The Official Parent's Sourcebook on Phenylketonuria

THE OFFICIAL PARENT’S SOURCEBOOK

on

PHENYLKETONURIA

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright Ó2002 by ICON Group International, Inc. Copyright Ó2002 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Tiffany LaRochelle Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended as a substitute for consultation with your child’s physician. All matters regarding your child’s health require medical supervision. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation, in close consultation with a qualified physician. The reader is advised to always check product information (package inserts) for changes and new information regarding dose and contraindications before administering any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960The Official Parent’s Sourcebook on Phenylketonuria: A Revised and Updated Directory for the Internet Age/James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary and index. ISBN: 0-597-83204-8 1. Phenylketonuria-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem or as a substitute for consultation with licensed medical professionals. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, or the authors are not responsible for the content of any Web pages nor publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this sourcebook for parent use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications are copyrighted. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs or other materials, please contact us to request permission (e-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this sourcebook.

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Dedication To the healthcare professionals dedicating their time and efforts to the study of phenylketonuria.

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this sourcebook which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which directly or indirectly are dedicated to phenylketonuria. All of the Official Parent’s Sourcebooks draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this sourcebook. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany LaRochelle for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for the Official Parent’s Sourcebook series published by ICON Health Publications.

Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for the Official Parent’s Sourcebook series published by ICON Health Publications.

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About ICON Health Publications In addition to phenylketonuria, Official Parent’s Sourcebooks are available for the following related topics: ·

The Official Patient's Sourcebook on Down Syndrome

·

The Official Patient's Sourcebook on Fragile X Syndrome

·

The Official Patient's Sourcebook on Infantile Apnea

·

The Official Patient's Sourcebook on Klinefelter Syndrome

·

The Official Patient's Sourcebook on Mccune Albright Syndrome

·

The Official Patient's Sourcebook on Pituitary Tumors

·

The Official Patient's Sourcebook on Primary Immunodeficiency

·

The Official Patient's Sourcebook on Sudden Infant Death Syndrome

To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

Contents vii

Table of Contents INTRODUCTION ................................................................................................................................. 1 Overview ....................................................................................................................................... 1 Organization ................................................................................................................................. 3 Scope.............................................................................................................................................. 3 Moving Forward............................................................................................................................ 4 PART I: THE ESSENTIALS ............................................................................................................. 7 CHAPTER 1. THE ESSENTIALS ON PHENYLKETONURIA: GUIDELINES ............................................. 9 Overview ....................................................................................................................................... 9 What Is Classical Phenylketonuria?............................................................................................ 10 Incidence and Prevalence............................................................................................................. 12 Newborn Screening ..................................................................................................................... 14 Treatment .................................................................................................................................... 16 Lifelong Management and Follow-up.......................................................................................... 20 Research Is Needed ...................................................................................................................... 25 Conclusions ................................................................................................................................. 26 More Guideline Sources .............................................................................................................. 26 Vocabulary Builder...................................................................................................................... 34 CHAPTER 2. SEEKING GUIDANCE ................................................................................................... 37 Overview ..................................................................................................................................... 37 Associations and Phenylketonuria .............................................................................................. 37 Finding More Associations ......................................................................................................... 46 Finding Doctors........................................................................................................................... 48 Finding a Pediatrician ................................................................................................................. 49 Selecting Your Doctor ................................................................................................................. 49 Working with Your Child’s Doctor ............................................................................................. 50 Broader Health-Related Resources .............................................................................................. 51 Vocabulary Builder...................................................................................................................... 51 CHAPTER 3. CLINICAL TRIALS AND PHENYLKETONURIA ............................................................. 53 Overview ..................................................................................................................................... 53 Recent Trials on Phenylketonuria ............................................................................................... 56 Benefits and Risks........................................................................................................................ 57 Keeping Current on Clinical Trials ............................................................................................. 60 General References....................................................................................................................... 61 PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL ........................... 63 CHAPTER 4. STUDIES ON PHENYLKETONURIA ............................................................................... 65 Overview ..................................................................................................................................... 65 The Combined Health Information Database .............................................................................. 65 Federally-Funded Research on Phenylketonuria ......................................................................... 70 E-Journals: PubMed Central ....................................................................................................... 81 The National Library of Medicine: PubMed................................................................................ 82 Vocabulary Builder...................................................................................................................... 83 CHAPTER 5. PATENTS ON PHENYLKETONURIA.............................................................................. 87 Overview ..................................................................................................................................... 87 Patents on Phenylketonuria ........................................................................................................ 88 Patent Applications on Phenylketonuria..................................................................................... 89 Keeping Current .......................................................................................................................... 90 Vocabulary Builder...................................................................................................................... 90 CHAPTER 6. BOOKS ON PHENYLKETONURIA ................................................................................. 93 Overview ..................................................................................................................................... 93

viii Contents

Book Summaries: Federal Agencies ............................................................................................. 94 Book Summaries: Online Booksellers .......................................................................................... 96 The National Library of Medicine Book Index............................................................................. 97 Chapters on Phenylketonuria .................................................................................................... 100 General Home References .......................................................................................................... 107 Vocabulary Builder.................................................................................................................... 108 CHAPTER 7. MULTIMEDIA ON PHENYLKETONURIA .................................................................... 111 Overview ................................................................................................................................... 111 Bibliography: Multimedia on Phenylketonuria ......................................................................... 111 CHAPTER 8. PERIODICALS AND NEWS ON PHENYLKETONURIA ................................................. 113 Overview ................................................................................................................................... 113 News Services & Press Releases ................................................................................................ 113 Newsletters on Phenylketonuria................................................................................................ 116 Academic Periodicals covering Phenylketonuria....................................................................... 117 Vocabulary Builder.................................................................................................................... 118 CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES .............................................................. 121 Overview ................................................................................................................................... 121 NIH Guidelines ......................................................................................................................... 121 NIH Databases .......................................................................................................................... 122 Other Commercial Databases .................................................................................................... 127 The Genome Project and Phenylketonuria ................................................................................ 127 Specialized References ............................................................................................................... 132 CHAPTER 10. DISSERTATIONS ON PHENYLKETONURIA ............................................................... 133 Overview ................................................................................................................................... 133 Dissertations on Phenylketonuria ............................................................................................. 133 Keeping Current ........................................................................................................................ 134 PART III. APPENDICES .............................................................................................................. 135 APPENDIX A. RESEARCHING YOUR CHILD’S MEDICATIONS....................................................... 137 Overview ................................................................................................................................... 137 Your Child’s Medications: The Basics....................................................................................... 138 Learning More about Your Child’s Medications....................................................................... 139 Commercial Databases............................................................................................................... 140 Contraindications and Interactions (Hidden Dangers)............................................................. 141 A Final Warning ....................................................................................................................... 142 General References..................................................................................................................... 143 APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE ............................................................... 145 Overview ................................................................................................................................... 145 What Is CAM? .......................................................................................................................... 145 What Are the Domains of Alternative Medicine? ..................................................................... 146 Can Alternatives Affect My Child’s Treatment? ...................................................................... 149 Finding CAM References on Phenylketonuria.......................................................................... 150 Additional Web Resources......................................................................................................... 158 General References..................................................................................................................... 162 Vocabulary Builder.................................................................................................................... 163 APPENDIX C. RESEARCHING NUTRITION..................................................................................... 165 Overview ................................................................................................................................... 165 Food and Nutrition: General Principles .................................................................................... 166 Finding Studies on Phenylketonuria ......................................................................................... 170 Federal Resources on Nutrition................................................................................................. 174 Additional Web Resources......................................................................................................... 175 Vocabulary Builder.................................................................................................................... 177 APPENDIX D. FINDING MEDICAL LIBRARIES ............................................................................... 179 Overview ................................................................................................................................... 179

Contents

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Preparation ................................................................................................................................ 179 Finding a Local Medical Library ............................................................................................... 180 Medical Libraries Open to the Public ........................................................................................ 180 APPENDIX E. YOUR CHILD’S RIGHTS AND INSURANCE............................................................... 187 Overview ................................................................................................................................... 187 Your Child’s Rights as a Patient ............................................................................................... 187 Parent Responsibilities .............................................................................................................. 191 Choosing an Insurance Plan...................................................................................................... 192 Medicaid .................................................................................................................................... 194 NORD’s Medication Assistance Programs............................................................................... 195 Additional Resources................................................................................................................. 195 Vocabulary Builder.................................................................................................................... 196 ONLINE GLOSSARIES ............................................................................................................... 197 Online Dictionary Directories................................................................................................... 200 PHENYLKETONURIA GLOSSARY.......................................................................................... 201 General Dictionaries and Glossaries ......................................................................................... 210 INDEX.............................................................................................................................................. 212

Introduction

1

INTRODUCTION Overview Dr. C. Everett Koop, former U.S. Surgeon General, once said, “The best prescription is knowledge.”1 The Agency for Healthcare Research and Quality (AHRQ) of the National Institutes of Health (NIH) echoes this view and recommends that all parents incorporate education into the treatment process. According to the AHRQ: Finding out more about your [child’s] condition is a good place to start. By contacting groups that support your [child’s] condition, visiting your local library, and searching on the Internet, you can find good information to help guide your decisions for your [child’s] treatment. Some information may be hard to find—especially if you don't know where to look.2 As the AHRQ mentions, finding the right information is not an obvious task. Though many physicians and public officials had thought that the emergence of the Internet would do much to assist parents in obtaining reliable information, in March 2001 the National Institutes of Health issued the following warning: The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.3 Quotation from http://www.drkoop.com. The Agency for Healthcare Research and Quality (AHRQ): http://www.ahcpr.gov/consumer/diaginfo.htm. 3 From the NIH, National Cancer Institute (NCI): http://cancertrials.nci.nih.gov/beyond/evaluating.html. 1 2

2

Phenylketonuria

Since the late 1990s, physicians have seen a general increase in parent Internet usage rates. Parents frequently enter their children’s doctor's offices with printed Web pages of home remedies in the guise of latest medical research. This scenario is so common that doctors often spend more time dispelling misleading information than guiding children through sound therapies. The Official Parent’s Sourcebook on Phenylketonuria has been created for parents who have decided to make education and research an integral part of the treatment process. The pages that follow will tell you where and how to look for information covering virtually all topics related to phenylketonuria, from the essentials to the most advanced areas of research. The title of this book includes the word “official.” This reflects the fact that the sourcebook draws from public, academic, government, and peerreviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on phenylketonuria. Given parents’ increasing sophistication in using the Internet, abundant references to reliable Internet-based resources are provided throughout this sourcebook. Where possible, guidance is provided on how to obtain free-ofcharge, primary research results as well as more detailed information via the Internet. E-book and electronic versions of this sourcebook are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). Hard copy users of this sourcebook can type cited Web addresses directly into their browsers to obtain access to the corresponding sites. Since we are working with ICON Health Publications, hard copy Sourcebooks are frequently updated and printed on demand to ensure that the information provided is current. In addition to extensive references accessible via the Internet, every chapter presents a “Vocabulary Builder.” Many health guides offer glossaries of technical or uncommon terms in an appendix. In editing this sourcebook, we have decided to place a smaller glossary within each chapter that covers terms used in that chapter. Given the technical nature of some chapters, you may need to revisit many sections. Building one’s vocabulary of medical terms in such a gradual manner has been shown to improve the learning process. We must emphasize that no sourcebook on phenylketonuria should affirm that a specific diagnostic procedure or treatment discussed in a research study, patent, or doctoral dissertation is “correct” or your child’s best option. This sourcebook is no exception. Each child is unique. Deciding on

Introduction

3

appropriate options is always up to parents in consultation with their children’s physicians and healthcare providers.

Organization This sourcebook is organized into three parts. Part I explores basic techniques to researching phenylketonuria (e.g. finding guidelines on diagnosis, treatments, and prognosis), followed by a number of topics, including information on how to get in touch with organizations, associations, or other parent networks dedicated to phenylketonuria. It also gives you sources of information that can help you find a doctor in your local area specializing in treating phenylketonuria. Collectively, the material presented in Part I is a complete primer on basic research topics for phenylketonuria. Part II moves on to advanced research dedicated to phenylketonuria. Part II is intended for those willing to invest many hours of hard work and study. It is here that we direct you to the latest scientific and applied research on phenylketonuria. When possible, contact names, links via the Internet, and summaries are provided. It is in Part II where the vocabulary process becomes important as authors publishing advanced research frequently use highly specialized language. In general, every attempt is made to recommend “free-to-use” options. Part III provides appendices of useful background reading covering phenylketonuria or related disorders. The appendices are dedicated to more pragmatic issues facing parents. Accessing materials via medical libraries may be the only option for some parents, so a guide is provided for finding local medical libraries which are open to the public. Part III, therefore, focuses on advice that goes beyond the biological and scientific issues facing children with phenylketonuria and their families.

Scope While this sourcebook covers phenylketonuria, doctors, research publications, and specialists may refer to your child’s condition using a variety of terms. Therefore, you should understand that phenylketonuria is often considered a synonym or a condition closely related to the following: ·

Classical Phenylketonuria

·

Folling Syndrome

4

Phenylketonuria

·

Hyperphenylalanemia

·

Hyperphenylalaninemia

·

Phenylalanine Hydroxylase Deficiency

·

Phenylalaninemia

·

Phenylpyruvic Oligophrenia

In addition to synonyms and related conditions, physicians may refer to phenylketonuria using certain coding systems. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) is the most commonly used system of classification for the world's illnesses. Your physician may use this coding system as an administrative or tracking tool. The following classification is commonly used for phenylketonuria:4 ·

270.1 phenylketonuria

For the purposes of this sourcebook, we have attempted to be as inclusive as possible, looking for official information for all of the synonyms relevant to phenylketonuria. You may find it useful to refer to synonyms when accessing databases or interacting with healthcare professionals and medical librarians.

Moving Forward Since the 1980s, the world has seen a proliferation of healthcare guides covering most illnesses. Some are written by parents, patients, or their family members. These generally take a layperson's approach to understanding and coping with an illness or disorder. They can be uplifting, encouraging, and highly supportive. Other guides are authored by physicians or other healthcare providers who have a more clinical outlook. Each of these two styles of guide has its purpose and can be quite useful. As editors, we have chosen a third route. We have chosen to expose you to as many sources of official and peer-reviewed information as practical, for the purpose of educating you about basic and advanced knowledge as

4 This list is based on the official version of the World Health Organization's 9th Revision, International Classification of Diseases (ICD-9). According to the National Technical Information Service, “ICD-9CM extensions, interpretations, modifications, addenda, or errata other than those approved by the U.S. Public Health Service and the Health Care Financing Administration are not to be considered official and should not be utilized. Continuous maintenance of the ICD-9-CM is the responsibility of the federal government.”

Introduction

5

recognized by medical science today. You can think of this sourcebook as your personal Internet age reference librarian. Why “Internet age”? When their child has been diagnosed with phenylketonuria, parents will often log on to the Internet, type words into a search engine, and receive several Web site listings which are mostly irrelevant or redundant. Parents are left to wonder where the relevant information is, and how to obtain it. Since only the smallest fraction of information dealing with phenylketonuria is even indexed in search engines, a non-systematic approach often leads to frustration and disappointment. With this sourcebook, we hope to direct you to the information you need that you would not likely find using popular Web directories. Beyond Web listings, in many cases we will reproduce brief summaries or abstracts of available reference materials. These abstracts often contain distilled information on topics of discussion. While we focus on the more scientific aspects of phenylketonuria, there is, of course, the emotional side to consider. Later in the sourcebook, we provide a chapter dedicated to helping you find parent groups and associations that can provide additional support beyond research produced by medical science. We hope that the choices we have made give you and your child the most options in moving forward. In this way, we wish you the best in your efforts to incorporate this educational approach into your child’s treatment plan. The Editors

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PART I: THE ESSENTIALS

ABOUT PART I Part I has been edited to give you access to what we feel are “the essentials” on phenylketonuria. The essentials typically include a definition or description of the condition, a discussion of who it affects, the signs or symptoms, tests or diagnostic procedures, and treatments for disease. Your child’s doctor or healthcare provider may have already explained the essentials of phenylketonuria to you or even given you a pamphlet or brochure describing the condition. Now you are searching for more in-depth information. As editors, we have decided, nevertheless, to include a discussion on where to find essential information that can complement what the doctor has already told you. In this section we recommend a process, not a particular Web site or reference book. The process ensures that, as you search the Web, you gain background information in such a way as to maximize your understanding.

Guidelines

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CHAPTER 1. THE ESSENTIALS ON PHENYLKETONURIA: GUIDELINES Overview Official agencies, as well as federally-funded institutions supported by national grants, frequently publish a variety of guidelines on phenylketonuria. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. The great advantage of guidelines over other sources is that they are often written with the parent in mind. Since new guidelines on phenylketonuria can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

The National Institutes of Health (NIH)5 The National Institutes of Health (NIH) is the first place to search for relatively current guidelines and fact sheets on phenylketonuria. Originally founded in 1887, the NIH is one of the world's foremost medical research centers and the federal focal point for medical research in the United States. At any given time, the NIH supports some 35,000 research grants at universities, medical schools, and other research and training institutions, both nationally and internationally. The rosters of those who have conducted research or who have received NIH support over the years include the world's most illustrious scientists and physicians. Among them are 97 scientists who have won the Nobel Prize for achievement in medicine.

5

Adapted from the NIH: http://www.nih.gov/about/NIHoverview.html.

10 Phenylketonuria

There is no guarantee that any one Institute will have a guideline on a specific medical condition, though the National Institutes of Health collectively publish over 600 guidelines for both common and rare disorders. The best way to access NIH guidelines is via the Internet. Although the NIH is organized into many different Institutes and Offices, the following is a list of key Web sites where you are most likely to find NIH clinical guidelines and publications dealing with phenylketonuria and associated conditions: ·

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

·

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines available at http://www.nlm.nih.gov/medlineplus/healthtopics.html

·

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

Among those listed above, the National Institute of Child Health and Human Development (NICHD) is especially noteworthy. The mission of the NICHD, a part of the National Institutes of Health (NIH), is to support and conduct research on topics related to the health of children, adults, families, and populations. NICHD research focuses on the idea that events that happen prior to and throughout pregnancy as well as during childhood have a great impact on the health and well-being of adults. The following guideline is one the NICHD provides concerning phenylketonuria.6

What Is Classical Phenylketonuria?7 Classical phenylketonuria (PKU) is a rare metabolic disorder (and orphan disease) that usually results from a deficiency of a liver enzyme known as phenylalanine hydroxylase (PAH). This enzyme deficiency leads to elevated levels of the amino acid phenylalanine (Phe) in the blood and other tissues. The untreated state is characterized by mental retardation, microcephaly, delayed speech, seizures, eczema, behavior abnormalities, and other symptoms. Approximately one of every 15,000 infants in the United States is born with PKU.

6 This and other passages have been adapted from the NIH and NICHD: http://www.nichd.nih.gov/default.htm. “Adapted” signifies that the text has been reproduced with attribution, with some or no editorial adjustments. 7 Adapted from The National Institute of Child Health and Human Development (NICHD): http://www.nichd.nih.gov/publications/pubs/pku/sub3.htm.

Guidelines 11

Because effective treatments exist to prevent symptoms, all States screen infants for PKU. The current treatment for this disorder involves strict metabolic control using a low-Phe diet that includes specialized medical foods. The newborn screening programs for PKU have been remarkably successful: infants, when diagnosed early in the newborn period and treated to achieve good metabolic control, have normal health and development and can likely expect a normal life span. Metabolic control of PKU can be difficult to achieve, and poor control can result in significant decline of mental and behavioral performance. Women with PKU must also maintain strict metabolic control before and during pregnancy to prevent fetal damage. Scientists are actively exploring nondietary treatments for PKU. Research on PKU continues to broaden the knowledge base from which informed decisions regarding screening and treatment can be made. After a day and a half of expert presentations and public discussion of the biology and biochemistry of PKU, epidemiology and genetics, screening strategies, and treatment regimens, an independent, non-Federal panel weighed the scientific evidence and drafted a statement that was presented on the third day. The consensus development panel's statement addressed the following questions: ·

What are the incidence and prevalence of PKU and other forms of hyperphenylalaninemia, and what is known about the genetic and clinical variability?

·

What newborn screening strategies are available for diagnosis, what is the effectiveness of these strategies, and what cost-savings are generated by screening and treatment?

·

What treatment regimens are used to prevent the adverse consequences of PKU? What is known about the effectiveness of these treatment and management strategies overall and with respect to variables such as time of initiation of medical nutritional therapy, levels of phenylalanine at various ages, methods for enhancing dietary compliance, duration of dietary management, and dietary regimens for women of childbearing age and other adults?

·

Based on this information, what are the recommended strategies for optimal newborn screening and diagnosis and lifelong management and followup of PKU?

·

What research is needed to gather information that will optimize the outcomes for individuals with PKU and their families?

12 Phenylketonuria

This conference was presented by the National Institute of Child Health and Human Development and the NIH Office of Medical Applications of Research. The cosponsors included the National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, the National Institute of Nursing Research, the NIH Office of Rare Diseases, and the Maternal and Child Health Bureau of the Health Resources and Services Administration.

Incidence and Prevalence Hyperphenylalaninemia results from impaired metabolism of Phe due to deficient activity of the enzyme PAH. Persons with PKU have a complete absence or profound deficiency of enzyme activity, typically show very high elevations of blood Phe (>20 mg/dL), and accumulate phenylketones. A partial deficiency of PAH results in non-PKU hyperphenylalaninemia and a lower degree of blood Phe elevation without phenylketone accumulation. Both forms of hyperphenylalaninemia, which account for the vast majority of cases, are autosomal recessive disorders caused by mutations in the PAH gene. Rarely, mutations in other genes that are necessary for the synthesis or recycling of the tetrahydrobiopterin cofactor of PAH also result in hyperphenylalaninemia, but will not be addressed in this consensus statement.

Incidence and Prevalence Newborn screening has been under way for nearly 40 years in the United States. Nevertheless, little useful data are available regarding the incidence and prevalence of PKU and other forms of hyperphenylalaninemia. Data from the 1994 Newborn Screening Report of the Council of Regional Networks for Genetic Services (CORN) were used to address the incidence of this clinically heterogeneous metabolic disease. The nature of the data allows only an estimate of the PKU and non-PKU hyperphenylalaninemia incidence. For PKU, the reported incidence ranges from 1 per 13,500 to 1 per 19,000 newborns. For non-PKU hyperphenylalaninemia, a wide range of variation in reporting exists among States, resulting in a composite estimate of 1 per 48,000 newborns. The report also identified large variations in the incidence of PKU by ethnic group: a higher incidence in Whites and Native Americans, and a lower incidence in Blacks, Hispanics, and Asians.

Guidelines 13

The data available in the CORN report are limited, and there is nonuniformity concerning the blood Phe levels used by individual States for defining positive screening tests. Definitions of classical PKU and non-PKU hyperphenylalaninemia vary. Some States failed to report data by sex and ethnicity, and two failed to report the total number of newborns screened. Also, some State laboratories were noncompliant with regard to reporting newborn screening data. Instances where data from first screens were not reported separately from followup test results added to the dilemma. In contrast to incidence, composite data were unavailable on the prevalence of PKU and non-PKU hyperphenylalaninemias.

Genetic and Clinical Variability Like all genetic disorders, PKU demonstrates extensive genetic and clinical variability. The PAH gene is a single locus with more than 400 identified different mutations, including deletions, insertions, missense mutations, splicing defects, and nonsense mutations. The fact that most individuals with PKU are compound heterozygotes generates the potential for numerous possible genotypic combinations and undoubtedly contributes to the clinical heterogeneity. These mutations also contribute to the biochemical heterogeneity and may be chiefly responsible for the biochemical phenotype. Genetic contributions to the phenotype are complex, consisting of documented allelic heterogeneity within the PAH gene. Certain PAH alleles are associated with non-PKU hyperphenylalaninemia and others with PKU. In addition, genes at other loci may influence Phe transport within the brain and the size and metabolic control of the Phe pool. This molecular heterogeneity for PKU results in wide phenotypic heterogeneity, contributing to biochemical individuality. In some cases, predicting enzymatic activity based on the PAH genotype may be possible. The relationship between the clinical phenotype and the genotype, however, is not always constant. The existence of discordant phenotypes among siblings who share the same genotype at the PAH locus implies the existence of other genetic and environmental factors that influence clinical phenotype. The presence of modifier genes would be consistent with clinical variation, but modifier genes have not yet been identified. Indeed, a small number of individuals with PKU have no mental retardation even without dietary treatment. There is variation in the transport of Phe into the brain, which may explain, in part, different clinical symptoms and severity. The pathophysiologic mechanisms leading to mental retardation are undoubtedly complex. Evidence implicates Phe as the “toxic” agent in PKU. Hyperphenylalaninemia inhibits the

14 Phenylketonuria

transport of large, neutral amino acids (LNAA) into the brain. Reduction of LNAA in the brain is thought to cause inhibition of protein synthesis and neurotransmitter synthesis leading to deficient dopamine and serotonin levels. Studies are beginning to explore the relationship between specific genotypes and response to supplementation with tetrahydrobiopterin, the cofactor for PAH. The observed clinical variability among individuals is partly due to these genetic factors, but environmental and lifestyle factors undoubtedly contribute to the variation. For example, age at diagnosis, age at commencement of metabolic control, and degree of metabolic control can explain the variation between two individuals with genetically identical mutations. Moreover, the variation observed depends on the specific trait examined, whether it is mental retardation in untreated cases, blood Phe level, neurological and neuropsychiatric deficits, or brain Phe concentration. There are no data yet on the clinical manifestations of PKU as early treated individuals age, because few are past 40 years of age. Consequently, new clinical features of PKU may become evident over time, and there is no scientific basis from which to predict future clinical outcomes.

Newborn Screening Since the early 1960's, newborn infants in the United States have been screened for PKU through the collection of neonatal blood samples on special paper cards within the first days of life. Blood samples are evaluated for the presence of abnormally elevated levels of Phe, and those infants found to have high levels of Phe are referred for diagnostic evaluation and comprehensive treatment and care.

Screening Strategies The three main laboratory methods used for population-based screening of newborns for PKU in the United States are the Guthrie Bacterial Inhibition Assay (BIA), fluorometric analysis, and tandem mass spectrometry. The Guthrie BIA is inexpensive, relatively simple, and reliable. Fluorometric analysis and tandem mass spectrometry are quantitative, can be automated, and produce fewer false positives than BIA. Tandem mass spectrometry has the ability to simultaneously obtain tyrosine levels that can be used to assist in the interpretation of Phe levels and the identification of numerous other metabolic disorders on a single sample.

Guidelines 15

Effectiveness Effective screening of newborn infants for PKU requires competence in a number of complex, interrelated systems: specimen collection; specimen transport and tracking; laboratory analysis; data collection and analysis; locating and contacting families of infants with abnormal results; diagnosis; treatment; and long-term management, including psychological, nursing, and social services and medical nutritional therapy, genetic, and family counseling. Although the U.S. screening programs have been highly effective, there is concern that individuals with PKU could be missed. This could occur at any step in the process-in collection of specimens, laboratory procedures, or initiation of treatment and clinical followup. Although missing an individual with PKU through screening is considered to be extremely rare, there are few recent data available to accurately determine the magnitude of the problem or to define the actual cause of the missed cases. Home births and early hospital discharge may contribute to missed cases. All States include PKU testing in their newborn screening programs. Through these programs, the nation has been quite successful in identifying children affected with PKU and in preventing the mental retardation associated with PKU through comprehensive treatment and care. Nonetheless, there is great variation in practice in all areas of newborn screening protocols in the United States. All but four States permit parental refusal. Even criteria for defining a positive PKU screen varies among States. Some States have newborn screening advisory boards to guide policy decisions, while others rely on State health department staff. Some States fund their programs by charging fees; other programs are supported only by appropriated funds. For States that charge a fee, some bill patients, while others bill referring physicians, hospitals, or third-party payers. Funding sources and the services covered vary greatly. The levels of followup services also vary immensely. The availability of psychological nursing services, social services, genetic counseling, medical nutrition therapy, parent education about PKU, medical foods, and modified low-protein foods, and the resulting economic burden on families also show discrepancies. Many families require these and other ancillary services to address difficulties in school, family problems, and behavioral disorders. Because of this variation in practice, not all newborns and their families have access to the same level of care. States also differ in policies relative to how information is provided to parents concerning test results and whether parents can decline testing of their children. In addition, there appears to be a lack of explicit policies

16 Phenylketonuria

regarding retention, ownership, and use of blood specimens for purposes other than PKU detection.

Cost Savings Most economic analyses of PKU screening are more than 10 years old. Methodological approaches vary widely among the studies. All published studies, however, find that PKU screening and treatment represent a net direct cost savings to society, although the analyses assume 100 percent compliance, and typically exclude the costs of operating data systems and followup components of a newborn screening program.

Treatment Implementation of a Phe-restricted diet early in life can significantly reduce mental deficiencies associated with PKU. Professionals agree that infants with PKU who have blood Phe levels > 10 mg/dL should be started on treatment to establish metabolic control of Phe levels as soon as possible, ideally by the time the neonate is 7-10 days of age. Most physicians will begin medical nutritional therapy in newborns with levels between 7-10 mg/dL that persist more than a few days. Before starting treatment, however, tetrahydrobiopterin deficiency must be excluded. Metabolic control via medical nutrition therapy involves the use of medical foods including medical protein sources and modified low-protein products in addition to the provision of required amounts of Phe through small amounts of natural protein. The response is monitored through periodic measurement of blood Phe levels in conjunction with analysis of nutritional intake and review of nutrition status. Metabolic control via dietary treatment, however, is only one component of a comprehensive treatment program. There is no consensus concerning optimal levels of blood Phe, either across different countries or among treatment centers in the United States. The British policy for dietary treatment recommends that blood Phe levels in infants and young children be maintained between 2-6 mg/dL with relaxation of Phe levels after childhood. The British policy statement, however, acknowledges that these higher limits in older children may be associated with impaired cognitive performance. The German Working Group for Metabolic Diseases recommended that Phe levels be maintained between 0.7-4 mg/dL until the age of 10 years, 0.7-15 mg/dL between 10 and

Guidelines 17

15 years, and 0.7-20 mg/dL after 15 years, along with a need for lifelong followup to evaluate for possible late sequelae. Criteria in France are similar. Formally recommended guidelines for blood Phe levels do not exist in the United States. The most commonly reported blood Phe recommendations in U.S. clinics are 2-6 mg/dL for individuals < 12 years and 2-10 mg/dL for persons more than 12 years of age. Frequent monitoring of blood levels of Phe is necessary especially during the early years of life, with less frequent monitoring as age increases. Current practices relative to the frequency of monitoring during the first year vary from once every week to once a month, with once a week being more common. Frequencies after 1 year of age range from once every month to once every 3 months, with monitoring occurring approximately once a month by 18 years of age in most U.S. clinics. Surveys of clinical practices suggest that most clinics advocate lifelong dietary treatment for metabolic control of blood Phe levels. Reinstitution of diet after discontinuation is very difficult and requires expertise in issues of adherence. Issues pertaining to adherence, cost of treatment, independence, and prepregnancy management become salient during adolescence and young adulthood. Somatic gene therapy for PKU is currently being explored in animal model studies and holds promise for the possible treatment for PKU in the future. Other avenues involving enzymes that degrade Phe in the digestive system also hold promise. Supplementation of diet with a variety of additives has not borne fruit, but is an active area of research.

Efficacy of Treatments for Early-Treated PKU Questions remain concerning the extent to which individuals treated early for PKU demonstrate subtle problems involving cognitive functions, school achievement, behavioral adjustment, and quality of life. Related issues concern how early to begin treatment, effects of fluctuations in metabolic control, level of optimal metabolic control, and relaxation of metabolic control. Controversy surrounds these issues. Many studies of intellectual, cognitive, and behavioral outcomes have attempted to address treatment efficacy. There are limitations to these studies, however, including small samples, inconsistent use of comparison groups, and excessive reliance on intelligence tests as the primary outcome

18 Phenylketonuria

measure. Given this situation, the panel carefully reviewed the literature and commissioned an empirical synthesis of these studies via meta-analysis. Although many individuals with PKU manifest no cognitive and behavioral deficits, many comparisons of individuals with PKU to controls show lower performance on IQ tests, with larger differences in other cognitive domains. Children with PKU score somewhat lower than expected on IQ tests based on parent and sibling IQs, but their performance is still in the average range. Evidence for differences in behavioral adjustment is inconsistent despite anecdotal reports suggesting greater risk for internalizing psychopathology and attention disorders. The mechanism mediating this phenotypic variation is unknown, and current hypotheses are inadequate for accounting for this variation. Age at treatment initiation and level of metabolic control clearly influence outcomes. There is an inverse relationship between age at treatment initiation and IQ even in early treated PKU. Moreover, new evidence suggests that high plasma Phe levels during the first 2 weeks of life can affect the structural development of the visual system. Although the visual deficits are mild, this warrants efforts at earlier treatment initiation. The degree of metabolic control is related to the development of cognitive skills and behavioral adjustments. Those with poorer metabolic control, i.e., elevated Phe levels, show significantly lower scores on measures of IQ, attention, and reaction time. Similarly, levels of Phe show moderate relationships with performance on measures of cognitive functions and the presence of behavioral difficulties. These studies combine results from children and adults who vary widely in age, but the evidence suggests that good metabolic control is associated with better cognitive performance across the lifespan. Dietary discontinuance before 8 years of age is associated with poorer performance on measures of IQ. The effects of dietary discontinuance at older ages (12 years and above) are less clear. Adults with PKU who are not on restricted diets show stable IQ scores, but also manifest poorer performance on measures of attention and speed of processing. Thus, European countries do not recommend complete discontinuance of the restricted diet. Higher levels of Phe are accepted with frequent monitoring. Evidence shows that the individual with PKU must be maintained on a lifelong restricted Phe diet, though some relaxation may be tolerable, in some cases, as the individual ages.

