONCLUSION In paediatric rehabilitation, particularly when treating patients affected by rare genetic disorders, the individual rehabilitation project must be defined together with the family, by a “patient manager” from the referring, specialist centre, working in collaboration with a local “patient manager”. All those involved in the management of these patients should remember that a life span perspective encompasses all the changes that naturally occur as a part of the lifelong developmental process and that these changes can be progressive, re-organizational, or regressive. Development cannot be viewed linearly. Development, rather implies change over time, which can be viewed both negatively and positively, throughout the course of an individual’s life. Development is not just due to physical changes within the body; it is also a result of environmental influences. Paediatric rehabilitation has to be interfaced with education, in particular, special education. Many educational and behavioural interventions have been shown to be effective, as have been physical and occupational therapies, speech and language interventions, behaviour modification, and parent training. Trained specialists can assess sensory problems and develop a variety of treatment strategies to help children overcome many of the challenges, associated with these disorders.

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Gath, A., Gumley, D. (1984) Down’s syndrome and the family: follow up of children first seen in infancy. Dev Med Child Neurol, 26-500. Gath, A., Gumley, D. (1986) Behaviour problems in retarded children with special reference to Down’s syndrome. Br J Psichiatr, 149-156. Glover, G. et al. (1987) De novo 10q(21q22q) interstitial deletion. Hum Genet (Berlin), 76205. Goldberg, M.F., Hardy, J.E. (1971) X-linked cataract: Two pedigrees. Birth Defects Original Article Series, New York, 7(3), 164-165. Golden, J.A., Hyman, B.T. (1994) Development of the superior temporal neocortex is anomalous in trisomy 21. J Neuropathol Exp Neurol, 53(5), 513-520. Gorinati, M. et al. (1989) Terminal deletion of the long arm of chromosome 10: Case report and review of the literature. Am J Med Genet, 33, 502-4. Gray, D.L., Crane, J.P. (1994) Optimal nuchal skin-fold thresholds based on gestational age for prenatal detection of Down syndrome. Am J Obstet Gynecol, 171-1282. Haines, D.E. (1997) Fundamental neuroscience. New York: Churchill Livingstone. Hanton, L., Axelrod, L., Bakalov, V. & Bondy, C.A. (2003) The importance of estrogen replacement in young women with Turner syndrome. J Womens Health, 12-971. Hassold, T., Benham, F. & Leppert, M. (1988) Cytogenetic and molecular analysis of sexchromosome monosomy. Am J Hum Genet, 42-534. Hook, E.B., Cross, P.K. (1989) Maternal age-specific rates of chromosome abnormalities at chorionic villus study: a revision. Am J Hum Genet, 45-474. Horan, M.B., Billson, F.A. (1974) X-linked cataract and hutchinsonian teeth. Australian Paediatric Journal,10, 98-102. I Quaderni di Orphanet (2007). Prevalenza delle malattie rare: una inchiesta bibliografica.. Online at: http://www.orpha.net/orphacom/cahiers/docs/IT/Prevalenza_delle_malattie_rare.pdf Imms, C. (2006) The International Classification of Functioning, Disability and Health: They’re talking our language. Australian Occupational Therapy Journal, 53, 65–66. Irving, M., Hanson, H., Turnpenny, P., Brewer, C., Ogilvie, C.M., Davies, A. & Berg, J. (2003) Deletion of the distal long arm of chromosome 10q; is there a characteristic phenotype? A report of 15 de novo and familial cases. Am J Med Genet, 123A, 153-163. Iwatsubo, T., Mann, D.M., Odaka, A., et al. (1995) Amyloid β protein (Aβ) deposition : Aβ42(43) precedes Aβ 40 in Down syndrome. Am Neurol, 37-294. Jackobs, P.A., Betts, P.R., Cockwell, A.E., et al. (1990) A cytogenetic and molecular reappraisal of a series of patients with Turner’s syndrome. Ann Hum Genet, 54-209. Jackson, J.F., North, E.R.I. & Thomas, J.G. (1976) Clinical diagnosis of Down’s Syndrome. Clin Genet, 9-483. Johannsen, P., Christensen, J.E. & Mai, J. (1996) The prevalence of dementia in Down syndrome. Dementia, 7-221. Keogh, J., Sugden, D. (1985) Movement skill development. New York: Macmillan. Kernan, K.T. (1990) Comprehension of syntactically indicated sequence by Down’s syndrome and other mentally retarded adults. J Ment Defic Res, 34-169. Kernan, K.T., Sabsay, S. (1996) Linguistic and cognitive ability of adults with Down syndrome and mental retardation of unknown etiology. J Commun Disord, 29-401.

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Kondo, I. et al. (1984) Ring chromosome 10 syndrome: Case report and the possibility of clinical diagnosis. Clin Genet (Copenhagen), 25, 196-200. Kuznetzova, T., Baranov, A., Schwed, N., et al. (1995) Cytogenetic and molecular findings in patients with Turner’s syndrome stigmata. J Med Genet, 32-962. Lai, F., Williams, R.S. (1989) A prospective study of Alzheimer disease in Down syndrome. Arch Neurol, 46-849. Lansky, S. (1977) Physical retardation association with ring chromosome mosaicism: 46,XX,r(10)/45,XX.10. J Med Genet (London), 14, 61-80. Larson, L.M., et al. (1982) Familial reciprocal translocation t(2;10)(p24;q26) resulting in duplication 2p and deletion 10q. Clin Genet (Copenhagen), 21, 187-95. Leonard, C.T. (1994) Major behavior and neural changes following perinatal and adult-onset brain damage: Implications for therapeutic interventions. Physical Therapy, 74, 753–767. Lewandowski, R.C. Jr., Kukolich, M.K., Sears, J.W. & Mankinen, C.B.(1978) Partial deletion 10q. Hum Genet, 42, 339-343. Lewis, R.A. (1989) Mapping the gene for X-linked cataracts and microcornea with facial, dental and skeletal features to Xp22: an appraisal of the Nance-Horan syndrome. Trans Am Ophthalmol Soc, 87, 658-728. Lobo, S. et al. (1992) Interstitial deletion of 10q: Clinical features and literature review. Am J Med Genet, 43, 701-3. Lott, I.T. (1986) The neurology of Down syndrome. In C.J. Epstein (Ed.), Neurobiology of Down syndrome New York:Raven Press. Lott, I.T., Osann K., Doran, E. & Nelson, L. (2002) Down syndrome and Alzheimer disease: response to donepezil. Arch Neurol, 59-1133. Lott, I.T., Richardson, E.P. (1981) Neuropathological findings and the biology of neurofibromatosis. Adv Neurol, 29-23. Mori, M.A. et al. (1988) De novo 10q23 interstitial deletion. J Med Genet (London), 22, 20910. Morton, R.E., Alì Khan, M., Murray-Leslie, C., et al. (1995) Atlantoaxial instability in Down’s syndrome: a five year follow up study. Arch Dis Child, 72-115. Mutton, D., Albermann, E. & Hook, E.B. (1996) Cytogenetic and epidemiological findings in Down sindrome, England and Wales 1989 to 1993. National Down Syndrome Cytogenetic Register and The Association of Clinical Cytogeneticists. J Med Genet, 33387. Myers, B.A., Pueschel, S. (1991) Psychiatric disorders in persons with Down syndrome. J Nerv Ment Dis, 179(10), 609-613. Nakai, H. et al. (1983) Ring chromosome 10 and its clinical features. J Med Genet (London), 20, 142-4. Nance, W.E., Warburg, M., Bixler, D. & Helveston, E.M. (1974) Congenital X-linked cataract, dental anomalies and brachymetacarpalia. Birth Defects Original Article Series, 10(4), 285-291. Neistadt, M.E., Crepeau, E. (1998) Occupational Therapy. Philadelphia: Lippincott Williams & Wilkins,.

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Nijhuis-Van der Sanden, M.V., Eling, P.A. & Otten, B.J. (2003) A review of neuropsycological and motor studies in Turner syndrome. Neurosci Biobehav Rev, 27329. Owens, R.E., Metz, D.E. & Haas, A. (2003) Introduction to Communication Disorders: A Life Span Perspective. In S.D. Dragin (Ed), Boston: Pearson Education. Pedretti, L., Early, M.B. (2001) Occupational Therapy – Practice for Physical Dysfunction. St. Louis: Mosby. Pennington, B.F., Bender, B., Puck, M., et al. (1982) Learning disabilities in children with sex chromosome anomalies. Child Dev, 53-1182. Placek, P.J. (2005) International Classificational of Functioning, Disability and Health (ICF): Crosscutting Breakout Session. Neurorehabil and Neural Repair, 19, 61S-63S. Preus, M. (1977) A diagnostic index for Down Syndrome. Clin Genet, 12-47. Pueschel, S.M., Bernier, J.C. & Pezzullo, J.C. (1991) Behavioural observations in children with Down’s syndrome. J Ment Defic Res, 35-502. Pueschel, S.M., Gallagher, P.L. Zartler, A.S., et al. (1987) Cognitive and learning processes in children with Down syndrome. Res Dev Disabil, 8-21. Ranke, M.B. (1995) Growth hormone therapy in Turner syndrome. Analysis of long-term results. Horm Res, 44(Suppl), 3-35. Risser, W.L., Anderson, S.J., Bolduc, S.P., et al. (1995) Atlantoaxial instability in Down syndrome: Subject review. Pediatrics, 96-151. Rocchiccioli, P., Battin, J., Bertrand, A.M., et al. (1995) Final height in Turner syndrome patients treated with growth hormone. Horm Res, 44-172. Rosenfeld, R.G., Tesch, L.G., Rodriguez-Rigau, L.J., et al. (1994) Recommendations for diagnosis, treatment, and management of individuals with Turner syndrome. Endocrinologist, 4-351. Salbenblatt, J.A., Bender, B.G., Puck, M.H., et al. (1981) Development of eight puberal males with 47, XXY karyotype. Clin Genet, 20-141. Salbenblatt, J.A., Meyers, D.C., Bender, B.G., et al. (1987) Gross and fine motor development in 47, XXY and 47, XYY males. Pediatrics, 80-240. Salbenblatt, J.A., Meyers, D.C., Bender, B.G., et al. (1989) Gross and fine motor development in 45, X and 47, XXX girls. Pediatrics, 84-678. Schrander-Stumpel, C., Fryns, J.P. & Hamers, G. (1991) The partial monosomy 10q syndrome: report on two patients and review of the developmental data. J Ment Defic Res, 35, 259-267. Schupf, N., Kapell, D., Lee, J.H., et al. (1996) Onset of dementia is associated with apolipoprotein E ε4 in Down’s syndrome. Ann Neurol, 40-799. Seashore, M.R., Cho S., Desposito, F., et al. (1995) Health supervision for children with Turner syndrome. Pediatrics, 96-1166. Seow, W.K., Brown, J.P., Romaniuk, K. (1985) The Nance-Horan syndrome of dental anomalies, congenital cataracts, microphthalmia and anteverted pinna: case report. Pediatric dentistry, 7, 307-311. Serville, F. et al. (1982) Chromosome 10 en anneau: 46,XX,r((10)(p15q26). Ann Génét (Paris), 25, 168-71.

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Simoni, G., et al. (1979) Ring chromosome 10 associated with multiple congenital malformations. Hum Genet (Berlin), 51, 117-21. Smith, A., den Dulk, G. (1982) A severely retarded male with deletion of chromosome 15(pter-q13) and 10(q26-qter). J Med Genet (London), 19, 77-8. Sparkes, R.S., et al. (1978) Ring 10 chromosome: 46,XX,r10(p15q26). Hum Genet (Berlin), 43, 341-5. Stafstrom, C.E., Patxot, O.F., Gilmore, H.E., et al. (1991) Seizures in children with Down syndrome: etiology, characteristics and outcome. Dev Med Child Neurol, 33-191. Stambolian, D., Lewis, R.A., Buetow, K., Bond, A. & Nussbaum, R. (1990) Nance-Horan syndrome: localization within region Xp21.1-Xp22.3 by linkage analysis. Am J Hum Genet, 47, 13-19. Stein, R.E.K. (2005) Measurement of childhood disability. In Children with disabilities: crosscutting breakout session (pp.19, 25S-30S). Neurorehabil Neural Repair. Tanabe, S., Akiba, T., Katoh, M., Satoh, T. (1999) Terminal deletion of chromosome 10q: clinical features and literature review. Pediat Int, 41, 565-567. Teller, J.K., Russo, C., DeBusk, L.M., et al. (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med, 2-93. Tilton, A.H., Weimer, M.B. (2006) Pediatric Neurorehabilitation Medicine. In K.F. Swaiman, S. Ashwal, D.M. Ferriero (Ed.) Pediatric Neurology: principles and practice. Mosby Elsevier, Philadelphia, 92, 2355-2371. Toutain, A., Ayrault, A.D., Moraine, C.I. (1997) Mental retardation in Nance-Horan syndrome: clinical and neuropsycological assessment in four families. Am J Med Genet, 71, 305-314. Toutain, A., Dessay, B., Ronce, N., Ferrante, M.I., Tranchemontagne, J., Newbury-Ecob, R., Wallgren-Pettersen, C., Burn, J., Kaplan, J., Russo, S., Walpole, I., Hartsfield, J.K., Oyen, N., Nemeth, A., Bitoun, P., Trump, D., Moraine, C. & Franco, B. (2002) Refinement of NHS locus on chromosome Xp22.13 and analysis of five candidates genes. Aur J Hum Genet, 10, 516-20. Tsukino, R., et al. (1980) Ring chromosome 10 46,XX,r(10)(p15,q26). J Med Genet (London), 17, 148-50. Van de Vooren, M.J. et al. (1984) Familial balanced insertion (5,10) and monosomy and trisomy (10)(q24.2-q25.3). Clin Genet (Copenhagen), 25, 52-8. Wagner, R.D. et al. (1981) Monosomy 10qter due to a balanced familial translocation: t(10;16)(q25.2;q24). Clin Genet (Copenhagen), 19, 130-3. Walpole, R., Hockey, A. & Nicoll, A. (1990) The Nance-Horan syndrome. Journal of Medical Genetics, London, 27(10), 632-634. Walsh, F.B., Wegman, M.E. (1937) Pedigree of hereditary cataract, illustrating sex-limited type. Bulletin of the Johns Hopkins Hospital, Baltimore, 61,125-135. Warburton, D., Kline, J., Stein, Z., et al. (1997) Monosomy X: a chromosome anomaly associated with young maternal age. Lancet, 1-161. Whitt-Glover, M.C., O’Neil, K.L. & Stettler, N. (2006) Physical activity patterns in children with and without Down Syndrome. Pediatric Rehabilitation, 9(2), 158-164. Wisniewski, K.E. (1990) Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesis. Am J Med Genet, 7(Suppl)-274.

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In: Life Span Development in Genetic Disorders Editor: Annapia Verri

ISBN: 978-1-60456-839-4 © 2008 Nova Science Publishers, Inc.

Chapter XII

NARRATIVE BASED MEDICINE IN GENETIC SYNDROMES WITH INTELLECTUAL DISABILITY Ciro Ruggerini1,2,4 , Federica Vezzosi2,3, Angela Solmi3,4 and Sumire Manzotti2,4,5 1

University-Hospital Policlinico di Modena, Modena, Italy 2 University of Modena and Reggio Emilia, Italy 3 Local Health Unit Agency of Reggio Emilia, Italy 4 Associazione Personae, Reggio Emilia, Italy 5 Minamiyachimata Mental Hospital, Chiba, Japan.

ABSTRACT According to Charon (2001), the Narrative Based Medicine (NBM) is a “medicine practiced with the narrative competence to recognize, interpret, and be moved to action by the predicaments of others”. In this chapter we present our experience of the application of the NBM practice to persons with the condition of intellectual disability caused by genetic syndromes. First of all we will give a brief description of the methodology of collecting life stories from families; it is based on an application of cognitive constructionist concept to the knowledge and the relationship shared by the interviewer and the story-teller. Then two real life stories follow. The first story shows clearly the effect of medical records on life environments. The second story gives us some ideas of conditions necessary for a successful work experience. In both of the stories the subjective points of view of the individual or of their families are fully enhanced. The last part of the chapter is base on publicly available materials from a web site of life stories of children with a quite rare genetic syndrome (The Syndrome of Ring 14); a close examination of these stories tell us what kind of information can be obtained from narratives of families; and these information often prove to be full of implications for the care system.