Guidelines 19

Adherence to Treatment Regimens The treatment of PKU is complex, requiring regular collection of blood samples, recording of food intake, maintenance of a highly restrictive diet, and regular and frequent visits to a PKU clinic. Barriers to adherence include factors associated with the treatment regimen itself, as well as economic resources, psychosocial issues, social and emotional factors, and health care system issues. A coordinated approach to the treatment of PKU is required, necessitating development of a comprehensive, multidisciplinary, integrated system for delivery of care. Crucial to achieving adherence to treatment is assurance of equal access to routine monitoring and care, including periodic monitoring; initial and ongoing patient and family education; patient followup by physicians, dieticians, nurses, social workers, and other members of the health care team; and low- or no-Phe medical foods and modified lowprotein foods. Adherence improves if individuals with PKU have a social support system, positive attitudes regarding the benefits of treatment, and a belief that PKU is manageable in their daily lives. Creative use of community and regional-based support mechanisms hold promise for improving adherence to the comprehensive PKU treatment regimen. Metabolic Control in Women of Child Bearing Age Metabolic control in women planning conception and those whose pregnancies are unplanned is important because of the serious consequences to the fetus exposed to elevated Phe levels in-utero. Most observed adverse consequences reflect processes that originate in the first trimester. The fetus is vulnerable to potentially serious sequelae, which include microcephaly, mental deficiency, and congenital heart disease. There is a strong relationship between increasing levels of Phe and abnormalities in the neonate. Reports indicate that fetuses exposed to maternal Phe levels of 3-10 mg/dL had a 24 percent incidence of microcephaly, while those exposed to levels > 20 mg/dL had a 73 percent incidence. Similarly, congenital heart disease was not seen among offspring of women with Phe levels < 10 mg/dL and 12 percent for levels > 20 mg/dL. Recent data indicate that levels of Phe above 6 mg/dL during pregnancy are associated with significant linear decrements in the IQ of the child through 7 years of age.

20 Phenylketonuria

Unfortunately, few women who have discontinued dietary treatment achieve metabolic control preconception and maintain it during pregnancy. The acceptable target levels vary among U.S. clinics, with some considering targets < 10 mg/dL acceptable, with others considering a more liberal target < 15 mg/dL acceptable. These levels are higher than the current United States Maternal Phenylketonuria Collaborative Study recommendation of 2-6 mg/dL. British and German standards set lower acceptable target ranges (14 mg/dL). Several interventions have been used to increase adherence to diet, including mentoring by well-trained mothers of children with PKU and peer counseling. British guidelines for PKU management strongly recommend strategies to help children take responsibility for their own diets and blood testing by school age, thus preparing them to be more responsible for their own care when they are contemplating conception.

Lifelong Management and Follow-up Comprehensive Approach to Lifelong Care A programmatic, multidisciplinary approach to lifelong care is required for the treatment of PKU with sensitivity to the transition from screening to treatment. Continuity of care from infancy through adulthood is considered medically necessary for optimal outcomes for individuals with PKU. Treatment guidelines should be established that are consistent across U.S. clinical facilities that serve individuals with PKU and their families so they can expect consistent treatment. Equal access to treatment for all individuals with PKU is highly desirable. Current barriers to access include inconsistent policies on the part of third-party payers, Medicaid/Medicare, and other State and Federal entities concerning funding of medical foods and lowprotein products, followup for metabolic control, and psychosocial support and educational programs. Mandated screening for PKU implies a societal responsibility for comprehensive long-term followup and treatment. Outcome monitoring should consist of periodic intellectual, neurological, neuropsychological, and behavioral assessment. Access to medical foods is essential for maintenance of metabolic control throughout life. Specialized medical foods and low-protein products are a medical necessity and should be treated as such. Reimbursement for these medical foods and products should be covered by third-party providers.

Guidelines 21

Age of Initiation of Treatment for Infants with PKU Treatment of neonates born with PKU should be initiated as soon as possible, but no later than 7-10 days after birth. Phe levels should be reduced as rapidly as possible. Breast-feeding is encouraged along with Phe-free formula. Because of the need for early initiation of treatment, hospitals should ensure that screening samples are sent for analyses within 24 hours of collection and results are returned to responsible parties within 7 days of an infant's birth.

Recommended Levels of Phe for Classical PKU Maintenance of Phe levels between 2-6 mg/dL for neonates through 12 years of age appears to be medically necessary for ensuring optimal outcome. Furthermore, in light of findings that Phe levels are related to cognitive function in adolescents and adults, it is recommended that Phe levels be maintained between 2-15 mg/dL after 12 years of age. Considering the paucity of data on the relationship between Phe level and brain function after 12 years of age, and the fact that brain development is ongoing during adolescence, even lower Phe levels (between 2-10 mg/dL) are strongly encouraged during this age period. Related to achievement of these levels, treatment decisions need to consider factors related to individual differences in inherent metabolic control, gender, age, childbearing status, and behavioral and cognitive functioning.

Frequency of Phe Monitoring The frequency of Phe monitoring will vary according the individual's needs. Suggested guidelines are as follows: (a) once weekly during the first year; (b) twice monthly from 1-12 years of age; (c) monthly after 12 years of age; and (d) twice weekly during pregnancy of a woman with PKU. There should be increased emphasis on patient participation in monitoring programs with age, and recognition that individual factors, such as inherent metabolic control, age, and child-bearing status, will influence decisions regarding frequency of monitoring. Development of a reliable home-testing method is recommended, as well as measures to increase adherence.

22 Phenylketonuria

Duration of Dietary Treatment The goal in the treatment of PKU is to maintain metabolic control of Phe for optimal adaptation and outcome. Treatment will vary to some extent depending on each individual's characteristics. To achieve optimal metabolic control and outcome, a restricted-Phe diet, including medical foods and lowprotein products, most likely will be medically required for virtually all individuals with classical PKU for their entire lifetimes. Although no definitive studies on the effects of dietary treatment in adults exist, data suggest that elevated Phe levels in adolescents and adults adversely affect aspects of cognitive function, and individual case reports have documented deterioration of adult PKU patients after diet discontinuation. Persons who have discontinued the diet should contact their clinic or treating physician(s) to evaluate the need or advisability of resuming dietary treatment.

Maternal PKU It is recommended that Phe levels below 6 mg/dL be achieved at least 3 months before conception. Therefore, outreach and educational programs for adolescents and women of child-bearing age, which focus on social support, positive attitudes toward metabolic control of Phe and its effectiveness, family planning, conscious reproductive choice, and information related to the management of maternal PKU, are strongly recommended. Participation in such programs should occur before planned pregnancy so that optimal metabolic control of Phe can be obtained before conception. If conception occurs when the woman is not in metabolic control, counseling should be offered. Metabolic control should be achieved as soon as possible, and monitoring of Phe levels should occur twice weekly, at a minimum, once per week. The recommended level is 2-6 mg/dL during pregnancy. Focusing on the overall nutritional status of the pregnant mother, including intake of vitamins (folic acid and vitamin B12, in particular), and other nutrients is essential. Furthermore, a comprehensive approach that provides psychosocial support for the family as a whole and continuity of care for infants should be developed and followed. Parenting classes that focus on infant stimulation and maternal mental health (e.g., maternal depression) and adherence to dietary treatment may be indicated for high-risk mothers. Social support systems are especially important in such instances.

Guidelines 23

Screening and Treatment of Previously Untreated Patients Individuals with mental retardation and/or severe behavioral disturbances of undetermined etiology, such as hyperactivity, aggression, self-injurious behavior, and pica, should be screened for PKU regardless of the individual's age. Individuals with mental retardation due to PKU who are experiencing severe behavioral disturbances should be considered for dietary treatment lasting for at least 6 months, because metabolic control has been reported to improve behavior in such patients.

Uniform Standards States should adopt a uniform definition of the Phe level for establishing the diagnosis of PKU and non-PKU hyperphenylalaninemia. Standardized reporting of data must include the number of individuals with PKU and non-PKU hyperphenylalaninemia, the number of individuals tested, and reports by gender and self-reported ethnicity.

Genotyping Mutation analysis and genotype determination should be accomplished on all persons with PKU for initial diagnosis, genetic and management counseling, followup, and long-term prognosis. Additional laboratories capable of performing genotype analysis will need to be developed. Optimal therapeutic management might in time require mutation analysis. Information about mutation frequency can be useful for calculating allele frequency and incidence of PKU.

Storage and Use of Samples States and others who store samples should develop a policy that addresses the following issues surrounding the storage and use of blood samples remaining after newborn screening: ·

Length of time that all samples will be stored.

·

Ownership of samples.

·

Uses, other than the followup of newborn screening, which will be allowed and under what conditions.

·

Informed consent procedures.

24 Phenylketonuria

Development of a Systems-Oriented Program for Screening Newborn screening strategies should take a total systems approach. This system needs to include the following: ·

A method for sending samples to the laboratory for analysis within 24 hours of collection.

·

A standard approach nationwide of reporting abnormal results that leads to the referral of the newborn into appropriate care for diagnostic evaluation and management.

·

Assurance that infants and families have access to the full complement of services necessary to treat the disorder (i.e., physicians, geneticists, dietitians, and other health care professionals with expertise in treatment of metabolic disorders, genetic counseling, nursing, psychological and social services, medical food protein sources, and age-appropriate lowprotein modified products).

·

Clinical services that meet the needs of the adolescent and adult individual with PKU. New Laboratory Technologies

Adoption of new laboratory technologies should be based upon benefits to the screened population, improvements in sensitivity and specificity of testing, and cost effectiveness. Instrumentation that quantitatively measures Phe and tyrosine concentrations is beneficial in the early positive identification of PKU, while reducing the incidence of false-positive results. Any new laboratory technology must be thoroughly evaluated and carefully implemented to avoid temporary or long-term negative effects on established PKU screening programs.

Regionalization Often, especially for States with smaller populations, regional associations for PKU screening and therapeutic oversight will provide greater laboratory and patient care efficiencies and will promote common standards.

Guidelines 25

Research Is Needed ·

Studies are needed to determine the relationship between variations in the behavioral and neural phenotypes associated with blood phenylalanine concentrations. These phenotypes should be based on quantitative assessment of brain structure and function, and contemporary neuropsychological assessment. Research on basic pathophysiology is essential.

·

What is the relationship between genetic mutation and phenotypic variation in PKU?

·

What aspects of treatment programs are associated with optimal longterm outcomes? Potential factors that include genetic variation, sociodemographic predictors, age, duration of treatment, and Phe levels should be studied.

·

Evaluation and analyses are necessary to measure the clinical utility, validation, and cost effectiveness of the use of tandem mass spectrometry for screening PKU. This evaluation should include awareness of broader issues of its application to neonatal screening for a variety of genetic disorders.

·

Longitudinal studies of treated PKU individuals to study effects of aging on PKU persons should be performed.

·

Evaluation of various modalities to increase dietary adherence in preconceptional and maternal PKU is indicated.

·

Studies are needed to identify the factors that enhance maintenance of metabolic control throughout life, which could be used for program development. It will be important to evaluate the effects of variations in metabolic control on cognitive functions and behavioral adjustment, especially in adolescents and adults.

·

Investigations should examine a wide range of potential new treatments other than medical nutritional therapy for PKU to include, at a minimum, enzymes that might degrade Phe in the intestine, the role of LNAA, tetrahydrobiopterin supplementation and the potential role of somatic gene therapy. PKU animal model(s) will be valuable in these studies.

·

Research studies on individuals who did not receive early treatment for PKU, including those in institutions, would be valuable.

26 Phenylketonuria

Conclusions ·

Genetic testing for PKU has been in place for almost 40 years and has been very successful in the prevention of severe mental retardation in thousands of children and adults. Many questions, however, remain unanswered.

·

Metabolic control is necessary across the lifespan of individuals with PKU.

·

A comprehensive, multidisciplinary, integrated system is required for the delivery of care to individuals with PKU.

·

Greatly needed are consistency and coordination among screening, treatment, data collection, and patient support programs.

·

There should be equal access to culturally sensitive, age-appropriate treatment programs.

·

Ethically sound, specific policies for storage, ownership, and use in future studies of archived samples remaining from PKU testing should be established.

·

Research into the pathophysiology of PKU and relationship to genetic, neural, and behavioral variation is strongly encouraged.

·

Uniform policies need to be established to remove from the individual and the family financial barriers to the acquisition of medical foods and modified low-protein foods, as well as to provide access to support services required to maintain metabolic control in individuals with PKU.

·

Research on nondietary alternatives to treatment of PKU is strongly encouraged.

·

To achieve optimal statistical power, as well as cross-cultural applicability, it will be beneficial to use data acquired via national and international collaboration.

More Guideline Sources The guideline above on phenylketonuria is only one example of the kind of material that you can find online and free of charge. The remainder of this chapter will direct you to other sources which either publish or can help you find additional guidelines on topics related to phenylketonuria. Many of the guidelines listed below address topics that may be of particular relevance to your child’s specific situation, while certain guidelines will apply to only some children with phenylketonuria. Due to space limitations these sources

Guidelines 27

are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly.

Topic Pages: MEDLINEplus For parents wishing to go beyond guidelines published by specific Institutes of the NIH, the National Library of Medicine has created a vast and parentoriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages.” You can think of a health topic page as a guide to patient guides. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following as being relevant to phenylketonuria: ·

Guides On phenylketonuria Phenylketonuria http://www.nlm.nih.gov/medlineplus/phenylketonuria.html Phenylketonuria http://www.nlm.nih.gov/medlineplus/ency/article/001166.htm

·

Guides on Human Anatomy and Systems Brain and Nervous System Topics http://www.nlm.nih.gov/medlineplus/brainandnervoussystem.htm l Genetics/Birth Defects Topics http://www.nlm.nih.gov/medlineplus/geneticsbirthdefects.html

·

Other Guides Epilepsy http://www.nlm.nih.gov/medlineplus/ency/article/000694.htm Mental retardation http://www.nlm.nih.gov/medlineplus/ency/article/001523.htm

Within the health topic page dedicated to phenylketonuria, the following was recently recommended to parents:

28 Phenylketonuria

·

General/Overviews PKU Source: March of Dimes Birth Defects Foundation http://www.modimes.org/HealthLibrary/334_607.htm What is PKU? Source: University of Washington PKU Clinic http://depts.washington.edu/pku/whatis.html

·

Diagnosis/Symptoms How Is Phenylketonuria Diagnosed? Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/ygyh/mason/ygyh.html?sect ion=diagnosis&syndrome=pku&video=0

·

Nutrition Aspartame - What the Body Does With It Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=HQ00267 Look-Alike Foods: A Solution or a Pandora's Box? Source: img src='/medlineplus/images/linkpdf.gif' width='100' height='17' border=0 alt='Links to PDF File'> (University of Washington PKU Clinic http://depts.washington.edu/pku/pdfs/lookalike.pdf What is the Diet for PKU? Source: University of Washington PKU Clinic http://depts.washington.edu/pku/diet.html

·

Specific Conditions/Aspects How Is Phenylketonuria Inherited? Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/ygyh/mason/ygyh.html?sect ion=inherited&syndrome=pku&video=0 Introduction to Drug Products Containing Phenylalanine Source: National PKU News http://205.178.182.34/diet/aspartame.htm

Guidelines 29

What Causes Phenylketonuria? Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/ygyh/mason/ygyh.html?sect ion=cause&syndrome=pku&video=0 ·

Lists of Print Publications Phenylketonuria (PKU): Screening and Management Source: National Library of Medicine http://www.nlm.nih.gov/pubs/cbm/pku.html

·

Organizations March of Dimes Source: March of Dimes Birth Defects Foundation http://www.modimes.org/ National Institute of Child Health and Human Development http://www.nichd.nih.gov/ National PKU News http://205.178.182.34/index.htm Your Genes, Your Health Source: Dolan DNA Learning Center http://www.yourgenesyourhealth.org/ygyh/

·

Prevention/Screening Newborn Screening Tests Source: March of Dimes Birth Defects Foundation http://www.modimes.org/HealthLibrary/334_595.htm

·

Teenagers Off-Diet Young Adults with PKU: Lives in Danger Source: National PKU News http://205.178.182.34/adults/Livesin.htm

If you do not find topics of interest when browsing health topic pages, then you can choose to use the advanced search utility of MEDLINEplus at http://www.nlm.nih.gov/medlineplus/advancedsearch.html. This utility is similar to the NIH Search Utility, with the exception that it only includes material linked within the MEDLINEplus system (mostly parent-oriented information). It also has the disadvantage of generating unstructured results.

30 Phenylketonuria

We recommend, therefore, that you use this method only if you have a very targeted search.

The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and educational guidelines on phenylketonuria and related conditions. One of the advantages of CHID over other sources is that it offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: ·

NutraSweet Use During Pregnancy Source: Deerfield, IL: NutraSweet Company. 1990. 4 p. Contact: Available from NutraSweet Consumer Center. P.O. Box 830, Deerfield, IL 60015. (800) 321-7254 or (708) 405-7679. PRICE: Single copy free. Summary: This brief brochure describes NutraSweet brand sweetener: what it is and why it is safe for use during pregnancy and breast feeding. The brochure presents evidence to show that NutraSweet is safe for the general population, including children and pregnant and breast-feeding women. Two figures compare the components of NutraSweet with those found in common dietary items including milk, tomato juice, and hamburger. A brief sidebar presents information about phenylketonuria.

·

NutraSweet Use During Pregnancy: Information for the Health Care Provider Source: Deerfield, IL: NutraSweet Company. 1990. 8 P. Contact: NutraSweet Company. The NutraSweet Center, Box 830, 01751 Lake Cook Road, Deerfield, IL 60015. (800)321-7254. PRICE: Single copy free. Summary: This brochure presents information for health care providers on the safety of aspartame (NutraSweet) during pregnancy. Topics covered include the chemical composition of aspartame, a summary of preclinical studies of aspartame, clinical studies of aspartame and its effects, information about phenylketonuria, phenylalanine blood levels, acute and chronic clinical studies conducted with aspartame, aspartame

Guidelines 31

use in normal pregnant women, and the safety of aspartame use for pregnant women. A contact address and toll-free telephone number for NutraSweet is included. ·

Teacher's Guide to PKU Source: Austin, TX, Texas Department of Health, Literature and Forms Division, 14 p., July 1985. Contact: Texas Department of Health, Literature and Forms Division, 1100 West 49th Street, Austin, TX 78756. (512) 458-7700. (TDH Stock No. 1-65). Summary: A Teacher's Guide To PKU, developed by the Arizona Department of Health Services and distributed by the Texas Department of Health, is a booklet that explains the facts about phenylketonuria (PKU). The booklet describes what PKU is and how parents can help the situation. A question and answer section provides information about often-asked topics surrounding this disease. A section lists activities that can be conducted in the classroom to help classmates understand the child with PKU. The brochure also gives references and phone numbers for more contact information.

·

All about maternal PKU Source: Williamsville, NY: People, Inc. ca. 1993. 4 pp. Contact: Available from People, Inc., 1219 North Forest Road, Williamsville, NY 14221-3230. Summary: This short brochure conveys to pregnant women with phenylketonuria (PKU) the importance of taking dietary precautions to protect the fetus from the effects of high levels of phenylalanine (phe) in the mother's blood. These effects can include mental retardation, heart disease, and low birthweight. The low-phe diet is briefly described.

·

Children's PKU Network Source: San Diego, CA: Children's PKU Network. 8 p. Contact: Available from Children's PKU Network. P.O. Box 910312, San Diego, CA 92191-0312. (619) 587-9421. Price: Free. Summary: There are over 5 million Americans (1 in 50) who are symptomless carriers of the gene which causes phenylketonuria (PKU). Approximately one of every 10,000 newborns in the United States has the disease. Established in 1991, the Children's PKU Network, Inc., is a national non-profit organization dedicated to addressing the special

32 Phenylketonuria

needs and concerns of those living with PKU and similar metabolic disorders.

The National Guideline Clearinghouse™ The National Guideline Clearinghouse™ offers hundreds of evidence-based clinical practice guidelines published in the United States and other countries. You can search their site located at http://www.guideline.gov by using the keyword “phenylketonuria” or synonyms. The following was recently posted: ·

Maternal phenylketonuria. Source: American Academy of Pediatrics.; 2001 February; 2 pages http://www.guideline.gov/FRAMESETS/guideline_fs.asp?guideline=00 2003&sSearch_string=phenylketonuria

·

Phenylketonuria: screening and management. Source: National Institute of Child Health and Human Development/National Institutes of Health (NIH) Consensus Development Panel on Phenylketonuria Screening and Management.; 2000 October 18; 28 pages http://www.guideline.gov/FRAMESETS/guideline_fs.asp?guideline=00 1942&sSearch_string=phenylketonuria

Healthfinder™ Healthfinder™ is an additional source sponsored by the U.S. Department of Health and Human Services which offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: ·

Phenylketonuria (PKU) Summary: This public health education information fact sheet provides general information about this genetic disorder including causes, diagnosis, treatment and symptom prevention. Source: March of Dimes Birth Defects Foundation http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=3268

Guidelines 33

·

Phenylketonuria (PKU): Screening and Management Summary: This NIH consensus statement covers the incidence and prevalence of phenylketonuria (PKU), screening strategies, strategy effectiveness, and treatment regimens. Source: National Institutes of Health, U.S. Department of Health and Human Services http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&R ecordID=6336 The NIH Search Utility

After browsing the references listed at the beginning of this chapter, you may want to explore the NIH Search Utility. This allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEBSPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to phenylketonuria. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and parents. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html.

NORD (The National Organization of Rare Disorders, Inc.) NORD provides an invaluable service to the public by publishing, for a nominal fee, short yet comprehensive guidelines on over 1,000 medical conditions. NORD primarily focuses on rare medical conditions that might not be covered by the previously listed sources. NORD’s Web address is www.rarediseases.org. To see if a recent fact sheet has been published on phenylketonuria, simply go to the following hyperlink: http://www.rarediseases.org/cgi-bin/nord/alphalist. A complete guide on phenylketonuria can be purchased from NORD for a nominal fee.

34 Phenylketonuria

Additional Web Sources A number of Web sites that often link to government sites are available to the public. These can also point you in the direction of essential information. The following is a representative sample: ·

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

·

drkoop.comÒ: http://www.drkoop.com/conditions/ency/index.html

·

Family Village: http://www.familyvillage.wisc.edu/specific.htm

·

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

·

Med Help International: http://www.medhelp.org/HealthTopics/A.html

·

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

·

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

·

WebMDÒHealth: http://my.webmd.com/health_topics

Vocabulary Builder The material in this chapter may have contained a number of unfamiliar words. The following Vocabulary Builder introduces you to terms used in this chapter that have not been covered in the previous chapter: Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]

Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Chronic: Persisting over a long period of time. [EU] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents, characterized in the acute stage by

Guidelines 35

erythema, edema associated with a serous exudate between the cells of the epidermis (spongiosis) and an inflammatory infiltrate in the dermis, oozing and vesiculation, and crusting and scaling; and in the more chronic stages by lichenification or thickening or both, signs of excoriations, and hyperpigmentation or hypopigmentation or both. Atopic dermatitis is the most common type of dermatitis. Called also eczematous dermatitis. [EU] Enzyme: A protein molecule that catalyses chemical reactions of other substances without itself being destroyed or altered upon completion of the reactions. Enzymes are classified according to the recommendations of the Nomenclature Committee of the International Union of Biochemistry. Each enzyme is assigned a recommended name and an Enzyme Commission (EC) number. They are divided into six main groups; oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Individuality: Those psychological characteristics which differentiate individuals from one another. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Neonatal: Pertaining to the first four weeks after birth. [EU] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of the spinal axis, as the neutral arch. [EU] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Pediatrics: A medical specialty concerned with maintaining health and providing medical care to children from birth to adolescence. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of YEASTS. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH]

36 Phenylketonuria

Preclinical: Before a disease becomes clinically recognizable. [EU] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Somatic: 1. pertaining to or characteristic of the soma or body. 2. pertaining to the body wall in contrast to the viscera. [EU] Toxic: Pertaining to, due to, or of the nature of a poison or toxin; manifesting the symptoms of severe infection. [EU] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH]

Seeking Guidance 37

CHAPTER 2. SEEKING GUIDANCE Overview Some parents are comforted by the knowledge that a number of organizations dedicate their resources to helping people with phenylketonuria. These associations can become invaluable sources of information and advice. Many associations offer parent support, financial assistance, and other important services. Furthermore, healthcare research has shown that support groups often help people to better cope with their conditions.8 In addition to support groups, your child’s physician can be a valuable source of guidance and support. In this chapter, we direct you to resources that can help you find parent organizations and medical specialists. We begin by describing how to find associations and parent groups that can help you better understand and cope with your child’s condition. The chapter ends with a discussion on how to find a doctor that is right for your child.

Associations and Phenylketonuria In addition to associations or groups that your child’s doctor might recommend, we suggest that you consider the following list (if there is a fee for an association, you may want to check with your child’s insurance provider to find out if the cost will be covered):

Churches, synagogues, and other houses of worship might also have groups that can offer you the social support you need. 8

38 Phenylketonuria

·

Association for Neuro-Metabolic Disorders Address: Association for Neuro-Metabolic Disorders 5223 Brookfield Lane, Sylvania, OH 43560-1809 Telephone: (419) 885-1497 Toll-free: (800) 433-5255 Email: [email protected] Background: The Association for Neuro-Metabolic Disorders is a national not-for- profit voluntary organization that is composed of families with children who have metabolic disorders that affect the central nervous system and brain. Established in 1981, the Association shares support and information with other members through a variety of activities. These include a yearly parent conference featuring discussions by experts on neuro-metabolic disorders; an annual family picnic; informal meetings; and phone calls with concerned parents. Other activities include formal lobbying and educational efforts; contact with similar organizations throughout the United States and other countries; and expanded efforts in offering support to teens and adults with neuro-metabolic disorders. The Association produces a brochure and regular newsletter. Relevant area(s) of interest: Phenylketonuria

·

Canadian Society for Metabolic Disease Address: Canadian Society for Metabolic Disease 3134 Plimsoll Street, Coquitlam, British Columbia, V3C 3X6, Canada Telephone: (604) 464-1017 Toll-free: (800) 945-2188 Fax: (604) 464-1016 Email: [email protected] Web Site: Non Background: The Canadian Society for Metabolic Disease (CSMD) is an international voluntary not-for-profit organization dedicated to providing information, support, and resources to parents of children with metabolic disorders. The term 'metabolism' refers to the complex chemical processes in organisms that result in generation of energy, growth, waste elimination, and other bodily functions. Inborn errors of metabolism are genetic disorders in which a particular substance (enzyme) that promotes a metabolic reaction is absent or deficient. The symptoms and physical findings associated with particular metabolic disorders may vary greatly in range and severity. Many such disorders may affect the brain and spinal cord (central nervous system), potentially resulting in uncontrolled episodes of electrical disturbances in the brain (seizures), mental retardation, developmental delay, and/or other

Seeking Guidance 39

abnormalities. In some cases, additional symptoms and physical findings may occur in association with certain metabolic disorders including abnormally diminished muscle tone (hypotonia); failure to grow and gain weight at the expected rate (failure to thrive); progressive visual and/or hearing impairment; abnormal enlargement of certain organs; abnormal yellowish discoloration of the skin, the mucous membranes, and the whites of the eyes (jaundice); kidney abnormalities; and/or other findings. In some cases, life-threatening complications may result. The Canadian Society for Metabolic Disease was established in 1988 and currently has approximately 180 members. The Society is committed to providing a forum where parents and professionals may exchange knowledge and experience; supporting and promoting research into improved diagnosis, more effective treatments, and potential cures; and creating a central pool of information for each metabolic disease of interest to its members. In addition, the Society is dedicated to promoting a greater understanding concerning the detection, treatment, and control of metabolic disease; working with government to improve services for families of children with special needs; educating the public about metabolic disease; and encouraging information sharing in an effort to improve the management of such disorders. The Canadian Society for Metabolic Disease also offers a variety of educational materials including brochures and a regular newsletter. Relevant area(s) of interest: Phenylketonuria ·

Centre for Rare Disorders (Norway) Address: Centre for Rare Disorders (Norway) Web Site on the Internet, Telephone: 0845 603 9136 Toll-free: (800) 945-2188 Email: [email protected] Web Site: http://rhpc205.uio.no/ssss/English/engindex.ht Background: The Centre for Rare Disorders (Norway) at The National Hospital in Oslo is a project under the Government Action Plan for the Handicapped. The objective of the project is to develop a model for improving the organization and implementation of the services available for persons with rare disorders in Norway. The Centre has been a trial project from 1994-1995. The Ministry of Health and Social Affairs prolonged the project by two years so that the present activities will continue through 1997. Within this period, the Government will have approved the subsequent mode of operation. The Centre currently has responsibilities related to 15 rare disorders and syndromes. The Centre is located in The National Hospital since many patients with these disorders visit this hospital concerning diagnosis, treatment, and/or

40 Phenylketonuria

follow-up. Use is made of the medical expertise at the hospital when the Centre works on the disorders. The Centre also establishes close cooperation with other regional hospitals, central hospitals, and rehabilitation services. The Centre's main goals are to disseminate information and coordinate assistance given to affected individual and their families. The Centre is a source of information and knowledge that affected individuals, relatives, and professionals at all levels can contact about facts related to a disorder. The information is collected, systematized, edited, and disseminated by the Centre, thus increasing local qualifications in relation to a rare disorder. The Centre is not meant to replace existing offers of treatment, but supplements the municipal and regional services. The Centre's web site includes detailed information on the 15 rare disorders and syndromes it is dedicated to supporting; includes links to information on several resources including habilitation services, family counseling, mental health services, special education, etc.; and includes dynamic links to several additional web sites that may provide additional helpful information. Relevant area(s) of interest: Phenylketonuria ·

Children's PKU Network Address: Children's PKU Network 1520 State Street, Suite 111, San Diego, CA 92101 Telephone: (619) 233-3202 Toll-free: (800) 433-5255 Fax: (619) 233-0838 EBackground: The Children's PKU Network (CPN) is a not-for-profit organization dedicated to providing support and services to children with Phenylketonuria (PKU), their families, and all those involved in the treatment of this disorder. PKU is a metabolic disorder characterized by severe mental retardation, seizures, and/or other abnormalities that may be prevented through early restriction of dietary phenylalanine. The Network serves as a central operational base to assist in the gathering and dissemination of information on PKU and other related disorders, operates a national network hotline to provide PKU families with information about PKU clinics and support groups in their area, seeks to educate legislators concerning the needs of PKU families, and establishes programs for college scholarships, crisis intervention, and research. The Children's PKU Network also provides a variety of educational and support materials through its informational database, regular newsletter, reprints of medical journal articles, pamphlets, booklets, brochures, videos, and materials specifically for affected children. Relevant area(s) of interest: Hyperphenylalaninemia, Phenylketonuria

Seeking Guidance 41

·

March of Dimes Birth Defects Foundation Address: March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue, White Plains, NY 10605 Telephone: (914) 428-7100 Toll-free: (888) 663-4637 Fax: (914) 997-4763 Email: [email protected] Web Site: http://www.modimes.or Background: The March of Dimes Birth Defects Foundation is a national not-for- profit organization that was established in 1938. The mission of the Foundation is to improve the health of babies by preventing birth defects and infant mortality. Through the Campaign for Healthier Babies, the March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the Foundation and to that end it produces a wide variety of printed informational materials and videos. The March of Dimes public health educational materials provide information encouraging health- enhancing behaviors that lead to a healthy pregnancy and a healthy baby. Relevant area(s) of interest: Down Syndrome, Fragile X Syndrome, Klinefelter Syndrome, McCune Albright Syndrome, Phenylketonuria

·

Metabolic Information Network (PHYSICIAN CALLS ONLY) Address: Metabolic Information Network (PHYSICIAN CALLS ONLY) P.O. Box 670847, Dallas, TX 75367-0847 Telephone: (214) 696-2188 Toll-free: (800) 945-2188 Fax: (214) 696-3258 Email: [email protected] Background: The Metabolic Information Network (MIN) is a not-forprofit organization dedicated to facilitating research and enhancing care of families affected by inborn errors of metabolism. Established in 1989, the organization publishes a newsletter, a directory, and reports. The Network maintains a Case Register for 10 groups of disorders (representing 86 diagnoses); a physician directory for 200 inborn errors of metabolism; and a listing of worldwide genetic, and a listing of worldwide genetic metabolic patient registries and patient databases. Research investigators and other health care professionals may use the MIN database. Information in the case database for any genetic metabolic disorder includes contact information, relevant diagnoses based on McKusick Codes, 1CD9 codes, and whether tracking/outcome

42 Phenylketonuria

assessment is performed. The progress of these cases is tracked on an annual basis. The MIN case and master databases contain no patient names. Research investigators and other professionals may obtain individual case details only by contacting physicians associated with a particular case recorded in the database. Relevant area(s) of interest: Phenylketonuria ·

National PKU Foundation Address: National PKU Foundation 6301 Tejas Drive, Pasadena, TX 77503 Telephone: (281) 487-4802 Toll-free: (800) 433-5255 Fax: (281) 487-208 Background: The National PKU Foundation is a voluntary not-for-profit organization dedicated to promoting awareness of Phenylketonuria (PKU). This is a rare metabolic disorder of infancy caused by a deficiency of the liver enzyme phenylalanine hydroxylase. Impairment in the metabolism of the amino acid phenylalanine results in excess accumulation of phenylalanine. Phenylketonuria is a severe progressive disorder that can produce mental retardation if it is not treated early. The National PKU Foundation provides parents of affected children with information and support, engages in patient advocacy, and promotes and supports research. Relevant area(s) of interest: Phenylketonuria

·

National PKU News Address: National PKU News 6869 Woodlawn Avenue NE Number 116, Seattle, WA 98115-5469 Telephone: (206) 525-8140 Toll-free: (800) 433-5255 Fax: (206) 525-5023 Email: [email protected] Web Site: http://pkunews.or Background: National PKU News is a not-for-profit organization devoted to providing news and information to all persons involved in the treatment of Phenylketonuria (PKU). This is a rare metabolic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase. Impairment in the metabolism of the amino acid phenylalanine results in excess accumulation of phenylalanine. Phenylketonuria is a severe progressive disorder that, if not treated early, can produce mental retardation. Founded in 1989, National PKU News publishes a newsletter three times a year and has approximately 2,000 subscribers from the

Seeking Guidance 43

United States, Canada, and 30 foreign countries. National PKU News also publishes educational materials regarding treatment of PKU. Food lists and cookbooks are also distributed by the organization. Relevant area(s) of interest: Phenylketonuria ·

National Society for Phenylketonuria (UK) Address: National Society for Phenylketonuria (UK) 7 Lingey Lane, Wardley, Gateshead, Tyne and Wear, NE10 8BR, United Kingdom Telephone: 0845 603 9136 Toll-free: (800) 945-2188 Email: [email protected] Web Site: http://web.ukonline.co.uk/nspku Background: The National Society for Phenylketonuria (NSPKU) is a nonprofit organization in the United Kingdom that is dedicated to providing information and support to people with phenylketonuria (PKU), their families, and their caregivers. PKU is a metabolic disorder characterized by deficiency of the enzyme phenylalanine hydroxylase, which is responsible for converting the amino acid phenylalanine into tyrosine. Without early diagnosis and restricted dietary intake of phenylalanine, an abnormal accumulation of phenylalanine may affect the normal growth and development of the brain, resulting in progressive, severe mental retardation. The National Society for Phenylketonuria was established in 1973. Its membership currently consists of over 900 families and individuals as well as more than 170 medical professionals. The Society is committed to offering a network of local support groups; conducting annual conferences as well as other events throughout the year; developing and distributing targeted publications, such as materials for people with PKU, parents, medical professionals, or other professionals, such as employers or teachers; and funding the analysis of foods and the provision of equipment for PKU genetic research. In addition, the Society publishes a quarterly newsletter entitled 'News and Views,' publishes a consensus paper from medical authorities on PKU entitled the 'Management of PKU,' and maintains a web site on the Internet. The Society's web site discusses the organization's mission and services, provides access to a recent edition of the Society's newsletter, offers updates on upcoming conferences and other events, provides a publication order form, and offers linkage to additional sources of information and support. Relevant area(s) of interest: Phenylketonuria

44 Phenylketonuria

·

Phenylalanine Hydroxylase Locus Database (PAHdb) Home Page Address: Phenylalanine Hydroxylase Locus Database (PAHdb) Home Page Web Site on the Internet, Telephone: 0845 603 9136 Toll-free: (800) 945-2188 Email: [email protected] Web Site: http://www.mcgill.ca/pahdb Background: The objectives of the Phenylalanine Hydroxylase Locus Database (PAHdb) web site are twofold. First, the site provides affected individuals, family members, health care professionals, and others with understandable information concerning phenylketonuria (PKU), an inborn error of metabolism characterized by progressive severe mental retardation, episodes of uncontrolled electrical disturbances of the brain (seizures), and/or other abnormalities that may be prevented through early restriction of dietary phenylalanine. The site posts the indepth booklet entitled the 'Montreal Children's Hospital's Hyperphenylalaninemia Resource Booklet for Families' and offers dynamic linkage to additional sources of information and support. The web site is also dedicated to providing researchers, physicians, and other interested individuals with access to current information concerning mutations of the phenylalanine hydroxylase (PAH) gene. The majority of such mutations result in deficient activity of the liver enzyme phenylalanine hydroxylase and abnormal accumulation and excretion of dietary phenylalanine (hyperphenylalaninemia). The most severe manifestation may be PKU, while, in other cases, affected individuals may have benign conditions that cause few or no apparent symptoms. PAH mutation data within the database is collated from both published articles as well as communications from approximately 90 investigators across the world who are members of the PAH Mutation Analysis Consortium. The database provides online users several searchable fields including mutation name, population, geographic location, gene region, mutation type, phenotype, author's name, etc. The complete information provided for each mutation is regularly updated from both published data and personal communications from consortium members. Relevant area(s) of interest: Phenylketonuria

·

Research Trust for Metabolic Diseases in Children Address: Research Trust for Metabolic Diseases in Children The Quadrangle, Crewe Hall, Weston Road, Crewe, Cheshire, CW1 6UR, United Kingdom Telephone: 1270 250221

Seeking Guidance 45

Fax: 1270 250244 Web Site: http://www.RTMDC.org.u Background: The Research Trust for Metabolic Diseases in Children (RTMDC) is an international voluntary health agency located in the United Kingdom. Established in 1981, the Trust is dedicated to furthering medical research into the nature of metabolic diseases in children; encouraging the ongoing investigations of the prenatal diagnosis of these diseases; providing information, counseling, and financial support to caregivers; and providing information to health care professionals. In addition, the organization is dedicated to assisting in the care of affected children in hospitals, homes, or institutions and educating the public about metabolic diseases. The Research Trust for Metabolic Diseases networks parents of affected children for mutual benefit and support. The Trust also provides a regular newsletter, brochures, videos, and other educational materials. Relevant area(s) of interest: Phenylketonuria ·

The Arc (a national organization on mental retardation) Address: The Arc (a national organization on mental retardation) 500 East Border Street, Suite 300, Arlington, TX 76010 Telephone: (817) 261-6003 Toll-free: (800) 433-5255 Fax: (817) 277-3491 Email: [email protected] Web Site: http://thearc.org Background: The Arc is the largest organization in the United States that is solely devoted to improving the lives of all children and adults with mental retardation. The organization offers support to families affected by mental retardation and fosters research and educational programs on the prevention of mental retardation. The Arc is committed to securing opportunities for all people with mental retardation. To this end, the organization emphasizes personal opportunities for choice in education, housing, employment, and entertainment. The Arc is further committed to reducing the incidence and limiting the consequences of mental retardation through research, advocacy, and mutual support. The Arc provides leadership in the field of mental retardation and develops necessary human and financial resources to attain its goals. In addition, the Arc provides a wide variety of educational materials for parents, teachers, health care professionals, and others, including a regular newsletter, handbooks, instruction packets, reports, booklets, audio-

46 Phenylketonuria

visual aids, posters, and brochures. Many materials are available in Spanish. Relevant area(s) of interest: Down Syndrome, Phenylketonuria

Finding More Associations There are a number of directories that list additional medical associations that you may find useful. While not all of these directories will provide different information than what is listed above, by consulting all of them, you will have nearly exhausted all sources for parent associations.

The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about phenylketonuria. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

DIRLINE A comprehensive source of information on associations is the DIRLINE database maintained by the National Library of Medicine. The database comprises some 10,000 records of organizations, research centers, and government institutes and associations which primarily focus on health and biomedicine. DIRLINE is available via the Internet at the following Web site: http://dirline.nlm.nih.gov. Simply type in “phenylketonuria” (or a synonym) or the name of a topic, and the site will list information contained in the database on all relevant organizations.

The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “phenylketonuria”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop

Seeking Guidance 47

boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” By making these selections and typing in “phenylketonuria” (or synonyms) into the “For these words:” box, you will only receive results on organizations dealing with phenylketonuria. You should check back periodically with this database since it is updated every 3 months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by specific medical conditions. You can access this database at the following Web site: http://www.rarediseases.org/cgi-bin/nord/searchpage. Select the option called “Organizational Database (ODB)” and type “phenylketonuria” (or a synonym) in the search box.

Online Support Groups In addition to support groups, commercial Internet service providers offer forums and chat rooms to discuss different illnesses and conditions. WebMDÒ, for example, offers such a service at their Web site: http://boards.webmd.com/roundtable. These online communities can help you connect with a network of people whose concerns are similar to yours. Online support groups are places where people can talk informally. If you read about a novel approach, consult with your child’s doctor or other healthcare providers, as the treatments or discoveries you hear about may not be scientifically proven to be safe and effective. ·

Association for Neuro-Metabolic Disorders http://www.medhelp.org/HealthTopics/Phenylketonuria.html

·

NSPKU http://www.kumc.edu/gec/support/pku.html

·

The CaF Directory - PHENYLKETONURIA http://www.cafamily.org.uk/Direct/p21.html

48 Phenylketonuria

Finding Doctors All parents must go through the process of selecting a physician for their children with phenylketonuria. While this process will vary, the Agency for Healthcare Research and Quality makes a number of suggestions, including the following:9 ·

If your child is in a managed care plan, check the plan's list of doctors first.

·

Ask doctors or other health professionals who work with doctors, such as hospital nurses, for referrals.

·

Call a hospital’s doctor referral service, but keep in mind that these services usually refer you to doctors on staff at that particular hospital. The services do not have information on the quality of care that these doctors provide.

·

Some local medical societies offer lists of member doctors. Again, these lists do not have information on the quality of care that these doctors provide.

Additional steps you can take to locate doctors include the following: ·

Check with the associations listed earlier in this chapter.

·

Information on doctors in some states is available on the Internet at http://www.docboard.org. This Web site is run by “Administrators in Medicine,” a group of state medical board directors.

·

The American Board of Medical Specialties can tell you if your child’s doctor is board certified. “Certified” means that the doctor has completed a training program in a specialty and has passed an exam, or “board,” to assess his or her knowledge, skills, and experience to provide quality patient care in that specialty. Primary care doctors may also be certified as specialists. The AMBS Web site is located at 10 http://www.abms.org/newsearch.asp. You can also contact the ABMS by phone at 1-866-ASK-ABMS.

·

You can call the American Medical Association (AMA) at 800-665-2882 for information on training, specialties, and board certification for many licensed doctors in the United States. This information also can be found in “Physician Select” at the AMA's Web site: http://www.amaassn.org/aps/amahg.htm.

This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. 10 While board certification is a good measure of a doctor's knowledge, it is possible to receive quality care from doctors who are not board certified. 9

Seeking Guidance 49

If the previous sources did not meet your needs, you may want to log on to the Web site of the National Organization for Rare Disorders (NORD) at http://www.rarediseases.org/. NORD maintains a database of doctors with expertise in various rare medical conditions. The Metabolic Information Network (MIN), 800-945-2188, also maintains a database of physicians with expertise in various metabolic diseases.

Finding a Pediatrician The American Academy of Pediatrics (AAP) mission is “to attain optimal physical, mental, and social health and well-being for all infants, children, adolescents, and young adults.”11 The AAP maintains an online pediatrician referral service which is available to the public and free of charge. This service allows you to search the AAP’s database of its 55,000 members which include pediatricians, pediatric medical subspecialists, and pediatric surgical specialists practicing in the U.S., Canada, and internationally. To access the pediatrician referral service, log on to http://www.aap.org/referral/ and read the terms and conditions of use. Once you accept the terms, you can search for pediatricians by name, city, state, or country. All AAP members listed in the referral service database are boardcertified pediatricians.

Selecting Your Doctor12 When you have compiled a list of prospective doctors, call each of their offices. First, ask if the doctor accepts your child’s health insurance plan and if he or she is taking new patients. If the doctor is not covered by your child’s plan, ask yourself if you are prepared to pay the extra costs. The next step is to schedule a visit with your first choice. During the first visit you will have the opportunity to evaluate your child’s doctor and to find out if your child feels comfortable with him or her.

The American Academy of Pediatrics: http://www.aap.org/. section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm. 11

12 This

50 Phenylketonuria

Working with Your Child’s Doctor13 Research has shown that parents who have good relationships with their children’s doctors tend to be more satisfied with their children’s care. Here are some tips to help you and your child’s doctor become partners: ·

You know important things about your child’s symptoms and health history. Tell the doctor what you think he or she needs to know.

·

Always bring any medications your child is currently taking with you to the appointment, or you can bring a list of your child’s medications including dosage and frequency information. Talk about any allergies or reactions your child has had to medications.

·

Tell your doctor about any natural or alternative medicines your child is taking.

·

Bring other medical information, such as x-ray films, test results, and medical records.

·

Ask questions. If you don't, the doctor will assume that you understood everything that was said.

·

Write down your questions before the doctor’s visit. List the most important ones first to make sure that they are addressed.

·

Ask the doctor to draw pictures if you think that this will help you and your child understand.

·

Take notes. Some doctors do not mind if you bring a tape recorder to help you remember things, but always ask first.

·

Take information home. Ask for written instructions. Your child’s doctor may also have brochures and audio and videotapes on phenylketonuria.

By following these steps, you will enhance the relationship you and your child have with the physician.

This section has been adapted from the AHRQ: www.ahrq.gov/consumer/qntascii/qntdr.htm.

13

Seeking Guidance 51

Broader Health-Related Resources In addition to the references above, the NIH has set up guidance Web sites that can help parents find healthcare professionals. These include:14 ·

Caregivers: http://www.nlm.nih.gov/medlineplus/caregivers.html

·

Choosing a Doctor or Healthcare Service: http://www.nlm.nih.gov/medlineplus/choosingadoctororhealthcareserv ice.html

·

Hospitals and Health Facilities: http://www.nlm.nih.gov/medlineplus/healthfacilities.html

Vocabulary Builder The following vocabulary builder provides definitions of words used in this chapter that have not been defined in previous chapters: Benign: Not malignant; not recurrent; favourable for recovery. [EU] Hypotonia: A condition of diminished tone of the skeletal muscles; diminished resistance of muscles to passive stretching. [EU] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH] Membrane: A thin layer of tissue which covers a surface, lines a cavity or divides a space or organ. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Surgical: Of, pertaining to, or correctable by surgery. [EU]

You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html.

14

Clinical Trials 53

CHAPTER 3. CLINICAL TRIALS AND PHENYLKETONURIA Overview Very few medical conditions have a single treatment. The basic treatment guidelines that your child’s physician has discussed with you, or those that you have found using the techniques discussed in Chapter 1, may provide you with all that you will require. For some patients, current treatments can be enhanced with new or innovative techniques currently under investigation. In this chapter, we will describe how clinical trials work and show you how to keep informed of trials concerning phenylketonuria.

What Is a Clinical Trial?15 Clinical trials involve the participation of people in medical research. Most medical research begins with studies in test tubes and on animals. Treatments that show promise in these early studies may then be tried with people. The only sure way to find out whether a new treatment is safe, effective, and better than other treatments for phenylketonuria is to try it on patients in a clinical trial.

The discussion in this chapter has been adapted from the NIH and the NEI: www.nei.nih.gov/netrials/ctivr.htm.

15

54 Phenylketonuria

What Kinds of Clinical Trials Are There? Clinical trials are carried out in three phases: ·

Phase I. Researchers first conduct Phase I trials with small numbers of patients and healthy volunteers. If the new treatment is a medication, researchers also try to determine how much of it can be given safely.

·

Phase II. Researchers conduct Phase II trials in small numbers of patients to find out the effect of a new treatment on phenylketonuria.

·

Phase III. Finally, researchers conduct Phase III trials to find out how new treatments for phenylketonuria compare with standard treatments already being used. Phase III trials also help to determine if new treatments have any side effects. These trials--which may involve hundreds, perhaps thousands, of people--can also compare new treatments with no treatment.

How Is a Clinical Trial Conducted? Various organizations support clinical trials at medical centers, hospitals, universities, and doctors' offices across the United States. The “principal investigator” is the researcher in charge of the study at each facility participating in the clinical trial. Most clinical trial researchers are medical doctors, academic researchers, and specialists. The “clinic coordinator” knows all about how the study works and makes all the arrangements for your child’s visits. All doctors and researchers who take part in the study on phenylketonuria carefully follow a detailed treatment plan called a protocol. This plan fully explains how the doctors will treat your child in the study. The “protocol” ensures that all patients are treated in the same way, no matter where they receive care. Clinical trials are controlled. This means that researchers compare the effects of the new treatment with those of the standard treatment. In some cases, when no standard treatment exists, the new treatment is compared with no treatment. Patients who receive the new treatment are in the treatment group. Patients who receive a standard treatment or no treatment are in the “control” group. In some clinical trials, patients in the treatment group get a new medication while those in the control group get a placebo. A placebo is a harmless substance, a “dummy” pill, that has no effect on phenylketonuria. In other clinical trials, where a new surgery or device (not a medicine) is being tested, patients in the control group may receive a “sham treatment.”

Clinical Trials 55

This treatment, like a placebo, has no effect on phenylketonuria and will not harm your child. Researchers assign patients “randomly” to the treatment or control group. This is like flipping a coin to decide which patients are in each group. If you choose to have your child participate in a clinical trial, you will not know which group he or she will be appointed to. The chance of any patient getting the new treatment is about 50 percent. You cannot request that your child receive the new treatment instead of the placebo or “sham” treatment. Often, you will not know until the study is over whether your child has been in the treatment group or the control group. This is called a “masked” study. In some trials, neither doctors nor patients know who is getting which treatment. This is called a “double masked” study. These types of trials help to ensure that the perceptions of the participants or doctors will not affect the study results. Natural History Studies Unlike clinical trials in which patient volunteers may receive new treatments, natural history studies provide important information to researchers on how phenylketonuria develops over time. A natural history study follows patient volunteers to see how factors such as age, sex, race, or family history might make some people more or less at risk for phenylketonuria. A natural history study may also tell researchers if diet, lifestyle, or occupation affects how a medical condition develops and progresses. Results from these studies provide information that helps answer questions such as: How fast will a medical condition usually progress? How bad will the condition become? Will treatment be needed? What Is Expected of Your Child in a Clinical Trial? Not everyone can take part in a clinical trial for a specific medical condition. Each study enrolls patients with certain features or eligibility criteria. These criteria may include the type and stage of the condition, as well as, the age and previous treatment history of the patient. You or your child’s doctor can contact the sponsoring organization to find out more about specific clinical trials and their eligibility criteria. If you would like your child to participate in a clinical trial, your child’s doctor must contact one of the trial's investigators and provide details about his or her diagnosis and medical history.

56 Phenylketonuria

When participating in a clinical trial, your child may be required to have a number of medical tests. Your child may also need to take medications and/or undergo surgery. Depending upon the treatment and the examination procedure, your child may be required to receive inpatient hospital care. He or she may have to return to the medical facility for followup examinations. These exams help find out how well the treatment is working. Follow-up studies can take months or years. However, the success of the clinical trial often depends on learning what happens to patients over a long period of time. Only patients who continue to return for follow-up examinations can provide this important long-term information.

Recent Trials on Phenylketonuria The National Institutes of Health and other organizations sponsor trials on various medical conditions. Because funding for research goes to the medical areas that show promising research opportunities, it is not possible for the NIH or others to sponsor clinical trials for every medical condition at all times. The following lists recent trials dedicated to phenylketonuria.16 If the trial listed by the NIH is still recruiting, your child may be eligible. If it is no longer recruiting or has been completed, then you can contact the sponsors to learn more about the study and, if published, the results. Further information on the trial is available at the Web site indicated. Please note that some trials may no longer be recruiting patients or are otherwise closed. Before contacting sponsors of a clinical trial, consult with your child’s physician who can help you determine if your child might benefit from participation. ·

Study of a Phenylalanine Restricted Diet During Pregnancy to Prevent Symptoms in Offspring of Patients With Phenylketonuria Condition(s): Phenylketonuria Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); University of Texas Purpose - Excerpt: Objectives: I. Assess the impact of a phenylalanine restricted diet during pregnancy on symptoms in offspring of patients with phenylketonuria. Study Type: Interventional Contact(s):. Study chairs or principal investigators: Bobbye M. Rouse, Study Chair; University of Texas

16

These are listed at www.ClinicalTrials.gov.

Clinical Trials 57

Web Site: http://clinicaltrials.gov/ct/gui/show/NCT00006142;jsessionid=B910656 1A23353536541733827452228

Benefits and Risks

17

What Are the Benefits of Participating in a Clinical Trial? If you are considering a clinical trial, it is important to realize that your child’s participation can bring many benefits: ·

A new treatment could be more effective than the current treatment for phenylketonuria. Although only half of the participants in a clinical trial receive the experimental treatment, if the new treatment is proved to be more effective and safer than the current treatment, then those patients who did not receive the new treatment during the clinical trial may be among the first to benefit from it when the study is over.

·

If the treatment is effective, then it may improve your child’s health.

·

Clinical trial patients receive the highest quality of medical care. Experts watch them closely during the study and may continue to follow them after the study is over.

·

People who take part in trials contribute to scientific discoveries that may help others with phenylketonuria. In cases where certain medical conditions run in families, your child’s participation may lead to better care or prevention for you and other family members. The Informed Consent

Once you agree to have your child take part in a clinical trial, you will be asked to sign an “informed consent.” This document explains a clinical trial's risks and benefits, the researcher’s expectations of you and your child, and your child’s rights as a patient.

17 This section has been adapted from ClinicalTrials.gov, a service of the National Institutes of Health: http://www.clinicaltrials.gov/ct/gui/c/a1r/info/whatis?JServSessionIdzone_ct=9jmun6f291.

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What Are the Risks? Clinical trials may involve risks as well as benefits. Whether or not a new treatment will work cannot be known ahead of time. There is always a chance that a new treatment may not work better than a standard treatment. There is also the possibility that it may be harmful. The treatment your child receives may cause side effects that are serious enough to require medical attention.

How Is Your Child’s Safety Protected? Clinical trials can raise fears of the unknown. Understanding the safeguards that protect your child can ease some of these fears. Before a clinical trial begins, researchers must get approval from their hospital's Institutional Review Board (IRB), an advisory group that makes sure a clinical trial is designed to protect your child’s safety. During a clinical trial, doctors will closely watch your child to see if the treatment is working and if he or she is experiencing any side effects. All the results are carefully recorded and reviewed. In many cases, experts from the Data and Safety Monitoring Committee carefully monitor each clinical trial and can recommend that a study be stopped at any time. Your child will only be asked to participate in a clinical trial as a volunteer with your informed consent.

What Are Your Child’s Rights in a Clinical Trial? If your child is eligible for a clinical trial, you will be given information to help you decide whether or not you want him or her to participate. You and your child have the right to: ·

Information on all known risks and benefits of the treatments in the study.

·

Know how the researchers plan to carry out the study, for how long, and where.

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Know what is expected of your child.

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Know any costs involved for you or your child’s insurance provider.

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Know before any of your child’s medical or personal information is shared with other researchers involved in the clinical trial.

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Talk openly with doctors and ask any questions.

Clinical Trials 59

After your child joins a clinical trial, you and your child have the right to: ·

Leave the study at any time. Participation is strictly voluntary.

·

Receive any new information about the new treatment.

·

Continue to ask questions and get answers.

·

Maintain your child’s privacy. Your child’s name will not appear in any reports based on the study.

·

Know whether your child participated in the treatment group or the control group (once the study has been completed).

What about Costs? In some clinical trials, the research facility pays for treatment costs and other associated expenses. You or your child’s insurance provider may have to pay for costs that are considered standard care. These things may include inpatient hospital care, laboratory and other tests, and medical procedures. You also may need to pay for travel between your home and the clinic. You should find out about costs before committing your child to participation in the trial. If your child has health insurance, find out exactly what it will cover. If your child does not have health insurance, or if your child’s insurance policy will not cover care, talk to the clinic staff about other options for covering the costs. What Questions Should You Ask before Your Child Participates in a Clinical Trial? Questions you should ask when deciding whether or not to enroll your child in a clinical trial include the following: ·

What is the purpose of the clinical trial?

·

What are the standard treatments for phenylketonuria? Why do researchers think the new treatment may be better? What is likely to happen to my child with or without the new treatment?

·

What tests and treatments will my child need? Will my child need surgery? Medication? Hospitalization?

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How long will the treatment last? How often will my child have to come back for follow-up exams?

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What are the treatment's possible benefits to my child’s condition? What are the short- and long-term risks? What are the possible side effects?

60 Phenylketonuria

·

Will the treatment be uncomfortable? Will it make my child sick? If so, for how long?

·

How will my child’s health be monitored?

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Where will my child need to go for the clinical trial?

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How much will it cost to participate in the study? What costs are covered by the study? How much will my child’s health insurance cover?

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Who will be in charge of my child’s care?

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Will taking part in the study affect my child’s daily life?

·

How does my child feel about taking part in a clinical trial? Will other family members benefit from my child’s contributions to new medical knowledge?

Keeping Current on Clinical Trials Various government agencies maintain databases on trials. The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide the public and physicians with current information about clinical research across the broadest number of medical conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to their Web site (www.clinicaltrials.gov) and search by “phenylketonuria” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: ·

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

·

For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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General References The following references describe clinical trials and experimental medical research. They have been selected to ensure that they are likely to be available from your local or online bookseller or university medical library. These references are usually written for healthcare professionals, so you may consider consulting with a librarian or bookseller who might recommend a particular reference. The following includes some of the most readily available references (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

A Guide to Patient Recruitment : Today's Best Practices & Proven Strategies by Diana L. Anderson; Paperback - 350 pages (2001), CenterWatch, Inc.; ISBN: 1930624115; http://www.amazon.com/exec/obidos/ASIN/1930624115/icongroupinterna

·

A Step-By-Step Guide to Clinical Trials by Marilyn Mulay, R.N., M.S., OCN; Spiral-bound - 143 pages Spiral edition (2001), Jones & Bartlett Pub; ISBN: 0763715697; http://www.amazon.com/exec/obidos/ASIN/0763715697/icongroupinterna

·

The CenterWatch Directory of Drugs in Clinical Trials by CenterWatch; Paperback - 656 pages (2000), CenterWatch, Inc.; ISBN: 0967302935; http://www.amazon.com/exec/obidos/ASIN/0967302935/icongroupinterna

·

The Complete Guide to Informed Consent in Clinical Trials by Terry Hartnett (Editor); Paperback - 164 pages (2000), PharmSource Information Services, Inc.; ISBN: 0970153309; http://www.amazon.com/exec/obidos/ASIN/0970153309/icongroupinterna

·

Dictionary for Clinical Trials by Simon Day; Paperback - 228 pages (1999), John Wiley & Sons; ISBN: 0471985961; http://www.amazon.com/exec/obidos/ASIN/0471985961/icongroupinterna

·

Extending Medicare Reimbursement in Clinical Trials by Institute of Medicine Staff (Editor), et al; Paperback 1st edition (2000), National Academy Press; ISBN: 0309068886; http://www.amazon.com/exec/obidos/ASIN/0309068886/icongroupinterna

·

Handbook of Clinical Trials by Marcus Flather (Editor); Paperback (2001), Remedica Pub Ltd; ISBN: 1901346293; http://www.amazon.com/exec/obidos/ASIN/1901346293/icongroupinterna

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PART II: ADDITIONAL RESOURCES AND ADVANCED MATERIAL

ABOUT PART II In Part II, we introduce you to additional resources and advanced research on phenylketonuria. All too often, parents who conduct their own research are overwhelmed by the difficulty in finding and organizing information. The purpose of the following chapters is to provide you an organized and structured format to help you find additional information resources on phenylketonuria. In Part II, as in Part I, our objective is not to interpret the latest advances on phenylketonuria or render an opinion. Rather, our goal is to give you access to original research and to increase your awareness of sources you may not have already considered. In this way, you will come across the advanced materials often referred to in pamphlets, books, or other general works. Once again, some of this material is technical in nature, so consultation with a professional familiar with phenylketonuria is suggested.

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CHAPTER 4. STUDIES ON PHENYLKETONURIA Overview Every year, academic studies are published on phenylketonuria or related conditions. Broadly speaking, there are two types of studies. The first are peer reviewed. Generally, the content of these studies has been reviewed by scientists or physicians. Peer-reviewed studies are typically published in scientific journals and are usually available at medical libraries. The second type of studies is non-peer reviewed. These works include summary articles that do not use or report scientific results. These often appear in the popular press, newsletters, or similar periodicals. In this chapter, we will show you how to locate peer-reviewed references and studies on phenylketonuria. We will begin by discussing research that has been summarized and is free to view by the public via the Internet. We then show you how to generate a bibliography on phenylketonuria and teach you how to keep current on new studies as they are published or undertaken by the scientific community.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and phenylketonuria, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the

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format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type in “phenylketonuria” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is a sample of what you can expect from this type of search: ·

Risk Assessment and Health Hazard Appraisal Source: Annual Review of Public Health. 2:31-47, 1981. Summary: Three different types of risk assessment are discussed. These are screening programs for specific diseases, multiphasic screening projects, and Health Hazard Appraisal. Specific screening programs are examined in terms of their likely contributions to health maintenance and the reduction of morbidity and mortality. Sensitivity, specificity, and predictive value must all be considered; criteria developed by the World Health Organization are listed as a good standard for screening tests. The area where screening activities have been most intense in the past decade is in cardiovascular diseases; hypertension programs are probably the most common form of screening. Another screening that has demonstrated efficacy is the identification of infants with phenylketonuria. Significant cost savings have been claimed for this procedure. An example typical of the manner in which many new technologies are introduced is the use of mammography in screening for breast cancer. First viewed as an enormous breakthrough, it was eventually recognized as a useful adjunct to routine breast examination. Multiphasic screening programs involve the use of multiple examination and tests in an effort to identify any potential health problems at as early a stage as possible. The contents of such programs vary from small sets to large complex batteries, and exact definitions are not in use. The difficulties of evaluating multiphasic screening tests are enormous and although they may contain the potential for substantial reductions in morbidity and mortality, there is little evidence that they are used in such a way that significant benefit accrues. Until further work is completed it is recommended that money spent on such programs be limited to systems where aggressive followup coexists with screening efforts. Health Hazard Appraisal is a technique for estimating the risk of illness and death in individuals which involves the use of chemical, actuarial, and epidemiologic findings to create estimates of risk. Despite the claims of efficacy and the proliferation of private organizations offering Health

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Hazard Appraisal inventories, little reliable data exist that show that this technique leads to improved health. Current inventories are almost exclusively used to predict mortality, leaving morbidity unexamined. The value of specific and multiple screening tests and personal inventories of selected health-related characteristics undoubtedly varies and is strongly related to the characteristics measured and the effort given to implementing changes and therapies. Risk assessment techniques must be carefully examined in light of intended outcomes and costs. 68 references. ·

An Overview of Genetic Counseling Source: Arizona Medicine. 38(10):769-771, October 1981. Summary: Although genetic services expanded rapidly in many States of the United States after World War II, growth of these services was very slow in Arizona until 1978. At that time, the Genetics Center was established in Tempe. The Center was designed to provide clinical genetic diagnosis and counseling and to participate in special care areas such as phenylketonuria and other metabolic diseases, Down's syndrome, Turner's syndrome, and other genetic and related diseases. The State of Arizona has assisted in expanding genetic services, but prenatal genetic services are still inadequate. Despite provision of services by the University of Arizona and the Genetics Center in Tempe, the program has not reached enough people. With the trend towards women beginning to have children at a later age, the total number of patients receiving these services in Arizona represents a small fraction of the families at increased risk. To expand genetic services beyond the Phoenix and Tucson metropolitan areas, genetic clinics are being initiated in other important areas of Arizona. While Arizona cannot be considered a leading State in genetic services, it now has the opportunity to initiate and develop a coordinated statewide program for genetic diagnosis, counseling, and care. 13 references.