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INTRODUCTION In some countries the Narrative Based Medicine (NBM) has become a common practice to reassemble life stories of persons with chronic disable condition. According to Charon (2001), the Narrative Based Medicine is a “medicine practiced with the narrative competence to recognize, interpret, and be moved to action by the predicaments of others”. The NBM has been built up as a complementary alternative to the “regular” and “standard” ways of retracing a patient and contributed to improving the standards for support and care system (Meininger, 2005). The NBM has a deep anthrolopological value especially with conditions of disability; it has shifted the concept of disability from the traditional one, taken as “impairment” (= application of linear medical model of disability to every aspect of life), to a new concept where relational, social and environmental components of a person’s life are taken into account. The espistemological paradigm introduced by NBM provides the experiences and knowledge of care-givers, by means of their narratives, for care planning of persons with disability. With bio-medical model, on the other hand, the disability is considered to be a natural and unavoidable result of impairment and, as a consequence, the care aims at recovering or rehabilitating the impaired function. Usually the patients’ narratives are used almost exclusively as a means of obtaining “information regarding specific symptoms of disease or of abnormality” (Goodley & Tregaskis, 2006), which often misleads medical professionals to make an erroneous assessment on patients’ everyday life. Too much emphasis on the diagnosis in itself for their developmental opportunities may fix the future perspectives in limited biological context (Goodley & Tregaskis, 2006). . The NBM gives us a better understanding of the patients and their families, redeeming the lineality of bio-medical model, and promotes the Empowerment. Narrative life stories of patients, based on their real and concrete experiences, permit us to overcome the “institutionalized narrativity”, which, failing to read subtle meanings, tends to overlook possible solutions and needs to deal with disability (Meininger, 2005). Moreover, the NBM helps professionals realize the fact that any care system is “socially constructed”, where a variety of factors –social, cultural, professional and institutional practices- comes into play. The narrative-based approach allows “to investigate how meanings of “impairment” and “disability” are negotiated and constructed, and to consider how these meanings impact on the provision of care, perception of the disabled baby and the understanding of parenting and professional care “ (Fisher & Goodley, 2007). Sometimes the deterministic bio-medical model, based on one-on-one relationship between diagnosis and therapy, represses the possibility for alternative resources to be discovered and fails to consider relational and evolutional characteristics of life stories of persons with disability and their families.

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To sum up the NBM could indicate a care system with which attributes to parents a sense of self-efficacy/confidence and, thus, to the disable child her existential significance in the family (Fisher & Goodley, 2007). As a monitoring device for care provision assessment, the narrative-based method can serve as the driving force for an effort among the professionals to share information and to exchange their views on any proposal for adjustments in care provision (Greenhalg et al., 2005). Another application of the NBM to care and support practices is asserted in a growing number of scientific literature on the importance of making the best use of personal experiences of patients for care planning especially for rare genetic syndromes. The narratives of personal experiences, most frequently used in a self-help group context, give precious information on how genetically determined conditions influence their daily living or how these persons get manage with their disabilities, which often prove to be out of reach by far for professionals (Petersen, 2006).

OVERVIEW In this chapter we present our experience of the NBM application to persons with the condition of intellectual disability caused by genetic syndromes. First of all we will give a brief description of the methodology of collecting life stories from families; it is based on an application of cognitive constructionist concept to the knowledge and the relationship shared by the interviewer and the story-teller. Then two real life stories follow. The first story shows clearly the effect that medical records bring on life environments. The second story gives us some ideas of conditions necessary for a successful work experience. In both of the stories the subjective points of view of the individual or of their families are fully enhanced. The last part of the chapter is base on publicly available materials from a web site of life stories of children with a quite rare genetic syndrome (The Syndrome of Ring 14); a close examination of these stories tell us what kind of information can be obtained from narratives of families; and these information often prove to be full of implications for the care system.

METHOD a. Premises The Intellectual Disability can be a consequence of various different neurobiologic causes, among which are included genetic ones. The state of Mental Retardation is not a disease by itself but a different state of being and its developmental achievement depends largely on environmental factors (AAMR, 2002).

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Among persons with Intellectual Disability there could be expected, from a formal point of view, and could be observed, from an empirical point of view, a quite wide range of different degrees of Quality of Life, determined by environmental or individual factors.

b. Limitations of Psychometric Methods Bilsbury e Richman (2002) pointed out methodological problems of evaluating levels of the QoL. Sometimes this kind of evaluation is based on psychometric devices not centered on patients, that is to say, without spontaneous narratives of their experiences nor assessment of the trigger for QoL change according to their personal points of view. These instruments may yield results as some abstract conception. In a patient-centered evaluation, instead, the focus is fixed on each single patient; her or his point of view is identified and integrated with the care prompted. Psychometric devices which put priority on patients’ talk are defined as “clinimetrics” (Feinstein, 1987). This kind of approach makes it easier to identify factors related to a change in QoL in itself. Both researchers and clinicians need standardized methodologies to evaluate variations in QoL. Measurement is often based on psychometric scales which are less likely to be patient-centred, but instead focus on the purpose for which they are intended - abstract constructs. “At the core of a patient- centred approach is the belief that patient’s perspectives can be identified, understood, and ultimately integrated into essential aspects of medical care (…)” (Zatzick et al., 2001). Clinimetrics put the primary importance on the patients’ verbal descriptions of their problems; a patient is encouraged to describe in full detail not only the nature and the severity, but also the course of their symptoms. In defining clinimetrics, Feinstein (1982) urged clinicians to develop innovative methods for studying clinical phenomena directly and to “keep in mind what is important to the patient”.

c. Our Unique Method of Collecting Life Stories In order to collect narratives of life stories of individuals with intellectual disability we designed an original method for evaluation of time-series variations in QoL.

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SOME CONSIDERATIONS ON UNDERLYING EPISTEMOLOGICAL ASPECTS In a quantitative study the basic assumption is that the reality, including psychological ones, relies on a witness who describes it as “it really is” and that her knowledge about the reality is convertible to something objective by means of quantitative analysis. We should, instead, acknowledge the fact that every narrative of some personal experience is a subjective expression; it is just one possibility to give form to her personal experience The story-teller, on one hand, uses her epistemic paradigm, the basis for her to choose the contents of her personal experience and the interviewer, on the other, picks up the elements from narratives according to an interpretative paradigm. We choose the paradigm of “Developmental Psychopathology” (Sroufe & Rutter, 1984) as the basis for interpretation of changes in adoptive levels of an individual in his or her living contexts. According to this paradigm an efficient adoptative ability depends on the dynamic equilibrium, at any point of life-time, between risk factors and protective factors in all the life domains. Both the data source (the story-teller) and the recipient (the interviewer) are influenced by the setting circumstances; the setting shapes not only the objective but also the relationship between them, including cognitive and emotional dimensions, of the meeting To sum up our method attempts to apply the concept of the post-modernism or constructionism to the area of knowledge.

The methodology The procedure of gathering narratives is as follows: Step 1: Setting Outline The firsts step consists of a kind of therapeutic agreement, where the aim, the method and the end-term are defined. Aim: the interviewer claims clearly her professional background –cognitive psychotherapist- and states explicitly that the theoretical base of this approach makes the most of real experiences and that he or she would like to know the story of persons with intellectual disability or of their families in order to identify what kind of supports were and have been critical for the QoL of the family. Method: the interviewer suggests to make a chart of QoL with age in the x-axis and QoL in the Y. The interviewer points out that, even though the QoL consists of many dimensions, it can be well represented by the concept of “well-being”. Term: the time limit to make the QoL chart is fixed to be, a priori, one hour or one hour and a half at most; at the end of the meeting another appointment is fixed to discuss further on one of the elements in the narrative story, only if the story-teller agrees.

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Step II: Making the QoL Chart At this stage the families or the care-givers trace a rough sketch of their narrative, following the guidelines given by the interviewer (the scaled QoL evaluation) for data selection from their memory. Then they proceed to making the chart: the families/care-givers assign a QoL score for different life-time points of the person with disability. To make the chart plotting easier, permitting chronological variations, the participant is invited to: 1) choose the best period (or more than one period) and assign a score; 2) choose the worst period/periods and assign a score; 3) and then figure out other intermediate periods. Step III: Accounts for the Braking Factors In this step the storytellers are requested to identify the breakthrough factors (actions or events) related to well-being shifts. Again, the identification of these factors and the judgement regarding their relation to a well-being shift depend solely on subjective choice. The interviewer brings on the discussion with the teller on the dynamic mechanism of these factors. Step IV: Choice of a Predominant Topic Once the QoL chart is completed, the interviewer invites the storyteller to identify, if possible, a representative title of their story, the one that summaries its meaning or one of its essential meanings.

TWO STORIES a. Eleonora: Title: Power of Information Eleonora is 22 years old. Her intellectual efficiency evaluated by psychometric tests gives a lower value (on the Wechsler Scale she scores as follows: QIV and QIP equal to 45) as a result of Down Syndrome. Eleonora doesn’t have no other associated impairments nor physical or mental disorders. Eleonora’s parents are in good health, her father is 58 years old, her mother 55, both are entrepreneurs, and so are the 34 and 35 year old brothers who are married but help out their family of origin whenever necessary. Actually Eleonora enjoys her life in an intense and satisfying way. She has a job as a secretary in the company of her father and one of her brothers, within her community she’s a member with an active role in different groups (she is photographer in one of them, in another one she appears in the documentaries that are being produced). Chart of the Quality of Life The chart that describes the variations in time of her QoL have been worked on in a clinical setting. The chart is characterised by a sharp decline when Eleonora starts to attend the third grade at high school and later by a rapid recovery that goes on for years until the present levels of excellence. Throughout the school age the chart shows frequent oscillations

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of her QoL, the parents identify the quality of the school experience as the main factor of these oscillations. Example: That maximum score of 9 at kindergarten is being explained in relation to a constant improvement in social skills and learning, which is facilitated by a competent remedial teacher; the deterioration of scores in the fourth and fifth year of elementary school are being explained in relation to the change of a teacher and Eleonora’s difficulty to establish a cooperative and trustful relationship with the new remedial teacher (Figure 1). Q U A L IT Y O F L IF E 10 9 8 7 6 5 4 3 2 1 0 AG E

3

4

5

6

7

8

9

10

11

12

13

14

15

Figure 1. The Quality of Life Chart of Eleonora.

The Reason for a Psychiatric Consultation Eleonora is taken for psychiatric consultation when she is in the third year of high school. The reason is the following: after the first months at school Eleonora starts to refuse doing the homework her remedial teacher has given her and she loses all interest for school, she spends the afternoon in front of the television, doesn’t help in the household anymore, neglects her social contacts. These changes are the result of a couple of things that happened at school: the new remedial teacher, who is a low faculty graduate, has little expertise and gives Eleonora homework that is boring, repetitive and difficult to understand; her class teacher misinterprets a message –with affective and sexual contents- that Eleonora has written to a classmate and she tells her off in public. The effect has got better after a consultation by the school. The Recovery Within a few months after this consultation Eleonora makes great progress; her QoL goes up significantly, as the chart shows. The changes Eleonora makes in the time span of 6 months at the age of 17 are listed in detail in table… The Cause of the Changes The parents identify the cause of the changes in the new information about her intellectual impairments during the psychiatric consultation. All the previous consultation reports have been so disappointing enough to make the parents pessimistic on future perspectives of the daughter. In one of the reports, written at the end of the fifth year of elementary school, Eleonora was described as following: “the girl shows a Moderate - Severe

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Mental Retardation that significantly influences learning at school and makes it necessary to help her with everyday activities…”. The new information given to the parents – in accordance with the AAMR 2002 definition – is: A. The level of Intellectual Efficiency measured by Psychometric Tests is useful for administrative procedual purposes: it is linked to the possibility of getting support regarding school or social activities; B. The level of Intellectual Efficiency is an indicative measure: it doesn’t say anything about the quality of different types of intelligence; in many fields of learning (learning to be, to do, to be with others) the level of Intellectual Efficiency measured by psychometric tests is hardly predictive; C. The development of any aspect of the personality is based on interaction: it’s a synthesis of neurobiological potential and opportunities offered by the environment. This is how Eleonora’s parents describe the effects this information had on them: “… until that consultation no specialist had ever proposed an attainable perspective; we’ve had the opportunity of looking at our daughter from a different perspective … in the past we’ve always done with whatever Eleonora did because from the catastrophic perspective we were given, anything extra that she did meant a little miracle to us…” The new perspective of the parents is passed on to their relatives, the teachers and Eleonora’s friends; every one of them has changed his or her view on her potentials and offers her matching opportunities. What is to be Learned from the Story Eleonora’s story is very important for medical specialists and psychologists; it teaches them that the documents they write, just as the words they use in interviews, partly determine the social representation of the level of impairment. Sameroff (1995) has used the term “Environtype” to indicate the resulting aggregation of the factors – of the individual, the family-related and the cultural code – that determine the way humans integrate among them in society. Specialists have a particular responsibility in forming the Environtype of the living circumstances of people with an impairment. The social representation of impairment – embodied by the Environtype – has a strong influence because it guides family and people in the community offering the disable persons opportunities of personal development. Guarlnick (2005) has made a model for development of people with disability in which scientific information plays a role that can be either helpful or harmful. Studying life stories like that of Eleonora helps to understand which scientific information to be spread out for its utility and which are mistakes specialists often make (Table 1).

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Table 1. The changes in Eleonora’s behaviour before and after her parents acquired a new concept of her intellectual impairment.

1

Before She rarely helps in the household – she lays the table or makes the bed

2

She doesn’t know how to cook

3

She doesn’t want to do her homework, she copies down parts of a book that is written in dialect and every weekend she gets homework from the same book She doesn’t know basic maths like adding and subtracting She doesn’t know how to use money

4 5

8

She doesn’t know how to tell time She doesn’t know how to use a camera properly She doesn’t know how to ski

9

She can’t dance

10

She doesn’t phone her friends to go out, but waits for them to call her

11

She used to work at a barber’s shop once a week – she cleaned the floor and passed on the rollers -; she wasn’t very enthusiastic

12

She didn’t use to care much about personal hygiene

6 7

After She lays the table every night, helps in the house and dusts, puts the cutlery in the dishwasher without being asked to; she offers to help spontaneously She learns to make pizza dough and pasta; she writes down the recipes of the things she is making There is a drastic change in the teaching: she’s being proposed to write a biography of her friends in the music group; she interviews them, writes down their stories; she writes down the lyrics of her favourite songs; she’s passionate about her homework After 15 lessons by an elementary teacher she’s able to add and subtract After 15 lessons she recognises Euro coins and uses them for purchases up to 10 Euro She has learned to tell time She becomes the photographer of the musical group and learns how to take pictures In less than a week’s time she learns the technique of the “snow shovel” and how to use the ski lift, so that she can go skiing with her friends She takes dancing classes and learns steps of ballroom dancing and Latin-American dances; in the evenings with her group she dances without making any mistakes; she wears the same uniform as her friends in the music group Now it’s her who calls her friends to see if they go out, saying: “I’m free tonight, if you’re organising anything let me know..” She works in an office a couple of hours a week and uses a computer, numbering pages and giving them headings, photocopying documents. To the question “what kind of work would you like to do?”, her answer is: “secretary work!” She wants to have highlights and a perm; she epilates her body by herself using a cream and she goes to the beautician to have her face waxed; she has started to use make up

b. Alberto: Title: At work with a fever Alberto is 28 years old. His intellectual efficiency is slightly impaired as a result of Down syndrome. His a daptive skill level is high; his score on the Vineland Scale (Sparrow, Balla et al., 2003) – compared to adults with Mild Mental Retardation that live with their family – is below average in the area of communication, average in the area of Motor Skills,

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above average in the area of daily activity skills and social skills. Alberto has had an ophthalmic surgery at the age of 11 months and another one at the age of 5 years for congenital bilateral cataract. He doesn’t take any medication. Alberto’s parents are in good health. His father is 62 years old; his mother 57. He has one brother who is 31 years old and married. He helps out the family whenever necessary. Alberto went to high school; he can’t read, write or draw. He’s been working for an electronic material supplier. Chart of the Quality of Life The chart that describes the temporal variation of his QoL have been worked on in a research setting. The chart is as the figure 2. In the following we report some of the comments that highlight the factors that, according to the family, are connected to the level of QoL. QUALITY OF LIFE 12 10 8 6 4 2 0 AGE

6

7

8

9

10

11

12

13

14

15

16

17

17-26

Figure 2. The Quality of Life Chart of Alberto.