·

Developing and Testing a Programmed Instruction Unit on PKU Source: Journal of the American Dietetic Association. 76(1):29-34, January 1980. Summary: A study involving 10 mothers from the phenylketonuria (PKU) clinic of the Children's Hospital Center in Boston, Massachusetts, was conducted to evaluate a programmed instruction unit for teaching principles of dietary management to parents of children with PKU. The first stage in formulating the unit involved developing a goal and 12 behavioral objectives; the goal was to provide the parent with an understanding of the disease and the low-phenylalanine diet. The

68 Phenylketonuria

objectives of the unit were based on the needs of parents in effecting adequate dietary management of PKU, personal professional experiences, and interviews with three parents from the PKU clinic. The objectives formed the basis for developing two criterion-referenced tests to be used as pre- and postprogram tests during the evaluation phase. The tests were pilot tested with 10 graduate nutrition students. The programmed unit was divided into separate sections to deal with the basics of the disease, inheritance of the disease, and dietary treatment. Each section included an introduction, content development, and a summary. The content subsections were written in instructional segments consisting of information, followed by practice exercises and immediate reinforcement through feedback on the results of the exercise. After the unit was reviewed by a panel of 5 nutritionists, it was tested with the 10 parents. Results from pre- and postprogram tests indicate that (1) all 10 mothers showed significant improvement when pretest scores were compared with posttest scores; (2) the mothers' responses to the material were notably favorable; and (3) programmed instruction may be useful in other areas of patient nutrition education. 30 references. ·

A Review of the Economic Evidence on Prevention Source: Medical Care. 18(5):473-484, May 1980. Summary: This study examines the economic evidence on preventive health care. Prevention strategies can be divided into three categories: (1) lifestyle changes, (2) public health measures, and (3) screening programs. Lifestyle changes include altering behavior patterns that relate to alcohol and drug abuse, smoking, and automobile safety regulations. Examples of public health measures are water fluoridation, food inspection, and immunizations against communicable diseases. Screening programs include (1) phenylketonuria (PKU) and congenital hypothyroidism screening in newborn infants, (2) spina bifida cystica screening in the unborn fetus, and (3) screening for hypertension. The author discusses cost-benefit analysis and cost-effectiveness analysis and explains the problems inherent in implementing these approaches to preventive health care. Because only quantifiable changes in health status or costs are included in the cost-benefit and cost-effectiveness analyses, the actual value of prevention strategies may be understated since reductions in pain and suffering usually are omitted. The results of the study suggest that many of these preventive health measures represent an efficient use of resources.

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·

Lifetime Health-Monitoring Program: A Practical Approach to Preventive Medicine Source: New England Journal of Medicine. 296(11):601-608, March 17, 1977. Summary: Current patterns of health care and health care financing need to be improved by the incorporation of cost-effective preventive measures. The Lifetime Health-Monitoring Program, which would use clinical and epidemiological criteria to identify specific health goals and professional services appropriate for 10 different age groups, is a model for future programs. The 10 periods of the lifespan are based on changing lifestyles, health needs, and problems. These periods are pregnancy and perinatal; infancy; preschool (1-5); school (6-11); adolescence (12-17); young adulthood (18-24); young middle age (25-39); older middle age (40-59); elderly (60-74); and old age (75 and over). During infancy, for example, screening procedures to detect anemia, hemorrhagic diseases, phenylketonuria and developmental deficiencies, and gonorrheal ophthalmia are recommended. In the older middle-age group, tests for hypertension, obesity and smoking control, and cervical, mammary, and gastrointestinal cancer would be provided. The cost of such preventive measures would not be prohibitive and could be covered by health insurance programs on a fee-for-service basis or through increasing capitation or salaried practice at the primary care level. By incorporating prevention into routine care, the proposed program would strengthen the patient-physician relationship, since counseling on the basis of individual findings and an epidemiological framework, rather than routine tests, enhances discussion. 15 references.

·

Oral Health Implications in Children with Inborn Errors of Intermediary Metabolism: A Review Source: International Journal of Paediatric Dentistry. 7(3): 133-141. September 1997. Contact: Available from Blackwell Science Ltd. Journal Subscriptions, P.O. Box 88, Oxford OX2 0NE, United Kingdom. +44 1865 206180. Fax +44 1865 206219. E-mail: [email protected]. Summary: Children with inborn errors of metabolism form an important group of children at risk of oral pathology. Their management includes dietary therapies which aim to promote normal growth and development, but which are often highly cariogenic. This article reviews these disorders and the limited literature that exists on the oral health implications of those conditions that rely on dietary manipulation for their management. The authors conclude with suggestions for dental care

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for these children. Metabolic disorders discussed include phenylketonuria (PKU), Maple Syrup Urine Disease (MSUD), organic acidemias, urea cycle disorders, homcystinuria, tyrosinemia, galactosemia, glycogen storage disorders (GSD), hereditary fructose intolerance (HFI), and disorders of fat oxidation. Management issues discussed include the prevalence of dental caries in these children, soft tissue pathology, preventive care, operative treatment (restorative), and medications. The authors warn that provision of dental treatment may be complicated by their metabolic disorder, and they therefore require careful multidisciplinary management. 2 tables. 33 references. (AA-M).

Federally-Funded Research on Phenylketonuria The U.S. Government supports a variety of research studies relating to phenylketonuria and associated conditions. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.18 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally-funded biomedical research projects conducted at universities, hospitals, and other institutions. Visit the CRISP Web site at http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket. You can perform targeted searches by various criteria including geography, date, as well as topics related to phenylketonuria and related conditions. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally-funded studies use animals or simulated models to explore phenylketonuria and related conditions. In some cases, therefore, it may be difficult to understand how some basic or fundamental research could eventually translate into medical practice. The following sample is typical of the type of information found when searching the CRISP database for phenylketonuria: ·

Project Title: Diet Phenylketonuria

Intervention

and

Clinical

Outcomes

in

Principal Investigator & Institution: Rouse, Bobbye M.; ; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77550 18 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Timing: Fiscal Year 2000 Summary: Phenylketonuria (PKU) is a disorder usually diagnosed by newborn screening. Persons with PKU cannot properly process phyenylalanine (phe), an amino acid found in food. The only known treatment for PKU is a diet consisting of a protein source without Phe called a Medical Food (formula) plus limited amounts of low protein foods. The diet is started immediately after PKU is diagnosed to prevent mental retardation in newborns. In the past, many persons with PKU were taken off the diet around school age. Some of them stopped the diet on their own. Researchers found that the children off diet began losing IQ points. The current recommendation is for all persons with PKU to remain on the Medical Food and protein restricted diet throughout life. Of special concern is the effect of PKU on pregnancy. Women with PKU who were not on the diet before and during pregnancy delivered babies with serious birth defects. The Maternal PKU Study began collecting information from women with PKU in 1984 to determine the effects of the phe-restricted diet and Medical Food before and during pregnancy. The purpose of the study is to determine the proper blood phe levels needed for the woman to have the best chance of having a healthy baby. The study checks the dietary intake of the women and their blood phe levels and other nutrients in the blood such as, iron and protein. The children born to women in the study receive a thorough physical at birth and yearly thereafter. Developmental testing is done on each child at 1, 2, 4, 7 and 10 years of age. The mother's blood phe levels and diet before and during pregnancy are compared to the child's growth and development. From this information the study aims to develop guidelines for clinics caring for women with PKU. The project has significant implications for preventing birth defects in the babies born to women with PKU. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Effects of Maternal Phenylketonuria on Pregnancy Outcome Principal Investigator & Institution: Koch, Richard; ; Children's Hospital Los Angeles 4650 Sunset Blvd Los Angeles, Ca 90027 Timing: Fiscal Year 2000; Project Start 1-MAY-1992; Project End 0-APR2000 Summary: The primary purpose of this project is to determine the best method of managing women during pregnancy who have hyperphenylalaninemia (HPA) including: classical phenylketonuria (PKU) - blood phenylalanine concentrations of more than 20 mg/dl while on a normal diet; variant PKU - 10-20 mg/dl; or benign HPA - 4-10

72 Phenylketonuria

mg/dl. Fetal morbidity, with subsequent problems in growth and development, associated with maternal PKU will be assessed in relation to maternal phenylalanine levels. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Gene Therapy for Phenylketonuria Principal Investigator & Institution: Laipis, Philip J.; Professor; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2000; Project Start 5-SEP-2000; Project End 1-JUL-2005 Summary: Phenylketonuria (PKU) is one of the most common genetic disorders affecting children in North America and Europe, with an incidence of about 1 in 10,000 births. Mutations in the enzyme phenylalanine hydroxylase (PAH) are the major cause of PKU. PAH deficiency results in elevated serum phenylalanine (Phe) levels, leading to abnormal brain development and mental retardation. PKU's frequency, coupled with the ability of early dietary modification to greatly reduce the severe neurological problems associated with the disorder, has led to neonatal testing programs in all states. Unfortunately, there is a widespread impression that dietary control effects a "cure" for this disease. In reality, strict adherence to the diet is exceedingly difficult and lapses can cause serious long-term neuro-development sequelae, particularly in offspring of PAH-deficient women. Given the wellunderstood single gene defect, gene therapy for PKU is both technically feasible and therapeutically desirable. Recent important advances in gene therapy have come from the use of AAV-based vectors to provide effective, stable, and safe correction of metabolic. It is hypothesized that AAV vectors will be useful in PKU. To this hypothesis, the ability of AAV vectors to: 1) Provide effective rescue of defective Phe metabolism in the Pah/enu2 mouse will be examined. Serum Phe levels will be related to the number of vector genomes and transfected cells as well as to the degree of reduction of PKU symptoms. 2) Give safe PAH delivery to liver with non germ-line transmission of vector sequences in either adult and neonatal Pah/enu2 mice will be tested. The potential for liver toxicity and immune responses to vector will also be examined. 3) Optimize PAH expression and hepatocyte delivery by using alternative control elements and tissue-specific targeting. These experiments provide a rational approach to examining the potential of AAV-driven gene therapy to truly cure PKU. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

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·

Project Title: Nutrients and Growth in Phenylketonuria Principal Investigator & Institution: Elsas, Louis J.; ; Emory University 1380 S Oxford Rd Atlanta, Ga 30322 Timing: Fiscal Year 2000 Summary: This proposal is designed to test the hypothesis that different types of formulas commercially available for children with PKU have different capacities to support their growth. The investigators will measure growth and nutritional parameters in children aged 2-12 years on one of three different formulas: Phenex-2, Periflex and Phenyl-Free. Children to be studied are already receiving one of these therapies. They will be followed for one year. Enrollment is ongoing. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

·

Project Title: Phenylketonuria

Pathophysiology/Outcome

of

Early

Treated

Principal Investigator & Institution: Wasserstein, Melissa; ; Mount Sinai School of Medicine of Cuny New York, Ny 10029 Timing: Fiscal Year 2000; Project Start 1-OCT-1975; Project End 0-NOV2000 Summary: The purpose of this study is to develop improved methods to predict disease severity, to develop improved methods for diagnosis and prenatal diagnosis, and to determine the outcome of early treated phenylketonuria (PKU). Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Structural Understanding of Phenylketonuria (Pku) Principal Investigator & Institution: Stevens, Raymond C.; ; Scripps Research Institute 10550 N Torrey Pines Rd San Diego, Ca 92037 Timing: Fiscal Year 2000; Project Start 1-APR-2000; Project End 1-MAR2005 Summary: The three-dimensional structure of the enzymes phenylalanine hydroxylase and tryptophan hydroxylase will be studied using crystallographic methods. The structures of the catalytic domain of human phenylalanine hydroxylase, catalytic domain plus tetramerization domain, catalytic domain plus regulatory domain, and catalytic domain with catecholamine inhibitors have previously been determined in my lab at various resolutions (1.9 Angstroms to 3.0 Angstroms). The family of aromatic amino acid hydroxylases are known to be involved in inherited metabolic disorders. The enzyme phenylalanine hydroxylase is the known cause of the disease known as PKU (phenylketonuria). The

74 Phenylketonuria

enzyme normally converts the essential amino acid phenylalanine to tyrosine. Failure of the conversion results in a buildup of phenylalanine. Excessive amounts of phenylalanine are toxic to the central nervous system and causes severe problems associated with PKU. Based on the three-dimensional structure of the modeled full-length enzyme, the mutations will be mapped and site- specific mutagenesis will be conducted to understand the structural basis of PKU. As a complement to the studies on phenylalanine hydroxylase, tryptophan hydroxylase will be studied as comparisons of it and phenylalanine hydroxylase may provide important insights into the mechanisms of PKU. A second goal of the research is to understand the structural basis of pterin-dependent hydroxylase catalysis. The three-dimensional structure of both enzymes will be determined in the presence of co-factors, substrates, and inhibitors in order to understand the mechanism of catalysis and role of inhibitors. The last goal is to crystallize and determine the three-dimensional structure of the intact holoenzyme. By combining the structures of the isolated domains with adequate overlap, a proposed full-length enzyme model can be assembled. However it is important to determine the three dimensional structure of the full-length enzyme in order to fully understand the complex regulatory, catalytic, and stability issues associated with this family of enzymes. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Aromatic Amino Acid Hydroxylases as Therapeutics Principal Investigator & Institution: Bouyer, James H.; ; Florida Agricultural and Mechanical Univ Tallahassee, Fl 32307 Timing: Fiscal Year 2001; Project Start 5-JUN-2000; Project End 0-APR2005 Summary: Development of Aromatic Amino Acid Hydroxylases as Therapeutics The long-term goal of the research is to develop mammalian aromatic amino acid hydroxylases as therapeutics in the treatment of metabolic disorders such as Parkinson's disease (tyrosine (tyrosine hydroxylase), Segawa's syndrome (tyrosine hydroxylase) and phenylketonuria (phenylalanine hydroxylase). The research design is to develop a high throughput screen that will detect mutant hydroxylases with increased activity and/or stability. The mutant enzymes that possess the desired characteristics of increased activity and/or stability will be targeted as candidates for gene therapy in the treatment of Parkinson's, Segawa's syndrome and phenylketonuria. The highthroughput screen will be based on a co-expression system that produces the hydroxylase and a second enzyme that converts the product of the hydroxylase into a colored compound that can be easily detected and

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assay. The proposed research provides the first step in achieving the long-term goal, because it supports the development of co-expression systems that will serve as the starting material for the mutagenesis and screening process. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Biological Oxidation of Phenylalanine by Nonheme Iron Principal Investigator & Institution: Caradonna, John P.; Professor; Chemistry; Boston University 121 Bay State Rd Boston, Ma 02215 Timing: Fiscal Year 2000; Project Start 1-MAR-2000; Project End 8-FEB2004 Summary: The major objective of this research is to elucidate the chemical and physical properties of the mononuclear non-heme iron dependent metalloenzyme, phenylalanine hydroxylase (PAH, phenylalanine 4monooxygenase, E.C. 1.14.16.1). PAH is a mixed-function oxidase whose active site ferrous iron center catalyzes the hydroxylation of Lphenylalanine (L-phe) to L-tyrosine (L-tyr) in the presence of dioxygen and the reduced cofactor, tetrahydropterin. Genetic defects in the PAH gene that induce a significant decrease in PAH activity lead to the autosomal recessive human genetic disorder, classic phenylketonuria (PKU). This disorder is characterized by an increase in serum L-phe concentrations and the abnormal accumulation of phenylalanine-based metabolic products that are thought to cause defective myelination of the central nervous system, leading to postnatal brain damage and severe mental retardation. PKU is the most common inborn error in amino acid metabolism that is of clinical importance; approximately 1 in 50 individuals carry the disease trait with an average incidence of about 1 in 10,000 for Caucasians. Early detection and strict dietary management have significantly reduced the neurological defects and mental retardation characteristics of untreated PKU. Among the specific aims of this project is to identify and interpret, in terms of their structural and chemical implications, changes in the active site iron environment as a function of the requisite allosteric activation process, and the binding of substrate(s) and cofactor. Advanced methodologies, including MCD, XAS, M ssbauer, ESEEM, and ENDOR spectroscopies, will be utilized to probe the active site structures of multiple physiologically relevant enzyme states, all of which can be generated in homogeneous forms. A comparison of the active site characteristics of native, homotetrameric PAH with dimeric/monomeric forms of the enzyme will be performed; truncated dimeric forms of PAH support promiscuous oxidation chemistry in terms of which substrates can be oxidized versus wildtype full length PAH, which only efficiently accepts L-phe as substrate.

76 Phenylketonuria

Additional objectives are to compare wildtype PAH with selected PKU inducing missense mutations as a further probe of PAH mechanism and to initiate studies designed to defining the chemical basis for hyperphenylalaninemic disorders. Finally, the use of double mixing stopped-flow UV/vis and florescence experiments will be utilized to probe the compulsory reduction of the ferric active site prior to catalytic oxidation of substrate. Kinetic and mechanistic experiments will be performed to identify the factors that control and regulate iron reduction. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Device for Rapid Screening of Plasma Homocysteine Principal Investigator & Institution: Davies, Malonne I.; ; Bioanalytical Systems, Inc. 2701 Kent Ave West Lafayette, in 47906 Timing: Fiscal Year 2001; Project Start 1-SEP-1999; Project End 1-MAY2003 Summary: (Applicant's abstract) The objective of the proposed work is fast, sensitive integrated clinical analyzers for the diagnosis of two metabolism disorders, homocysteinuria and phenylketonuria (PKU). The assays are based on microchip capillary electrophoresis with electrochemical detection. This format has several advantages, including small sample requirements, fast analysis times, and inexpensive manufacture of multiple chips. Electrochemical detectors are ideally suited to microchip CE because they can be easily miniaturized and integrated into the analysis system. Monitoring phenylanlanine concentration in plasma samples of newborns is required by law. The current assay has a relatively high rate of failure (1:70) and requires instrumentation frequently not found in-house, especially in small hospitals. High levels of homocysteine in plasma has been associated with cerebrovascular, peripheral vascular, and coronary heart diseases. The assay for homocysteine involves online reduction of the proteinbound homocysteine with tris-(2-carboxyethyl)phosphine, separation by electrophoresis, and electrochemical detection at a gold/mercury electrode. Phenylalanine will be determined in plasma in a similar manner using a copper electrode. The chips will be used with a portable analysis system based on a battery-powered high voltage power supply, miniaturized potentiostat, and integrated data analysis system. The chips we develop will generate a foundation for other clinical assays based on electrochemical detection. PROPOSED COMMERCIAL APPLICATION: The current trend in clinical analysis is away form large centralized labs and toward point of care testing. Thus, a compact device for performance of assays for homocysteine and other clinically relevant animo acids in the clinic or physician's office has large commercial potential. Recently,

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the American Heart Association recommended homocysteine screening for patients at risk for cardiovascular disease. This should lead to a large demand for accurate and cost-effective assays for homocysteine similar to the current cholesterol screening assays. The development of a small, fast and reliable assay for phenylalanine in blood will make it possible to test infants quickly and accurately for PKU. The electrochemical based clinical analyzers developed here will provide a format that can be used for the development of a number of other assays for clinically important analytes. What is demonstrated with homocysteine and phenylalanine is just the beginning of a large array of clinical analyzers based on microchip CEEC. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Dietary Adherence in Children with Chronic Conditions Principal Investigator & Institution: Ievers-Landis, Carolyn E.; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 1-JUN-2001; Project End 1-MAY2006 Summary: (Adapted from applicant's description): The candidate is a research associate in pediatric psychology who is advancing to a junior faculty position. This award is expected to help transition the focus of the candidate's research and provide additional training in measurement of dietary adherence, particularly of barriers associated with following prescribed diets for children with various chronic conditions. The candidate's career goals are to develop an independent research career related to elucidation of barriers and family interaction patterns that interfere with dietary adherence and development of intervention programs to promote adherence. Specific objectives are: 1) learn specialized methods of measurement to identify the challenges related to the dietary management of chronic conditions of childhood, including indepth interviews and behavioral analyses of family interactions at mealtimes, and 2) use data from these methods to develop family-based interventions to promote adherence to dietary regimens. The candidate proposes a five-year training program with faculty mentors from a strong pediatric research department and medical school. Her sponsor is a very experienced pediatric psychology researcher whose work has focused on identifying factors that enhance or disrupt the psychosocial adaptation of children with chronic illness. Mentors represent subspecialty divisions that are directly relevant to the research and career development plan. The career development plan describes activities focused on enhancing knowledge of research-related approaches to the identification of barriers to dietary adherence and design of intervention programs through

78 Phenylketonuria

clinical observation, course work, and independent studies with mentors. Other activities include research training in statistical methods and supervised experience in preparation of grant proposals for individual research support. The candidate's proposed research involves two studies. Study 1 is a two-phase assessment of barriers to dietary adherence in children with hyperlipidemia, insulin-dependent diabetes mellitus, phenylketonuria, and Prader-Willi syndrome. Study 2 is a pilot study to develop and evaluate family-based intervention programs to improve dietary adherence for children in the target populations. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Metabolic Engineering as Therapy for Murine PKU Principal Investigator & Institution: Harding, Cary O.; Pediatrics; Oregon Health & Science University 3181 Sw Sam Jackson Park Rd Portland, or 97201 Timing: Fiscal Year 2001; Project Start 1-JUL-2001; Project End 0-JUN2003 Summary: adapted from applicant's abstract): The overall objective of this project is to investigate the efficacy of liver or muscle-directed gene therapy using recombinant adeno-associated virus (rAAV) vectors in the treatment of phenylketonuria (PKU) using, as a model, the phenylalanine hydroxylase (PAH) deficient Pahenu2 mouse. Recombinant adenoassociated virus has in recent studies shown promise as a gene delivery vector for both liver and muscle. We propose to compare the effects of muscle-directed vs. liver-directed rAAV-mediated gene therapy upon hyperphenylalaninemia in the Pahenu2 mouse. Restoration of liver enzyme activity is the most obvious approach for gene therapy of PKU. However, the disease pathophysiology associated with PKU is caused by circulating toxins, namely phenylalanine and its metabolites; PAH deficiency has no direct pathologic effect upon the liver. Therefore, any treatment approach that can effectively remove the toxic metabolites from the body could prevent disease-associated pathology. We have shown previously that PAH expression in muscle can lower serum phenylalanine levels if the enzyme is supplied with sufficient tetrahydrobiopterin (BH4), a required cofactor for PAH activity. However, attaining a sufficient continuous supply through exogenous administration of BH4 is very difficult and expensive. We propose two potential methods for avoiding this complication: engineering of skeletal muscle to express, along with PAH, components of the BH4 synthetic pathway or alternatively to induce muscle expression of phenylalanine ammonia lyase (PAL), an enzyme from yeast that requires no exogenous cofactors. In this project, we will first compare the ability of rAAV vectors

Studies 79

to produce stable PAH expression in liver and muscle and assess the effect upon hyperphenyl-alaninemia in Pabenu2 mice. Secondly, we will develop germline modified mice that carry a muscle-specific transgene containing the PAH cDNA and elements of the BH4 synthetic pathway (GTP cyclohydrolase I (GTPCH) or GTPCH and pyruvoyltetrahydropterin synthase (PTPS)) in an attempt to induce both constitutive PAH expression and BH4 synthesis. We will breed these animals to Pahenu2 mice to determine whether muscle PAH expression together with BH4 synthesis can correct hyperphenylalaninemia in PKU. Finally, we will investigate PAL expression induced either by germline modification or rAAV-mediated gene transfer in Pahenu2 mouse muscle, as a possible treatment of hyperphenylalaninemia. The ultimate goal of our research is the development of effective and safe gene therapy for phenylketonuria. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Pathophysiology of PKU Principal Investigator & Institution: Dyer, Charissa A.; ; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, Pa 19104 Timing: Fiscal Year 2000; Project Start 1-AUG-2000; Project End 1-JUL2002 Summary: (Adapted from the applicant's Description) The focus of this revised application is to determine if a correlation exists between myelination and neurotransmitter production in phenylketonuria. The investigator's preliminary data show that myelination, demyelination, and remyelination take place in PKU mice as they are cycled on rounds of low Phenylalanine diet and regular diet. Since blood Phe levels change rapidly compared to changes in myelination, she proposed to examine the relationship between gain and loss of myelin and neurotransmitter production. The investigator will employ histochemical, immunohistochemical, molecular, and biochemical techniques to better understand the pathophysiology of PKU, and ultimately lead to the development of additional therapies for PKU. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

·

Project Title: Phenylalanine Hydroxylase Deficiency: Response to BH4 Principal Investigator & Institution: Matalon, Reuben; Head, Section of Genetics & Metabolism; Pediatrics; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77550

80 Phenylketonuria

Timing: Fiscal Year 2001; Project Start 1-AUG-2001; Project End 1-JUL2003 Summary: (provided by applicant): Phenylketonuria (PKU), due to phenylalanine hydroxylase (PAH) deficiency, is treated by dietary restriction of phenylalanine (Phe). Treatment of PKU with Phe-restricted diet has been difficult and often not possible to achieve the desired level of blood Phe for many patients. Reports indicate poor school performance, loss of IQ, and white matter deterioration in the brain when diet is relaxed. Furthermore, there is no agreed upon criteria for follow up and what blood Phe levels need to be pursued in older children and adults. Another complicating factor is pregnancy with PKU, which is at risk for offspring with neurological deficits and congenital heart defects. Recently, some patients with PAH deficiency have been found to respond to high doses of tetrahydrobiopterin (BH4). Tetrahydrobiopterin is a cofactor required for PAH activity. The reports of PAH deficiency responding to BH4 suggest Km mutations of PAH while the metabolism of BH4 is normal. Analysis of PAH in these patients showed various mutations, suggesting that there may be a wide range of PAH mutations that should respond to BH4. This pilot study is intended to investigate, over a period of two years, patients with PKU and their response to BH4 loading. The metabolism of BH4 will be studied, mutations of PAH will be determined, and the response to BH4 will be studied by monitoring blood Phe levels, in situ directed mutagenesis, enzyme expression, and enzyme kinetics in the presence of varying levels of BH4. Earlier studies of in vitro expression of PKU mutations were not aimed to identify mutations that respond to BH4, so such data are not available on approximately 400 mutations of PAH. Success of these studies will lead to new research on the treatment for many patients with PKU, and for a systematic new study of the mutations of PAH in order to identify which mutations respond to BH4. Treatment with BH4 should lead to a better outcome for PKU patients and for maternal PKU. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket ·

Project Title: Serotonin Receptors in Phenylketonuric Rats Principal Investigator & Institution: Ike, Justus O.; Biology; Fisk University Nashville, Tn 37203 Timing: Fiscal Year 2000; Project Start 8-AUG-2000; Project End 1-JUL2003 Summary: (adapted from applicant's abstract) Phenylketonuria (PKU) causes mental retardation in children. The underlying cause of PKU is not well understood. The critical biochemical parameters and reaction in the development of PKU is plasma phenylalanine elevation whereas

Studies 81

tyrosine is maintained at a relatively low level. The serotonergic system has consistently been implicated in the pathogenesis of PKU. The goal of this research is to determine if changes in serotonin receptors (5-HT2C) contribute to the conditions associated with PKU by inducing the primary characteristics of PKU beginnings in 9-day-old rats. To achieve this goal, animal models of PKU will be used to examine a number of pharmacological parameters, including quantitation of serotonin levels by means of high performance liquid chromatography (HPLC), and radioligand binding assays that are coupled with determinations of blood phenylalanine levels. The findings of this work may contribute toward an understanding of the mechanisms involved in this disease. Website: http://commons.cit.nih.gov/crisp3/CRISP.Generate_Ticket

E-Journals: PubMed Central19 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).20 Access to this growing archive of e-journals is free and unrestricted.21 To search, go to http://www.pubmedcentral.nih.gov/index.html#search, and type “phenylketonuria” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for phenylketonuria in the PubMed Central database: ·

A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase by Christineh N. Sarkissian, Zhongqi Shao, Francoise Blain, Rosalie Peevers, Hongsheng Su, Robert Heft, Thomas M. S. Chang, and Charles R. Scriver; 1999 March 2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=26785

·

Cerebral protein synthesis in a genetic mouse model of phenylketonuria by Carolyn Beebe Smith and Julia Kang; 2000 September 26 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=27140

Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html. 20 With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 21 The value of PubMed Central, in addition to its role as an archive, lies the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print. 19

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·

Commentary:Phenylketonuria: Old disease, new approach to treatment by Harvey L. Levy; 1999 March 2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=33523

·

Founder Effect of a Prevalent Phenylketonuria Mutation in the Oriental Population by T Wang, Y Okano, RC Eisensmith, ML Harvey, WHY Lo, S Huang, Y Zeng, L Yuan, J Furuyama, T Oura, SS Sommer, and SLC Woo; 1991 March 15 http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abst ract&artid=51186

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine. The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to the public.22 If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with phenylketonuria, simply go to the PubMed Web site at www.ncbi.nlm.nih.gov/pubmed. Type “phenylketonuria” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for “phenylketonuria” (hyperlinks lead to article summaries): ·

Cognition and tyrosine supplementation among school-aged children with phenylketonuria. Author(s): Mazzocco MM, Yannicelli S, Nord AM, van Doorninck W, Davidson-Mundt AJ, Greene CL.

PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

22

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Source: Am J Dis Child. 1992 November; 146(11): 1261-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1415060&dopt=Abstract ·

Know your organizations: the National Society for Phenylketonuria and Allied Disorders. Author(s): Thorne C. Source: Health Visit. 1982 January; 55(1): 26. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6915915&dopt=Abstract

·

Sensory restriction and isolation experiences in children with phenylketonuria. Author(s): Friedman CJ, Sibinga MSMS, Steisel IM, Sinnamon HM. Source: Journal of Abnormal Psychology. 1968 August; 73(4): 294-303. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=5672220&dopt=Abstract

Vocabulary Builder Ammonia: Ammonia. A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aromatic: Having a spicy odour. [EU] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU]

Cardiovascular: Pertaining to the heart and blood vessels. [EU] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU]

Cervical: Pertaining to the neck, or to the neck of any organ or structure. [EU]

84 Phenylketonuria

Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Criterion: A standard by which something may be judged. [EU] Diurnal: Occurring during the day. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH] Epidemiological: Relating to, or involving epidemiology. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Gastrointestinal: Pertaining to or communicating with the stomach and intestine, as a gastrointestinal fistula. [EU] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hypertension: Persistently high arterial blood pressure. Various criteria for its threshold have been suggested, ranging from 140 mm. Hg systolic and 90 mm. Hg diastolic to as high as 200 mm. Hg systolic and 110 mm. Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). [EU] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Immunization: The induction of immunity. [EU] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulindependent diabetes mellitus. [NIH]

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Kinetic: Pertaining to or producing motion. [EU] Mammary: Pertaining to the mamma, or breast. [EU] Mammography: Radiographic examination of the breast. [NIH] Metabolite: process. [EU]

Any substance produced by metabolism or by a metabolic

Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU] Paediatric: Of or relating to the care and medical treatment of children; belonging to or concerned with paediatrics. [EU] Pathologic: 1. indicative of or caused by a morbid condition. 2. pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Receptor: 1. a molecular structure within a cell or on the surface characterized by (1) selective binding of a specific substance and (2) a specific physiologic effect that accompanies the binding, e.g., cell-surface receptors for peptide hormones, neurotransmitters, antigens, complement fragments, and immunoglobulins and cytoplasmic receptors for steroid hormones. 2. a sensory nerve terminal that responds to stimuli of various kinds. [EU] Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU]

86 Phenylketonuria

Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Serum: The clear portion of any body fluid; the clear fluid moistening serous membranes. 2. blood serum; the clear liquid that separates from blood on clotting. 3. immune serum; blood serum from an immunized animal used for passive immunization; an antiserum; antitoxin, or antivenin. [EU] Skeletal: Pertaining to the skeleton. [EU] Substrate: A substance upon which an enzyme acts. [EU] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH]

Patents 87

CHAPTER 5. PATENTS ON PHENYLKETONURIA Overview You can learn about innovations relating to phenylketonuria by reading recent patents and patent applications. Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.23 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information.

23Adapted

from The U. S. Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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Patents on Phenylketonuria By performing a patent search focusing on phenylketonuria, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. The following is an example of the type of information that you can expect to obtain from a patent search on phenylketonuria: ·

Method for treating phenylketonuria Inventor(s): Berry; Helen K. (Cincinnati, OH) Assignee(s): Children's Hospital Medical Center (Cincinnati, OH) Patent Number: 4,252,822 Date filed: December 26, 1979 Abstract: A method for improving motor and cognitive functions in mammalian subjects affected with phenylketonuria by administering a mixture of valine, isoleucine and leucine as a supplement to the restriction of phenylalanine content of their diets. The invention described herein was made in the course of work under a grant from the Department of Health, Education and Welfare. Excerpt(s): In spite of numerous efforts directed toward the study of phenylketonuria (PKU) over four decades, the exact mechanism whereby the enzymatic defect in metabolism of phenylalanine leads to abnormal development of the central nervous system remains obscure. Once the mechanism is understood, therapeutic attempts could be directed toward correcting the basic defect. At present, a restriction of phenylalanine content of the diet, thereby reducing concentration of phenylalanine and/or its metabolites in blood and tissues, including the brain, is the only empirical treatment used. Treatment of children with phenylketonuria by use of phenylalanine restriction in the diet was initiated in this country in about 1955. However, there have been no significant improvements in this highly restrictive treatment since its inception. ... It is apparent that the present empirical treatment for the restriction of phenylalanine in diet is not completely satisfactory. Moreover, continuance of the treatment diet becomes increasingly difficult as the patient grows older. Phenylalanine requirements steadily

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decrease while the desire for a more normal life, particularly regarding food habits, becomes urgent as the treatment is successful in producing normal physical and intellectual development. Therefore, there is a need for new methods in the treatment of phenylketonuria to control levels of phenylalanine and to inhibit its deleterious effects on the central nervous system. ... This invention is directed to the method of improving motor and cognitive functions in mammalian subjects afflicted with phenylketonuria by the administration of a mixture of valine, isoleucine and leucine. It has been found that the addition of valine, isoleucine and leucine (herein sometimes simply "VIL") to a low phenylalanine diet prevents learning deficits observed in mammalian subjects with high concentrations of phenylalanine in the blood. Furthermore, it has been discovered that a supplement of VIL, given together with a phenylketonuria-inducing diet, prevented behavioral deficits. Supplements of VIL have also been added to a phenylalanine diet for children and adults under treatment for phenylketonuria; and improved performance in motor and cognitive functions were observed. Web site: http://www.delphion.com/details?pn=US04252822__

Patent Applications on Phenylketonuria As of December 2000, U.S. patent applications are open to public viewing.24 Applications are patent requests which have yet to be granted (the process to achieve a patent can take several years). The following patent applications have been filed since December 2000 relating to phenylketonuria: ·

Use of Threonine for the Treatment of Phenylketonuria Inventor(s): Georgi, Gilda ; (Friedrichsdorf, De), Sawatzki, Gunther ; (Munzenberg, De) Correspondence: Bacon & Thomas; 625 Slaters Lane 4th Floor; Alexandria; VA; 22314 Patent Application Number: 20010011070 Date filed: March 2, 1998 Abstract: The invention relates to the use of threonine for the treatment of phenylketonuria. The invention is based on the surprising discovery that the concentration of phenylalanine in the plasma of PKU patients can be reduced by additional doses of threonine. The object of the invention is therefore an composition for dietetic or pharmaceutical use in

24

This has been a common practice outside the United States prior to December 2000.

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phenylketonuria, which composition contains at least 8 g threonine per 100 g amino acids. This composition may consist of foods, in particular formula foods and PKU dietetic products. Excerpt(s): The invention relates to a composition for the dietetic or pharmaceutical treatment of phenyl-ketonuria and the use of threonine for the treatment of phenylketonuria. ... Phenylketonuria (referred to below as PKU) is among the genetically determined diseases and is a metabolic disorder which if untreated usually leads to severe impairment of physical and mental development. Under normal nutritional conditions, phenylalanine is absorbed with all proteins of animal and plant origin. In persons with the disease, phenylalanine accumulates in the blood and tissues because of the metabolic disorder. The consequences of the sometimes excessively high phenylalanine level are metabolic imbalances, which can lead via various symptoms to irreversible, progressive mental disability. ... The purpose of the present invention is to provide an improved and simpler means for the dietary treatment or pharmaceutical treatment of phenylketonuria. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with phenylketonuria, you can access the U.S. Patent Office archive via the Internet at no cost to you. This archive is available at the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” You will see two broad options: (1) Patent Grants, and (2) Patent Applications. To see a list of granted patents, perform the following steps: Under “Patent Grants,” click “Quick Search.” Then, type “phenylketonuria” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on phenylketonuria. You can also use this procedure to view pending patent applications concerning phenylketonuria. Simply go back to the following Web address: http://www.uspto.gov/main/patents.htm. Under “Services,” click on “Search Patents.” Select “Quick Search” under “Patent Applications.” Then proceed with the steps listed above.

Vocabulary Builder Isoleucine: An essential branched-chain amino acid found in many proteins.

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It is an isomer of leucine. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]

Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH]

Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

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CHAPTER 6. BOOKS ON PHENYLKETONURIA Overview This chapter provides bibliographic book references relating to phenylketonuria. You have many options to locate books on phenylketonuria. The simplest method is to go to your local bookseller and inquire about titles that they have in stock or can special order for you. Some parents, however, prefer online sources (e.g. www.amazon.com and www.bn.com). In addition to online booksellers, excellent sources for book titles on phenylketonuria include the Combined Health Information Database and the National Library of Medicine. Once you have found a title that interests you, visit your local public or medical library to see if it is available for loan.

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Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “phenylketonuria” (or synonyms) into the “For these words:” box. You will only receive results on books. You should check back periodically with this database which is updated every 3 months. The following is a typical result when searching for books on phenylketonuria: ·

Genetic Disorders and Birth Defects: A Compendium of AAP Guidelines and Resources for the Primary Care Practitioner Source: Elk Grove Village, IL: American Academy of Pediatrics (AAP). 1997. 130 p. Contact: Available from American Academy of Pediatrics (AAP). 141 Northwest Point Boulevard, Elk Grove Village, IL 60007-1098. (800) 4339016 (members) or (888) 227-1773 (nonmembers). Fax (847) 434-8000. Website: www.aap.org. PRICE: $24.95 each (members); $29.95 each (nonmembers); plus shipping and handling. Order Number B-MA0097. Summary: This volume provides a compendium of the American Academy of Pediatrics (AAP) guidelines and resources for health care providers who are working with patients who have genetic disorders and birth defects. The compendium serves as a diagnostic and management resource guide for pediatricians and primary care physicians. Although some of the disorders covered are relatively uncommon, it is likely that most pediatricians will encounter and care for a few such patients in their practice panel. The authors emphasize that early intervention services, multidisciplinary care, and developmental assessment and management form a major part of continuing care for many children with genetic conditions. The AAP Policy Statements are provided on folic acid for the prevention of neural tube defects, issues in newborn screening, maternal phenylketonuria, maternal serum alpha-fetoprotein screening, newborn screening for congenital hypothyroidism, newborn screening fact sheets, and prenatal genetic diagnosis for pediatricians. In addition, policy statements are provided for the health supervision of children born with the following conditions: achondroplasia, Down syndrome, fragile X syndrome, Marfan syndrome, neurofibromatosis, sickle cell disease, and Turner syndrome. Each Policy Statement includes references. The

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compendium includes extensive appendices, covering topics including fetal alcohol syndrome, general principles of care for children and adolescents with genetic and other chronic health conditions, hospital stays, medical homes, preventive pediatric health care, and transition of care provided for adolescents with special health care needs. The compendium also lists the references where the policy statements were first published, the contact information for national and regional genetic organizations, and the members of the AAP Section on Genetics and Birth Defects. ·

Nutrition Services in Perinatal Care. Second Edition Source: Washington, DC, National Academy Press, 114 p., 1992. Contact: National Academy Press, 2101 Constitution Avenue, NW., Washington, DC 20418. Summary: Nutrition Services in Perinatal Care describes two basic types of nutrition services: (1) Basic nutrition services, which should be available to all women and infants in the course of usual health care; and (2) special nutrition services, which should be provided to women with health problems that complicate their nutritional care, to preterm infants, and to full-term infants with serious health problems. Basic nutritional services that address the mother's nutritional needs include (1) early identification of women at risk for nutritional health problems; (2) health maintenance activities for promoting adequate nutrition; and, (3) as needed, basic nutrition interventions including counseling, food or vitamin-mineral supplementation, support, and referrals. Special nutrition services, which address complex nutritional problems related to medical or surgical conditions, usually require that a nutrition specialist, ordinarily an experienced registered dietitian, serve on the health care team. Examples of such health problems include insulin dependent diabetes mellitus, severe gastrointestinal disorders, and phenylketonuria. Chapters cover (1) the nutritional concerns of women in the preconceptional, prenatal, and postpartum periods; (2) basic and special nutritional services for women in the preconceptual, prenatal, and postpartum periods; (3) the basic nutrition services available for newborn infants; (4) newborns who need special nutritional care; and (5) the continuity of nutritional care.

·

Education of students with phenylketonuria (PKU) Source: Bethesda, MD: National Institute of Child Health and Human Development, U.S. Department of Health and Human Services. 1991.

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Contact: Available from National Institute of Child Health and Human Development, Building 31, 2A32, MSC 2425, 9000 Rockville Pike, Bethesda, MD 20892. Telephone: (301) 496-5133 / fax: (301) 496-7101 / Web site: http://www.nih.gov/nichd/. Available at no charge. Summary: This booklet, designed for teachers, school nurses, administrators, and other school personnel, provides an overview of current knowledge about phenylketonuria (PKU) and the psychoeducational implications of the condition. Topics include the benefits of treatment; screening, diagnosis, and incidence; diet management; the role of school personnel; and issues for elementary and adolescent students with PKU. Resources for further information about PKU and its associated problem, maternal PKU, are listed. Updates of this publication, now in its third edition, are based primarily on the knowledge gained from the Collaborative Study of Children Treated for PKU, a project started in 1965 as a joint research effort of 15 PKU clinical programs throughout the United States.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes & Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in PrintÒ). The following have been recently listed with online booksellers as relating to phenylketonuria (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com): ·

Genetic Disorders and Pregnancy Outcome by Lawrence D. Platt (Editor), et al; ISBN: 1850707219; http://www.amazon.com/exec/obidos/ASIN/1850707219/icongroupin terna

·

Low protein cookery for phenylketonuria ; ISBN: 0299073203; http://www.amazon.com/exec/obidos/ASIN/0299073203/icongroupin terna

·

Low Protein Cookery for Phenylketonuria by Virginia E. Schuett; ISBN: 0299153843; http://www.amazon.com/exec/obidos/ASIN/0299153843/icongroupin terna

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Phenylketonuria and some other inborn errors of amino acid metabolism: biochemistry, genetics, diagnosis, therapy ; ISBN: 3134669013; http://www.amazon.com/exec/obidos/ASIN/3134669013/icongroupin terna

·

Practical Developments in Inherited Metabolic Disease : DNA Analysis, Phenylketonuria and Screening for Congenital Adrenal Hyperplasia by G.M. Addison, et al (1987); ISBN: 085200690X; http://www.amazon.com/exec/obidos/ASIN/085200690X/icongroupi nterna

·

State laws and regulations governing newborn screening by Lori B. Andrews; ISBN: 0910059047; http://www.amazon.com/exec/obidos/ASIN/0910059047/icongroupin terna

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Tetrahydrobiopterin : Basic Biochemistry and Role in Human Disease by Seymour Kaufman, Seymour Kaurman (1997); ISBN: 0801853443; http://www.amazon.com/exec/obidos/ASIN/0801853443/icongroupin terna

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The child with phenylketonuria by J. B. Holton; ISBN: 0855370211; http://www.amazon.com/exec/obidos/ASIN/0855370211/icongroupin terna

The National Library of Medicine Book Index The National Library of Medicine at the National Institutes of Health has a massive database of books published on healthcare and biomedicine. Go to the following Internet site, http://locatorplus.gov/, and then select “Search LOCATORplus.” Once you are in the search area, simply type “phenylketonuria” (or synonyms) into the search box, and select “books only.” From there, results can be sorted by publication date, author, or relevance. The following was recently catalogued by the National Library of Medicine:25 In addition to LOCATORPlus, in collaboration with authors and publishers, the National Center for Biotechnology Information (NCBI) is adapting biomedical books for the Web. The books may be accessed in two ways: (1) by searching directly using any search term or phrase (in the same way as the bibliographic database PubMed), or (2) by following the links to PubMed abstracts. Each PubMed abstract has a “Books” button that displays a facsimile of the abstract in which some phrases are hypertext links. These phrases are also found in the books available at NCBI. Click on hyperlinked results in the list of books in which the phrase is found. Currently, the majority of the links are between the books and PubMed. In the future, more links will be created between the books and other types of

25

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·

Blackwell's underground clinical vignettes. Pediatrics. Author: Vikas Bhushan ... [et al.]; Year: 2002; Malden, Mass.: Blackwell Science, c2002; ISBN: 063204571X (pbk) http://www.amazon.com/exec/obidos/ASIN/063204571X/icongroupi nterna

·

Child with phenylketonuria [by] John Holton [and] Linda Tyfield. Author: Holton, J. B. (John B.); Year: 1974; [London] National Society for Mentally Handicapped Children [c1974]; ISBN: 0855370211 http://www.amazon.com/exec/obidos/ASIN/0855370211/icongroupin terna

·

Cost and availability of dietary treatment of phenylketonuria (PKU): report of a national survey. Author: California Department of Health Services, Genetic Disease Branch; Year: 1997; Berkeley, Calif.: The Branch, 1997

·

Dental health in children with Phenylketonuria, PKU: and other inborn errors of metabolism managed by diet. Author: Paul S. Casamassimo ... [et al.]; Year: 1984; Rockville, Md.: U.S. Dept. of Health & Human Services, Public Health Service, Health Resources and Services Administration, Bureau of Health Care Delivery and Assistance, Division of Maternal and Child Health, 1984

·

Diet and nutrition sourcebook: basic consumer health information about dietary guidelines, recommended daily intake values, vitamins, minerals, fiber, fat, weight control, dietary supplements, and food additives: along with special sections on nutrition. ; Year: 1999; Detroit, MI: Omnigraphics, c1999; ISBN: 0780802284 (lib. bdg.: alk. paper) http://www.amazon.com/exec/obidos/ASIN/0780802284/icongroupin terna

·

Dietary management of inherited metabolic disease: phenylketonuria, galactosemia, tyrosinemia, homocystinuria, maple syrup urine disease. Author: by Phyllis B. Acosta and Louis J. Elsas; Year: 1976; Atlanta: ACELMU publishers, c1976

·

Genetic Screening: Programs, Principles, and Research. Author: Patrias, Karen; Year: 1975; Washington: National Academy of Sciences, 1975

·

Management of newborn infants with phenylketonuria. Author: [prepared by a committee of the Collaborative Study of Children Treated for Phenylketonuria]; Year: 1978; [Rockville, Md.]: U. S. Dept. of Health, Education, and Welfare, Public Health Service, Health Services Administration, Bureau of Community Health Services, 1978

information, such as gene and protein sequences and macromolecular structures. See http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Books.

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·

Phenylketonuria (PKU) [electronic resource]: screening and management: January 1980 through July 2000, plus selected earlier citations: 3,394 citations. Author: prepared by Karen Patrias, Felix F. de la Cruz; Year: 2000; Bethesda, Md. (8600 Rockville Pike): U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Library of Medicine, Reference Section, [2000]

·

Phenylketonuria and other inborn errors of metabolism: the Oregon program. Author: by Carl G. Ashley; Year: 1965; [Portland, Ore.: Maternal and Child Health Section, Preventive Medical Services Division, Oregon State Board of Health, 1965?]

·

Phenylketonuria detection in the newborn infant as a routine hospital procedure; a trial of a phenylalanine screening method in 400,000 infants [by] Robert Guthrie and Stewart Whitney. Author: Guthrie, Robert, 1916-; Year: 1965; Washington, Children's Bureau [1965]

·

Phenylketonuria. Author: Lyman, Frank Lewis, 1921-; Year: 1963; Springfield, Ill., Thomas [c1963]

·

Phenylketonuria; a selected bibliography. [Listing prepared by Gladys M. Krueger. Author: United States. Children's Bureau; Year: 1963; Washington] 1963

·

Phenylketonuria; an inherited metabolic disorder associated with mental retardation [by] Willard R. Centerwall [and] Siegried A. Centerwall. Author: Centerwall, Willard R., 1924-; Year: 1972; [Bethesda, Md.] U. S. Maternal and Child Health Service; [for sale by the Supt. of Docs., U. S. Govt. Print. Off., Washington] 1972

·

PKU; a diet guide for parents of children with phenylketonuria. Author: California. Bureau of Public Health Nutrition; Year: 1962; [Berkeley, 1962]

·

Practical developments in inherited metabolic disease: DNA analysis, phenylketonuria, and screening for congenital adrenal hyperplasia: proceedings of the 23rd Annual Symposium of the SSIEM, Liverpool, Septmember 1985. Author: edited by G.M. Addison ... [et al; Year: 1986; Lancaster; Boston: MTP Press, c1986; ISBN: 085200690X http://www.amazon.com/exec/obidos/ASIN/085200690X/icongroupi nterna

·

Proceedings, edited by Bernard E. Cohen, Mitchell I. Rubin [and] Arieh Szeinberg. Author: International Symposium on Phenylketonuria and Allied Disorders, Tel Aviv, 1969; Year: 1971; [Tel Aviv, Printed by Translators' Pool, 1971]

·

Report of the NIH Consensus Development Conference on Phenylketonuria (PKU): screening and management. Author: U.S. Department of Health and Human Services, Public Health Service,

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National Institutes of Health, National Institute of Child Health and Human Devel; Year: 2001; Bethesda, Md.: The Institutes, 2001 ·

State laws pertaining to phenylketonuria as of November 1970. Author: United States. Maternal and Child Health Service; Year: 1971; Rockville, Md., 1971

Chapters on Phenylketonuria Frequently, phenylketonuria will be discussed within a book, perhaps within a specific chapter. In order to find chapters that are specifically dealing with phenylketonuria, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and phenylketonuria using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” By making these selections and typing in “phenylketonuria” (or synonyms) into the “For these words:” box, you will only receive results on chapters in books. The following is a typical result when searching for book chapters on phenylketonuria: ·

Differential Diagnosis of Scleroderma-like Disorders Source: in Clements, P.J.; Furst, D.E., Eds. Systemic Sclerosis. Baltimore, MD: Williams and Wilkins. 1996. p. 99-120. Contact: Available from Williams and Wilkins, Special Sales Department. (800) 358-3583. Summary: This chapter for health professionals focuses on the differential diagnosis of scleroderma-like disorders. These disorders include scleredema, scleredema associated with paraproteinemia or myeloma, scleromyxedema, scleroderma-like lesions in endocrine disorders, Werner's syndrome, progeria, sclerodermiform neonatal progeria, restrictive dermopathy, sclerodermiform chronic graft-versus-host disease, and scleroderma-like changes of porphyria cutanea tarda. Other disorders include scleroderma-like lesions in phenylketonuria, congenital fascial dystrophy, scleroderma-like changes induced by bleomycin, scleroderma-like plaques after vitamin K injection, progressive facial hemiatrophy, fibroblastic rheumatism, localized lipoatrophies, lichen sclerosus et atrophicus, sclerodermiform variety of acrodermatitis chronica atrophicans, and atrophoderma Pasini- pierini. Most of these disorders are discussed in terms of their clinical features, pathology and

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pathophysiology, differential diagnosis, and treatment. 115 references and 10 figures. ·

Inborn Errors of Metabolism Source: in Thoene, J.G., ed. Physicians' Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Company. 1995. p. 167-248. Contact: Available from Dowden Publishing Company, Inc. 110 Summit Avenue, Montvale, NJ 07645. (201) 391-9100. Fax (201) 391-2778. Price: $97.50 plus shipping and handling. ISBN: 0962871613. Summary: This chapter, from a physicians' guidebook to rare diseases, discusses inborn errors of metabolism. The book's intent is to help doctors and their patients identify rare disorders and find treatments and support groups. After an introductory section, this chapter covers more than ninety disorders, including the following, which relate to the digestive system: Andersen disease; Fabry disease; Forbes disease; fructose intolerance; galactosemia; Gaucher disease; Menkes disease; phenylketonuria; porphyria; Refsum syndrome; Sandhoff disease; Tangier disease; vitamin E deficiency; von Gierke disease; Wilson disease; and Zellwinger syndrome. For each disorder, the author includes a description, synonyms, and information about signs and symptoms, etiology, epidemiology, related disorders, standard and investigational treatments, and support groups and additional resources. A brief reference list for each disorder is also included.

·

Nutrition and Disorders of the Liver Source: in Whitney, E.N., Cataldo, C.B., and Rolfes, S.R. Understanding Normal and Clinical Nutrition. 4th ed. St. Paul, MN: West Publishing Company. 1994. p. 822-841. Contact: Available from West Publishing. 620 Opperman Drive, St. Paul, MN 55164. (800) 340-9378 or (612) 687-7000. Price: $67.00. ISBN: 0314041788. Summary: This chapter on nutrition and disorders of the liver is from an introductory medical textbook on nutrition. Topics include fatty liver, hepatitis, cirrhosis, liver transplantation, and nutrition assessment. The authors focus on the appropriate diet therapy for each of these liver disorders. The chapter concludes with study questions, clinical application questions, and a 'highlight' section describing inborn errors of metabolism, most notably phenylketonuria and galactosemia. 8 figures. 1 table. 19 references. (AA-M).

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·

Food Intolerance Source: in Gerber, J.M. Handbook of Preventive and Therapeutic Nutrition. Frederick, MD: Aspen Publishers, Inc. 1993. p. 42-45. Contact: Available from Aspen Publishers, Inc. 7201 McKinney Circle, Frederick, MD 21701-9782. (800) 638-8437 or (301) 417-7500. Price: $34. ISBN: 0834203189. Summary: This chapter, from a handbook of preventive and therapeutic nutrition, provides an overview about food intolerance. Sections include maldigestion disorders; gastrointestinal disease, including celiac sprue, cystic fibrosis, and cholecystitis; metabolic defects, including phenylketonuria, and galactosemia; psychologic reactions; natural substances causing food intolerance, including phenylethylamine, tyramine, histamine, and histamine-releasing agents; food additives causing food intolerance, including tartrazine (yellow No. 5), benzoic acid, sulfites, and monosodium glutamate (MSG); and microorganism contamination causing food intolerance, including proteus and gonyaulax catenella. In each section, brief information is presented on the type of reaction common to the agent described.

·

Genetic Disorders Source: in Roe, S.N., ed. Dietitian's Patient Education Manual. Frederick, MD: Aspen Publishers, Inc. 1991. p. 11: 1-11: 30. Contact: Available from Aspen Publishers, Inc. 7201 McKinney Circle, Frederick, MD 21701-9782. (800) 638-8437 or (301) 417-7500. Price: $255; plus shipping and handling. ISBN: 0834201968. Summary: This book chapter, from a dietitian's patient education manual, discusses four genetic disorders: phenylketonuria (PKU), galactosemia, maple syrup urine disease, and homocystinuria. For each disorder covered, the author presents a definition and rationale for treatment, considerations for diet counseling, and details of food intake. Specific topics include requirements for infants and children with various inherited disorders of amino acid metabolism, the use of food exchange lists, snacks, a meal plan for maternal PKU, foods to avoid, reading food labels, strategies for enhancing patient compliance, teaching children to use a scale, special considerations for the teenager with PKU, and common questions and answers about each disorder. Also included are numerous suggestions for games to play with children as part of their patient education. This manual contains numerous charts and short sidebars for easy photocopying and incorporation into any patient education program. The chapter concludes with recipes and a list of related publications and resource organizations.

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·

Marriage, Pregnancy, and Children Source: in Seizures and Epilepsy in Childhood: A Guide for Parents. Second Edition. Freeman, J.M.; Vining, E.; Pillas, D.J. Baltimore, MD, Johns Hopkins University Press, pp. 290-296, 1997. Contact: Johns Hopkins University Press, 2715 North Charles Street, Baltimore, MD 21218-4319. Summary: Marriage, Pregnancy, and Children, a chapter in Seizures and Epilepsy in Childhood: A Guide for Parents, explains that marriage and parenthood are perfectly reasonable for individuals with epilepsy. While marriage of persons with epilepsy used to be illegal, those laws were abolished. However, many misconceptions still abound, for example, about the effects of pregnancy on epilepsy and about the effects of epilepsy and its treatment on a fetus. Physicians often give outdated answers to these questions. The truth is, people with epilepsy can marry, and most women with epilepsy can bear children. They can be competent parents, even if they still have seizures. Although pregnancy may affect a person's seizures, the woman's risks during pregnancy are little different from the risks other women face. Pregnancy is not a good time to change or adjust anticonvulsant medications. There is little evidence that brief seizures injure the fetus, although prolonged seizures could affect it. There are risks to the fetus from anticonvulsant drugs, although the risks vary with the drug and are usually small. Most anticonvulsants affect the metabolism of vitamin K in the newborn and may lead to bleeding, so the mother should receive vitamin K during the last week of pregnancy or the infant should receive it immediately after birth. It is possible to breast-feed while taking anticonvulsants, because concentrations in breast milk are usually low. Anticonvulsants increase the metabolism of birth control steroids and make them less effective. There is a very small risk of the children of parents with epilepsy developing epilepsy. Epilepsy may be a manifestation of some other diseases, such as phenylketonuria, Tay-Sachs, and metachromatic leukodystrophy. There is a genetic tendency to inherit epilepsy, but the risk is small for the children of the person with epilepsy.

·

Promoting Health for People With Learning Disabilities Source: in Health Promotion: Concepts and Practice. Dines, A.; Cribb, A.; eds., Cambridge, MA, Blackwell Scientific Publications, Inc., pp. 112-128, 1993. Contact: Blackwell Scientific Publications, Inc., 238 Main Street, Cambridge, MA 02142. (800) 759-6102.

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Summary: Promoting Health for People With Learning Disabilities, a chapter in Health Promotion: Concepts and Practice, addresses the role of nurses and other health care workers in meeting the general and specific health needs of the learning disabled. The term learning disability is often used as a euphemism for a collection of clinical types or syndromes such as Down's Syndrome. The British government requires the integration and full participation of the learning disabled in housing, leisure, and employment opportunities in the community. Under the National Health Service and Community Care Act, local authorities have the responsibility for planning and coordinating services for the learning disabled. The Act advocates the care management approach, which emphasizes providing individualized services for people and considering each client's needs. Care management requires that each person with significant social or health care needs have access to a named person who acts as the designated care manager. Social workers, nurses, and other community workers act as care managers. Under the care management system, health and social service agencies work closely together at both the planning stage and at the point of service delivery. The strategic intent of the National Health Service in Wales identified three commitments for people with learning disabilities: (1) Focusing on quality of life, (2) valuing people as individuals, and (3) achieving a costeffective balance in the use of available resources. Areas of special consideration for people with learning disabilities include (1) heart disease in people with Down's syndrome, (2) the inhibitive effect of epilepsy on lifestyle, (3) specialized care for people with cerebral palsy, and (4) management of metabolic disorders such as phenylketonuria. In the movement to de-institutionalize, the community must respond by developing the capacity to meet the general and specific needs of people with learning disabilities. 2 tables, 15 references. ·

Screening Source: in Health Promotion Throughout the Lifespan. Third Edition. Edelman, C. L.; Mandle, C. A. St. Louis, MO, Mosby-Year Book, pp. 222241, 1994. Contact: Mosby-Year Book, Inc., 11830 Westline Industrial Drive, St. Louis, MO 63146. Summary: Screening, a chapter in Health Promotion Throughout the Lifespan (Third Edition), seeks to assist nurses by (1) defining screening and its relation to preventive health care intervention, (2) identifying advantages and disadvantages of the screening process, (3) defining the disease-specific criteria that determine a screenable disease, (4) discussing the medical and economic issues related to the screening process that

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result in ethical implications, (5) explaining sensitivity and specificity as they relate to the efficacy of screening, (6) identifying the broad range of community resources included in and affected by the screening system, (7) describing the role of nurses in the screening process, and (8) examining various health maintenance examination protocols. As a method of precritical, secondary prevention, screening involves the rapid administration of a simple test to delineate individuals who probably have a condition from those who probably do not. The authors mention three issues as the criteria for screening: (1) The significance of the disease as a public health concern; (2) the presence of diagnostic criteria, along with a screening instrument and sufficient community resources to support a program; and (3) the level of knowledge about the condition, the safety of the treatment, and ethical considerations. These questions act as guidelines for selection of a screenable disease; however, screening often occurs without full compliance with these criteria. The authors discuss the following in detail: Diagnostic criteria; screening instruments (and their reliability, validity, sensitivity, and specificity); medical and economic ethics; cost/benefits of screening, cost effectiveness, and cost efficiency; selection of a screenable population; types of programs (individual, group or mass screening, one-test disease-specific screening, and multiple-test screening); and considerations of commonly screened conditions including phenylketonuria, breast cancer, colorectal cancer, prostate cancer, cholesterol levels, hypertension, glaucoma, and human immunodeficiency virus (HIV). Screening in health care presents numerous roles for nurses and provides them with a valuable preventive tool in their care for healthy people. 3 figures, 2 tables, 29 references. ·

Evaluation of Teachers' Knowledge of Students' Chronic Health Problems Source: in Advances in Health Education: Current Research, Volume One. Humphrey, J.H., ed. New York, NY, AMS Press, pages 67-74, 1988. Contact: AMS Press, Inc., 56 East 13th Street, New York, NY 10003. Summary: Evaluation of Teachers' Knowledge of Students' Chronic Health Problems, a book chapter in Advances in Health Education: Current Research, Volume One, describes a study that assessed the knowledge of practicing teachers about various chronic childhood health problems that could require alterations in classroom methods and/or environment. Study staff developed a 45-item, self-administered Survey of Teacher's Knowledge of Students' Chronic Health Problems (SKCHP). During 1984, the study administered the SKCHP and a personal data sheet to a sample of 77 practicing regular and special education teachers; the sample comprised teachers at two elementary schools, one junior

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high school, and one senior high school from a large midwestern school district. Findings indicated that 73 percent of the teachers surveyed had 10 years or more of experience. Less than 20 percent of the sample reported having received training in the management of students' chronic health problems. Results showed teachers to have limited knowledge about the management of certain chronic health problems (i.e., juvenile rheumatoid arthritis, spina bifida, phenylketonuria, diabetes, and respiratory problems). Special education teachers scored significantly higher than other teachers did. Teachers who were over the age of 40 and had more than 20 years experience scored lower than did teachers of less experience. Results show that older teachers who are not special educators have a need for formal training in the management of chronic health problems. 3 tables, 2 references. ·

Metabolic and Endocrine Disorders Source: in Grundy, M.C.; Shaw, L.; and Hamilton, D.V. Illustrated Guide to Dental Care for the Medically Compromised Patient. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 51-59. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax (800) 535-9935 or (314) 432-1380; E-mail: [email protected]; http://www.mosby.com. Price: $24.95 plus shipping and handling. ISBN: 0815140223. Summary: This chapter, from an illustrated guide to dental care for medically compromised patients, discusses metabolic and endocrine disorders. The chapter's topics include diabetes mellitus (insulindependent and noninsulin-dependent), including hypoglycemia and hyperglycemia; phenylketonuria; adrenocortical diseases; Addison's disease, including secondary adrenal insufficiency and Cushing's syndrome; thyroid disorders, including hyperthyroidism and hypothyroidism; and parathyroid disorders. For each condition, the authors provide a brief description, the components of medical management, and suggestions for dental care. Illustrations, including photographs, are included. 5 figures.

·

Problems Related to the Prevention of Oral Disease Source: in Grundy, M.C.; Shaw, L.; and Hamilton, D.V. Illustrated Guide to Dental Care for the Medically Compromised Patient. St. Louis, MO: Mosby-Year Book, Inc. 1993. p. 111-122. Contact: Available from Mosby-Year Book, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-9934. (800) 426-4545 or (314) 872-8370; Fax

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(800) 535-9935 or (314) 432-1380; E-mail: [email protected]; http://www.mosby.com. Price: $24.95 plus shipping and handling. ISBN: 0815140223. Summary: This chapter, from an illustrated guide to dental care for medically compromised patients, discusses problems related to the prevention of oral disease. Topics covered include dietary related disorders, including obesity, anorexia nervosa and bulimia nervosa, dietary habits, carbohydrate metabolism, phenylketonuria, cystic fibrosis, chronic renal failure, and celiac disease; medication and caries; erosion of the dental tissues; preventive therapy, including prevention and control of dental caries, fissure sealants, prevention and control of periodontal disease, chemical plaque control, and involvement of the caregiver; druginduced gingival hyperplasia, including that dependent on phenytoin, cyclosporin, and nifedipine; and self-mutilation, including Lesch-Nyhan syndrome, congenital insensitivity to pain, and gingivitis artefacta. For each condition, the authors provide a brief description, the components of medical management, and suggestions for dental care. Illustrations, including photographs, are included. 15 figures. 2 tables.