Elementary school age (6-10 years): the parents give a maximum score for the QoL; the factor the parents find most relevant for this result is the quality of integration at school, which is made possible by a teacher who is particularly good in her relationship with Alberto and in teaching him directly. First period of junior high school (11-14 years): the scores are getting worse until a minimum score (5) in the second year of junior high school; the parents identify a single factor that is responsible for the poor quality of the relationship between Alberto and his teachers. In the first period of junior high school Alberto suffered from Alopecia caused by stress due to maladoption at school. Period of job training (14-17 years): in this period Alberto goes to a school that prepares intellectually impaired people for work; according to his parents the level of his QoL improves without reaching optimal levels. The critical factor was the fact that Alberto had difficulty establishing relationships with the other disable trainees. From the age of 18 until today Alberto has been able to enjoy a higher QoL (Figure 2). There are several factors that define the actual level. Alberto’s got an intense social life: he joins two groups run by volunteers that organise activities for spare time; he has got a hobby – he goes to a dancing school - .His most satisfying experience is, however, work – which explains the title chosen by the parents for this story -.

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His parents describe his satisfaction with these words: Alberto “gets an allowance for people with disability and could stay at home living on social benefits; he still wants to go to work, even if he’s ill and feverish”. Alberto works in a small family-run company – that employs four relatives of the owner and two external employees -; his working hours are 8 hours a day. Alberto is “placed in the production line: he performs simple tasks that would be a waste of time for others to do because they are too basic”; once a month he receives a small salary; his tasks need to be checked but are usually performed correctly; his efficiency is low: “he takes five hours to do a job that’s usually done by a worker in just one hour”. According to Alberto’s parents he’s satisfied with his work because the interpersonal relationships at work follow three rules: “engagement and responsibility: … the rule is that there are no individual rules for him, but the rules for the rest apply to him too; if he makes a mistake they get angry with him just as with the others”; ”satisfaction: the owner of the company is careful for what is satisfactory for him; for example: the owner understood he liked to take care of the delivery of the end products and he gives Alberto the satisfaction of accompanying him: he actually loves travelling by minibus and when he arrives at the destination he loves to be taken into consideration by the buyers”; “friendship: Alberto’s got a real friendship with the owners”. Alberto has found his working place thanks to different actors: -The medical specialists have worked together with the social workers; they have worked on the possibility of increasing the “allowance at work for the disabled or impaired in an organised context with goals linked to production but without manufacturing tasks”. -A small handcraft company: has chosen to take on Alberto amongst its workers “on ethical grounds taken by the owners” – the head of the family is engaged with volunteers. -Alberto’s parents: they wanted to pursue his wish to work in this particular company that he got to know during the internship. What is to be Learned from the Story Alberto enjoys the opportunity to be part of a welcoming and competent community, for many years by now. His experience is useful for his community to learn: a.

What the ingredients are that make a work situation subjectively satisfying (friendship, respect, use of common rules for interpersonal behaviour) b. What steps are necessary to organise a job opportunity (follow the wish of the impaired person; use companies where there is an ethical attitude, interpret the law in a creative way)

A Rare Syndrome The syndromes due to an aberration of the chromosome 14 are considered to be rare. In May 2003 the mother of a child with one if theses syndrome has founded the International Association of Ring 14 in Reggio Emilia (Italy) with two objectives: to study the cases of Ring 14 in all countries in the world and put families in contact with each other to create a self help group; to make the medical profession more aware of the diagnosis promoting it and to create an archive with enough information to promote and finance research (Azzali, 2003).

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To realise the first objective a website has been created (www. Ring14.com), through which the Association has identified 90 cases. The information about this syndrome that can be found in scientific literature regards medical aspects only: types of alterations of chromosome 14; mosaicism; morphological characteristics; associated diseases – epilepsy, alterations of the retina and recurrent infections -. There is a section on the Ring 14 website called “the stories of our children” that contains 33 spontaneous narrations of families. We’ve examined the type of information they contain; it can be classified into several categories: a. Emotions and thoughts of Parents in Different Moments of their Experience: Two segments clearly stand out: 1) In 9 stories out of 33 there is a striking emphasis on emotional turbulence provoked at the moment of communication about the diagnosis. Understandably, in the story of the parents, the contents of this communication are characterized invariably by the absence of information: the parents feel that they are being put in front of nothing. And in front of that same nothing the medical specialists place themselves next to the parents in very different ways. Sometimes in a way that parents find detached: Quentin (France), born in 2001: “… given the lack of information about this disease, the parents are given little general information: it causes a psycho-motor delay, it’s a very rare genetic abnormality, there is some common malformations in this abnormality, it is very difficult to deal with…”. Sometimes in a way that parents find inappropriate: Alexandre (France), born in 2002: “ … (mother) I particularly remember the victorious smile of the head of department. She was happy and relieved that she had “ found” one and immediately said: it’s a genetic malformation that we don’t know at all, there are very few cases worldwide…”. Sometimes prophesying dramatic horizons – even without evidence: Ashely (Canada), born in 1992: “ … after the diagnosis … she was labelled immediately … the prognosis was horrible … dead at the age of one or, if she survived, she would be a “vegetable” to put in a home or just to bring home and love her if we could. We spent the next 12 years cuddling her, paying attention to her, loving her, trying everything for her to make progress. We spent the first 7 years hoping she managed to learn anything… I wish someone could have said something else when she was born, because we “spoiled” her – we gave her everything she wanted and tried everything to make her “normal”. “I wish I could start and do it all over again…”. Sometimes in a realistic and cooperative way: Celine (Norway), born in 2002: “… the doctor told us we were the only case in the world with this type of chromosomal disorder. He told us they would do everything in their might to understand a little bit more about it…”

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Summary: The needs of parents regarding the syndrome really are about the prognosis of the syndrome or, more appropriately, the Quality of Life the syndrome implies; the narratives of this group of parents magnify the general problem of the specialists who deal with all kinds of conditions in children, considering that it is only in a few cases that some prediction is supported by extensive evidence. Parents give two take home messages about this subject: - the most respectable attitude for a specialist is a realistic and cooperative attitude (like the one Celine’s parents hit on); - the communication about the diagnosis must take into account that there are different kinds of prognosis (they can regard controlling or curing associated diseases, development of cognitive functions, Quality of Life) and each of them is a result of different factors, which include the progress of medical treatments, the genetically determined limits, the opportunity for development, the amount and type of support available). 2) The other feeling that stands out could be defined as eagerness to share experiences and knowledge. Their eagerness seems to have two dimensions: a personal one and one that refers to a collective project where the experiences of single people can become the knowledge of many. For example: Matthew (USA), born in 1982: “ … It seems I have so much to share with all of you and perhaps even give you a bit of hope! I could help out thanks to the experience I had with Matthew in the past 21 years… if you want to know what we have been through as a family, or if you want to know how Matthew was at a certain age, what we did, which mistakes we’ve made, which medical problems or “miracles” we’ve been through, I am willing to help…”. b. Information about the Characteristics of Neurological and other Associated Medical Conditions and the Efficacy of Various Therapies Many stories give information about the presence of neurological and other medical conditions, their characteristics, the efficacy of therapy and the prognosis. They lead to the conclusion that sometimes neurological and other medical associated conditions, even very severe ones, completely disappear. In the stories of Tim, Kristy, Peter and Jay for example, it is said that epileptic seizures disappear at an early age. Information about possible courses of various medical conditions contained in the stories of older children, can be very valuable for parents and clinicians, even if they still have to be confirmed by systematic research; the current research aims to do so by constructing a database using the information of the family members (involved in Association Ring 14). c. Information about Opportunities for Development 12 Stories are about the given opportunities for development in communication, sport and joining social events. For example:

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Elijah (USA), born in 2000: “ … Has started horseback riding … Yippee!! He likes it. He can’t stand the heat, so we go in the morning. He also likes swimming, sometimes he falls asleep in the water…”. Elizabeth (USA), born in 1986: “… She is sportive and active in the Special Olympics: she started this activity when she was 8 years old. She goes to summer camp… We still help her with some autonomous tasks such as washing herself and getting dressed, especially when we are in a hurry. In a way we continue to treat her like a child, but now that she’s an adolescent we try to give her more freedom in some of her choices such as clothes and so on. Elizabeth helps me with some things in the household: she knows how to use the microwave and she loves the TV and videos, especially Walt Disney cartoons and music… We are active in the Special Olympics and we’re a member of the Arch; so we’ve always got volunteers who want to babysit Lizzy…”. The stories about these aspects of life are important because they communicate in an explicit and simple way: no individual “coincides” with his or her syndrome; development can happen only in the presence of opportunity; the opportunities are to be created/ facilitated/ made possible; the opportunities are widely available in the social organisation and not in the places for therapy or rehabilitation. d. Information about the Developmental Perspectives of Intellectual Efficiency, Language, adaptive Skills and social Participation Most of the reports contain very detailed descriptions of development. The only comprehensive conclusion that we can draw from them is that of remarkable heterogeneity: regarding the general intellectual efficiency, linguistic competence, adaptation and participation. For example: Quentin (France), born in 2001: “ … he just started to clap his hands, he adores to leaf through books, catalogues and magazines. He tries to copy other people’s gestures. He isn’t able to concentrate on a game, he doesn’t watch television, he hasn’t got any patience. It’s a child that always needs to be reassured, he’s always near his parents and when he isn’t it means he’s up to something. He always needs to be supervised, he isn’t afraid of danger even if he hurts himself. He’s been very aggressive with his sister Cloè (5 years old), up to the point where he hurt her. He’s very strong, but she’s been very patient and it’s going better now. He still teases her a lot, but he doesn’t hurt her anymore. He’s a very sweet boy, sociable, smart, cuddly…”. Sabrina (Italy), born in 1995: “ She is now a beautiful 6 year old, lively, curious, steadily growing; she goes to the last year of kindergarten – she’s done an extra year -; compared to the other children her progress is slower, but it’s constant… She interacts a lot more with peers, she uses her fantasy when she plays, she creates situations and explains them to others so they can join the game. She is better at concentrating, that is if the activity has her interest…”. e. Information about the Quality of Life At least in 5 stories the Quality of Life is evaluated explicitly on the bases of the dimensions of being (“feeling comfortable”: Peter), belonging (“have significant relationships with others”: Jay), becoming (“ face life”: Tegan).

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Peter (USA), born in 1978: “Had epilepsy, microcephaly, scoliosis, a hernia, his testicles had not descended, he had an aortic stenosis and just one kidney. Moreover he frequently had respiratory problems. This is all terrible, isn’t it? It wasn’t really like that. He went to school by bus and he enjoyed it. He had a low IQ but he laughed, played and enjoyed life. His speech was slow, but we managed to communicate…”. Jay (England), born in 1987: “ … Jay joined the Boy Scouts until he was 18, but now he’s losing his interest … we are members of the local theatre group and so is Jay, he helps us with the scenography, he gives the ushers a hand and so on. … We are completely dedicated to him and try to get him involved in activities that are more suitable for his age so he will always have friends. It has helped us a lot being involved in this voluntary work … he has started to take driving lessons with some difficulty, but also with successes … he goes back to high school next Monday for half a day and the other half of the day he goes to an institution where he follows a special educational program, we think it’s best if he goes to both…”. Tegan (Australia): … I’m one of the oldest people known with this particular chromosomal translocation … I went to university, graduated, and even if I couldn’t do everything my friends did, like playing sports in a team, I could, however, always participate by accompanying them and cheering… I’m an office worker for an important company that builds powerhouses in my home town, and it’s just behind my house … I’ve been head of European Affairs for over a year now… Living at boarding school taught me that in spite of the challenges my chromosomes faced me with, and almost certainly will continue to do, I can look after myself, be independent and prove myself … I learned that the best way to face a situation is to deal with it with a sense of humour and a optimism…”. We can conclude that the stories these parents tell about their experience with their children is extremely up-to-date: it’s about stories in which the concept of Quality of Life is person-centered (Renwick, Brown et al., 2000). What is new with these stories is in putting the Quality of Life as the ultimate goal to which the courses of development should be directed.

CONCLUDING REMARKS In this chapter we have described some of the characteristics that define the NBM, we have described the method we use to gather the life stories of our patients and then we have presented two stories that we got using this method. The Eleonora’s story has a high educational value for medical specialists and psychologists; it actually forces to reflect on the effects of medical information; the story of Alberto has got a high educational value for the community: it could give an opportunity for fruitful discussion among social workers that help people with an impairment or disability to find a job; it could be spread amongst voluntary associations where, in every community, people who wish to realise their ethical aspirations are being served. Both the stories of Eleonora and Alberto have got a predominant meaning specified by their families and listeners. These meanings can be considered the message their experience gives to society. In

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order that individual experiences can enhance the experience of other these messages should be identified and spread over. What we consider scientific knowledge has traditionally ignored the identification of these meanings. The study of the stories of people with Ring 14 shows how much information gets lost in a small sample if the subjective dimensions of the experience are neglected. These stories contain information regarding subjective dimensions relevant to the wellbeing of people that could be gathered from quantitative studies only with extreme effort. As the case matters, their potential contribution to assistance doesn’t seem inferior to the (little) medical information that is available. The key message of this chapter is that NBM and EBM are complementary. We shall conclude by adding that the application of the NBM paradigm to the condition of Intellectual Disability is only at its beginning and further development will most likely provide wide contributions in the future.

ACKNOWLEDGEMENTS The authors are grateful to Stefania Azzali, president of the International Association of Ring 14, for permitting us to access the data-base of the Association. Our special thanks go to Paola Martinelli, psychologist of the Association Ring 14, who has checked the data on our early draft.

REFERENCES American Association on Mental Retardation. (2002) Mental Retardation: definition, classification and system of supports. Washington: AAMR. Azzali, S. (2003) Un sostegno per tutte le persone con un’aberrazione del cromosoma 14. Associazione Internazionale Ring 14 Onlus. Sito web, www.ring14.com. Bilsbury, C.D., Richman, A. (2002) A staging approach to measuring patient-centred subjective outcomes. Acta Psychiatrica Scand, 106 (Suppl. 414), 5-40. Charon, R. (2001) Narrative Medicine: Form, Function and Ethics. Annals of Internal Medicine, 134(1), 83-87. Feinstein, AR. (1987) Clinimetrics. New Haven: Yale University Press. Fisher, P., Goodley, D. (2007) The linear medical model of disability: mothers of disabled babies resist with counter-narratives. Sociology of Health & Illness, 29(1), 66-81. Goodley, D., Tregaskis, C. (2006) Storyng disability and impairment: retrospective accounts of disabled family life. Qualitative Health Research, 16(5), 630-646. Greenhalg, T., Russel, J., Swinglehurst, D. (2005) Narrative methods in quality improvement research. Quality & safety in Health Care, 14, 443-449. Guralnick, M.J. (2005) Early intervention for children with intellectual disabilities: current knowledge and future prospects. Journal of Applied Reserch in Intellectual Disabilities, 18, 313-324.