General Home References In addition to references for phenylketonuria, you may want a general home medical guide that spans all aspects of home healthcare. The following list is a recent sample of such guides (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · American Academy of Pediatrics Guide to Your Child's Symptoms : The Official, Complete Home Reference, Birth Through Adolescence by Donald Schiff (Editor), et al; Paperback - 256 pages (January 1997), Villard Books; ISBN: 0375752579; http://www.amazon.com/exec/obidos/ASIN/0375752579/icongroupinterna · The Children's Hospital Guide to Your Child's Health and Development by Alan D. Woolf (Editor), et al; Hardcover - 796 pages, 1st edition (January 15, 2001), Perseus Books; ISBN: 073820241X; http://www.amazon.com/exec/obidos/ASIN/073820241X/icongroupinterna · Helping Your Child in the Hospital: A Practical Guide for Parents by Nancy Keene, Rachel Prentice; Paperback - 176 pages, 3rd edition (April 15, 2002), O'Reilly & Associates; ISBN: 0596500114; http://www.amazon.com/exec/obidos/ASIN/0596500114/icongroupinterna

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· Medical Emergencies & Childhood Illnesses: Includes Your Child's Personal Health Journal (Parent Smart) by Penny A. Shore, William Sears (Contributor); Paperback - 115 pages (February 2002), Parent Kit Corporation; ISBN: 1896833187; http://www.amazon.com/exec/obidos/ASIN/1896833187/icongroupinterna · Taking Care of Your Child: A Parent's Guide to Complete Medical Care by Robert H. Pantell, M.D., et al; Paperback - 524 pages, 6th edition (March 5, 2002), Perseus Press; ISBN: 0738206016; http://www.amazon.com/exec/obidos/ASIN/0738206016/icongroupinterna

Vocabulary Builder Acrodermatitis: Inflammation involving the skin of the extremities, especially the hands and feet. Several forms are known, some idiopathic and some hereditary. The infantile form is called Gianotti-Crosti syndrome. [NIH] Anorexia: Lack or loss of the appetite for food. [EU] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, poly- and heterosaccharides. [EU] Cholecystitis: Inflammation of the gallbladder. [EU] Cirrhosis: Liver disease characterized pathologically by loss of the normal microscopic lobular architecture, with fibrosis and nodular regeneration. The term is sometimes used to refer to chronic interstitial inflammation of any organ. [EU] Colorectal: Pertaining to or affecting the colon and rectum. [EU] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Cookery: The art or practice of cooking. It includes the preparation of special foods for diets in various diseases. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU]

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Facial: Of or pertaining to the face. [EU] Fibrosis: The formation of fibrous tissue; fibroid or fibrous degeneration [EU] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Hepatitis: Inflammation of the liver. [EU] Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Hyperthyroidism: 1. excessive functional activity of the thyroid gland. 2. the abnormal condition resulting from hyperthyroidism marked by increased metabolic rate, enlargement of the thyroid gland, rapid heart rate, high blood pressure, and various secondary symptoms. [EU] Lesion: Any pathological or traumatic discontinuity of tissue or loss of function of a part. [EU] Microorganism: A microscopic organism; those of medical interest include bacteria, viruses, fungi and protozoa. [EU] Myeloma: A tumour composed of cells of the type normally found in the bone marrow. [EU] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Parathyroid: 1. situated beside the thyroid gland. 2. one of the parathyroid glands. 3. a sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Porphyria: A pathological state in man and some lower animals that is often due to genetic factors, is characterized by abnormalities of porphyrin metabolism, and results in the excretion of large quantities of porphyrins in

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the urine and in extreme sensitivity to light. [EU] Progeria: An abnormal congenital condition characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature greying, hair loss, hearing loss, cataracts, arthritis,osteoporosis, diabetes mellitus, atrophy of subcutaneous fat, skeletal hypoplasia, and accelerated atherosclerosis. Many affected individuals develop malignant tumors, especially sarcomas. [NIH] Proteus: A genus of gram-negative, facultatively anaerobic, rod-shaped bacteria that occurs in the intestines of humans and a wide variety of animals, as well as in manure, soil, and polluted waters. Its species are pathogenic, causing urinary tract infections and are also considered secondary invaders, causing septic lesions at other sites of the body. [NIH] Respiratory: Pertaining to respiration. [EU] Rheumatoid: Resembling rheumatism. [EU] Sclerosis: A induration, or hardening; especially hardening of a part from inflammation and in diseases of the interstitial substance. The term is used chiefly for such a hardening of the nervous system due to hyperplasia of the connective tissue or to designate hardening of the blood vessels. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Sulfites: Inorganic salts of sulfurous acid. [NIH] Systemic: Pertaining to or affecting the body as a whole. [EU] Tartrazine: An anionic, hydrophilic azo dye with an orange-yellow color used in fabrics, foods and cosmetics, and as a biological stain. [NIH] Transplantation: The grafting of tissues taken from the patient's own body or from another. [EU] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH]

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CHAPTER 7. MULTIMEDIA ON PHENYLKETONURIA Overview Information on phenylketonuria can come in a variety of formats. Among multimedia sources, video productions, slides, audiotapes, and computer databases are often available. In this chapter, we show you how to keep current on multimedia sources of information on phenylketonuria. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine. If you see an interesting item, visit your local medical library to check on the availability of the title.

Bibliography: Multimedia on Phenylketonuria The National Library of Medicine is a rich source of information on healthcare-related multimedia productions including slides, computer software, and databases. To access the multimedia database, go to the following Web site: http://locatorplus.gov/. Select “Search LOCATORplus.” Once in the search area, simply type in phenylketonuria (or synonyms). Then, in the option box provided below the search box, select “Audiovisuals and Computer Files.” From there, you can choose to sort results by publication date, author, or relevance. The following multimedia has been indexed on phenylketonuria. For more information, follow the hyperlink indicated: ·

Biochemical genetics in man: enzyme defects and DNA. Source: National Foundation - The March of Dimes; under the technical direction of Division of Medical Genetics, Dept. of Medicine, Johns Hopkins University School of Medicine; produced by; Year: 1969; Format: Motion

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picture; [White Plains, N. Y.]: The Foundation; [Atlanta: for loan by National Medical Audiovisual Center; Baltimore: for sale by MilnerFenwick, 1969] ·

Genetic counseling. Source: U. S. Public Health Service, [Georgia Regional Medical Television Network]; Year: 1970; Format: Videorecording; [Atlanta: The Network; for loan or sale by Calhoun (A. W.) Medical Library], 1970

·

Neurocutaneous disorders. Source: William Reed; filmed by Cinema Pictures, inc; Year: 1965; Format: Motion picture; [Kenilworth, N. J.]: Schering Corp., c1965

·

Pathology of lesions of the central nervous system. Source: Summer I. Zacks; Year: 1972; Format: Slide; [New York]: Medcom, c1972

·

Phenylketonuria. Source: a presentation of Films for the Humanities & Sciences; a Leeds University Television production for Shotlist; Year: 2001; Format: Videorecording; Princeton, N.J.: Films for the Humanities & Sciences, c2001

·

Prenatal detection of genetic disorders. Source: Academy of Health Sciences, United States Army Medical Department; Year: 1973; Format: Videorecording; Fort Sam Houston, Tex.: The Academy: [for loan by its Health Sciences Media Division 1973

·

Role of metabolic disorders in disease. Source: Harry I. Lurie; [made by] Visual Education Dept., Medical College of Virginia; Year: 1975; Format: Slide; Richmond: Medical College of Virginia Learning Resource Centers; [Chapel Hill, N.C.: for loan or sale by Health Sciences Consortium], c1975

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CHAPTER 8. PERIODICALS PHENYLKETONURIA

AND

NEWS

ON

Overview Keeping up on the news relating to phenylketonuria can be challenging. Subscribing to targeted periodicals can be an effective way to stay abreast of recent developments on phenylketonuria. Periodicals include newsletters, magazines, and academic journals. In this chapter, we suggest a number of news sources and present various periodicals that cover phenylketonuria beyond and including those which are published by parent associations mentioned earlier. We will first focus on news services, and then on periodicals. News services, press releases, and newsletters generally use more accessible language, so if you do chose to subscribe to one of the more technical periodicals, make sure that it uses language you can easily follow.

News Services & Press Releases Well before articles show up in newsletters or the popular press, they may appear in the form of a press release or a public relations announcement. One of the simplest ways of tracking press releases on phenylketonuria is to search the news wires. News wires are used by professional journalists, and have existed since the invention of the telegraph. Today, there are several major “wires” that are used by companies, universities, and other organizations to announce new medical breakthroughs. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing.

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PR Newswire Perhaps the broadest of the wires is PR Newswire Association, Inc. To access this archive, simply go to http://www.prnewswire.com. Below the search box, select the option “The last 30 days.” In the search box, type “phenylketonuria” or synonyms. The search results are shown by order of relevance. When reading these press releases, do not forget that the sponsor of the release may be a company or organization that is trying to sell a particular product or therapy. Their views, therefore, may be biased. The following is typical of press releases that can be found on PR Newswire: Reuters The Reuters' Medical News database can be very useful in exploring news archives relating to phenylketonuria. While some of the listed articles are free to view, others can be purchased for a nominal fee. To access this archive, go to http://www.reutershealth.com/frame2/arch.html and search by “phenylketonuria” (or synonyms). The following was recently listed in this archive for phenylketonuria: ·

Women with phenylketonuria should restrict diet before and during pregnancy Source: Reuters Medical News Date: January 12, 2000 http://www.reuters.gov/archive/2000/01/12/professional/links/20000 112clin002.html

·

Recombinant enzyme may improve therapy for phenylketonuria Source: Reuters Medical News Date: March 04, 1999 http://www.reuters.gov/archive/1999/03/04/professional/links/19990 304scie003.html

·

Psychiatric Symptoms In Adults With Phenylketonuria Of Psychologic Origin Source: Reuters Medical News Date: March 11, 1997 http://www.reuters.gov/archive/1997/03/11/professional/links/19970 311clin006.html

The NIH Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can

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be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within their search engine.

Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com. You can scan the news by industry category or company name. Internet Wire Internet Wire is more focused on technology than the other wires. To access this site, go to http://www.internetwire.com and use the “Search Archive” option. Type in “phenylketonuria” (or synonyms). As this service is oriented to technology, you may wish to search for press releases covering diagnostic procedures or tests that you may have read about.

Search Engines Free-to-view news can also be found in the news section of your favorite search engines (see the health news page at Yahoo: http://dir.yahoo.com/Health/News_and_Media/, or use this Web site’s general news search page http://news.yahoo.com/. Type in “phenylketonuria” (or synonyms). If you know the name of a company that is relevant to phenylketonuria, you can go to any stock trading Web site (such as www.etrade.com) and search for the company name there. News items across various news sources are reported on indicated hyperlinks.

BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “phenylketonuria” (or synonyms).

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Newsletters on Phenylketonuria Given their focus on current and relevant developments, newsletters are often more useful to parents than academic articles. You can find newsletters using the Combined Health Information Database (CHID). You will need to use the “Detailed Search” option. To access CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Your investigation must limit the search to “Newsletter” and “phenylketonuria.” Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter.” By making these selections and typing in “phenylketonuria” or synonyms into the “For these words:” box, you will only receive results on newsletters. The following list was generated using the options described above: ·

PKU CORPS bulletin Source: Boston, MA: PKU Community Outreach Resource Programs, Children's Hospital. 1995-. irregular. Contact: Available from Ildiko Szabo, Children's Hospital, PKU Community Outreach Resource Programs, 300 Longwood Avenue, Boston, MA 02115. Telephone: (617) 355-7346 / fax: (617) 730-0461 / email: [email protected]. Summary: This newsletter contains articles on topics of interest to families affected by phenylketonuria (PKU) who live in the New England region. Among other topics, it includes news from the readers, notices from state agencies regarding services, news about future social events, and dietary suggestions. [Funded by the Maternal and Child Health Bureau].

·

National PKU News Source: Seattle, WA: National PKU News. 1995. 12 p. (average). Contact: Available from National PKU News. 6869 Woodlawn Avenue NE, Suite 116, Seattle, WA 98115-5469. (206) 525-8140; FAX (206) 5255023. Price: Free with membership. Summary: This newsletter, published by the National PKU News, includes articles about the medical and social aspects of phenylketonuria (PKU). A typical issue includes PKU News updates and announcements, reports about research and treatment advances, suggestions for coping with PKU, dietary guidelines and recipes, personal essays, notices of legislative efforts in health insurance, publication reviews, and previews of upcoming seminars and programs.

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Academic Periodicals covering Phenylketonuria Academic periodicals can be a highly technical yet valuable source of information on phenylketonuria. We have compiled the following list of periodicals known to publish articles relating to phenylketonuria and which are currently indexed within the National Library of Medicine's PubMed database (follow hyperlinks to view more information, summaries, etc., for each). In addition to these sources, to keep current on articles written on phenylketonuria published by any of the periodicals listed below, you can simply follow the hyperlink indicated or go to the following Web site: www.ncbi.nlm.nih.gov/pubmed. Type the periodical's name into the search box to find the latest studies published. If you want complete details about the historical contents of a periodical, you can also visit http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/ you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.” The following is a sample of periodicals which publish articles on phenylketonuria: ·

Archives of Disease in Childhood. (Arch Dis Child) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Ar chives+of+Disease+in+Childhood&dispmax=20&dispstart=0

·

Biological Trace Element Research. (Biol Trace Elem Res) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Bi ological+Trace+Element+Research&dispmax=20&dispstart=0

·

Clinica Chimica Acta; International Journal of Clinical Chemistry. (Clin Chim Acta) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Cli nica+Chimica+Acta;+International+Journal+of+Clinical+Chemistry&dis pmax=20&dispstart=0

·

European Journal of Pediatrics. (Eur J Pediatr) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Eu ropean+Journal+of+Pediatrics&dispmax=20&dispstart=0

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·

Journal of Abnormal Psychology. (J Abnorm Psychol) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Jo urnal+of+Abnormal+Psychology&dispmax=20&dispstart=0

·

Journal of Inherited Metabolic Disease. (J Inherit Metab Dis) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Jo urnal+of+Inherited+Metabolic+Disease&dispmax=20&dispstart=0

·

Journal of Intellectual Disability Research : Jidr. (J Intellect Disabil Res) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Jo urnal+of+Intellectual+Disability+Research+:+Jidr&dispmax=20&dispstar t=0

·

Journal of Paediatrics and Child Health. (J Paediatr Child Health) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Jo urnal+of+Paediatrics+and+Child+Health&dispmax=20&dispstart=0

·

Journal of Pediatric Gastroenterology and Nutrition. (J Pediatr Gastroenterol Nutr) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Jo urnal+of+Pediatric+Gastroenterology+and+Nutrition&dispmax=20&dis pstart=0

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Pediatric Research. (Pediatr Res) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Pe diatric+Research&dispmax=20&dispstart=0

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The American Journal of Clinical Nutrition. (Am J Clin Nutr) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Th e+American+Journal+of+Clinical+Nutrition&dispmax=20&dispstart=0

·

The Journal of Pediatrics. (J Pediatr) http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi?field=0®exp=Th e+Journal+of+Pediatrics&dispmax=20&dispstart=0

Vocabulary Builder Dyskinesia: Impairment of the power of voluntary movement, resulting in

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fragmentary or incomplete movements. [EU] Schizophrenia: A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, hallucinations, emotional disharmony, and regressive behavior. [NIH]

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CHAPTER 9. PHYSICIAN GUIDELINES AND DATABASES Overview Doctors and medical researchers rely on a number of information sources to help children with phenylketonuria. Many will subscribe to journals or newsletters published by their professional associations or refer to specialized textbooks or clinical guides published for the medical profession. In this chapter, we focus on databases and Internet-based guidelines created or written for this professional audience.

NIH Guidelines For the more common medical conditions, the National Institutes of Health publish guidelines that are frequently consulted by physicians. Publications are typically written by one or more of the various NIH Institutes. For physician guidelines, commonly referred to as “clinical” or “professional” guidelines, you can visit the following Institutes: ·

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

·

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

·

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

·

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.26 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:27 ·

Bioethics: Access to published literature on the ethical, legal and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

·

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

·

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

·

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

·

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

·

Cancer Information: Access to caner-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 27 See http://www.nlm.nih.gov/databases/databases.html. 26

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·

Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

·

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

·

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

·

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

·

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

·

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

·

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

While all of the above references may be of interest to physicians who study and treat phenylketonuria, the following are particularly noteworthy.

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The Combined Health Information Database A comprehensive source of information on clinical guidelines written for professionals is the Combined Health Information Database. You will need to limit your search to “Brochure/Pamphlet,” “Fact Sheet,” or “Information Package” and phenylketonuria using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For the publication date, select “All Years,” select your preferred language, and the format option “Fact Sheet.” By making these selections and typing “phenylketonuria” (or synonyms) into the “For these words:” box above, you will only receive results on fact sheets dealing with phenylketonuria. The following is a sample result: ·

Cost and availability of dietary treatment of phenylketonuria (PKU): Report of a national survey Source: Berkeley, CA: Genetic Disease Branch, California Department of Health Services. 1997. ca. 200 pp. Contact: Available from National Maternal and Child Health Clearinghouse, 2070 Chain Bridge Road, Suite 450, Vienna, VA 221822536. Telephone: (703) 356-1964 or (888) 434-4MCH / fax: (703) 821-2098 / e-mail: [email protected] / Web site: http://www.nmchc.org. Available at no charge. Summary: This survey discusses the costs of treating children with phenylketonuria (PKU), who need low protein formula and food products. A questionnaire was sent to parents of children with PKU, information about reimbursement was collected from private insurance companies, state health agencies were surveyed on their diet provision policies and applicable state laws, data on available dietary products was collected from manufacturers, and the costs of feeding a child with PKU were calculated using data on food costs from the U.S. Department of Agriculture. The survey ends with four appendices providing the parents' questionnaire, correspondence with the Health Insurance Association of America, state laws relating to a PKU diet, and an American Academy of Pediatrics statement. [Funded by the Maternal and Child Health Bureau].

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The NLM Gateway28 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing “one-stop searching” for many of NLM's information resources or databases.29 One target audience for the Gateway is the Internet user who is new to NLM's online resources and does not know what information is available or how best to search for it. This audience may include physicians and other healthcare providers, researchers, librarians, students, and, increasingly, parents and the public.30 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “phenylketonuria” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Items Found Journal Articles 5203 Books / Periodicals / Audio Visual 133 Consumer Health 44 Meeting Abstracts 4 Other Collections 2 Total 5386

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x. The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 30 Other users may find the Gateway useful for an overall search of NLM's information resources. Some searchers may locate what they need immediately, while others will utilize the Gateway as an adjunct tool to other NLM search services such as PubMed® and MEDLINEplus®. The Gateway connects users with multiple NLM retrieval systems while also providing a search interface for its own collections. These collections include various types of information that do not logically belong in PubMed, LOCATORplus, or other established NLM retrieval systems (e.g., meeting announcements and pre-1966 journal citations). The Gateway will provide access to the information found in an increasing number of NLM retrieval systems in several phases. 28 29

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HSTAT31 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.32 HSTAT's audience includes healthcare providers, health service researchers, policy makers, insurance companies, consumers, and the information professionals who serve these groups. HSTAT provides access to a wide variety of publications, including clinical practice guidelines, quick-reference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ's Put Prevention Into Practice.33 Simply search by “phenylketonuria” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

Coffee Break: Tutorials for Biologists34 Some parents may wish to have access to a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. To this end, we recommend “Coffee Break,” a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.35 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.36 This site has new Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. The HSTAT URL is http://hstat.nlm.nih.gov/. 33 Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 34 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html. 35 The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 36 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 31 32

Physician Guidelines and Databases 127

articles every few weeks, so it can be considered an online magazine of sorts, and intended for general background information. Access the Coffee Break Web site at http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are a few examples that may interest you: ·

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

·

Image Engine: Multimedia electronic medical record system that integrates a wide range of digitized clinical images with textual data stored in the University of Pittsburgh Medical Center's MARS electronic medical record system; see the following Web site: http://www.cml.upmc.edu/cml/imageengine/imageEngine.html.

·

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

·

MedWeaver: Prototype system that allows users to search differential diagnoses for any list of signs and symptoms, to search medical literature, and to explore relevant Web sites; see http://www.med.virginia.edu/~wmd4n/medweaver.html.

·

Metaphrase: Middleware component intended for use by both caregivers and medical records personnel. It converts the informal language generally used by caregivers into terms from formal, controlled vocabularies; see the following Web site: http://www.lexical.com/Metaphrase.html.

The Genome Project and Phenylketonuria With all the discussion in the press about the Human Genome Project, it is only natural that physicians, researchers, and parents want to know about how human genes relate to phenylketonuria. In the following section, we will discuss databases and references used by physicians and scientists who work in this area.

128 Phenylketonuria

Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).37 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI's Entrez database of MEDLINE articles and sequence information. Go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html to search the database. Type “phenylketonuria” (or synonyms) in the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. By following these links, especially the link titled “Database Links,” you will be exposed to numerous specialized databases that are largely used by the scientific community. These databases are overly technical and seldom used by the general public, but offer an abundance of information. The following is an example of the results you can obtain from the OMIM for phenylketonuria: ·

Phenylketonuria Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?261600

·

Phenylketonuria Ii Web site: http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?261630

Genes and Disease (NCBI - Map) The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by the system of the body associated with it. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

37

Physician Guidelines and Databases 129

have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to re-visit it from time to time. The following systems and associated disorders are addressed: ·

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn's disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

·

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, Atherosclerosis, Best disease, Gaucher disease, Glucose galactose malabsorption, Gyrate atrophy, Juvenile onset diabetes, Obesity, Paroxysmal nocturnal hemoglobinuria, Phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

·

Nervous System: Mind and body. Examples: Alzheimer disease, Amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, Fragile X syndrome, Friedreich's ataxia, Huntington disease, NiemannPick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, Spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

·

Signals: Cellular messages. Examples: Ataxia telangiectasia, Baldness, Cockayne syndrome, Glaucoma, SRY: sex determination, Tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

·

Transporters: Pumps and channels. Examples: Cystic Fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson's disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html

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Entrez Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: ·

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

·

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

·

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

·

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

·

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

·

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

·

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

·

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

·

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

·

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

·

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

·

NCBI's Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez, and then select the database that you would like to search. The databases available are listed in

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the drop box next to “Search.” In the box next to “for,” enter “phenylketonuria” (or synonyms) and click “Go.”

Jablonski's Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database38 This online resource can be quite useful. It has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html you can also search across syndromes using an alphabetical index. You can also search at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database39 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB's mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “phenylketonuria” (or synonyms) into the search box, and review the Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 39 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html#mission. 38

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results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms). This database is extremely technical as it was created for specialists. The articles are the results which are the most accessible to nonprofessionals and often listed under the heading “Citations.” The contact names are also accessible to non-professionals.

Specialized References The following books are specialized references written for professionals interested in phenylketonuria (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): · Atlas of Pediatric Physical Diagnosis by Basil J. Zitelli, Holly W. Davis (Editor); Hardcover, 3rd edition (March 1997), Mosby-Year Book; ISBN: 0815199309; http://www.amazon.com/exec/obidos/ASIN/0815199309/icongroupinterna · The 5-Minute Pediatric Consult by M. William Schwartz (Editor); Hardcover - 1050 pages, 2nd edition (January 15, 2000), Lippincott, Williams & Wilkins; ISBN: 0683307444; http://www.amazon.com/exec/obidos/ASIN/0683307444/icongroupinterna · Nelson Textbook of Pediatrics by Richard E. Behrman (Editor), et al; Hardcover - 2414 pages, 16th edition (January 15, 2000), W B Saunders Co; ISBN: 0721677673; http://www.amazon.com/exec/obidos/ASIN/0721677673/icongroupinterna

Dissertations 133

CHAPTER 10. DISSERTATIONS ON PHENYLKETONURIA Overview University researchers are active in studying almost all known medical conditions. The result of research is often published in the form of Doctoral or Master's dissertations. You should understand, therefore, that applied diagnostic procedures and/or therapies can take many years to develop after the thesis that proposed the new technique or approach was written. In this chapter, we will give you a bibliography on recent dissertations relating to phenylketonuria. You can read about these in more detail using the Internet or your local medical library. We will also provide you with information on how to use the Internet to stay current on dissertations.

Dissertations on Phenylketonuria ProQuest Digital Dissertations is the largest archive of academic dissertations available. From this archive, we have compiled the following list covering dissertations devoted to phenylketonuria. You will see that the information provided includes the dissertation’s title, its author, and the author’s institution. To read more about the following, simply use the Internet address indicated. The following covers recent dissertations dealing with phenylketonuria: ·

A Profile of Learning Abilities and Behavioral Characteristics of Elementary School-age Children with Phenylketonuria by Falk, Libby Janet, Edd from Temple University, 1971, 214 pages http://wwwlib.umi.com/dissertations/fullcit/7126510

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·

Cognitive Functioning of Children with Phenylketonuria (learning Disabilities) by Mollen, Eileen, Phd from The University of Michigan, 1984, 151 pages http://wwwlib.umi.com/dissertations/fullcit/8412212

·

Does Metabolic Control and Nutrition Support Influence Bone Status in Mice and Children with Phenylketonuria? by Yannicelli, Steven; Phd from The Ohio State University, 2000, 227 pages http://wwwlib.umi.com/dissertations/fullcit/9983013

·

Learning Patterns in Children with Phenylketonuria. by Hagovsky, Mathias Ralph, Phd from Fordham University, 1977, 96 pages http://wwwlib.umi.com/dissertations/fullcit/7714868

·

Parental Adaptation to Phenylketonuria by Schild, Sylvia, Dsw from University of Southern California, 1968, 208 pages http://wwwlib.umi.com/dissertations/fullcit/6812061

·

Sensory Motor Integration, School Achievement, and Behavior of Children with Phenylketonuria by Skarin, Susan Marne, Phd from University of Southern California, 1981 http://wwwlib.umi.com/dissertations/fullcit/f460246

·

Variant Hyperphenylalaninemia: Psychoeducational Outcome of Treated and Untreated Individuals by Lang, Mary Joann, Phd from University of Southern California, 1988 http://wwwlib.umi.com/dissertations/fullcit/f44933

Keeping Current As previously mentioned, an effective way to stay current on dissertations dedicated to phenylketonuria is to use the database called ProQuest Digital Dissertations via the Internet, located at the following Web address: http://wwwlib.umi.com/dissertations. The site allows you to freely access the last two years of citations and abstracts. Ask your medical librarian if the library has full and unlimited access to this database. From the library, you should be able to do more complete searches than with the limited 2-year access available to the general public.

135

PART III. APPENDICES

ABOUT PART III Part III is a collection of appendices on general medical topics relating to phenylketonuria and related conditions.

Researching Your Child’s Medications 137

APPENDIX A. RESEARCHING YOUR CHILD’S MEDICATIONS Overview There are a number of sources available on new or existing medications which could be prescribed to treat phenylketonuria. While a number of hard copy or CD-Rom resources are available to parents and physicians for research purposes, a more flexible method is to use Internet-based databases. In this chapter, we will begin with a general overview of medications. We will then proceed to outline official recommendations on how you should view your child’s medications. You may also want to research medications that your child is currently taking for other conditions as they may interact with medications for phenylketonuria. Research can give you information on the side effects, interactions, and limitations of prescription drugs used in the treatment of phenylketonuria. Broadly speaking, there are two sources of information on approved medications: public sources and private sources. We will emphasize free-to-use public sources.

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Your Child’s Medications: The Basics40 The Agency for Health Care Research and Quality has published extremely useful guidelines on the medication aspects of phenylketonuria. Giving your child medication can involve many steps and decisions each day. The AHCRQ recommends that parents take part in treatment decisions. Do not be afraid to ask questions and talk about your concerns. By taking a moment to ask questions, your child may be spared from possible problems. Here are some points to cover each time a new medicine is prescribed: ·

Ask about all parts of your child’s treatment, including diet changes, exercise, and medicines.

·

Ask about the risks and benefits of each medicine or other treatment your child might receive.

·

Ask how often you or your child’s doctor will check for side effects from a given medication.

Do not hesitate to tell the doctor about preferences you have for your child’s medicines. You may want your child to have a medicine with the fewest side effects, or the fewest doses to take each day. You may care most about cost. Or, you may want the medicine the doctor believes will work the best. Sharing your concerns will help the doctor select the best treatment for your child. Do not be afraid to “bother” the doctor with your questions about medications for phenylketonuria. You can also talk to a nurse or a pharmacist. They can help you better understand your child’s treatment plan. Talking over your child’s options with someone you trust can help you make better choices. Specifically, ask the doctor the following: ·

The name of the medicine and what it is supposed to do.

·

How and when to give your child the medicine, how much, and for how long.

·

What food, drinks, other medicines, or activities your child should avoid while taking the medicine.

·

What side effects your child may experience, and what to do if they occur.

·

If there are any refills, and how often.

·

About any terms or directions you do not understand.

·

What to do if your child misses a dose.

40

This section is adapted from AHCRQ: http://www.ahcpr.gov/consumer/ncpiebro.htm.

Researching Your Child’s Medications 139

·

If there is written information you can take home (most pharmacies have information sheets on prescription medicines; some even offer large-print or Spanish versions).

Do not forget to tell the doctor about all the medicines your child is currently taking (not just those for phenylketonuria). This includes prescription medicines and the medicines that you buy over the counter. When talking to the doctor, you may wish to prepare a list of medicines your child is currently taking including why and in what forms. Be sure to include the following information for each: ·

Name of medicine

·

Reason taken

·

Dosage

·

Time(s) of day

Also include any over-the-counter medicines, such as: ·

Laxatives

·

Diet pills

·

Vitamins

·

Cold medicine

·

Aspirin or other pain, headache, or fever medicine

·

Cough medicine

·

Allergy relief medicine

·

Antacids

·

Sleeping pills

·

Others (include names)

Learning More about Your Child’s Medications Because of historical investments by various organizations and the emergence of the Internet, it has become rather simple to learn about the medications the doctor has recommended for phenylketonuria. One such source is the United States Pharmacopeia. In 1820, eleven physicians met in Washington, D.C. to establish the first compendium of standard drugs for the United States. They called this compendium the “U.S. Pharmacopeia (USP).” Today, the USP is a non-profit organization consisting of 800 volunteer scientists, eleven elected officials, and 400 representatives of state

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associations and colleges of medicine and pharmacy. The USP is located in Rockville, Maryland, and its home page is located at www.usp.org. The USP currently provides standards for over 3,700 medications. The resulting USP DIÒ Advice for the PatientÒ can be accessed through the National Library of Medicine of the National Institutes of Health. The database is partially derived from lists of federally approved medications in the Food and Drug Administration's (FDA) Drug Approvals database.41 While the FDA database is rather large and difficult to navigate, the Phamacopeia is both user-friendly and free to use. It covers more than 9,000 prescription and over-the-counter medications. To access this database, simply type the following hyperlink into your Web browser: http://www.nlm.nih.gov/medlineplus/druginformation.html. To view examples of a given medication (brand names, category, description, preparation, proper use, precautions, side effects, etc.), simply follow the hyperlinks indicated within the United States Pharmacopoeia. It is important to read the disclaimer by the United States Pharmacopoeia (http://www.nlm.nih.gov/medlineplus/drugdisclaimer.html) before using the information provided.

Commercial Databases In addition to the medications listed in the USP above, a number of commercial sites are available by subscription to physicians and their institutions. You may be able to access these sources from your local medical library or your child’s doctor's office.

Reuters Health Drug Database The Reuters Health Drug Database can be searched by keyword at the hyperlink: http://www.reutershealth.com/frame2/drug.html. The following medications are listed in the Reuters' database as associated with phenylketonuria (including those with contraindications):42 ·

Chlorpromazine HCI http://www.reutershealth.com/atoz/html/Chlorpromazine_HCI.htm

·

Cholestyramine http://www.reutershealth.com/atoz/html/Cholestyramine.htm

Though cumbersome, the FDA database can be freely browsed at the following site: www.fda.gov/cder/da/da.htm. 42 Adapted from A to Z Drug Facts by Facts and Comparisons. 41

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·

Diphenhydramine HCl http://www.reutershealth.com/atoz/html/Diphenhydramine_HCl.htm

·

Linezolid http://www.reutershealth.com/atoz/html/Linezolid.htm

·

Nelfinavir Mesylate http://www.reutershealth.com/atoz/html/Nelfinavir_Mesylate.htm

·

Promethazine HCl http://www.reutershealth.com/atoz/html/Promethazine_HCl.htm

Mosby's GenRx Mosby's GenRx database (also available on CD-Rom and book format) covers 45,000 drug products including generics and international brands. It provides information on prescribing and drug interactions. Information in Mosby's GenRx database can be obtained at the following hyperlink: http://www.genrx.com/Mosby/PhyGenRx/group.html.

Physicians Desk Reference The Physicians Desk Reference database (also available in CD-Rom and book format) is a full-text drug database. The database is searchable by brand name, generic name or by indication. It features multiple drug interactions reports. Information can be obtained at the following hyperlink: http://physician.pdr.net/physician/templates/en/acl/psuser_t.htm.