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Mair, M. (1988) Psychology as Storytelling. International Journal of Personal Construct Psychology, 1, 125-38. Meininger, H.P. (2005) Narrative ethics in nursing for person with intellectual disabilities. Nursing Philosophy, 6,106-118. Petersen, A. (2006) The best experts: the narratives of those who have a genetic condition. Social Science & Medicine, 63, 32-42. Renwick, R., Brown, I., Raphael, D. (2000) Person-Centered Quality of Life: Contributions from Canada to an International Understanding. In K.D. Keith & R.L. Shalock (eds.), Cross-Cultural Perspectives on Quality of Life. Washington: AAMR. Roberts, G.A. (2000) Narrative and severe mental illness: what place do stories have in an evidence-based world? Advances in Psychiatric Treatment, 6, 432-41. Ruggerini, C., Vezzosi, F., Dalla Vecchia, A., Lambrusche, F. Epistemologia postrazionalista e narrazione di storie di vita: i primi risultati di una proposta metodologica. Atti Congresso Nazionale CNIS sevolutivo. In: “ Esperienze e ricerche sull’integrazione scolastica e sociale” , Modena , 16 – 18 Marzo 2006 (Edizione Junior, in corso di stampa). Ruggerini, C., Coccia, M., Guaraldi, G.P. (2002) Evoluzione nell’arco della vita di persone con ritardo mentale: descrizione di una casistica secondo l’ottica della psicopatologia dello sviluppo. Saggi, 28(4), 7-40. Sameroff, J. (1996) Modelli di sviluppo e rischio evolutivo. In C.H. Zeanah (Ed.), Manuale di Salute Mentale Infantile. Milano: Masson. (Original title: Handbook of Infant mental Health, New York: the Guilford Press, 1993.) Sparrow, S.S., Balla, D.A., Cicchetti, D.V. (2003) Vineland Adaptive Behavior Scales. Firenze : Organizzazioni Speciali. (Original title: Vineland Adaptive Behavior Scales, Circle Pines, American Guidance Service, 1984) Sroufe, L.A., Rutter, M. (1984) The domain of developmental psychopathology. Child Development, 55(1), 17-29. Zatzick, J., Russo, D.C., Grossman, G.J., Janice, S., et al. (2001) Posttraumatic stress and depressive symptoms, alcohol use, and recurrent traumatic life events in a representative sample of hospitalized injured adolescents and their parents. Medical Care, 39 , 327-339

INDEX 3 3D, 184

A Abdullah, 95, 102 aberrant, 35, 55, 61, 63, 129, 143 abnormalities, 30, 35, 36, 45, 48, 49, 51, 52, 56, 59, 66, 67, 86, 89, 92, 94, 98, 103, 104, 113, 124, 125, 136, 137, 140, 141, 144, 151, 169, 177, 178, 180, 181, 189, 190 absorption, 47 academic, 1, 72, 87, 89, 90, 92, 163 academic difficulties, 87, 90 academic success, 92 Acanthosis nigricans, 59 access, 3, 113, 183, 210 accounting, 34, 168, 175 accuracy, 148, 151, 160 acetic acid, 35 achievement, 197 acid, 139 acrocentric chromosome, 175 activation, 49, 51, 61, 70, 98, 117, 119 acute leukemia, 42, 43, 61, 91 acute myeloid leukaemia, 62 acute renal failure, 180 Adams, 112, 115, 116, 119, 121 adaptation, 69, 163, 208 addiction, 74, 126 adenoids, 109 ADHD, 109, 114, 121 adhesion, 49, 62 adipose tissue, 85, 86

adjustment, 74, 82, 98 administration, 77, 78, 89, 90, 150, 178 administrative, 202 adolescence, 35, 37, 45, 50, 65, 66, 67, 75, 81, 89, 92, 93, 99, 109, 110, 174, 175, 178 adolescents, 4, 35, 37, 45, 72, 82, 103, 143, 169, 170, 182, 187, 189, 211 adult (s), 4, 35, 36, 37, 42, 44, 48, 49, 51, 53, 55, 56, 58, 60, 66, 67, 81, 82, 83, 87, 89, 102, 108, 127, 131, 142, 143, 153, 159, 167, 177, 182, 185, 187, 189, 190, 191, 203 adulthood, 4, 5, 8, 65, 67, 92, 98, 109, 124, 131, 174, 184 advocacy, 186 aetiology, 142, 180 affective disorder, 105 African-American, 116 afternoon, 201 age, 4, 5, 10, 16, 27, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 56, 58, 59, 69, 70, 74, 75, 77, 80, 87, 88, 89, 90, 91, 93, 94, 97, 98, 99, 100, 107, 111, 113, 114, 121, 127, 131, 138, 139, 141, 149, 151, 158, 159, 163, 166, 167, 177, 181, 182, 183, 184, 187, 189, 190, 199, 200, 201, 204, 206, 207, 209 ageing, 38, 45, 48 agent (s), 113, 114 aggregation, 202 aggression, 40, 68, 110, 151, 180 aggressive behavior, 88 aggressiveness, 95 aging, 34, 36, 37, 40, 61, 62, 108, 111, 175 agnosia, 37 agoraphobia, 100 aid, 187 AIDS, 100

214

Index

alcohol abuse, 150, 151 alcohol consumption, 151 alcohol use, 211 algorithm, 23, 25, 27, 28 ALL, 43 allele (s), 39, 56, 87, 109, 116, 121 allergic reaction, 127 allergy, 51 alpha, 35, 46, 48, 56, 62, 98, 114 alternative, 67, 75, 126, 131, 158, 168, 183, 196 Alzheimer, 37, 40, 48, 52, 55, 57, 58, 59, 60, 61, 62, 63, 147, 152, 154, 176, 189, 191 Alzheimer disease, 40, 55, 59, 61, 152, 191 amenorrhea, 70, 75 American Academy of Pediatrics, 54, 176, 181, 188 American Psychiatric Association (APA), 37, 54, 73, 153 amino acids, 35 AML, 43 amniocentesis, 89 amniotic fluid, 89 amorphous, 163 AMPA, 113, 120 Amsterdam, 82 amygdala, 112 amyloid, 34, 38, 39, 40, 55, 58, 61, 62, 111, 122, 152, 176, 190, 193 amyloid angiopathy, 38 amyloid beta, 38, 40, 193 amyloid plaques, 38 Amyloid Precursor Protein (APP), 38, 39, 61, 62, 111, 152, 176, 189 analogical thinking, 130 androgen (s), 85, 87, 89, 90, 92 anemia, 47 aneuploid, 54, 60 Aneuploidies, 177 aneuploidy, 21, 94, 96, 101, 102, 177 aneurysm, 91 anger, 127 angioma, 70 animal models, 113, 114 animal studies, 107 animals, 74, 100 aniridia, 22 anomalous, 190 anoxia, 180 antagonist (s), 107, 114, 115, 122 antibody, 51, 55 anticonvulsant, 110

antigen, 48, 49, 53, 61, 62 antioxidants, 117 antipsychotic, 80, 114 anti-social, 95, 101 antisocial behaviour, 102, 103 antiviral, 61 anxiety, 40, 66, 72, 73, 74, 77, 82, 87, 99, 100, 108, 110, 111, 112, 114, 126, 163 anxiety disorder, 73, 126 anxiolytic, 114 aorta, 70, 177 aortic stenosis, 209 aortic valve, 177 apathy, 40, 79, 80, 112 aphasia, 37 apnea, 109 Apolipoprotein E (APOE), 38, 39, 40, 53 apoptosis, 48 apoptotic, 35 application, 16, 26, 160, 164, 168, 175, 183, 185, 195, 196, 197, 210 apraxia, 37 aripiprazole, 114 Aristotle, 42 arithmetic, 151, 163, 167 arousal, 95, 101, 166 arrest, 90 arrhythmias, 112 arthrogryposis, 153 articulation, 37, 97 Asian, 133 assessment, 45, 56, 67, 72, 78, 98, 100, 124, 129, 150, 159, 170, 185, 193, 196, 197, 198 assets, 187 assignment, 133 associations, 1, 2, 40, 41, 65, 79, 209 assumptions, 148 astrocytes, 112 asymmetry, 70, 96, 98, 103 asymptomatic, 46, 47 ataxia, 77, 107, 108, 111, 112, 113, 115, 116, 117, 118, 119, 121, 180 atopic dermatitis, 59 ATP, 40 atresia, 176 atrial septal defect, 180 atrophy, 38, 47, 56, 88, 90, 112, 118, 123, 125, 181 atropine, 63 attachment, 73 attacks, 80, 97

Index attention, 66, 67, 68, 72, 73, 74, 75, 78, 79, 87, 107, 109, 114, 116, 117, 129, 150, 151, 161, 163, 164, 165, 166, 174, 206 attitudes, 67, 73, 140, 187 attribution, 166 atypical, 26, 38, 47, 74, 93, 96, 101, 114, 131 auditory evoked potentials, 135, 141 auditory hallucinations, 99 Australia, 209 autism, 8, 102, 107, 108, 109, 110, 111, 114, 115, 117, 118, 120, 121, 130, 136, 142, 145, 170, 171 autistic spectrum disorders, 131 autoantibody (ies), 43, 45, 46, 52 autoimmune, 33, 43, 44, 45, 46, 47, 49, 51, 53, 55, 86, 107, 136 autoimmune disease (s), 33, 44, 53 autoimmune disorders, 43, 44, 47, 86 autoimmunity, 34, 40, 43, 44, 45, 54, 55, 57, 58, 86, 177 autonomic, 112 autonomous, 130, 158, 208 autonomy, 100, 124, 130, 184 autopsy, 38, 136 autosomal dominant, 61, 136 autosomal recessive, 13, 14, 24, 136 averaging, 94 avoidance, 74, 113 avoidant, 73 awareness, 95, 162 axons, 182 Aβ, 190

B B cell (s), 51, 55 B lymphocytes, 50, 51 babies, 210 bacterial infection, 33, 48 barrier (s), 113, 187 basal ganglia, 135, 139, 141, 142, 143, 144, 145 basement membrane, 137 batteries, 2 beating, 69 behavior, 65, 67, 68, 73, 74, 75, 79, 82, 88, 90, 100, 104, 114, 115, 118, 120, 123, 143, 144, 148, 150, 151, 159, 160, 161, 162, 163, 164, 165, 166, 167, 169, 191 behavioral aspects, 62 behavioral assessment, 66, 71, 73, 78, 147, 150 behavioral difficulties, 92

215

behavioral disorders, 76 behavioral problems, 87, 88, 89, 90, 107, 113, 114, 149 behaviours, 119, 139, 176 benefits, 76, 114, 115, 176 benign, 26, 27, 46 beta, 20, 38, 39, 40, 48, 52, 53, 54, 55, 58, 59, 61, 113 beta blocker, 113 bias, 91 bilateral, 96, 98, 127, 133, 138, 139, 141, 142, 143, 149, 181, 204 binding, 39, 40, 49, 59, 89, 136, 137, 143 binding globulin, 89 biochemical, 13 biological, 1, 2, 4, 6, 33, 41, 42, 46, 47, 81, 142, 173, 174, 196 biologically, 89 biology, 4, 56, 191 biomarker, 53 biomedical, 186 biopsy, 91, 92, 139 bipolar, 105, 154 birth (s), 34, 35, 37, 41, 42, 47, 48, 69, 94, 96, 111, 124, 148, 173, 174, 175, 178, 179, 180 birth weight, 94, 96, 180 bladder, 112, 178, 179 blood, 38, 44, 45, 50, 56, 60, 113, 114, 138 BMI, 39 bone, 70, 87, 89, 90, 136, 144 bone density, 87 bone resorption, 89 borderline, 10, 36, 74, 109, 140, 147, 151 borderline personality disorder, 74 Boston, 189, 192 bowel, 112 boys, 87, 89, 90, 92, 103, 109, 117, 118, 119, 120, 121, 169 brachycephaly, 175, 179 brachydactyly, 179 brain, 2, 3, 4, 5, 6, 7, 8, 33, 34, 35, 36, 37, 38, 39, 40, 45, 48, 52, 54, 56, 58, 61, 63, 74, 81, 96, 98, 101, 104, 112, 113, 114, 115, 118, 126, 128, 142, 152, 153, 175, 191, 193 brain abnormalities, 52 brain activity, 5 brain damage, 3, 191 brain development, 35, 36, 45, 63 brain functions, 35 brain growth, 7, 101

Index

216 brain lateralization, 96, 104 brain structure, 8 brainstem auditory evoked potentials, 58 Brazil, 75 breakdown, 75 breast, 70, 88, 89, 90, 91 breast cancer, 89, 90 breast carcinoma, 88, 91 brothers, 11, 75, 136, 200 bruxism, 127

C calcification, 141, 144 calcium, 39, 136, 138 California, 107 Canada, 109, 206, 211 canals, 175 Cancer, 56, 57, 58, 92 candidates, 193 candidiasis, 55 capacity, 89, 150, 157, 158, 160, 163, 166, 187 capillary, 45 carcinoma, 88 cardiovascular, 48 caregivers, 183 caretaker, 68 carrier, 107, 116, 119, 121 casein, 52 cataract, 124, 125, 126, 127, 132, 133, 134, 138, 139, 141, 180, 189, 190, 191, 193, 204 cataract extraction, 124 catatonic, 148 catechol, 5 categorization, 166 Caucasian population, 47 CD28, 51 CD3, 48, 49, 51, 54, 55, 59, 61, 139 CD3+, 54 CD4, 49, 51, 53, 62, 139 CD8+, 49, 51, 53 CD95, 49 celiac sprue, 59 cell, 34, 35, 49, 51, 53, 57, 59, 61, 62, 66, 88, 89, 91, 112, 126, 137, 140, 177 cell culture, 36 cell death, 35, 57 cell division, 137 cell growth, 61 cell line (s), 49, 62, 66, 112, 140, 177

central nervous system (CNS), 13, 39, 142, 175, 182 centromere, 21 cerebellum, 34, 36 cerebral amyloid angiopathy, 61 cerebral asymmetry, 96, 105 cerebral cortex, 40 cerebral metabolism, 56 cerebral palsy, 111 cerebrovascular diseases, 91 cerebrum, 34 certainty, 152 certificate, 75 cervical, 42, 176 cervix, 128 channels, 183 chemical, 80 chemotaxis, 48 chemotherapy, 43 childhood, 7, 8, 36, 45, 48, 51, 61, 66, 67, 69, 74, 81, 82, 95, 104, 108, 109, 110, 158, 173, 174, 175, 185, 187, 193 children, 6, 7, 9, 29, 31, 36, 37, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 80, 82, 87, 90, 91, 92, 103, 104, 110, 114, 118, 120, 121, 131, 149, 159, 166, 168, 169, 170, 171, 173, 174, 175, 176, 182, 183, 184, 185, 187, 188, 189, 190, 192, 193, 195, 197, 206, 207, 208, 209, 210 cholecalciferol, 138 cholesterol, 39, 55, 62, 63 choriocarcinoma, 91 chromatid, 31 chromosomal abnormalities, 6, 152, 173, 174 chromosome (s), 6, 20, 21, 22, 24, 26, 27, 30, 33, 34, 36, 38, 39, 40, 42, 44, 48, 49, 52, 53, 54, 58, 60, 61, 66, 67, 80, 82, 83, 86, 87, 92, 93, 94, 96, 101, 103, 105, 122, 133, 136, 138, 140, 143, 147, 148, 149, 152, 153, 154, 155, 169, 173, 174, 175, 178, 179, 180, 188, 189, 190, 191, 193, 205, 209 chronic, 67, 91, 137, 196 chronic myelogenous, 91 chronic renal failure, 137 cigarette smoking, 151 cisterna magna, 149 classes, 31, 40, 68, 203 classical, 10, 125, 136, 141, 145 classification, 11, 27, 30, 56, 57, 152, 171, 186, 187, 210 classified, 24, 68, 206 classroom, 68, 69, 90, 169

Index claustrophobia, 100 cleavage, 62 cleft lip, 148 cleft palate, 102, 148 clients, 182 clinical, 9, 10, 12, 13, 16, 18, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 37, 38, 40, 43, 45, 46, 55, 60, 62, 65, 66, 67, 68, 70, 74, 81, 82, 88, 89, 100, 102, 103, 105, 108, 111, 116, 119, 121, 123, 124, 129, 131, 132, 133, 136, 137, 138, 140, 141, 147, 148, 149, 159, 167, 174, 175, 176, 177, 178, 179, 180, 181, 182, 185, 186, 189, 191, 193, 194, 198, 200 clinical approach, 82 clinical assessment, 74, 131 clinical diagnosis, 13, 16, 21, 24, 25, 45, 129, 191 clinical examination, 70 clinical presentation, 132 clinical symptoms, 46, 124 clinical syndrome, 81 clinical trial (s), 62, 174, 176 clinician (s), 9, 152, 198, 207 clone (s), 26, 42, 43, 135, 140 clonidine, 114 cloning, 49 closure, 98 clothing, 77 clusters, 52 coarctation, 148, 177 codes, 49, 52, 126, 137, 186 coding, 151 coeliac disease, 57 cognition, 1, 2, 6, 37, 95, 114, 164, 165, 166, 168 cognitive, 1, 5, 6, 7, 8, 34, 36, 37, 53, 56, 59, 66, 67, 71, 73, 74, 77, 78, 79, 80, 81, 82, 83, 86, 93, 94, 100, 101, 103, 107, 108, 109, 113, 114, 117, 119, 120, 123, 131, 147, 150, 152, 157, 158, 159, 160, 161, 163, 164, 166, 167, 168, 169, 170, 171, 176, 177, 178, 181, 183, 184, 190, 195, 197, 199, 207 cognitive ability (ies) , 1, 5, 7, 8, 101, 107, 150, 183, 190 cognitive construction, 195, 197 cognitive deficits, 37, 67, 82, 107, 108, 113, 114, 170 cognitive development, 36, 74, 86, 94, 157, 159, 161, 163 cognitive domains, 160 cognitive dysfunction, 157, 159, 161 cognitive function, 56, 83, 117, 120, 159, 160, 168, 170, 207

217

cognitive impairment, 34, 36, 37, 53, 109, 160, 176, 178, 181, 184 cognitive involvement, 183 cognitive level, 166 cognitive performance, 36, 56 cognitive process, 158, 171 cognitive processing, 171 cognitive profile, 167 cognitive research, 159 coherence, 35 cohesion, 31 cohort, 83, 92, 132 collaboration, 6, 54, 185, 188 common findings, 101 common rule, 205 communication, 10, 29, 54, 73, 95, 119, 124, 127, 130, 152, 160, 168, 169, 186, 203, 206, 207 communication skills, 152 community, 29, 152, 184, 186, 200, 202, 205, 209 comorbidity, 95 competence, 42, 131, 162, 166, 168, 182, 195, 196, 208 compilation, 79 complementary, 196, 210 complexity, 9, 184 compliance, 68 complications, 10, 13, 18, 29, 67, 91, 125, 176, 181, 183 components, 3, 95, 96, 110, 150, 186, 196 composition, 33, 119 comprehension, 7, 71, 100, 124, 130, 151, 161, 164, 167, 168 compression, 56, 176 compulsive behavior, 111 computed tomography, 144 computer, 69, 183, 203 concentration, 40, 45, 51, 52, 78, 89, 150, 166 conception, 198 concordance, 19 concrete, 130, 151, 162, 163, 196 confidence, 197 configuration, 166 conflict, 167 confusion, 40, 77 congenital cataract, 123, 124, 132, 133, 180, 192 congruence, 168 connective tissue, 109 connectivity, 2, 40 consanguineous, 69, 138 consanguinity, 13

218

Index

consciousness, 73, 97, 98 consensus, 1, 113, 137 conservation, 160, 163 constipation, 29, 45 constitutional, 81 construction, 162, 185 constructionism, 199 contamination, 127 continuity, 162 control, 35, 38, 49, 51, 56, 62, 73, 77, 95, 96, 110, 138, 150, 151, 162, 163, 167, 168, 183 control group, 49, 95, 167 controlled, 46, 97, 103, 111, 115 controlled trials, 115 convex, 138 conviction, 79 coordination, 86, 88, 90, 174 Copenhagen, 189, 191, 193 copy number variations, (CNV), 26, 27 correlation (s), 2, 7, 4, 34, 47, 53, 96, 121, 132, 136, 169, 181 cortex, 35, 40, 48, 102, 175 cortical, 40, 63, 136, 151, 193 cortisol, 110, 118 costs, 184 counseling, 114, 120, 123, 129 couples, 91 coverage, 6 craniofacial, 98, 141 creatinine, 89, 138, 139, 141 crime (s), 99, 101, 103 criminal acts, 95 criminality, 91 criminals, 95 critical analysis, 148 critical period, 182 critical thinking, 157, 159 criticism, 73 crying, 138 cryopreservation, 91 cryopreserved, 91 cryptorchidism, 88, 89, 148, 178, 179, 180 crystallization, 161, 162, 165 CT scan, 135, 139, 142 cues, 160, 166 cultural, 16, 29, 151, 158, 159, 175, 196, 202 culture, 137 curing, 207 cycles, 76 cyst, 70

cytogenetic (s), 10, 13, 16, 20, 21, 22, 23, 24, 26, 30, 57, 80, 82, 89, 137, 152, 190 cytokine, 33, 40, 52, 53 cytoplasm, 49, 126 cytoskeleton, 40 cytotoxic, 43, 49, 50 cytotoxicity, 51, 139

D daily living, 183, 197 danger, 208 data collection, 186 data gathering, 160 database, 15, 207 de novo, 8, 26, 140, 143, 180, 190 deafness, 135, 136, 137, 140, 141, 143, 144, 145 death, 39, 42, 57, 136 decay, 129 deciduous, 125 decisions, 114 decoding, 161, 162, 164, 165, 166, 167 deduction, 162, 166 deductive reasoning, 71, 72, 73, 162 defects, 12, 13, 24, 27, 28, 41, 49, 51, 57, 88, 120, 136, 140, 176, 177, 178 defensiveness, 110 deficiency, 10, 13, 56, 58, 61, 66, 85, 86, 89, 90, 96, 108, 120, 136, 142, 157, 158, 159, 160 deficit (s), 13, 36, 37, 62, 66, 67, 77, 78, 79, 87, 96, 101, 102, 105, 107, 110, 112, 114, 116, 117, 121, 130, 151, 163, 164, 165, 166, 167, 168, 171, 177, 182, 183 definition, 1, 10, 16, 136, 150, 160, 168, 174, 182, 185, 202, 210 degree, 36, 89, 90, 104, 124, 127, 166, 177, 180, 181 delays, 168, 177, 183 delivery, 75, 96, 205 delusion (s), 77, 99, 100, 101, 148, 150 demand, 184 dementia, 37, 39, 40, 48, 52, 56, 60, 61, 63, 80, 111, 112, 115, 152, 164, 167, 176, 190, 192 Denmark, 92 densitometry, 90 density, 34, 52, 90, 175 dental abscess, 132 dentate gyrus, 34 dentistry, 192 deposition, 38, 39, 58, 190 depressed, 127

Index depression, 68, 80, 87, 104, 108, 112, 113, 163, 175 depressive symptoms, 76, 211 deprivation, 158 desire, 90 detachment, 125 detection, 16, 19, 23, 24, 25, 26, 31, 133, 190 deterministic, 196 developmental change, 175, 182 developmental delay, 29, 31, 89, 94, 109, 124, 144, 178 developmental disabilities, 31 developmental disorder, 1, 66, 82, 95, 121, 168, 171, 184 developmental dyslexia, 7 developmental process, 188 developmental psychopathology, 211 deviation, 26, 70, 97, 186 diabetes, 44, 47, 57, 80, 91, 126, 149 diabetes mellitus, 47, 91, 149 diagnostic, 9, 10, 12, 16, 18, 20, 21, 24, 27, 29, 47, 66, 71, 77, 78, 112, 147, 150, 175, 181, 192 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 37, 54, 73, 99, 100, 104, 129, 150, 152, 153 diagnostic criteria, 112 diet, 47 dietary, 56 differential approach, 7 differential diagnosis, 15, 18, 124 differentiation, 34, 42, 74, 81, 96, 101, 137, 142 diffusion, 92 digestive process, 47 digestive tract, 42 disability, 9, 10, 11, 13, 16, 22, 23, 24, 25, 26, 28, 29, 33, 36, 42, 67, 75, 98, 107, 123, 131, 141, 148, 149, 157, 159, 161, 163, 164, 165, 173, 174, 181, 185, 186, 187, 193, 195, 196, 197, 198, 199, 200, 202, 205, 209, 210 disabled, 196, 205, 210 discomfort, 126 Discover, 161, 162, 165, 166 discrimination, 71, 72, 73, 78, 82, 100, 159, 162 diseases, 23, 28, 29, 44, 57, 80, 91, 141, 174, 175, 181, 185, 206 disinhibition, 77 dislocation, 56, 109, 176 disorder, 3, 31, 33, 34, 35, 46, 56, 60, 65, 70, 74, 79, 81, 86, 87, 93, 96, 99, 105, 111, 113, 114, 117, 119, 124, 136, 147, 150, 151, 152, 163, 173, 174, 176, 180, 206

219

disposition, 158 disruptive behaviours, 175 dissociation, 1 distal, 66, 134, 136, 140, 144, 147, 159, 179, 180, 190, 194 distress, 99, 179, 180 distribution, 59, 62, 85, 86, 87, 96 divergent thinking, 162 division, 151, 175 dizygotic, 4 dizziness, 127 DNA, 7, 13, 21, 26, 33, 49, 52, 58, 122, 137, 143, 152, 154, 174, 188 DNA sequencing, 52 doctor, 206 dominance, 96, 102 dosage, 36, 60, 61, 90, 189 Down syndrome, 20, 34, 43, 48, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 168, 169, 170, 188, 189, 190, 191, 192, 193, 203 downsized, 185 draft, 210 drainage, 109 Drawing Family Test (DFT), 73 Drosophila, 30, 120 drowsiness, 76 drug treatment, 97 drugs, 97, 142, 184 dry, 45 ductus arteriosus, 179 duplication, 38, 61, 191 duration, 48, 60, 97 dusts, 203 duties, 80 dyscalculia, 81 dysfunctional, 182 dysgraphia, 98 dyslexia, 5, 6, 87, 98, 164 dysplasia, 136, 137, 141, 143, 144, 145, 151 dysregulation, 33, 36, 48, 53, 95, 108, 112, 175

E ears, 109, 125, 127, 138, 149, 175, 179, 180 eating, 127, 151, 183 echolalia, 167 economy, 185 Eden, 143 education, 67, 75, 87, 124, 183, 186, 188, 192 efficacy, 72, 207

220

Index

ego, 129, 148 EKG, 139 elaboration, 160 elderly, 38, 42 elective surgery, 113 electroencephalogram, 77, 94 Electroencephalography (EEG), 35, 56, 70, 98, 120, 128 Electromyographic (EMG), 128, 149 electronic, 204 elementary school, 43, 201 embryo, 92 embryonic, 142 embryonic development, 126, 135, 137 emerging issues, 115 emotion (s), 11, 77, 103, 127, 166, 167, 171 emotional, 72, 73, 74, 77, 79, 92, 107, 129, 161, 162, 164, 165, 166, 167, 176, 183, 199, 206 emotional distress, 72 emotional state, 73, 77 employees, 205 empowerment, 185 encoding, 31, 54, 162, 167 endocrine, 41, 42, 70, 80, 89, 91, 108 endocrinological, 70 endurance, 85, 86 engagement, 51, 205 England, 191, 209 Enhancement, 158, 170 enlargement, 70, 71, 77, 87, 91, 129 entrapment, 149 entrepreneurs, 200 environment, 5, 33, 35, 73, 129, 150, 158, 183, 186, 187, 202 environmental, 4, 6, 9, 10, 47, 95, 111, 173, 174, 184, 187, 188, 196, 197, 198 environmental factors, 111, 173, 174, 187, 197 environmental impact, 187 environmental influences, 4, 6, 188 environmental resources, 184 epidemiological, 10, 191 epidemiology, 57, 81 epigenetic, 26 epilepsy, 29, 40, 48, 80, 93, 94, 96, 101, 102, 103, 104, 105, 206, 209 epileptic seizures, 97, 207 epiphysis, 70 episodic, 160 epithelial cell, 59, 133 epithelium, 49, 126

equilibrium, 73, 199 equipment, 183, 184 erectile dysfunction, 89 esophageal, 29 esophagus, 42 ester, 51 estradiol, 88, 90 estrogen (s), 70, 75, 80, 83, 86, 91, 190 ethical, 55, 205, 209 ethics, 7, 211 etiology, 40, 67, 111, 152, 157, 159, 163, 190, 193 etiopathogenesis, 58 Ets, 42 eukaryotes, 137 euphoria, 80 Euro, 203 European, 209 event-related potential (ERP), 35, 82 evidence, 6, 7, 13, 35, 37, 47, 95, 96, 101, 105, 111, 137, 152, 157, 160, 163, 206, 207, 211 evoked potential, 77, 129, 139 evolution, 10, 11, 13, 16, 27, 102, 105, 126 examinations, 98, 149 excitement, 110 exclusion, 47 execution, 78, 98, 130, 186 executive function (s), 37, 66, 67, 79, 112, 147, 150, 163, 164, 166 executive functioning, 37, 166 exercise, 37 expertise, 185, 201 experts, 19, 211 exposure, 80, 158, 159, 160 extracellular, 38 extraction, 91 eye (s), 98, 109, 110, 111, 136, 149, 179 eye contact, 109, 110, 111 eyeball, 181

F face recognition, 82 facial asymmetry, 138, 179, 180 facial expression, 58, 79, 167 facies, 148, 179 failure, 47, 66, 70, 72, 80, 85, 86, 102, 185 false belief, 150 familial, 4, 39, 49, 141, 143, 147, 154, 180, 189, 190, 193

Index family, 4, 5, 6, 13, 22, 25, 29, 53, 72, 75, 76, 77, 80, 107, 114, 118, 124, 125, 126, 127, 132, 133, 137, 142, 144, 150, 153, 174, 176, 183, 184, 185, 188, 189, 190, 197, 199, 200, 202, 203, 204, 205, 207, 210 family environment, 5 family history, 124, 127 family life, 210 family members, 75, 114, 207 Fas, 49 fat, 87 fatigue, 68, 75, 89, 127 FDA, 114 fear (s), 68, 73, 79, 100, 126 febrile seizure, 96 feedback inhibition, 85, 86 feeding, 29, 69 feelings, 73, 100, 127, 162 feet, 14, 24, 102, 109, 177 females, 74, 81, 82, 87, 107, 108, 110, 111, 112, 115, 116, 118, 121, 163, 169, 170, 181, 189 fertilization, 87, 91 fetal, 35, 55 fetus (es), 13, 34, 57, 188 fever, 203 fibroblast (s), 112, 126 fibromyalgia, 107, 108, 113 fibrosis, 85, 86 finance, 205 flexibility, 151, 162 fluorescence, 26, 154 fluorescence in situ hybridization (FISH), 21, 22, 23, 26, 30, 31, 140, 154 focus groups, 120 focusing, 93, 175 follicles, 126 follicle-stimulating hormone (FSH), 85, 86, 89, 90, 101 food, 68 forgetfulness, 40 forgetting, 77 Fox, 7 fragile X syndrome (FXS), 30, 54, 107, 108, 109, 110, 111, 114, 115, 116, 118, 119, 120, 121, 163, 166, 168, 169, 170 fragility, 122 fragmentation, 79 France, 206, 208 freedom, 208 friendship, 205

221

frontal cortex, 35 frontal lobes, 34 function values, 46 functional MRI (fMRI), 98, 104 funding, 184 fungal, 31 fungi, 137 fusion, 42

G gait, 180, 184 gamete (s) , 125, 173, 174, 180 gametogenesis, 85, 86 ganglia, 142 gastrointestinal, 176 gel, 90 gender effects, 58 gender identity, 67, 74 gene (s), 5, 6, 7, 10, 13, 16, 20, 22, 24, 25, 26, 27, 28, 31, 33, 38, 39, 40, 42, 44, 46, 49, 52, 53, 54, 55, 58, 59, 60, 61, 66, 74, 79, 80, 81, 85, 87, 92, 95, 96, 101, 102, 105, 108, 111, 113, 116, 121, 123, 125, 126, 129, 132, 133, 134, 135, 136, 137, 139, 140, 141, 144, 152, 154, 173, 174, 175, 180, 188, 189, 191, 193 gene expression, 81, 102, 137, 188 general intelligence, 4, 5 generalization, 97, 162 generation, 13, 51, 98, 116 generators, 162, 167 genetic (s), 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 18, 20, 22, 23, 24, 25, 27, 28, 29, 30, 31, 33, 34, 46, 47, 55, 57, 59, 60, 61, 62, 65, 67, 68, 74, 79, 80, 81, 82, 86, 92, 94, 95, 96, 103, 111, 113, 114, 116, 120, 121, 125, 136, 152, 153, 154, 157, 158, 161, 163, 164, 166, 167, 168, 170, 173, 174, 175, 176, 178, 182, 183, 184, 188, 195, 197, 206, 211 genetic abnormalities, 5, 67, 79 genetic counselling, 11, 57 genetic defect, 20, 27, 154 genetic disease, 174, 184 genetic disorders, 30, 157, 163, 173, 174, 175, 183, 184, 188 genetic factors, 7, 111 genetic syndromes, 5, 157, 158, 161, 163, 164, 166, 167, 168, 195, 197 Geneva, 194 genome, 6, 26, 59 genomic (s), 7, 25, 30, 188