Other Web Sites A number of additional Web sites discuss drug information. As an example, you may like to look at www.drugs.com which reproduces the information in the Pharmacopeia as well as commercial information. You may also want to consider the Web site of the Medical Letter, Inc. which allows users to download articles on various drugs and therapeutics for a nominal fee: http://www.medletter.com/.

Contraindications and Interactions (Hidden Dangers) Some of the medications mentioned in the previous discussions can be problematic for children with phenylketonuria--not because they are used in

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the treatment process, but because of contraindications, or side effects. Medications with contraindications are those that could react with drugs used to treat phenylketonuria or potentially create deleterious side effects in patients with phenylketonuria. You should ask the physician about any contraindications, especially as these might apply to other medications that your child may be taking for common ailments. Drug-drug interactions occur when two or more drugs react with each other. This drug-drug interaction may cause your child to experience an unexpected side effect. Drug interactions may make medications less effective, cause unexpected side effects, or increase the action of a particular drug. Some drug interactions can even be harmful to your child. Be sure to read the label every time you give your child a nonprescription or prescription drug, and take the time to learn about drug interactions. These precautions may be critical to your child’s health. You can reduce the risk of potentially harmful drug interactions and side effects with a little bit of knowledge and common sense. Drug labels contain important information about ingredients, uses, warnings, and directions which you should take the time to read and understand. Labels also include warnings about possible drug interactions. Further, drug labels may change as new information becomes avaiable. This is why it's especially important to read the label every time you give your child a medication. When the doctor prescribes a new drug, discuss all overthe-counter and prescription medications, dietary supplements, vitamins, botanicals, minerals and herbals your child takes. Ask your pharmacist for the package insert for each drug prescribed. The package insert provides more information about potential drug interactions.

A Final Warning At some point, you may hear of alternative medications from friends, relatives, or in the news media. Advertisements may suggest that certain alternative drugs can produce positive results for phenylketonuria. Exercise caution--some of these drugs may have fraudulent claims, and others may actually hurt your child. The Food and Drug Administration (FDA) is the official U.S. agency charged with discovering which medications are likely to

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improve the health of patients with phenylketonuria. The FDA warns to watch out for43: ·

Secret formulas (real scientists share what they know)

·

Amazing breakthroughs or miracle cures (real breakthroughs don't happen very often; when they do, real scientists do not call them amazing or miracles)

·

Quick, painless, or guaranteed cures

·

If it sounds too good to be true, it probably isn't true.

If you have any questions about any kind of medical treatment, the FDA may have an office near you. Look for their number in the blue pages of the phone book. You can also contact the FDA through its toll-free number, 1888-INFO-FDA (1-888-463-6332), or on the World Wide Web at www.fda.gov.

General References In addition to the resources provided earlier in this chapter, the following general references describe medications (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

Complete Guide to Prescription and Nonprescription Drugs 2001 (Complete Guide to Prescription and Nonprescription Drugs, 2001) by H. Winter Griffith, Paperback 16th edition (2001), Medical Surveillance; ISBN: 0942447417; http://www.amazon.com/exec/obidos/ASIN/039952634X/icongroupinterna

·

The Essential Guide to Prescription Drugs, 2001 by James J. Rybacki, James W. Long; Paperback - 1274 pages (2001), Harper Resource; ISBN: 0060958162; http://www.amazon.com/exec/obidos/ASIN/0060958162/icongroupinterna

·

Handbook of Commonly Prescribed Drugs by G. John Digregorio, Edward J. Barbieri; Paperback 16th edition (2001), Medical Surveillance; ISBN: 0942447417; http://www.amazon.com/exec/obidos/ASIN/0942447417/icongroupinterna

·

Johns Hopkins Complete Home Encyclopedia of Drugs 2nd ed. by Simeon Margolis (Ed.), Johns Hopkins; Hardcover - 835 pages (2000), Rebus; ISBN: 0929661583; http://www.amazon.com/exec/obidos/ASIN/0929661583/icongroupinterna

This section has been adapted from http://www.fda.gov/opacom/lowlit/medfraud.html.

43

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·

Medical Pocket Reference: Drugs 2002 by Springhouse Paperback 1st edition (2001), Lippincott Williams & Wilkins Publishers; ISBN: 1582550964; http://www.amazon.com/exec/obidos/ASIN/1582550964/icongroupinterna

·

PDR by Medical Economics Staff, Medical Economics Staff Hardcover 3506 pages 55th edition (2000), Medical Economics Company; ISBN: 1563633752; http://www.amazon.com/exec/obidos/ASIN/1563633752/icongroupinterna

·

Pharmacy Simplified: A Glossary of Terms by James Grogan; Paperback 432 pages, 1st edition (2001), Delmar Publishers; ISBN: 0766828581; http://www.amazon.com/exec/obidos/ASIN/0766828581/icongroupinterna

·

Physician Federal Desk Reference by Christine B. Fraizer; Paperback 2nd edition (2001), Medicode Inc; ISBN: 1563373971; http://www.amazon.com/exec/obidos/ASIN/1563373971/icongroupinterna

·

Physician's Desk Reference Supplements Paperback - 300 pages, 53 edition (1999), ISBN: 1563632950; http://www.amazon.com/exec/obidos/ASIN/1563632950/icongroupinterna

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APPENDIX B. RESEARCHING ALTERNATIVE MEDICINE Overview Complementary and alternative medicine (CAM) is one of the most contentious aspects of modern medical practice. You may have heard of these treatments on the radio or on television. Maybe you have seen articles written about these treatments in magazines, newspapers, or books. Perhaps your child’s doctor or your friends have mentioned alternatives. In this chapter, we will begin by giving you a broad perspective on complementary and alternative therapies. Next, we will introduce you to official information sources on CAM relating to phenylketonuria. Finally, at the conclusion of this chapter, we will provide a list of readings on phenylketonuria from various authors. We will begin, however, with the National Center for Complementary and Alternative Medicine's (NCCAM) overview of complementary and alternative medicine.

What Is CAM?44 Complementary and alternative medicine (CAM) covers a broad range of healing philosophies, approaches, and therapies. Generally, it is defined as those treatments and healthcare practices which are not taught in medical schools, used in hospitals, or reimbursed by medical insurance companies. Many CAM therapies are termed “holistic,” which generally means that the healthcare practitioner considers the whole person, including physical, mental, emotional, and spiritual health. Some of these therapies are also known as “preventive,” which means that the practitioner educates and 44

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/faq/index.html#what-is.

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treats the person to prevent health problems from arising, rather than treating symptoms after problems have occurred. People use CAM treatments and therapies in a variety of ways. Therapies are used alone (often referred to as alternative), in combination with other alternative therapies, or in addition to conventional treatment (sometimes referred to as complementary). Complementary and alternative medicine, or “integrative medicine,” includes a broad range of healing philosophies, approaches, and therapies. Some approaches are consistent with physiological principles of Western medicine, while others constitute healing systems with non-Western origins. While some therapies are far outside the realm of accepted Western medical theory and practice, others are becoming established in mainstream medicine. Complementary and alternative therapies are used in an effort to prevent illness, reduce stress, prevent or reduce side effects and symptoms, or control or cure disease. Some commonly used methods of complementary or alternative therapy include mind/body control interventions such as visualization and relaxation, manual healing including acupressure and massage, homeopathy, vitamins or herbal products, and acupuncture.

What Are the Domains of Alternative Medicine?45 The list of CAM practices changes continually. The reason being is that these new practices and therapies are often proved to be safe and effective, and therefore become generally accepted as “mainstream” healthcare practices. Today, CAM practices may be grouped within five major domains: (1) alternative medical systems, (2) mind-body interventions, (3) biologicallybased treatments, (4) manipulative and body-based methods, and (5) energy therapies. The individual systems and treatments comprising these categories are too numerous to list in this sourcebook. Thus, only limited examples are provided within each. Alternative Medical Systems Alternative medical systems involve complete systems of theory and practice that have evolved independent of, and often prior to, conventional biomedical approaches. Many are traditional systems of medicine that are

45

Adapted from the NCCAM: http://nccam.nih.gov/nccam/fcp/classify/index.html.

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practiced by individual cultures throughout the world, including a number of venerable Asian approaches. Traditional oriental medicine emphasizes the balance or disturbances of qi (pronounced chi) or vital energy in health and illness, respectively. Traditional oriental medicine consists of a group of techniques and methods including acupuncture, herbal medicine, oriental massage, and qi gong (a form of energy therapy). Acupuncture involves stimulating specific anatomic points in the body for therapeutic purposes, usually by puncturing the skin with a thin needle. Ayurveda is India's traditional system of medicine. Ayurvedic medicine (meaning “science of life”) is a comprehensive system of medicine that places equal emphasis on body, mind, and spirit. Ayurveda strives to restore the innate harmony of the individual. Some of the primary Ayurvedic treatments include diet, exercise, meditation, herbs, massage, exposure to sunlight, and controlled breathing. Other traditional healing systems have been developed by the world’s indigenous populations. These populations include Native American, Aboriginal, African, Middle Eastern, Tibetan, and Central and South American cultures. Homeopathy and naturopathy are also examples of complete alternative medicine systems. Homeopathic medicine is an unconventional Western system that is based on the principle that “like cures like,” i.e., that the same substance that in large doses produces the symptoms of an illness, in very minute doses cures it. Homeopathic health practitioners believe that the more dilute the remedy, the greater its potency. Therefore, they use small doses of specially prepared plant extracts and minerals to stimulate the body's defense mechanisms and healing processes in order to treat illness. Naturopathic medicine is based on the theory that a medical condition is the manifestation of alterations in the processes by which the body naturally heals itself and emphasizes health restoration rather than treatment for the condition itself. Naturopathic physicians employ an array of healing practices, including the following: diet and clinical nutrition, homeopathy, acupuncture, herbal medicine, hydrotherapy (the use of water in a range of temperatures and methods of applications), spinal and soft-tissue manipulation, physical therapies (such as those involving electrical currents, ultrasound, and light), therapeutic counseling, and pharmacology.

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Mind-Body Interventions Mind-body interventions employ a variety of techniques designed to facilitate the mind's capacity to affect bodily function and symptoms. Only a select group of mind-body interventions having well-documented theoretical foundations are considered CAM. For example, patient education and cognitive-behavioral approaches are now considered “mainstream.” On the other hand, complementary and alternative medicine includes meditation, certain uses of hypnosis, dance, music, and art therapy, as well as prayer and mental healing.

Biological-Based Therapies This category of CAM includes natural and biological-based practices, interventions, and products, many of which overlap with conventional medicine's use of dietary supplements. This category includes herbal, special dietary, orthomolecular, and individual biological therapies. Herbal therapy employs an individual herb or a mixture of herbs for healing purposes. An herb is a plant or plant part that produces and contains chemical substances that act upon the body. Special diet therapies, such as those proposed by Drs. Atkins, Ornish, Pritikin, and Weil, are believed to prevent and/or control illness as well as promote health. Orthomolecular therapies aim to treat medical conditions with varying concentrations of chemicals such as magnesium, melatonin, and mega-doses of vitamins. Biological therapies include, for example, the use of laetrile and shark cartilage to treat cancer and the use of bee pollen to treat autoimmune and inflammatory conditions.

Manipulative and Body-Based Methods This category includes methods that are based on manipulation and/or movement of the body. For example, chiropractors focus on the relationship between structure and function, primarily pertaining to the spine, and how that relationship affects the preservation and restoration of health. Chiropractors use manipulative therapy as an integral treatment tool. In contrast, osteopaths place particular emphasis on the musculoskeletal system and practice osteopathic manipulation. Osteopaths believe that all of the body's systems work together and that disturbances in one system may

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have an impact upon function elsewhere in the body. Massage therapists manipulate the soft tissues of the body to normalize those tissues.

Energy Therapies Energy therapies focus on energy fields originating within the body (biofields) or those from other sources (electromagnetic fields). Biofield therapies are intended to affect energy fields (the existence of which is not yet experimentally proven) that surround and penetrate the human body. Some forms of energy therapy manipulate biofields by applying pressure and/or manipulating the body by placing the hands in or through these fields. Examples include Qi gong, Reiki and Therapeutic Touch. Qi gong is a component of traditional oriental medicine that combines movement, meditation, and regulation of breathing to enhance the flow of vital energy (qi) in the body, improve blood circulation, and enhance immune function. Reiki, the Japanese word representing Universal Life Energy, is based on the belief that, by channeling spiritual energy through the practitioner, the spirit is healed and, in turn, heals the physical body. Therapeutic Touch is derived from the ancient technique of “laying-on of hands.” It is based on the premises that the therapist’s healing force affects recovery and that healing is promoted when the body's energies are in balance. By passing their hands over the patient, these healers identify energy imbalances. Bioelectromagnetic-based therapies involve the unconventional use of electromagnetic fields to treat illnesses or manage pain. These therapies are often used to treat asthma, cancer, and migraine headaches. Types of electromagnetic fields which are manipulated in these therapies include pulsed fields, magnetic fields, and alternating current or direct current fields.

Can Alternatives Affect My Child’s Treatment? A critical issue in pursuing complementary alternatives mentioned thus far is the risk that these might have undesirable interactions with your child’s medical treatment. It becomes all the more important to speak with the doctor who can offer advice on the use of alternatives. Official sources confirm this view. Though written for women, we find that the National

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Women’s Health Information Center’s advice on pursuing alternative medicine is appropriate for everyone.46

Is It Okay to Want Both Traditional and Alternative Medicine? Should you wish to explore non-traditional types of treatment, be sure to discuss all issues concerning treatments and therapies with your child’s healthcare provider, whether a physician or practitioner of complementary and alternative medicine. Competent healthcare management requires that the practitioner know of all conventional and alternative therapies that your child is taking. The decision to use complementary and alternative treatments is an important one. Consider before selecting an alternative therapy, the safety and effectiveness of the therapy or treatment, the expertise and qualifications of the healthcare practitioner, and the quality of delivery. These topics should be considered when selecting any practitioner or therapy.

Finding CAM References on Phenylketonuria Having read the previous discussion, you may be wondering which complementary or alternative treatments might be appropriate for phenylketonuria. For the remainder of this chapter, we will direct you to a number of official sources which can assist you in researching studies and publications. Some of these articles are rather technical, so some patience may be required. National Center for Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health (http://nccam.nih.gov) has created a link to the National Library of Medicine's databases to allow parents to search for articles that specifically relate to phenylketonuria and complementary medicine. To search the database, go to the following Web site: www.nlm.nih.gov/nccam/camonpubmed.html. Select “CAM on PubMed.” Enter “phenylketonuria” (or synonyms) into the search box. Click “Go.” The following references provide information on particular aspects of

46

Adapted from http://www.4woman.gov/faq/alternative.htm.

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complementary and alternative medicine (CAM) that are related to phenylketonuria: ·

A conference for the education of families who have a member with phenylketonuria. Author(s): Kolb SE, Aguilar MC, Kaye C. Source: J Pediatr Nurs. 1999 August; 14(4): 270-2. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10467806&dopt=Abstract

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Antioxidant and thyroid hormone status in selenium-deficient phenylketonuric and hyperphenylalaninemic patients. Author(s): van Bakel MM, Printzen G, Wermuth B, Wiesmann UN. Source: The American Journal of Clinical Nutrition. 2000 October; 72(4): 976-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11010940&dopt=Abstract

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Antioxidant status in hyperphenylalaninemia. Author(s): Sierra C, Vilaseca MA, Moyano D, Brandi N, Campistol J, Lambruschini N, Cambra FJ, Deulofeu R, Mira A. Source: Clinica Chimica Acta; International Journal of Clinical Chemistry. 1998 August 10; 276(1): 1-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9760015&dopt=Abstract

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Cognition and tyrosine supplementation among school-aged children with phenylketonuria. Author(s): Mazzocco MM, Yannicelli S, Nord AM, van Doorninck W, Davidson-Mundt AJ, Greene CL. Source: Am J Dis Child. 1992 November; 146(11): 1261-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1415060&dopt=Abstract

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DGGE analysis as supplement to SSCP analysis of the phenylalanine hydroxylase gene: detection of eight (one de novo, seven inherited) of nine remaining Norwegian PKU mutations. Author(s): Eiken HG, Knappskog PM, Guldberg P, Apold J. Source: Human Mutation. 1996; 8(1): 19-22. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8807331&dopt=Abstract

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·

Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria.Author(s): Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK. Source: The Journal of Pediatrics. 1995 December; 127(6): 936-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8523192&dopt=Abstract

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Effects of selenium supplementation on thyroid hormone metabolism in phenylketonuria subjects on a phenylalanine restricted diet. Author(s): Calomme M, Vanderpas J, Francois B, Van Caillie-Bertrand M, Vanovervelt N, Van Hoorebeke C, Vanden Berghe D. Source: Biological Trace Element Research. 1995 January-March; 47(1-3): 349-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7779569&dopt=Abstract

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Fasting plasma amino acid concentrations in PKU children on two different levels of protein intake. Author(s): Kindt E, Lunde HA, Gjessing LR, Halvorsen S, Lie SO. Source: Acta Paediatr Scand. 1988 January; 77(1): 60-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3369307&dopt=Abstract

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Fatty acid supplementation in a case of maternal phenylketonuria. Author(s): Giovannini M, Biasucci G, Agostoni C, Bellu R, Riva E. Source: Journal of Inherited Metabolic Disease. 1994; 17(5): 630-1. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7837774&dopt=Abstract

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Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine. Author(s): Lykkelund C, Nielsen JB, Lou HC, Rasmussen V, Gerdes AM, Christensen E, Guttler F. Source: European Journal of Pediatrics. 1988 December; 148(3): 238-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=2463918&dopt=Abstract

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Inherited metabolic diseases: beyond newborn screening. Author(s): Leonard HM, Fletcher JM.

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Source: Med J Aust. 1999 June 21; 170(12): 573-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10416422&dopt=Abstract ·

Injury and insult--considerations of the neuropathological aetiology of mental subnormality. Author(s): Cowie V. Source: The British Journal of Psychiatry; the Journal of Mental Science. 1980 October; 137: 305-12. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7004555&dopt=Abstract

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Intake and blood levels of fatty acids in treated patients with phenylketonuria. Author(s): Acosta PB, Yannicelli S, Singh R, Eisas LJ 2nd, Kennedy MJ, Bernstein L, Rohr F, Trahms C, Koch R, Breck J. Source: Journal of Pediatric Gastroenterology and Nutrition. 2001 September; 33(3): 253-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11593118&dopt=Abstract

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Iron status and iron supplementation in children with classical phenylketonuria. Author(s): Miranda da Cruz BD, Seidler H, Widhalm K. Source: J Am Coll Nutr. 1993 October; 12(5): 531-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8263269&dopt=Abstract

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Know your organizations: the National Society for Phenylketonuria and Allied Disorders. Author(s): Thorne C. Source: Health Visit. 1982 January; 55(1): 26. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6915915&dopt=Abstract

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Long-chain polyunsaturated fatty acids in plasma and erythrocyte membrane lipids of children with phenylketonuria after controlled linoleic acid intake. Author(s): Poge AP, Baumann K, Muller E, Leichsenring M, Schmidt H, Bremer HJ.

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Source: Journal of Inherited Metabolic Disease. 1998 June; 21(4): 373-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9700594&dopt=Abstract ·

Metabolic disorders in children. Author(s): Morris AA, Turnbull DM. Source: Current Opinion in Neurology. 1994 December; 7(6): 535-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7866586&dopt=Abstract

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Molybdenum supplementation in phenylketonuria diets: adequate in early infancy? Author(s): Sievers E, Arpe T, Schleyerbach U, Schaub J. Source: Journal of Pediatric Gastroenterology and Nutrition. 2000 July; 31(1): 57-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10896072&dopt=Abstract

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Neuropsychological and neuroradiological (MRI) variations during phenylalanine load: protective effect of valine, leucine, and isoleucine supplementation. Author(s): Leuzzi V, Fois D, Carducci C, Antonozzi I, Trasimeni G. Source: Journal of Child Neurology. 1997 August; 12(5): 338-40. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9378904&dopt=Abstract

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Newborn mass screening and molecular genetics of phenylketonuria in east Asia. Author(s): Okano Y, Isshiki G. Source: Southeast Asian J Trop Med Public Health. 1995; 26 Suppl 1: 1239. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8629090&dopt=Abstract

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Noninvasive sampling of phenylalanine by reverse iontophoresis. Author(s): Merino V, Lopez A, Hochstrasser D, Guy RH.

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Source: Journal of Controlled Release : Official Journal of the Controlled Release Society. 1999 August 27; 61(1-2): 65-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10469903&dopt=Abstract ·

Nutritional management of the female with phenylketonuria during pregnancy. Author(s): Pueschel SM, Hum C, Andrews M. Source: The American Journal of Clinical Nutrition. 1977 July; 30(7): 115361. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=879079&dopt=Abstract

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Pediatric neurology. Author(s): Baird HW. Source: Prog Neurol Psychiatry. 1968; 23: 242-52. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=4977707&dopt=Abstract

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Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets. Author(s): van Spronsen FJ, van Rijn M, Bekhof J, Koch R, Smit PG. Source: The American Journal of Clinical Nutrition. 2001 February; 73(2): 153-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11157309&dopt=Abstract

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PKU in adolescents: rationale and psychosocial factors in diet continuation. Author(s): Levy HL, Waisbren SE. Source: Acta Paediatr Suppl. 1994 December; 407: 92-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7766970&dopt=Abstract

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Plasma arachidonic acid and serum thromboxane B2 concentrations in phenylketonuric children negatively correlate with dietary compliance. Author(s): Agostoni C, Marangoni F, Riva E, Giovannini M, Galli C.

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Source: Prostaglandins, Leukotrienes, and Essential Fatty Acids. 1997 March; 56(3): 219-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9089802&dopt=Abstract ·

Plasma glutathione peroxidase after selenium supplementation in patients with reduced selenium state. Author(s): Steiner G, Menzel H, Lombeck I, Ohnesorge FK, Bremer HJ. Source: European Journal of Pediatrics. 1982 March; 138(2): 138-40. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=7094933&dopt=Abstract

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Plasma phenylalanine and tyrosine responses to different nutritional conditions (fasting/postprandial) in patients with phenylketonuria: effect of sample timing. Author(s): van Spronsen FJ, van Rijn M, van Dijk T, Smit GP, Reijngoud DJ, Berger R, Heymans HS. Source: Pediatrics. 1993 October; 92(4): 570-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8414829&dopt=Abstract

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Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Author(s): Smith ML, Hanley WB, Clarke JT, Klim P, Schoonheyt W, Austin V, Lehotay DC. Source: Archives of Disease in Childhood. 1998 February; 78(2): 116-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9579151&dopt=Abstract

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Red blood cell glutathione peroxidase activity as a function of selenium supplementation in dietary treated children with phenylketonuria. Author(s): Zachara BA, Wasowicz W, Gromadzinska J, Sklodowska M, Cabalska B. Source: Biomed Biochim Acta. 1987; 46(2-3): S209-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3593299&dopt=Abstract

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Sensory restriction and isolation experiences in children with phenylketonuria. Author(s): Friedman CJ, Sibinga MSMS, Steisel IM, Sinnamon HM.

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Source: Journal of Abnormal Psychology. 1968 August; 73(4): 294-303. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=5672220&dopt=Abstract ·

The effect of immobilization and sensory restriction on children with phenylketonuria. Author(s): Sibinga MS, Friedman CJ, Steisel IM, Sinnamon HM. Source: Pediatric Research. 1968 September; 2(5): 371-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=5672698&dopt=Abstract

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The selenium status of children with phenylketonuria: results of selenium supplementation. Author(s): Lipson A, Masters H, O'Halloran M, Thompson S, Coveney J, Yu J. Source: Aust Paediatr J. 1988 April; 24(2): 128-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=3395305&dopt=Abstract

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The use of a low phenylalanine diet with amino acid supplement in the treatment of behavioural problems in a severely mentally retarded adult female with phenylketonuria. Author(s): Hoskin RG, Sasitharan T, Howard R. Source: Journal of Intellectual Disability Research : Jidr. 1992 April; 36 ( Pt 2): 183-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=1591502&dopt=Abstract

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Tyrosine supplementation during pregnancy in a woman with classical phenylketonuria. A case report. Author(s): Lenke RR, Koch R, Fishler K, Platt LD. Source: J Reprod Med. 1983 June; 28(6): 411-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=6887149&dopt=Abstract

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Tyrosine supplementation for phenylketonuria treatment. Author(s): Koch R.

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Source: The American Journal of Clinical Nutrition. 1996 December; 64(6): 974-5. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=8942426&dopt=Abstract ·

Tyrosine supplementation for phenylketonuria. Author(s): Poustie VJ, Rutherford P. Source: Cochrane Database Syst Rev. 2000; (2): Cd001507. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=10796799&dopt=Abstract

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Tyrosine supplementation in phenylketonuria. Author(s): Lines D, Magarey A, Raymond J, Robertson E. Source: Journal of Paediatrics and Child Health. 1997 April; 33(2): 177. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9145371&dopt=Abstract

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Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids. Author(s): Kalsner LR, Rohr FJ, Strauss KA, Korson MS, Levy HL. Source: The Journal of Pediatrics. 2001 September; 139(3): 421-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=11562623&dopt=Abstract

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Tyrosine supplementation in the treatment of maternal phenylketonuria. Author(s): Rohr FJ, Lobbregt D, Levy HL. Source: The American Journal of Clinical Nutrition. 1998 March; 67(3): 473-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db= PubMed&list_uids=9497192&dopt=Abstract

Additional Web Resources A number of additional Web sites offer encyclopedic information covering CAM and related topics. The following is a representative sample: ·

Alternative Medicine Foundation, Inc.: http://www.herbmed.org/

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AOL: http://search.aol.com/cat.adp?id=169&layer=&from=subcats

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·

Chinese Medicine: http://www.newcenturynutrition.com/

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drkoop.comÒ: http://www.drkoop.com/InteractiveMedicine/IndexC.html

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Family Village: http://www.familyvillage.wisc.edu/med_altn.htm

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Google: http://directory.google.com/Top/Health/Alternative/

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Healthnotes: http://www.thedacare.org/healthnotes/

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Open Directory Project: http://dmoz.org/Health/Alternative/

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TPN.com: http://www.tnp.com/

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Yahoo.com: http://dir.yahoo.com/Health/Alternative_Medicine/

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WebMDÒHealth: http://my.webmd.com/drugs_and_herbs

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WellNet: http://www.wellnet.ca/herbsa-c.htm

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

The following is a specific Web list relating to phenylketonuria; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: ·

General Overview Phenylketonuria Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm

·

Herbs and Supplements Amino acids Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Amino Acids Overview Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Amino_Acids.htm

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Branched-Chain Amino Acids Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Branched_Chain_Amino s.htm Coenzyme Q10 Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Coenzyme_Q10.htm L-Tyrosine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Tyrosine.htm L-Tyrosine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Phenylalanine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Phenylalanine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Phenylalanine.htm Phenylalanine Source: Integrative Medicine Communications; www.onemedicine.com Hyperlink: http://www.drkoop.com/interactivemedicine/ConsSupplements/Phen ylalaninecs.html Phenylalanine Source: Prima Communications, Inc. Hyperlink: http://www.personalhealthzone.com/pg000141.html Selenite Source: Healthnotes, Inc.; www.healthnotes.com

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Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Selenomethionine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Tyrosine Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Tyrosine Source: Prima Communications, Inc. Hyperlink: http://www.personalhealthzone.com/pg000197.html ·

Related Conditions Allergies and Sensitivities Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Allergies.htm Depression (Mild to Moderate) Source: Prima Communications, Inc. Hyperlink: http://www.personalhealthzone.com/pg000280.html

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General References A good place to find general background information on CAM is the National Library of Medicine. It has prepared within the MEDLINEplus system an information topic page dedicated to complementary and alternative medicine. To access this page, go to the MEDLINEplus site at: www.nlm.nih.gov/medlineplus/alternativemedicine.html. This Web site provides a general overview of various topics and can lead to a number of general sources. The following additional references describe, in broad terms, alternative and complementary medicine (sorted alphabetically by title; hyperlinks provide rankings, information, and reviews at Amazon.com): ·

Healthy Child, Whole Child: Integrating the Best of Conventional and Alternative Medicine to Keep Your Kids Healthy by Stuart H. Ditchek, M.D. and Russell H. Greenfield; Paperback - 464 pages (June 2002), Harper Resource; ISBN: 0062737465; http://www.amazon.com/exec/obidos/ASIN/0062737465/icongroupinterna

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Alternative Medicine for Dummies by James Dillard (Author); Audio Cassette, Abridged edition (1998), Harper Audio; ISBN: 0694520659; http://www.amazon.com/exec/obidos/ASIN/0694520659/icongroupinterna

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Complementary and Alternative Medicine Secrets by W. Kohatsu (Editor); Hardcover (2001), Hanley & Belfus; ISBN: 1560534400; http://www.amazon.com/exec/obidos/ASIN/1560534400/icongroupinterna

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Dictionary of Alternative Medicine by J. C. Segen; Paperback-2nd edition (2001), Appleton & Lange; ISBN: 0838516211; http://www.amazon.com/exec/obidos/ASIN/0838516211/icongroupinterna

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Eat, Drink, and Be Healthy: The Harvard Medical School Guide to Healthy Eating by Walter C. Willett, MD, et al; Hardcover - 352 pages (2001), Simon & Schuster; ISBN: 0684863375; http://www.amazon.com/exec/obidos/ASIN/0684863375/icongroupinterna

· Encyclopedia of Natural Medicine, Revised 2nd Edition by Michael T. Murray, Joseph E. Pizzorno; Paperback - 960 pages, 2nd Rev edition (1997), Prima Publishing; ISBN: 0761511571; http://www.amazon.com/exec/obidos/ASIN/0761511571/icongroupinterna ·

Integrative Medicine: An Introduction to the Art & Science of Healing by Andrew Weil (Author); Audio Cassette, Unabridged edition (2001), Sounds True; ISBN: 1564558541; http://www.amazon.com/exec/obidos/ASIN/1564558541/icongroupinterna

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New Encyclopedia of Herbs & Their Uses by Deni Bown; Hardcover - 448 pages, Revised edition (2001), DK Publishing; ISBN: 078948031X; http://www.amazon.com/exec/obidos/ASIN/078948031X/icongroupinterna

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· Textbook of Complementary and Alternative Medicine by Wayne B. Jonas; Hardcover (2003), Lippincott, Williams & Wilkins; ISBN: 0683044370; http://www.amazon.com/exec/obidos/ASIN/0683044370/icongroupinterna For additional information on complementary and alternative medicine, ask your child’s doctor or write to: National Institutes of Health National Center for Complementary and Alternative Medicine Clearinghouse P. O. Box 8218 Silver Spring, MD 20907-8218

Vocabulary Builder The following vocabulary builder gives definitions of words used in this chapter that have not been defined in previous chapters: Aetiology: Study of the causes of disease. [EU] Iontophoresis: Therapeutic introduction of ions of soluble salts into tissues by means of electric current. In medical literature it is commonly used to indicate the process of increasing the penetration of drugs into surface tissues by the application of electric current. It has nothing to do with ion exchange, air ionization nor phonophoresis, none of which requires current. [NIH]

Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH]

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APPENDIX C. RESEARCHING NUTRITION Overview Since the time of Hippocrates, doctors have understood the importance of diet and nutrition to health and well-being. Since then, they have accumulated an impressive archive of studies and knowledge dedicated to this subject. Based on their experience, doctors and healthcare providers may recommend particular dietary supplements for phenylketonuria. Any dietary recommendation is based on age, body mass, gender, lifestyle, eating habits, food preferences, and health condition. It is therefore likely that different patients with phenylketonuria may be given different recommendations. Some recommendations may be directly related to phenylketonuria, while others may be more related to general health. In this chapter we will begin by briefly reviewing the essentials of diet and nutrition that will broadly frame more detailed discussions of phenylketonuria. We will then show you how to find studies dedicated specifically to nutrition and phenylketonuria.

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Food and Nutrition: General Principles What Are Essential Foods? Food is generally viewed by official sources as consisting of six basic elements: (1) fluids, (2) carbohydrates, (3) protein, (4) fats, (5) vitamins, and (6) minerals. Consuming a combination of these elements is considered to be a healthy diet: ·

Fluids are essential to human life as 80-percent of the body is composed of water. Water is lost via urination, sweating, diarrhea, vomiting, diuretics (drugs that increase urination), caffeine, and physical exertion.

·

Carbohydrates are the main source for human energy (thermoregulation) and the bulk of typical diets. They are mostly classified as being either simple or complex. Simple carbohydrates include sugars which are often consumed in the form of cookies, candies, or cakes. Complex carbohydrates consist of starches and dietary fibers. Starches are consumed in the form of pastas, breads, potatoes, rice, and other foods. Soluble fibers can be eaten in the form of certain vegetables, fruits, oats, and legumes. Insoluble fibers include brown rice, whole grains, certain fruits, wheat bran and legumes.