Index

222

genotype (s), 7, 34, 39, 53, 62, 101, 102, 103 Germ cell (s), 89, 90 germ cell tumors, 88, 91 gestation, 34, 96, 138 gestational age, 34, 190 gestures, 208 gingival, 128 girls, 67, 75, 82, 109, 188, 192 gland, 40, 44, 48 glaucoma, 102, 181 glutamate, 113 glutathione, 55, 110 goal setting, 184 goal-directed behavior, 150 goals, 2, 157, 159, 160, 205 going to school, 68 gonadal dysgenesis, 75 gonadotropin, 85, 86, 89, 90 gonads, 177 graduate education, 92 grammatical development, 168 grants, 115 granulopoiesis, 43 gray matter, 38 grouping, 152 groups, 24, 39, 45, 46, 50, 51, 56, 81, 162, 166, 168, 174, 185, 200, 204 growth, 8, 12, 13, 16, 18, 19, 22, 23, 24, 29, 45, 48, 54, 61, 62, 63, 66, 90, 113, 136, 177, 180, 187, 189, 192, 193 growth hormone, 54, 66, 177, 189, 192 growth spurt, 66 guidance, 90 guidelines, 67, 116, 120, 176, 185, 200 guilt, 76, 77, 79, 99 gynecomastia, 85, 86, 87, 88, 89, 90 gyrus, 34, 35

H habituation, 110 hair loss, 45 hallucinations, 75, 79, 101, 148 haloperidol, 76 handedness, 102, 104 handicapped, 144, 153 hands, 14, 24, 102, 109, 111, 149, 175, 177, 180, 181, 208 haploinsufficiency, 137, 142, 152 haplotype analysis, 124, 129

harbour, 6 harm, 79, 100 harmful, 202 head, 13, 14, 42, 87, 94, 96, 98, 149, 153, 180, 205, 206, 209 health, 45, 67, 72, 75, 77, 81, 174, 182, 184, 185, 186, 187, 188, 200, 204 Health and Human Services, 115 health care, 184, 188 health problems, 72 health services, 174 health status, 45, 187 healthcare, 174, 175, 182, 184, 185, 187 hearing, 35, 109, 140, 177, 183 hearing impairment, 183 hearing loss, 140 heart, 41, 57, 69, 88, 112, 136, 140, 149, 176, 178 heart disease, 41, 149 heat, 112, 208 heat shock protein, 112 height, 13, 34, 45, 46, 47, 61, 66, 70, 77, 80, 87, 94, 98, 163, 192 hematological, 41 hematomas, 127 hematopoietic, 42 hemisphere, 35, 102, 104 hepatitis, 51, 54, 58 hepatitis B, 51, 54, 58 heritability, 5 hernia, 109, 209 heterodimer, 47 heterogeneity, 9, 27, 133, 166, 208 heterogeneous, 38, 68, 136 heterozygotes, 124, 180 high resolution, 140 high risk, 42, 45, 114 high school, 200, 201, 204, 209 high-level, 150 high-risk populations, 121 hippocampal, 35, 37, 57, 113, 119 hippocampus, 34, 36, 112 hips, 70 hirsutism, 24 HLA, 44, 47, 49 holistic approach, 174 Holland, 40, 60 homeostasis, 39, 136 homes, 152 homework, 69, 201, 203 homicide, 99, 101, 103

Index homocysteine, 141 homogeneous, 70 homolog, 30, 31 hormone (s), 46, 48, 66, 75, 85, 86, 89, 101, 105, 110, 136, 144, 177, 192 horse, 208 hospital care, 184 hospitalization, 75, 76, 77, 78, 79, 80 hospitalized, 75, 80, 138, 211 hospitals, 185 hostility, 100 household, 76, 201, 203, 208 human (s), 1, 8, 22, 30, 33, 34, 38, 39, 40, 42, 51, 53, 54, 58, 59, 60, 61, 73, 89, 102, 105, 114, 115, 126, 132, 144, 145, 147, 148, 154, 155, 158, 187, 189, 202 human brain, 102, 105, 126, 155 human cerebral cortex, 102 human chorionic gonadotropin, 89 human cognition, 1 human genome, 147 humane, 26 humoral immunity, 51 husband, 75, 76, 77 hybridization, 21, 140 hydronephrosis, 137, 178 hydroxyl, 89 hygiene, 77 hyperactivity, 76, 79, 95, 109, 110, 117, 151, 165, 166, 175 hyperarousal, 110, 114 hypercholesterolemia, 61 hyperconvex, 177 hyperphosphorylated tau protein, 40 hyperplasia, 90, 91 hypersomnia, 40 hypertelorism, 88, 148, 179, 180 hypertension, 48, 112, 113, 149 hyperthyroidism, 46 hypertrophy, 39, 47 Hypochondriasis, 72 hypogonadal, 87 hypogonadism, 81, 85, 86, 88, 89, 90, 91, 178 hypomagnesemia, 136 hypoparathyroidism, v, 91, 135, 136, 137, 140, 141, 143, 144, 145 hypoplasia, 135, 136, 137, 139, 141, 179 hypospadias, 89 hypothalamic, 46, 60, 86

223

hypothesis, 16, 19, 48, 49, 67, 93, 95, 101, 125, 142, 160, 168, 178 hypothyroidism, 43, 44, 45, 46, 48, 58, 60, 62, 91, 107, 108, 113, 153 hypotonia, 88, 90, 109, 135, 138, 175, 178

I identification, 7, 90, 114, 116, 121, 123, 129, 152, 162, 186, 200, 210 identity, 72, 73, 74 idiopathic, 30, 96, 121, 136, 144, 145 IFN, 51, 52, 53, 54 IGF-I, 48 IgG, 51, 52, 139 IL-2, 51 imaging, 58, 116 imbalances, 25, 31 immune function, 45, 49 immune response, 48, 51, 61 immune system, 33, 45, 48, 49, 56, 101, 104 immunity, 33, 48, 52, 53, 57, 59, 60 immunodeficiency, 49, 51, 93, 98, 99, 101, 136 immunoglobulin, 51, 55 immunological, 34, 42, 142 immunology, 59 immunoreactivity, 39 impairments, 90, 95, 130, 151, 159, 165, 167, 200, 201 imperforate anus, 148 implementation, 157, 158 impotence, 73, 91 imprinting, 27, 67 impulsive, 79, 101, 151, 159, 160 impulsiveness, 95, 150 impulsivity, 110, 150, 151, 153, 162, 163, 167 in situ, 21, 66 in situ hybridization, 21 in utero, 66 in vitro, 39, 49, 51, 122, 139 in vivo, 7, 39, 55, 62, 104 inactivation, 87, 181 inattention, 166 incidence, 39, 42, 43, 46, 85, 86, 92, 94, 108, 124, 174, 175, 177, 178, 180 incisor, 124, 181 inclusion, 23, 115, 117, 162 incongruity, 166 independence, 75, 92 Indian, 133

224

Index

indication, 10, 23, 42, 92, 102 indicators, 5, 187 individual differences, 2 inducible protein, 53 induction, 137, 162 ineffectiveness, 49 infancy, 35, 36, 50, 75, 88, 89, 98, 101, 131, 190 infants, 9, 35, 42, 57, 58, 87, 91, 114, 183, 189 infection (s), 29, 48, 51, 53, 58, 176, 206 infectious diseases, 43 inferences, 170 infertile, 88, 91 infertility, 85, 86, 88, 89, 90, 91, 177, 178 inflammation, 105 inflammatory, 42 influenza, 53 informed consent, 149 inguinal hernia, 138 inheritance, 23, 39 inherited, 26, 38, 41, 46, 189 inhibition, 35, 71, 72, 166 inhibitor (s), 111, 115, 176 inhibitory, 58, 61, 166 injections, 90 injury, 39 inmates, 58 insecurity, 68, 73 insertion, 189, 193 insight, 54, 143, 162 insomnia, 40 instability, 40, 42, 108, 112, 116, 122, 129, 188, 189, 191, 192 instruments, 66, 71, 78, 123, 130, 147, 149, 150, 157, 161, 163, 166, 167, 168, 185, 198 insulin, 47, 126, 149 insults, 9, 79, 95 integration, 60, 162, 184, 204 integrin (s), 48, 49, 58, 61 integrity, 2 intellectual disabilities, 210, 211 intellectual functioning, 10, 71, 73, 157, 163 intelligence, 1, 2, 4, 5, 6, 7, 8, 10, 85, 86, 87, 91, 93, 94, 95, 101, 150, 159, 166, 202 intelligence quotient, 10, 86 intensity, 26, 167 intentionality, 162 interaction (s), 33, 35, 55, 67, 71, 74, 77, 79, 105, 119, 127, 129, 137, 159, 160, 169, 202 intercellular adhesion molecule (ICAM), 49, 59 interdisciplinary, 182, 186

interface, 104 interferon, 33, 52, 53, 56, 58, 61 interleukin, 57 internalization, 113, 120 international, 75 internet, 16 interneuron, 144 internship, 205 interpersonal contact, 79 interpersonal interactions, 186 interpersonal relationships, 75, 205 interpretation, 25, 199 interrogations, 68 interstitial, 26, 138, 140, 141, 147, 148, 149, 153, 154, 178, 180, 190, 191 interval, 125, 129, 139 intervention, 59, 114, 116, 121, 147, 153, 157, 158, 159, 160, 174, 176, 182, 185, 210 interview (s), 79, 99, 100, 127, 202, 203 intestinal villi, 47 intestine, 47 intracytoplasmic sperm injection (ICSI), 86, 91, 92 intrinsic motivation, 162, 167 introversion, 129 invertebrates, 137, 144 IQ scores, 152, 167 iris, 175 irritability, 40, 76, 112 irritable colon, 68 isoforms, 126 isolation, 36, 98, 99, 124, 130, 142 Israel, 121 Italy, 9, 33, 65, 85, 93, 123, 135, 147, 157, 173, 195, 205, 208

J Japan, 195 job training, 204 jobs, 149 joints, 14, 88, 109 judgment, 162 Jung, 5, 7 junior high school, 204

K karyotype (s), 16, 20, 21, 26, 70, 75, 85, 86, 87, 89, 92, 94, 96, 101, 103, 105, 175, 177, 178, 192

Index karyotyping, 30, 89 keratin, 52 kidney, 135, 137, 139, 177, 209 killing, 100 kindergarten, 201, 208 King, 83 Kirchhoff, 30 knockout, 113 kyphosis, 179

L labeling, 81 lactoglobulin, 52 lamination, 175 language, 3, 35, 36, 37, 71, 86, 87, 88, 89, 90, 93, 95, 96, 98, 102, 103, 104, 109, 110, 114, 120, 127, 129, 130, 135, 138, 139, 140, 150, 151, 152, 164, 167, 168, 169, 170, 178, 181, 183, 186, 188, 190, 208 language acquisition, 87 language delay, 37, 89, 168, 183 language development, 93, 96, 103, 138, 167, 188 language impairment, 36, 37, 89, 139, 164, 167, 170 language skills, 36, 89, 95, 167 late-onset, 39 later life, 48 laterality, 98 laughing, 80 law, 205 LDL, 39 lead, 75, 89, 101, 107, 108, 109, 112, 113, 114, 131, 137, 142, 147, 153, 160, 207 learners, 158, 160, 162, 167 learning, 1, 35, 36, 45, 66, 67, 68, 69, 75, 87, 89, 95, 98, 107, 114, 149, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 178, 180, 186, 192, 201, 202 learning difficulties, 45, 66, 75 learning disabilities, 68, 69, 87, 89, 95, 107, 157, 163, 164, 165, 167, 178 learning process, 161, 163, 164, 192 lectin, 51 left hemisphere, 96, 102 left-handed, 93, 102, 104 left-handers, 102 lens, 126, 181 lesions, 48, 125, 181 leukaemia, 42, 43, 58, 60, 61, 176 leukemia (s), 42, 43, 48, 57, 63, 91 leukemic, 42, 43

225

leukocyte, 58, 61 Leydig cells, 90 libido, 85, 86, 89, 94 life expectancy, 55, 173, 176 life span, 123, 126, 168, 174, 175, 188 life stressors, 80 lifespan, 40, 41, 83 lifestyle, 187 lifetime, 44 likelihood, 6, 45, 167 limbic system, 108, 112 limitation (s), 10, 157, 158, 160, 186, 198 linear, 196, 210 linguistic, 75, 131, 168, 208 linkage, 6, 7, 40, 57, 125, 132, 133, 152, 154, 181, 189, 193 lipid, 40, 62 lipoprotein, 39 literature, 1, 4, 15, 52, 58, 60, 62, 65, 79, 93, 101, 124, 131, 147, 149, 152, 153, 178, 190, 191, 193, 197, 206 lithium, 113, 114 localization, 103, 126, 133, 154, 193 location, 53, 55, 79 locus, 7, 20, 26, 38, 61, 83, 125, 129, 132, 133, 144, 152, 154, 159, 176, 180, 189, 193 London, 105, 191, 193 loneliness, 77 longevity, 67 longitudinal study, 58 long term depression (LTD), 113 long-term, 37, 40, 67, 192 losses, 137 love, 206 low birthweight, 88 luteinizing hormone, 89, 101 lymph node, 51 lymphatic, 42, 177 lymphocyte (s), 48, 49, 50, 51, 53, 56, 59, 62, 96, 140 lymphocyte function associated antigen (LFA), 48, 49, 53, 59, 62 lymphoid, 62 lymphoma, 55

M macrophage, 53 magazines, 69, 208

226

Index

magnetic resonance imaging (MRI), 35, 37, 57, 60, 66, 70, 71, 77, 93, 98, 112, 123, 129, 135, 139, 144 maintenance, 182 malabsorption, 47 maladaptive, 126, 151, 169 male infertility, 194 males, 85, 86, 87, 89, 90, 91, 94, 95, 103, 105, 107, 108, 110, 111, 112, 115, 116, 117, 118, 120, 121, 169, 171, 178, 180, 192 malnutrition, 47 mammals, 142 management, 67, 81, 104, 176, 177, 183, 184, 188, 189, 192 mandible, 25, 177 mania, 151 manic, 104 manipulation, 73, 163 manufacturing, 205 mapping, 60, 125, 148, 153 Marfan syndrome, 20 masculinity, 74 maternal, 20, 25, 66, 73, 86, 124, 129, 148, 175, 177, 178, 193 maternal age, 86, 175, 177, 178, 193 mathematics, 163 Matrices, 66, 71, 72, 78, 100, 105, 123, 130, 133, 150, 151 maturation, 46, 49, 51, 63, 193 maxilla, 177 meanings, 196, 200, 209, 210 measurement, 5, 14, 43, 60, 174, 185 measures, 37, 148, 150, 185, 186 mechanical, 126 media, 109 median, 50, 51, 149 mediated learning experience (MLE), 159 medical care, 67, 198 medication (s), 76, 105, 110, 113, 114, 204 medicine, 195, 196 megakaryoblastic leukemia, 42 meiosis, 86, 175 meiotic nondisjunction, 86 membranes, 59 memory, 6, 35, 37, 49, 58, 130, 150, 163, 168, 169, 170, 200 men, 89, 91, 92, 95, 101, 102, 103, 105, 112, 119, 166, 171 menopause, 39 mental age, 37

mental capacity, 86 mental development, 10, 19, 20, 173, 174, 178 mental disorder, 148, 200 mental health, 105 mental illness, 151, 211 mental impairment, 7, 181 mental representation, 2 mental retardation, 29, 30, 31, 34, 35, 36, 38, 53, 54, 57, 61, 86, 88, 91, 94, 102, 107, 108, 113, 115, 117, 119, 120, 124, 130, 132, 135, 136, 140, 141, 145, 151, 152, 153, 169, 179, 180, 181, 190 messages, 111, 207, 210 messenger RNA (mRNA), 108, 113, 119, 121 meta-analysis, 4, 7 metabolic, 13, 19, 42, 48, 56, 189 metabolic syndrome, 48, 56 metabolism, 35, 39, 47, 62, 82 metabolite, 35 metatarsal, 177 methylation, 27 mGluR, 115 mice, 42, 51, 52, 53, 61, 116, 117, 126 microcephaly, 6, 7, 16, 175, 178, 180, 209 microwave, 208 midbrain, 142 middle cerebellar peduncles (MCP), 112 milk, 52, 69 mineralization, 142, 143 Minnesota, 71, 99, 104 minority, 24, 36, 91, 112 miscarriages, 154 mitochondria, 174 mitochondrial, 141, 173, 174 mitogenic, 139 mitotic nondisjunction, 87 mitral, 89 mitral valve prolapse, 89 mobility, 183, 186 modalities modality (ies), 159, 160, 165 models, 2, 6, 8, 80, 104 modernism, 199 modifier gene, 36 modulation, 53, 85, 87 modules, 2, 3 molecular cytogenetics, 31 molecular mechanisms, 35 molecules, 47, 52 money, 203

Index monosomy, 20, 67, 81, 136, 144, 148, 153, 154, 179, 180, 188, 190, 192, 193 monotherapy, 97 monotone, 129 mood, 40, 90, 95, 100, 108, 112, 114, 116, 127, 150, 180 mood disorder, 100 mood swings, 180 morbidity, 47, 67, 167 morning, 68, 208 morphogenesis, 155 morphological, 206 morphology, 36, 187 mortality, 41, 48, 86, 91, 92 mortality rate, 86, 91 mortality risk, 41 mosaic, 43, 66, 87, 91, 94, 175, 177 mothers, 210 motion, 183 motivation, 11, 129, 160, 166 motor activity, 142 motor coordination, 78, 151, 167 motor function, 103, 163 motor skills, 90, 150 motor task, 163 mouse, 33, 51, 54, 56, 57, 58, 60, 61, 81, 110, 113, 115, 119, 122, 189 mouse model, 54, 57, 61, 119, 122, 189 mouth, 97, 148, 179 movement, 137, 179, 180, 183, 184 movement disorders, 180 MTHFR, 139, 141 multidisciplinary, 41, 67, 81, 90, 184, 185 multiplication, 151, 166 murder, 100 muscle (s), 85, 86, 90, 179 music, 184, 203, 208 mutation (s), 6, 8, 20, 24, 26, 27, 28, 29, 30, 31, 37, 42, 46, 49, 56, 107, 108, 109, 110, 114, 116, 117, 118, 123, 124, 125, 126, 129, 132, 133, 136, 137, 173, 174, 180 myelin basic protein (MBP), 112 myelination, 35, 37, 58 myelinization, 35 myeloid, 43

N Nance-Horan Syndrome (NHS), 123, 124, 125, 126, 129, 132, 133, 180, 193

227

narratives, 195, 196, 197, 198, 199, 207, 210, 211 national, 186 National Education Association, 169 natural, 13, 27, 29, 30, 52, 176, 187, 196 neck, 15, 66, 88, 148, 153, 177, 179, 180 negative affectivity, 68 negative attitudes, 149 negative body image, 67 negative consequences, 45 negative reinforcement, 68 neglect, 77 neocortex, 190 neonatal, 13, 27, 46, 62, 127 neonate, 153, 154 neonates, 44, 46 neoplasia, 91 neoplasms, 42 nephrosis, 136, 143 nephrotic syndrome, 137 nerve, 35, 136, 137, 143, 149 nervous system, 104, 105, 182 Netherlands, 132, 189 network, 39, 59, 185 neural development, 74 neural function, 35 neuritic plaques, 38 neurobehavioral, 169 neurobiological, 108, 113, 202 neurobiology, 63, 107, 117 neurodegeneration, 34, 48, 52, 117 neurofibrillary tangles (NFT), 38 Neurofibromatosis, 20 neurogenesis, 35, 36 neurogenic, 128 neuroimaging, 7, 119 neuroinflammation, 104 neurological disease, 13 neurological disorder, 152 neurologist, 138, 183 neuromotor, 101, 178 neuronal loss, 38 neurons, 34, 40, 108, 112, 113, 136, 142, 144, 175 neuropathic pain, 113 neuropathological, 35, 38, 40, 52, 63 neuropathology, 34, 39, 58 neuropathy, 107, 108, 112, 113 neuroprotective agents, 113 neuropsychiatric disorders, 96 neuropsychological assessment, 133 neuropsychology, 1, 2, 6, 61

Index

228

neuroscience, 190 neurosurgery, 42 neurotoxicity, 112 neurotransmitters, 63 neutropenia, 24 neutrophils, 48 New England, 83 New Jersey, 105 New York, 7, 8, 29, 59, 61, 63, 104, 133, 134, 154, 189, 190, 191, 211 Newton, 31, 57 Nielsen, 80, 82, 86, 92, 95, 105 Nixon, 58 NK cells, 50 nondisjunction, 85, 86, 175 non-Hodgkin lymphoma, 91 nonsense mutation, 61, 123, 129, 137 nonverbal, 37, 67, 72, 75, 130, 151, 163, 168 nonverbal communication, 130 normal, 2, 4, 5, 12, 26, 27, 31, 34, 35, 38, 40, 42, 44, 46, 48, 49, 51, 52, 61, 63, 66, 67, 69, 70, 71, 75, 76, 77, 78, 79, 80, 85, 87, 88, 89, 90, 92, 93, 94, 96, 98, 99, 100, 101, 104, 107, 108, 109, 111, 127, 129, 131, 139, 140, 141, 142, 148, 151, 163, 185, 187, 206 North America, 60 Norway, 206 N-terminal, 126 Nuclear Magnetic Risonance (NMR), 149 nuclei, 135, 139, 142, 144 nucleus, 49, 112 nursery school, 69 nursing, 80, 211 nutrients, 47 nystagmus, 109, 127, 149, 180

O obesity, 27, 47, 75, 111 observations, 27, 39, 43, 51, 79, 192 obsessive-compulsive, 67, 129 obstruction, 178, 179 occipital lobe, 34 occupational, 37, 114, 181, 182, 183, 188 occupational therapists, 182, 183 occupational therapy, 114 oedema, 177 oestrogen, 66 offenders, 105 old age, 4, 5, 7

oligospermia, 85, 86 Oncology, 61, 63 operator, 98 ophthalmic, 204 optimal health, 185 optimism, 162, 209 oral, 179 organ, 12, 186 organic, 35, 80, 142, 148, 159 organism, 158, 173, 174 organization (s), 7, 71, 72, 100, 102, 130, 151, 160, 162, 185 orientation, 160, 161, 162, 163, 165 orthopaedic, 29 orthostatic hypotension, 112 oscillations, 200 osteocalcin, 89 osteoporosis, 85, 86, 89, 90, 91 otitis media, 109, 118 outpatient, 184 ovarian, 66, 107, 108, 113 ovarian failure, 66, 113 ovary (ies) , 66, 67, 70 overweight, 45, 47 ovum, 91 oxidative stress, 39, 108, 110, 113, 117

P pacemaker, 112 pain, 76, 113 palpebral, 12, 70, 138, 148, 175, 179 panic disorder, 152 paper, 8, 9, 113, 115, 126, 160 parathyroid glands, 137 parathyroid hormone, 136, 139, 142 parenchyma, 38 parenting, 196 parents, 10, 11, 13, 26, 31, 68, 69, 76, 80, 89, 100, 126, 138, 140, 142, 176, 197, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 211 paresis, 179 parietal lobes, 35 Paris, 83, 192 parkinsonism, 118 parotid, 52, 55 partnerships, 87 passive, 74, 88 pasta, 203 patent ductus arteriosus, 88, 148

Index paternal, 20, 27, 66, 86, 87 paternity, 89, 91 pathogenesis, 46, 175, 180 pathologists, 182 pathology, 43, 47, 61, 77 pathophysiological, 93, 101 pathophysiology, 136, 152 pathways, 11, 53, 75, 113, 131, 135, 141, 182 patient-centered, 198 patients, 3, 9, 10, 13, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 52, 54, 55, 59, 60, 65, 66, 67, 80, 81, 85, 86, 87, 88, 89, 90, 91, 94, 95, 98, 101, 102, 109, 124, 125, 126, 131, 132, 136, 137, 138, 140, 141, 142, 144, 152, 167, 170, 174, 175, 176, 177, 178, 180, 181, 182, 183, 184, 185, 188, 190, 191, 192, 194, 196, 197, 198, 209 pedagogical, 65, 68 pedal, 177 pediatrician, 41 pedigree, 125, 127 peer (s), 72, 74, 75, 98, 208 pelvis, 70, 148 penetrance, 125, 137, 180 penis, 85, 86, 88, 179 peptide (s), 38, 39, 40, 47, 52, 193 percentile, 45, 51, 94 perception (s), 78, 130, 148, 151, 159, 166, 177, 196 performance, 2, 4, 67, 71, 72, 73, 78, 79, 95, 100, 124, 130, 150, 158, 163, 166, 168, 180, 187 perinatal, 80, 191 periodontitis, 52, 63 peripheral blood, 48, 52, 54, 55 peripheral nerve, 39 periventricular, 112, 149 permeability, 57 permit, 18, 24, 162, 196 persecutory delusion, 150 personal, 76, 77, 98, 127, 129, 183, 187, 197, 198, 199, 202, 203, 207 personal communication, 129 personal hygiene, 203 personality, 40, 77, 80, 100, 148, 151, 187, 202 personality disorder, 100, 151 perturbation, 61 phagocytic, 48 pharmacotherapy, 117 phenotype (s), 6, 9, 10, 16, 18, 20, 22, 24, 25, 26, 27, 28, 33, 34, 36, 39, 40, 41, 49, 55, 59, 60, 65, 66, 67, 68, 74, 75, 79, 85, 87, 94, 103, 110, 111, 115,

229

116, 117, 120, 121, 122, 125, 135, 136, 140, 152, 163, 168, 169, 170, 177, 178, 190 phenotypic, 33, 86, 89, 124, 133, 144, 145, 181 Philadelphia, 104, 189, 191, 193 philtrum, 148, 179 phobia, 66, 73 phone, 203 phonological, 3, 95, 167 phonology, 37 phorbol, 51 phosphorylation, 61 physical therapist, 183 physical therapy, 176 physicians, 183, 189 physiological, 39, 186 Piagetian, 37, 158 pituitary, 46, 60, 85, 86, 87, 117 pituitary gland, 85, 86 placebo, 46, 75 planning, 72, 78, 90, 160, 161, 163, 164, 165, 167, 184, 186, 196, 197 plants, 137 planum temporale, 35, 57 plaque, 193 plasma, 39, 48, 89, 97 plastic surgery, 42, 58, 61 plasticity, 36, 111 platelet aggregation, 91 play, 5, 36, 74, 101, 137, 142, 173, 174, 183, 184, 187, 196 point mutation, 139, 141 polarization, 33 police, 100 pollen, 127 polygenic, 6 polygons, 165 polymerase chain reaction, 121 polymorphisms, 188 polypeptide, 136 poor, 25, 40, 47, 48, 67, 77, 87, 88, 89, 109, 110, 111, 124, 127, 149, 166, 167, 181, 204 population, 6, 10, 13, 24, 34, 37, 39, 40, 42, 43, 44, 46, 47, 48, 51, 63, 66, 67, 80, 87, 89, 92, 95, 107, 108, 116, 119, 121, 152, 153, 166, 186 position effect, 26 positive reinforcement, 68 positron emission tomography (PET), 35, 61 postoperative, 181 posture, 138 poverty, 77

230

Index

pragmatic, 168 preclinical, 62 precocious puberty, 91 prediction, 207 predictors, 119 prefrontal cortex, 36, 37 pregnancy, 13, 69, 127 prematurity, 179, 180 premutation carriers, 112, 113, 116, 117 prepubertal, 70, 82, 89, 90 preschool, 74, 176 preschoolers, 114 president, 210 pressure, 46 prevention, 58, 147, 153, 157, 159, 161 preventive, 63 primary care, 189 primary school, 68, 75 probability, 22 probable cause, 46 proband, 114, 140 probe, 21, 82 problem solving, 163 problem-solving behavior, 160 production, 34, 36, 39, 46, 51, 55, 87, 90, 121, 205 profession (s), 77, 186, 205 progenitors, 104 prognosis, 89, 181, 206, 207 program, 138, 157, 158, 159, 160, 209 progressive, 39, 51, 90, 99, 100, 131, 136, 142, 145, 166, 181, 188 proinflammatory, 40 projective test, 73 prolapse, 88 proliferation, 51, 137 promote, 90, 184, 205 prophylactic, 113 protection, 33, 42 protective factors, 199 protein (s), 31, 34, 38, 39, 40, 46, 49, 52, 53, 54, 55, 61, 108, 111, 112, 115, 118, 120, 121, 126, 129, 132, 133, 144, 152, 174, 190 protocols, 13 prototype, 115 proximal, 136, 147, 148, 159 pseudo, 3 psychiatric disorder (s), 60, 74, 93, 96, 101, 102, 152, 153 psychiatric illness, 80

psychological, 1, 67, 71, 74, 77, 80, 87, 90, 99, 100, 119, 131, 150, 176, 186, 187, 199 psychological development, 80 psychological distress, 87 psychological functions, 186 psychologist (s), 182, 184, 202, 209, 210 psychopathology, 96, 101, 163 psychopharmacological treatments, 143 psychosis (es), 66, 80, 82, 87, 93, 95, 100, 103, 105, 148, 151, 152, 154 psychosocial, 67, 74, 81, 85, 86, 87, 90, 103, 170, 182 psychosocial development, 87 psychosocial functioning, 103 psychotherapeutic, 114 psychotherapy, 76 psychotic, 65, 75, 79, 80, 81, 82, 95, 96, 99, 100, 102, 103, 104, 147, 148, 150, 152 psychotic symptoms, 100, 102 ptosis, 109, 179 pubertal development, 89 puberty, 85, 86, 87, 89, 90, 91, 104, 170, 177, 178 public, 201 pulmonary embolism, 88 pulp, 87, 125

Q quality improvement, 210 quality of life, 42, 67, 173, 200 questionnaire, 79, 150 quinacrine, 154

R race, 187 radiological, 101 random, 78 range, 2, 4, 9, 10, 23, 36, 39, 43, 51, 74, 89, 97, 100, 108, 112, 130, 139, 148, 151, 152, 163, 166, 167, 174, 182, 183, 185, 198 raphe, 142, 144 rating scale, 56, 150 reactive oxygen species, 110 reactivity, 79, 118 reading, 3, 5, 7, 69, 87, 161, 163, 164, 167, 168 reading comprehension, 168 reading difficulties, 87 reading skills, 161

Index reality, 73, 130, 148, 158, 160, 199 reasoning, 71, 72, 78, 100, 124, 130, 151 recall, 37, 72, 73, 119, 151 receptors, 52, 53, 113, 120 reciprocal translocation, 154, 191 reciprocity, 162 recognition, 35, 47, 58, 72, 162, 166 recombination, 92 reconstruction, 130, 151 recovery, 181, 200, 201 recreational, 184 recurrence, 92, 176 redistribution, 55 reduction, 24, 34, 36, 39, 47, 141 refractory, 93 regional, 4, 5, 34 regular, 45, 67, 75, 183, 196 regulation, 43, 49, 59, 111, 112, 113, 137, 162, 167 rehabilitation, 10, 11, 29, 173, 174, 175, 181, 182, 183, 184, 185, 188, 189, 208 rehabilitation program, 10, 11, 175 reinforcement, 68 rejection, 49 relationship (s), 1, 2, 7, 28, 39, 56, 65, 68, 73, 75, 77, 82, 93, 96, 100, 101, 104, 117, 124, 125, 130, 149, 151, 159, 160, 161, 162, 163, 165, 166, 167, 170, 186, 187, 195, 196, 197, 199, 201, 204, 208 relatives, 11, 80, 202, 205 relevance, 12, 152 reliability, 45, 185 remediation, 157, 159, 161, 163 remission, 97 remodelling, 136 renal, 135, 136, 137, 138, 139, 140, 141, 143, 144, 145, 177, 180 renal disease, 137, 143 renal failure, 136 renal function, 141 repetitions, 129 repetitive behavior, 166 replication, 6 repression, 73, 137 repressor, 62 reproduction, 122 reproductive age, 120 research, 1, 2, 4, 5, 6, 16, 19, 24, 29, 38, 42, 46, 57, 93, 95, 101, 102, 110, 114, 117, 131, 152, 168, 169, 170, 174, 185, 204, 205, 207, 210 researchers, 1, 2, 4, 6, 45, 49, 198 resistance, 46, 48, 53

231

resolution, 21, 26, 30, 60, 140 resources, 74, 90, 182, 184, 196 respiratory, 176, 179, 180, 209 responsibilities, 126, 182 responsiveness, 52, 55, 98, 129 retardation, 23, 24, 29, 34, 60, 63, 86, 87, 108, 125, 130, 131, 133, 136, 140, 151, 152, 177, 180, 181, 191, 193 retina, 126, 206 retinal detachment, 181 Rett syndrome, 24, 28, 171 Reynolds, 5, 8, 72, 148, 154 rheumatoid arthritis, 86 rhythm, 98 right hemisphere, 67, 96, 98, 102 ring chromosome, 178, 179, 180, 191 rings, 140 risk (s), 37, 39, 40, 42, 46, 47, 48, 56, 57, 63, 66, 81, 88, 90, 91, 92, 95, 101, 114, 141, 152, 159, 176, 177, 199 risk factors, 39, 57, 199 risperidone, 114 RNA, 108, 113, 115 Robertsonian translocation, 175 Rome, 85 routines, 110

S sadness, 127 safety, 63, 210 salary, 205 saliva, 55 sample, 7, 149, 170, 210, 211 Sao Paulo, 82 satisfaction, 205 scaling, 2 schizophrenia, 72, 80, 81, 82, 83, 96, 99, 102, 103, 104, 148, 149, 152, 153, 154, 170, 171 school, 8, 43, 45, 65, 66, 68, 69, 73, 74, 75, 77, 89, 95, 98, 110, 124, 127, 131, 138, 149, 151, 178, 181, 200, 201, 202, 204, 209 science, 7, 163 scientific, 80, 147, 197, 202, 206, 210 sclerosis, 90, 144 scoliosis, 70, 138, 179, 209 scores, 71, 79, 99, 100, 130, 200, 201, 204 scrotum, 178, 179 search, 6, 11, 16, 18, 24, 73, 77, 154, 167 searching, 22, 24, 161, 162, 164, 165, 166

232

Index

secondary sexual characteristics, 66, 87 secretion, 74, 136 segregation, 25, 26, 102 seizure (s), 94, 97, 102, 104, 107, 110, 111, 114, 138, 180, 184 selective attention, 71, 72, 166 selective mutism, 110, 118 Self, 73, 77, 83 self esteem, 73 self help, 205 self-care, 152, 186 self-concept, 67 self-efficacy, 197 self-esteem, 67, 87, 89 self-help, 152, 197 self-image, 72, 73, 74, 90 self-monitoring, 163 self-regulation, 162 self-report, 72 semantic (s), 3, 95, 100, 167 seminiferous tubules, 85, 86, 88, 90 senescence, 48, 49, 56 senile dementia, 37 senile plaques, 38, 39 sensation (s), 76, 77 sensitivity, 43, 58 sentences, 96, 167 separation, 66, 73 sepsis, 57 sequelae, 35 sequencing, 130, 151 series, 49, 53, 120, 162, 184, 190, 198 serotonin, 35, 143 Sertoli cells, 85, 86, 89 sertraline, 113 serum, 45, 51, 52, 90, 101, 139 services, 185, 186, 187 severity, 16, 33, 52, 72, 73, 85, 87, 124, 132, 152, 160, 173, 174, 181, 186, 198 sex, 10, 52, 53, 79, 82, 83, 85, 86, 88, 89, 92, 94, 95, 99, 101, 102, 103, 104, 134, 167, 169, 170, 187, 188, 189, 190, 192, 193 sex chromatin, 82 sex chromosome, 79, 82, 83, 85, 86, 94, 95, 102, 103, 104, 167, 169, 170, 188, 189, 192 sex hormones, 101 sex ratio, 10 sexual activity, 67, 92 sexual behavior, 76, 79 sexual development, 74, 94, 177, 178

sexual dimorphism, 74 sexual intercourse, 77, 100 sexual offending, 104 sexuality, 105 shape, 12, 34, 54, 125, 160, 166, 181 sharing, 11, 162, 185 short-term memory, 3, 62, 72, 87, 151 shoulder, 97 shyness, 68, 107 siblings, 75 sign (s) , 16, 22, 25, 40, 59, 74, 98, 101, 112, 113, 121, 124, 126, 131, 141, 167, 176, 179, 181, 183 signal transduction, 51 signaling pathways, 144 signalling, 53, 168 signals, 128, 140 silver, 38 similarity, 23 single nucleotide polymorphism, 26, 30 sites, 126, 178, 180, 182 skills, 37, 40, 59, 71, 74, 78, 87, 90, 100, 124, 130, 150, 151, 152, 157, 159, 160, 161, 164, 165, 167, 168, 169, 174, 185, 204, 208 skin, 14, 25, 45, 175, 177, 179, 190 sleep, 68, 76, 97, 98, 109, 138 sleep apnea, 109 sleep disturbance, 138 small intestine, 42 smoking, 113 social, 37, 40, 42, 55, 65, 67, 68, 72, 73, 74, 76, 82, 89, 94, 95, 98, 99, 100, 101, 107, 110, 115, 119, 124, 127, 130, 131, 140, 148, 151, 152, 161, 162, 163, 164, 165, 166, 169, 170, 171, 174, 175, 182, 184, 185, 186, 187, 196, 201, 202, 204, 205, 207, 208, 209 social activities, 202 social adjustment, 95, 166 social anxiety, 65, 68, 73, 74, 107, 170 social behavior, 74 social behaviour, 140 social benefits, 205 social cognition, 166, 169 social competence, 163 social events, 207 social impairment, 74, 124, 131 social isolation, 40 social life, 204 social participation, 73, 208 social phobia, 100 social problems, 89

Index social relationships, 67, 76 social services, 174 social skills, 98, 166, 201, 204 social support, 152 social workers, 182, 205, 209 socialisation, 174 socialization, 69, 127 socially, 72, 73, 99, 196 society, 202, 209 socioeconomic status, 163 solid tumors, 42 solutions, 11, 160, 196 Somalia, 149 somatic complaints, 68 somatosensory, 97 spatial, 66, 67, 71, 72, 78, 79, 130, 151, 160, 161, 162, 163, 165, 177 spatial ability, 66, 67, 79 spatial information, 165 spatial memory, 71, 78, 79, 130, 151 special education, 98, 109, 124, 188, 209 specialists, 182, 188, 202, 205, 206, 207, 209 specialization, 67, 96, 102, 104 spectrum, 20, 29, 74, 102, 107, 111, 117, 119, 136, 141, 144, 145 speculation, 89 speech, 3, 11, 37, 76, 77, 87, 88, 89, 90, 95, 97, 101, 102, 110, 114, 120, 121, 127, 148, 152, 168, 181, 182, 188, 209 speed, 7, 75, 130, 151 spelling, 6, 7 sperm, 91 spermatocyte, 90 spermatogenesis, 90, 91 spermatozoa, 91 spermatozoon, 91 sphincter, 138 spinal cord, 56, 144 spine (s), 42, 70, 113, 175 spleen, 49, 51 sporadic, 38, 39, 40, 67 sports, 176, 189, 209 St. Louis, 192 stability, 118 stabilization, 114 stages, 67, 70, 90, 98 standards, 120, 186, 196 stasis, 91 steroid, 136 stigma, 80

233

stimulus, 166 stomach, 69 storage, 3 strabismus, 109, 179, 180 strain, 60, 90 strategies, 34, 37, 81, 157, 158, 159, 160, 170, 188 strength, 85, 86, 90, 168 stress, 47, 72, 74, 75, 87, 110, 113, 131, 204, 211 stretching, 183 stroke, 149 subarachnoidal, 70 subdomains, 186, 187 subgroups, 115, 169 subjective, 195, 197, 199, 200, 210 substance abuse, 151 subtraction, 151 suffering, 68 summaries, 200 summer, 208 superior temporal gyrus, 34, 35 superoxide dismutase-1(SOD-1), 39, 58, 154 supervision, 54, 77, 152, 188, 192 supplements, 120 suppression, 42 surgery, 58, 109, 124, 125, 176, 181, 204 surgical, 12, 41, 42, 91, 138, 181 surveillance, 45, 67 survival, 41, 43, 57, 62, 176 surviving, 174 susceptibility, 33, 38, 39, 44, 48, 53, 79, 95, 147, 152, 154 susceptibility genes, 147, 153 swallowing, 13, 112 Sweden, 45 switching, 166, 168 Switzerland, 194 symbols, 13, 14 sympathetic, 110 symptom (s), 18, 37, 40, 45, 67, 68, 72, 73, 74, 77, 80, 89, 93, 94, 97, 102, 113, 114, 116, 119, 120, 121, 136, 140, 142, 148, 170, 181, 112, 196, 198 synapse (s), 36, 40, 113 synaptic plasticity, 111, 119, 120 syntactic, 95, 167, 168 syntax, 37, 167 synthesis, 122, 202 systematic, 160, 161, 162, 165, 168, 207 systemic lupus erythematosus, 86 systems, 3, 5, 18, 103, 158, 160, 162, 165, 186, 187

Index

234

T T cell (T-cell) (s), 45, 49, 51, 53, 55, 56, 57, 59, 61, 136, 139, 142 T lymphocytes, 50, 51 tangible, 68 tangles, 38 targets, 49 tau, 38, 112 T-cell receptor (TCR), 48, 51, 59 teachers, 68, 75, 202, 204 teaching, 69, 186, 203, 204 technicians, 184 technology, 26, 187 teenagers, 184 teeth, 87, 124, 125, 126, 128, 133, 180, 190 television, 201, 208 telomere (s), 21, 22, 30 temporal, 34, 35, 36, 71, 83, 96, 98, 103, 160, 162, 190, 204 temporal lobe, 34, 83, 103 temporal lobe epilepsy, 103 tension, 126 teratoma, 88, 91 testes, 85, 86, 88, 89, 90, 91, 94 testis, 88 testosterone, 86, 88, 89, 90, 91, 101, 178 testosterone levels, 89 testosterone supplementation, 91 tetralogy, 140, 179 Th cells, 137 theoretical, 22, 158, 199 theory, 1, 49, 102, 113, 115, 158, 159, 169 therapeutic (s), 34, 58, 97, 175, 184, 186, 191, 199 therapeutic interventions, 191 therapeutic targets, 184 therapists, 182, 183, 184 therapy, 11, 45, 66, 70, 75, 86, 87, 88, 90, 91, 114, 177, 184, 189, 192, 196, 207, 208 thinking, 23, 150, 151, 160, 161, 162, 164, 165, 166, 169 thorax, 14, 70, 148, 177 thresholds, 190 thrombosis, 88 thrombotic, 91 thymocytes, 48 thymus, 48, 59 thyroglobulin, 45 thyroid, 41, 43, 44, 45, 46, 52, 55, 57, 58, 60, 177 thyroiditis, 44, 45, 47

thyrotropin, 58 thyroxin, 45 time, 4, 26, 27, 38, 39, 40, 43, 60, 68, 72, 74, 75, 76, 79, 89, 92, 94, 98, 112, 139, 162, 166, 168, 175, 177, 182, 188, 198, 199, 200, 201, 203, 204, 205 timetable, 181 tin, 97 tissue, 35, 47, 74, 90, 91 title, 200, 204, 211 toddlers, 59 tonsils, 109 topological, 160 torque, 102 total cholesterol, 39 toxic, 9, 10 toxicity, 43, 108, 113 TPO, 46 tracking, 151, 187 trainees, 204 training, 75, 181, 183, 188 traits, 5, 15, 40, 74, 77, 80, 95, 99, 100, 123, 124, 131, 166 transcendence, 162 transcript (s), 115, 126, 129 transcription factor, 55, 135, 136, 137, 143, 144 transcriptional, 42 transducer, 53 transformation, 177 transgenic mice, 61 transgenic mouse, 61 transglutaminase, 53 transition (s), 67, 83, 174, 184 translation, 111 translocation, 26, 148, 154, 193, 209 transmembrane, 38 transmission, 125, 136, 180 transmits, 159 transport, 55, 160 trauma, 111 trees, 175 tremor, 94, 107, 108, 111, 112, 113, 115, 116, 117, 118, 119, 121, 149 trend, 95, 167 trial, 46, 160 trisomy, 20, 33, 34, 37, 38, 40, 43, 47, 52, 54, 57, 58, 59, 62, 87, 92, 152, 174, 175, 188, 189, 190, 193 trisomy 21, 37, 38, 40, 43, 47, 48, 56, 59, 62, 152, 175, 188, 189, 190 TSH, 43, 44, 45, 46, 60, 62 tubular, 90

Index tumor (s), 42, 49, 61, 62, 88, 91 tumor cells, 61 tumor resistance, 42 tumour (s), 22, 61 turbulence, 206 Twin studies, 4 twins, 7, 137 type 1 diabetes, 44, 47 tyrosine, 61

U ubiquitin, 38, 59, 112 ubiquitous, 38 ultrasound, 70, 141, 175 undifferentiated, 72, 73, 74 uniform, 67, 187, 203 unilateral, 137 United States, 47, 56, 63 universities, 182 unmasking, 26 urinary, 85, 86, 140 urinary tract, 140 uterus, 66, 70

V vaccination, 51, 54 vacuum, 79 vagina, 66 valgus, 88, 177, 179 validity, 185 values, 36, 43, 48, 49, 51, 139 valvular, 91 variability, 26, 27, 31, 37, 66, 124, 180, 181 variable, 2, 10, 16, 24, 25, 26, 33, 34, 66, 86, 89, 98, 124, 125, 137, 165, 178 variance, 4, 6, 44, 45 variation, 2, 5, 26, 36, 119, 152, 160, 170, 204 varicose veins, 91 vascular, 140, 141 vascular diseases, 141 vein, 88 velocity, 45, 48, 87 venipuncture, 45 venlafaxine, 113, 116 ventricles, 98 ventricular, 77 ventricular septal defect, 41, 140, 179

235

verbal fluency, 95, 161, 167 Verbal IQ, 71, 72, 78, 130, 150 vertebrates, 137, 144 video, 208 villus, 190 violent, 100, 101, 180 violent behaviour, 101 violent crimes, 101 viral, 33, 48, 53 virus, 33, 51, 53, 58, 61 virus infection, 33, 53 vision, 124 visual, 7, 24, 25, 35, 58, 66, 67, 71, 72, 77, 78, 79, 100, 124, 125, 129, 130, 151, 160, 163, 165, 168, 170, 180 visual acuity, 181 visual attention, 166 visual memory, 100 Visual-spatial, 71, 130, 151 visuospatial, 37, 67, 100, 165 vitamin B12, 139 vocabulary, 37, 59, 121, 161, 162, 165, 167, 168 vocational, 81, 182 voice, 79, 87, 127 vulnerability, 80, 108, 147, 151

W waking, 76 Wales, 191 war, 82 Washington, 169, 210, 211 waste, 205 water, 208 weakness, 89, 157, 163, 167, 168 wealth, 74, 78 wear, 77 web, 195, 197, 210 Wechsler Adult Intelligence Scale (WAIS),2, 78, 130, 150 Wechsler Intelligence Scale, 83, 154 weeping, 80 weight gain, 114 wellbeing, 184, 210 well-being, 90, 199, 200 white matter, 98, 112, 141, 149 wild type, 126 Wisconsin, 100, 104 withdrawal, 99 witness, 199

Index

236

women, 67, 80, 81, 82, 83, 100, 108, 112, 113, 116, 120 word recognition, 7 workers, 174, 184, 205 working hours, 205 working memory, 3, 7, 66, 67, 79, 164 World Health Organization (WHO), 186, 187, 194 writing, 80

X X chromosome, 66, 67, 74, 81, 86, 87, 129, 134, 177, 178, 181, 189, 194 X-linked, 30, 31, 83, 102, 123, 124, 125, 132, 133, 136, 180, 189, 190, 191 X-rays, 70

XYY syndrome, 93, 94, 95, 101, 102, 103, 105, 165

Y Y chromosome, 66, 86, 94, 95, 101, 102, 103, 105, 177 yield, 31, 198 young adults, 35, 184 young men, 91 young women, 190

Z zinc, 137 zygote, 87