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Proteins are eaten to build and repair human tissues. Some foods that are high in protein are also high in fat and calories. Food sources for protein include nuts, meat, fish, cheese, and other dairy products.

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Fats are consumed for both energy and the absorption of certain vitamins. There are many types of fats, with many general publications recommending the intake of unsaturated fats or those low in cholesterol.

Vitamins and minerals are fundamental to human health, growth, and, in some cases, disease prevention. Most are consumed in your child’s diet (exceptions being vitamins K and D which are produced by intestinal bacteria and sunlight on the skin, respectively). Each vitamin and mineral plays a different role in health. The following outlines essential vitamins: ·

Vitamin A is important to the health of eyes, hair, bones, and skin; sources of vitamin A include foods such as eggs, carrots, and cantaloupe.

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Vitamin B1, also known as thiamine, is important for the nervous system and energy production; food sources for thiamine include meat, peas, fortified cereals, bread, and whole grains.

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Vitamin B2, also known as riboflavin, is important for the nervous system and muscles, but is also involved in the release of proteins from

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nutrients; food sources for riboflavin include dairy products, leafy vegetables, meat, and eggs. ·

Vitamin B3, also known as niacin, is important for healthy skin and helps the body use energy; food sources for niacin include peas, peanuts, fish, and whole grains

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Vitamin B6, also known as pyridoxine, is important for the regulation of cells in the nervous system and is vital for blood formation; food sources for pyridoxine include bananas, whole grains, meat, and fish.

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Vitamin B12 is vital for a healthy nervous system and for the growth of red blood cells in bone marrow; food sources for vitamin B12 include yeast, milk, fish, eggs, and meat.

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Vitamin C allows the body's immune system to fight various medical conditions, strengthens body tissue, and improves the body's use of iron; food sources for vitamin C include a wide variety of fruits and vegetables.

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Vitamin D helps the body absorb calcium which strengthens bones and teeth; food sources for vitamin D include oily fish and dairy products.

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Vitamin E can help protect certain organs and tissues from various degenerative diseases; food sources for vitamin E include margarine, vegetables, eggs, and fish.

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Vitamin K is essential for bone formation and blood clotting; common food sources for vitamin K include leafy green vegetables.

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Folic Acid maintains healthy cells and blood; food sources for folic acid include nuts, fortified breads, leafy green vegetables, and whole grains.

It should be noted that one can overdose on certain vitamins which become toxic if consumed in excess (e.g. vitamin A, D, E and K). Like vitamins, minerals are chemicals that are required by the body to remain in good health. Because the human body does not manufacture these chemicals internally, we obtain them from food and other dietary sources. The more important minerals include: ·

Calcium is needed for healthy bones, teeth, and muscles, but also helps the nervous system function; food sources for calcium include dry beans, peas, eggs, and dairy products.

·

Chromium is helpful in regulating sugar levels in blood; food sources for chromium include egg yolks, raw sugar, cheese, nuts, beets, whole grains, and meat.

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·

Fluoride is used by the body to help prevent tooth decay and to reinforce bone strength; sources of fluoride include drinking water and certain brands of toothpaste.

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Iodine helps regulate the body's use of energy by synthesizing into the hormone thyroxine; food sources include leafy green vegetables, nuts, egg yolks, and red meat.

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Iron helps maintain muscles and the formation of red blood cells and certain proteins; food sources for iron include meat, dairy products, eggs, and leafy green vegetables.

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Magnesium is important for the production of DNA, as well as for healthy teeth, bones, muscles, and nerves; food sources for magnesium include dried fruit, dark green vegetables, nuts, and seafood.

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Phosphorous is used by the body to work with calcium to form bones and teeth; food sources for phosphorous include eggs, meat, cereals, and dairy products.

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Selenium primarily helps maintain normal heart and liver functions; food sources for selenium include wholegrain cereals, fish, meat, and dairy products.

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Zinc helps wounds heal, the formation of sperm, and encourage rapid growth and energy; food sources include dried beans, shellfish, eggs, and nuts.

The United States government periodically publishes recommended diets and consumption levels of the various elements of food. Again, the doctor may encourage deviations from the average official recommendation based on your child’s specific condition. To learn more about basic dietary guidelines, visit the Web site: http://www.health.gov/dietaryguidelines/. Based on these guidelines, many foods are required to list the nutrition levels on the food’s packaging. Labeling Requirements are listed at the following site maintained by the Food and Drug Administration: http://www.cfsan.fda.gov/~dms/lab-cons.html. When interpreting these requirements, the government recommends that consumers become familiar with the following abbreviations before reading FDA literature:47 ·

DVs (Daily Values): A new dietary reference term that will appear on the food label. It is made up of two sets of references, DRVs and RDIs.

·

DRVs (Daily Reference Values): A set of dietary references that applies to fat, saturated fat, cholesterol, carbohydrate, protein, fiber, sodium, and potassium.

47

Adapted from the FDA: http://www.fda.gov/fdac/special/foodlabel/dvs.html.

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·

RDIs (Reference Daily Intakes): A set of dietary references based on the Recommended Dietary Allowances for essential vitamins and minerals and, in selected groups, protein. The name “RDI” replaces the term “U.S. RDA.”

·

RDAs (Recommended Dietary Allowances): A set of estimated nutrient allowances established by the National Academy of Sciences. It is updated periodically to reflect current scientific knowledge. What Are Dietary Supplements?48

Dietary supplements are widely available through many commercial sources, including health food stores, grocery stores, pharmacies, and by mail. Dietary supplements are provided in many forms including tablets, capsules, powders, gel-tabs, extracts, and liquids. Historically in the United States, the most prevalent type of dietary supplement was a multivitamin/mineral tablet or capsule that was available in pharmacies, either by prescription or “over the counter.” Supplements containing strictly herbal preparations were less widely available. Currently in the United States, a wide array of supplement products are available, including vitamin, mineral, other nutrients, and botanical supplements as well as ingredients and extracts of animal and plant origin. The Office of Dietary Supplements (ODS) of the National Institutes of Health is the official agency of the United States which has the expressed goal of acquiring “new knowledge to help prevent, detect, diagnose, and treat disease and disability, from the rarest genetic disorder to the common cold.”49 According to the ODS, dietary supplements can have an important impact on the prevention and management of medical conditions and on the maintenance of health.50 The ODS notes that considerable research on the effects of dietary supplements has been conducted in Asia and Europe where the use of plant products, in particular, has a long tradition. However, the This discussion has been adapted from the NIH: http://ods.od.nih.gov/whatare/whatare.html. 49 Contact: The Office of Dietary Supplements, National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: (301) 435-2920, Fax: (301) 480-1845, E-mail: [email protected]. 50 Adapted from http://ods.od.nih.gov/about/about.html. The Dietary Supplement Health and Education Act defines dietary supplements as “a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, mineral, amino acid, herb or other botanical; or a dietary substance for use to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above; and intended for ingestion in the form of a capsule, powder, softgel, or gelcap, and not represented as a conventional food or as a sole item of a meal or the diet.” 48

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overwhelming majority of supplements have not been studied scientifically. To explore the role of dietary supplements in the improvement of health care, the ODS plans, organizes, and supports conferences, workshops, and symposia on scientific topics related to dietary supplements. The ODS often works in conjunction with other NIH Institutes and Centers, other government agencies, professional organizations, and public advocacy groups. To learn more about official information on dietary supplements, visit the ODS site at http://ods.od.nih.gov/whatare/whatare.html. Or contact: The Office of Dietary Supplements National Institutes of Health Building 31, Room 1B29 31 Center Drive, MSC 2086 Bethesda, Maryland 20892-2086 Tel: (301) 435-2920 Fax: (301) 480-1845 E-mail: [email protected]

Finding Studies on Phenylketonuria The NIH maintains an office dedicated to nutrition and diet. The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.51 IBIDS is available to the public free of charge through the ODS Internet page: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. We recommend that you start with the Consumer Database. While you may not find references for the topics that are of most interest to you, check back periodically as this database is frequently updated. More studies can be Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

51

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found by searching the Full IBIDS Database. Healthcare professionals and researchers generally use the third option, which lists peer-reviewed citations. In all cases, we suggest that you take advantage of the “Advanced Search” option that allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “phenylketonuria” (or synonyms) into the search box. To narrow the search, you can also select the “Title” field. The following is a typical result when searching for recently indexed consumer information on phenylketonuria: ·

Should dietary treatment of phenylketonuria be continued after infancy? Source: Nutrition-reviews (USA). (June 1985). volume 43(6) page 176-177. metabolic disorders children nutrient transport amino acids therapeutic diets tyrosine dopamine 0029-6643 Summary: trouble du metabolisme enfant transport des substances nutritives acide amine regime therapeutique tyrosine dopamine

Additional consumer oriented references include: ·

Importance of diet in maternal phenylketonuria. Author(s): Department of Nutrition & Food Sciences, University of Vermont, Burlington 05405, USA. Source: Sheard, N F Nutr-Revolume 2000 August; 58(8): 236-9 0029-6643

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New approaches to the treatment of phenylketonuria. Author(s): Departamento de Ciencias Farmaceuticas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Brazil. Source: de Freitas, O Izumi, C Lara, M G Greene, L J Nutr-Revolume 1999 March; 57(3): 65-70 0029-6643

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The Maternal Phenylketonuria Collaborative Study: a status report. Source: Anonymous Nutr-Revolume 1994 November; 52(11): 390-3 00296643

The following information is typical of that found when using the “Full IBIDS Database” when searching using “phenylketonuria” (or a synonym): ·

A new amino acid mixture permits new approaches to the treatment of phenylketonuria. Author(s): Department of Pediatrics, Oregon Health Sciences University, Portland 97207-0574, USA. Source: Buist, N R Prince, A P Huntington, K L Tuerck, J M Waggoner, D D Acta-Paediatr-Suppl. 1994 December; 40775-7 0803-5326

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·

A prefrontal dysfunction model of early-treated phenylketonuria. Author(s): Department of Psychology, University of Northern Colorado, Greeley 80639, USA. Source: Welsh, M C Eur-J-Pediatr. 1996 July; 155 Suppl 1S87-9 0340-6199

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A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria. Author(s): Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030. Source: Goltsov, A A Eisensmith, R C Naughton, E R Jin, L Chakraborty, R Woo, S L Hum-Mol-Genet. 1993 May; 2(5): 577-81 0964-6906

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Aberrant phenylalanine metabolism in phenylketonuria heterozygotes. Author(s): John F. Kennedy Institute, Glostrup, Denmark. Source: Guldberg, P Henriksen, K F Lou, H C Guttler, F J-Inherit-MetabDis. 1998 June; 21(4): 365-72 0141-8955

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Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Author(s): Postgraduate Centre, Middlesex Hospital, London, UK. [email protected] Source: Brenton, D P Pietz, J Eur-J-Pediatr. 2000 October; 159 Suppl 2S114-20 0340-6199

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An enzyme/brain-barrier theory of psychiatric pathogenesis: unifying observations on phenylketonuria, autism, schizophrenia and postpartum psychosis. Author(s): Department of General Practice, University of Oslo, Blindern, Norway. Source: Seim, A R Reichelt, K L Med-Hypotheses. 1995 November; 45(5): 498-502 0306-9877

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Atypical cases of phenylketonuria. Author(s): Laboratoire de Biochimie, Faculte Libre de Medecine, Lille, France. Source: Dhondt, J L Farriaux, J P Eur-J-Pediatr. 1987; 146 Suppl 1A38-43 0340-6199

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Behaviour in early treated phenylketonuria: a systematic review. Author(s): Phenylketonuria Register, Division of Biochemistry and Metabolism, University College, London, UK. [email protected] Source: Smith, I Knowles, J Eur-J-Pediatr. 2000 October; 159 Suppl 2S8993 0340-6199

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·

Biochemical control, genetic analysis and magnetic resonance imaging in patients with phenylketonuria. Author(s): Department of Child Health, Royal Hospital for Sick Children, Bristol, United Kingdom. Source: Walter, J H Tyfield, L A Holton, J B Johnson, C Eur-J-Pediatr. 1993 October; 152(10): 822-7 0340-6199

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Biochemical effects of supplemented long-chain polyunsaturated fatty acids in hyperphenylalaninemia. Author(s): Department of Pediatrics, San Paolo Hospital, Milan, 20142, Italy. [email protected] Source: Agostoni, C Scaglioni, S Bonvissuto, M Bruzzese, M G Giovannini, M Riva, E Prostaglandins-Leukot-Essent-Fatty-Acids. 2001 February; 64(2): 111-5 0952-3278

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Biopterin-dependent hyperphenylalaninemia due to deficiency of 6pyruvoyl tetrahydropterin synthase. Author(s): Department of Pediatrics, King Faisal Specialist Hospital Research Center, Riyadh, Saudi Arabia. Source: al Aqeel, A Ozand, P T Gascon, G Nester, M al Nasser, M BrisMarch, J Blau, N Hughes, H Subramanyan, S B Reynolds, C T Neurology. 1991 May; 41(5): 730-7 0028-3878

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Biopterin-responsive hyperphenylalaninemia. Author(s): Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, Maryland 20892. Source: Kaufman, S J-Nutr-Sci-Vitaminol-(Tokyo). 1992; Spec No601-6 0301-4800

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Brain MRI changes in phenylketonuria. Associations with dietary status. Author(s): Institute of Neurology, University College, London, UK. Source: Thompson, A J Tillotson, S Smith, I Kendall, B Moore, S G Brenton, D P Brain. 1993 August; 116 ( Pt 4)811-21 0006-8950

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Branched chain amino acids improve complex maze learning in rat offspring prenatally exposed to hyperphenylalaninemia: implications for maternal phenylketonuria. Author(s): Institute for Developmental Research, Children's Hospital Research Foundation, Cincinnati, OH 45229-2899. Source: Vorhees, C V Berry, H K Pediatr-Res. 1989 June; 25(6): 568-72 0031-3998

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Care of the adult with phenylketonuria. Author(s): Childrens Hospital Los Angeles, CA 90027, USA. Source: Koch, R Azen, C Friedman, E G Fishler, K Baumann Frischling, C Lin, T Eur-J-Pediatr. 1996 July; 155 Suppl 1S90-2 0340-6199

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·

Cerebral serotonin regulation by phenylalanine analogues and during hyperphenylalaninemia. Source: Greengard, O Wolfe, J Biochem-Pharmacol. 1987 March 15; 36(6): 965-70 0006-2952

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Coexistence of cystic fibrosis and phenylketonuria. Author(s): Royal Belfast Hospital for Sick Children. Source: Greeves, L G McCarthy, H L Redmond, A Carson, D J UlsterMed-J. 1997 May; 66(1): 59-61 0041-6193

·

Comments on behavior in early treated phenylketonuria. Author(s): Department of Paediatrics, University of Munster, Germany. [email protected] Source: Weglage, J Eur-J-Pediatr. 2000 October; 159 Suppl 2S94-5 03406199

·

Comments on diet and compliance in phenylketonuria. Author(s): Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA. [email protected] Source: Fisch, R O Eur-J-Pediatr. 2000 October; 159 Suppl 2S142-4 03406199

·

Comments on final intelligence in late treated patients with phenylketonuria. Author(s): Divison of Genetics, Children's Hospital, Harvard Medical School, Boston, MA, USA. Source: Levy, H L Eur-J-Pediatr. 2000 October; 159 Suppl 2S149 0340-6199

Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: ·

healthfinder®, HHS's gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

·

The United States Department of Agriculture's Web site dedicated to nutrition information: www.nutrition.gov

·

The Food and Drug Administration's Web site for federal food safety information: www.foodsafety.gov

Researching Nutrition 175

·

The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

·

The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

·

Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

·

Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

·

Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: ·

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

·

Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

·

Google: http://directory.google.com/Top/Health/Nutrition/

·

Healthnotes: http://www.thedacare.org/healthnotes/

·

Open Directory Project: http://dmoz.org/Health/Nutrition/

·

Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

·

WebMDÒHealth: http://my.webmd.com/nutrition

·

WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,,00.html

The following is a specific Web list relating to phenylketonuria; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: ·

Vitamins

176 Phenylketonuria

Vitamin B12 Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Vitamin_B12.htm Vitamin K Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Vitamin_K.htm ·

Minerals Biotin Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Molybdenum Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Selenium Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Supp/Selenium.htm Selenium Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm

·

Food and Diet Beverages Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Crackers Source: Healthnotes, Inc.; www.healthnotes.com

Researching Nutrition 177

Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Milk Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm Non-Nutritive and Artificial Sweeteners Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Food_Guide/Non_Nutritive_A rtificial_Sweeteners.htm Syrup Source: Healthnotes, Inc.; www.healthnotes.com Hyperlink: http://www.thedacare.org/healthnotes/Concern/Phenylketonuria.htm

Vocabulary Builder The following vocabulary builder defines words used in the references in this chapter that have not been defined in previous chapters: Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]

Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU]

178 Phenylketonuria

Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH]

Finding Medical Libraries 179

APPENDIX D. FINDING MEDICAL LIBRARIES Overview At a medical library you can find medical texts and reference books, consumer health publications, specialty newspapers and magazines, as well as medical journals. In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Before going to the library, highlight the references mentioned in this sourcebook that you find interesting. Focus on those items that are not available via the Internet, and ask the reference librarian for help with your search. He or she may know of additional resources that could be helpful to you. Most importantly, your local public library and medical libraries have Interlibrary Loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. NLM's interlibrary loan services are only available to libraries. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.52

52

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

180 Phenylketonuria

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries Open to the Public In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries that are generally open to the public and have reference facilities. The following is the NLM’s list plus hyperlinks to each library Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located):53 ·

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

·

Alabama: Richard M. Scrushy Library (American Sports Medicine Institute), http://www.asmi.org/LIBRARY.HTM

·

Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

·

California: Kris Kelly Health Information Center (St. Joseph Health System), http://www.humboldt1.com/~kkhic/index.html

·

California: Community Health Library of Los Gatos (Community Health Library of Los Gatos), http://www.healthlib.org/orgresources.html

·

California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

·

California: Gateway Health Library (Sutter Gould Medical Foundation)

·

California: Health Library (Stanford University Medical Center), http://www-med.stanford.edu/healthlibrary/

53

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 181

·

California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

·

California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

·

California: San José PlaneTree Health Library, http://planetreesanjose.org/

·

California: Sutter Resource Library (Sutter Hospitals Foundation), http://go.sutterhealth.org/comm/resc-library/sac-resources.html

·

California: University of California, Davis. Health Sciences Libraries

·

California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System), http://www.valleycare.com/library.html

·

California: Washington Community Health Resource Library (Washington Community Health Resource Library), http://www.healthlibrary.org/

·

Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.exempla.org/conslib.htm

·

Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

·

Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

·

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital), http://www.waterburyhospital.com/library/consumer.shtml

·

Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute), http://www.christianacare.org/health_guide/health_guide_pmri_health _info.cfm

·

Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine), http://www.delamed.org/chls.html

·

Georgia: Family Resource Library (Medical College of Georgia), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

·

Georgia: Health Resource Center (Medical Center of Central Georgia), http://www.mccg.org/hrc/hrchome.asp

·

Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library), http://hml.org/CHIS/

182 Phenylketonuria

·

Idaho: DeArmond Consumer Health Library (Kootenai Medical Center), http://www.nicon.org/DeArmond/index.htm

·

Illinois: Health Learning Center of Northwestern Memorial Hospital (Northwestern Memorial Hospital, Health Learning Center), http://www.nmh.org/health_info/hlc.html

·

Illinois: Medical Library (OSF Saint Francis Medical Center), http://www.osfsaintfrancis.org/general/library/

·

Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital), http://www.centralbap.com/education/community/library.htm

·

Kentucky: University of Kentucky - Health Information Library (University of Kentucky, Chandler Medical Center, Health Information Library), http://www.mc.uky.edu/PatientEd/

·

Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation), http://www.ochsner.org/library/

·

Louisiana: Louisiana State University Health Sciences Center Medical Library-Shreveport, http://lib-sh.lsuhsc.edu/

·

Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital), http://www.fchn.org/fmh/lib.htm

·

Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center), http://www.cmmc.org/library/library.html

·

Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare), http://www.emh.org/hll/hpl/guide.htm

·

Maine: Maine Medical Center Library (Maine Medical Center), http://www.mmc.org/library/

·

Maine: Parkview Hospital, http://www.parkviewhospital.org/communit.htm#Library

·

Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center), http://www.smmc.org/services/service.php3?choice=10

·

Maine: Stephens Memorial Hospital Health Information Library (Western Maine Health), http://www.wmhcc.com/hil_frame.html

·

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

·

Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre), http://www.deerlodge.mb.ca/library/libraryservices.shtml

Finding Medical Libraries 183

·

Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Md., Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

·

Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

·

Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://medlibwww.bu.edu/library/lib.html

·

Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

·

Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital), http://www.nebh.org/health_lib.asp

·

Massachusetts: St. Luke's Hospital Health Sciences Library (St. Luke's Hospital), http://www.southcoast.org/library/

·

Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

·

Massachusetts: UMass HealthNet (University of Massachusetts Medical School), http://healthnet.umassmed.edu/

·

Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

·

Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

·

Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

·

Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center), http://www.cancer.med.umich.edu/learn/leares.htm

·

Michigan: Sladen Library & Center for Health Information Resources Consumer Health Information, http://www.sladen.hfhs.org/library/consumer/index.html

·

Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center), http://www.saintpatrick.org/chi/librarydetail.php3?ID=41

184 Phenylketonuria

·

National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

·

National: National Network of Libraries of Medicine (National Library of Medicine) - provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

·

National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

·

Nevada: Health Science Library, West Charleston Library (Las Vegas Clark County Library District), http://www.lvccld.org/special_collections/medical/index.htm

·

New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

·

New Jersey: Consumer Health Library (Rahway Hospital), http://www.rahwayhospital.com/library.htm

·

New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center), http://www.englewoodhospital.com/links/index.htm

·

New Jersey: Meland Foundation (Englewood Hospital and Medical Center), http://www.geocities.com/ResearchTriangle/9360/

·

New York: Choices in Health Information (New York Public Library) NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

·

New York: Health Information Center (Upstate Medical University, State University of New York), http://www.upstate.edu/library/hic/

·

New York: Health Sciences Library (Long Island Jewish Medical Center), http://www.lij.edu/library/library.html

·

New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

·

Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

·

Oklahoma: Saint Francis Health System Patient/Family Resource Center (Saint Francis Health System), http://www.sfhtulsa.com/patientfamilycenter/default.asp

Finding Medical Libraries 185

·

Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center), http://www.mcmc.net/phrc/

·

Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center), http://www.hmc.psu.edu/commhealth/

·

Pennsylvania: Community Health Resource Library (Geisinger Medical Center), http://www.geisinger.edu/education/commlib.shtml

·

Pennsylvania: HealthInfo Library (Moses Taylor Hospital), http://www.mth.org/healthwellness.html

·

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System), http://www.hsls.pitt.edu/chi/hhrcinfo.html

·

Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

·

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System), http://www.shscares.org/services/lrc/index.asp

·

Pennsylvania: Medical Library (UPMC Health System), http://www.upmc.edu/passavant/library.htm

·

Quebec, Canada: Medical Library (Montreal General Hospital), http://ww2.mcgill.ca/mghlib/

·

South Dakota: Rapid City Regional Hospital - Health Information Center (Rapid City Regional Hospital, Health Information Center), http://www.rcrh.org/education/LibraryResourcesConsumers.htm

·

Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

·

Texas: Matustik Family Resource Center (Cook Children's Health Care System), http://www.cookchildrens.com/Matustik_Library.html

·

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

·

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center), http://www.swmedctr.com/Home/

Your Child’s Rights and Insurance 187

APPENDIX E. YOUR CHILD’S RIGHTS AND INSURANCE Overview Parents face a series of issues related more to the healthcare industry than to their children’s medical conditions. This appendix covers two important topics in this regard: your responsibilities and your child’s rights as a patient, and how to get the most out of your child’s medical insurance plan.

Your Child’s Rights as a Patient The President’s Advisory Commission on Consumer Protection and Quality in the Healthcare Industry has created the following summary of your child’s rights as a patient.54

54Adapted

from Consumer Bill of Rights and Responsibilities: http://www.hcqualitycommission.gov/press/cbor.html#head1.

188 Phenylketonuria

Information Disclosure Consumers have the right to receive accurate, easily understood information. Some consumers require assistance in making informed decisions about health plans, health professionals, and healthcare facilities. Such information includes: ·

Health plans. Covered benefits, cost-sharing, and procedures for resolving complaints, licensure, certification, and accreditation status, comparable measures of quality and consumer satisfaction, provider network composition, the procedures that govern access to specialists and emergency services, and care management information.

·

Health professionals. Education, board certification, and recertification, years of practice, experience performing certain procedures, and comparable measures of quality and consumer satisfaction.

·

Healthcare facilities. Experience in performing certain procedures and services, accreditation status, comparable measures of quality, worker, and consumer satisfaction, and procedures for resolving complaints.

·

Consumer assistance programs. Programs must be carefully structured to promote consumer confidence and to work cooperatively with health plans, providers, payers, and regulators. Desirable characteristics of such programs are sponsorship that ensures accountability to the interests of consumers and stable, adequate funding.

Choice of Providers and Plans Consumers have the right to a choice of healthcare providers that is sufficient to ensure access to appropriate high-quality healthcare. To ensure such choice, the Commission recommends the following: ·

Provider network adequacy. All health plan networks should provide access to sufficient numbers and types of providers to assure that all covered services will be accessible without unreasonable delay -including access to emergency services 24 hours a day and 7 days a week. If a health plan has an insufficient number or type of providers to provide a covered benefit with the appropriate degree of specialization, the plan should ensure that the consumer obtains the benefit outside the network at no greater cost than if the benefit were obtained from participating providers.

·

Access to specialists. Consumers with complex or serious medical conditions who require frequent specialty care should have direct access

Your Child’s Rights and Insurance 189

to a qualified specialist of their choice within a plan's network of providers. Authorizations, when required, should be for an adequate number of direct access visits under an approved treatment plan. ·

Transitional care. Consumers who are undergoing a course of treatment for a chronic or disabling condition at the time they involuntarily change health plans or at a time when a provider is terminated by a plan for other than cause should be able to continue seeing their current specialty providers for up to 90 days to allow for transition of care.

·

Choice of health plans. Public and private group purchasers should, wherever feasible, offer consumers a choice of high-quality health insurance plans. Access to Emergency Services

Consumers have the right to access emergency healthcare services when and where the need arises. Health plans should provide payment when a consumer presents to an emergency department with acute symptoms of sufficient severity--including severe pain--such that a “prudent layperson” could reasonably expect the absence of medical attention to result in placing that consumer's health in serious jeopardy, serious impairment to bodily functions, or serious dysfunction of any bodily organ or part.

Participation in Treatment Decisions Consumers have the right and responsibility to fully participate in all decisions related to their healthcare. Consumers who are unable to fully participate in treatment decisions have the right to be represented by parents, guardians, family members, or other conservators. Physicians and other health professionals should: ·

Provide parents with sufficient information and opportunity to decide among treatment options consistent with the informed consent process.

·

Discuss all treatment options with a parent in a culturally competent manner, including the option of no treatment at all.

·

Ensure that persons with disabilities have effective communications with members of the health system in making such decisions.

·

Discuss all current treatments a consumer may be undergoing.

·

Discuss all risks, nontreatment.

benefits,

and

consequences

to

treatment

or

190 Phenylketonuria

·

Give parents the opportunity to refuse treatment for their children and to express preferences about future treatment decisions.

·

Discuss the use of advance directives -- both living wills and durable powers of attorney for healthcare -- with parents.

·

Abide by the decisions made by parents consistent with the informed consent process.

Health plans, health providers, and healthcare facilities should: ·

Disclose to consumers factors -- such as methods of compensation, ownership of or interest in healthcare facilities, or matters of conscience -that could influence advice or treatment decisions.

·

Assure that provider contracts do not contain any so-called “gag clauses” or other contractual mechanisms that restrict healthcare providers' ability to communicate with and advise parents about medically necessary treatment options for their children.

·

Be prohibited from penalizing or seeking retribution against healthcare professionals or other health workers for advocating on behalf of their patients. Respect and Nondiscrimination

Consumers have the right to considerate, respectful care from all members of the healthcare industry at all times and under all circumstances. An environment of mutual respect is essential to maintain a quality healthcare system. To assure that right, the Commission recommends the following: ·

Consumers must not be discriminated against in the delivery of healthcare services consistent with the benefits covered in their policy, or as required by law, based on race, ethnicity, national origin, religion, sex, age, mental or physical disability, sexual orientation, genetic information, or source of payment.

·

Consumers eligible for coverage under the terms and conditions of a health plan or program, or as required by law, must not be discriminated against in marketing and enrollment practices based on race, ethnicity, national origin, religion, sex, age, mental or physical disability, sexual orientation, genetic information, or source of payment.

Your Child’s Rights and Insurance 191

Confidentiality of Health Information Consumers have the right to communicate with healthcare providers in confidence and to have the confidentiality of their individually identifiable healthcare information protected. Consumers also have the right to review and copy their own medical records and request amendments to their records.

Complaints and Appeals Consumers have the right to a fair and efficient process for resolving differences with their health plans, healthcare providers, and the institutions that serve them, including a rigorous system of internal review and an independent system of external review. A free copy of the Patient's Bill of Rights is available from the American Hospital Association.55

Parent Responsibilities To underscore the importance of finance in modern healthcare as well as your responsibility for the financial aspects of your child’s care, the President’s Advisory Commission on Consumer Protection and Quality in the Healthcare Industry has proposed that parents understand the following “Consumer Responsibilities.”56 In a healthcare system that protects consumers' rights, it is reasonable to expect and encourage consumers to assume certain responsibilities. Greater involvement by parents in their children’s care increases the likelihood of achieving the best outcome and helps support a quality-oriented, cost-conscious environment. Such responsibilities include: ·

Take responsibility for maximizing your child’s healthy habits.

·

Work collaboratively with healthcare providers in developing and carrying out your child’s agreed-upon treatment plans.

·

Disclose relevant information and clearly communicate wants and needs.

55 To order your free copy of the Patient's Bill of Rights, telephone 312-422-3000 or visit the American Hospital Association’s Web site: http://www.aha.org. Click on “Resource Center,” go to “Search” at bottom of page, and then type in “Patient's Bill of Rights.” The Patient’s Bill of Rights is also available from Fax on Demand, at 312-422-2020, document number 471124. 56 Adapted from http://www.hcqualitycommission.gov/press/cbor.html#head1.

192 Phenylketonuria

·

Use the insurance company's internal complaint and appeal processes to address your concerns.

·

Recognize the reality of risks, the limits of the medical science, and the human fallibility of the healthcare professional.

·

Be aware of a healthcare provider's obligation to be reasonably efficient and equitable in providing care to the community.

·

Become knowledgeable about health plan coverage and options (when available) including all covered benefits, limitations, and exclusions, rules regarding use of network providers, coverage and referral rules, appropriate processes to secure additional information, and the process to appeal coverage decisions.

·

Make a good-faith effort to meet financial obligations.

·

Abide by administrative and operational procedures of health plans, healthcare providers, and Government health benefit programs.

Choosing an Insurance Plan There are a number of official government agencies that help consumers understand their healthcare insurance choices.57 The U.S. Department of Labor, in particular, recommends ten ways to make your health benefits choices work best for your family.58 1. Your options are important. There are many different types of health benefit plans. Find out which one your employer offers, then check out the plan, or plans, offered. Your employer's human resource office, the health plan administrator, or your union can provide information to help you match your family’s needs and preferences with the available plans. The more information you have, the better your healthcare decisions will be. 2. Reviewing the benefits available. Do the plans offered cover preventive care, well-baby care, vision or dental care? Are there deductibles? Answers to these questions can help determine the out-of-pocket expenses you may face. Cheapest may not always be best. Your goal is high quality health benefits.

More information about quality across programs is provided at the following AHRQ Web site: http://www.ahrq.gov/consumer/qntascii/qnthplan.htm. 58 Adapted from the Department of Labor: http://www.dol.gov/dol/pwba/public/pubs/health/top10-text.html. 57

Your Child’s Rights and Insurance 193

3. Look for quality. The quality of healthcare services varies, but quality can be measured. You should consider the quality of healthcare in deciding among the healthcare plans or options available to your family. Not all health plans, doctors, hospitals and other providers give the highest quality care. Fortunately, there is quality information you can use right now to help you compare your healthcare choices. Find out how you can measure quality. Consult the U.S. Department of Health and Human Services publication “Your Guide to Choosing Quality Health Care” on the Internet at www.ahcpr.gov/consumer. 4. Your plan's summary plan description (SPD) provides a wealth of information. Your health plan administrator can provide you with a copy of your plan’s SPD. It outlines your family’s benefits and your legal rights under the Employee Retirement Income Security Act (ERISA), the federal law that protects your family’s health benefits. It should contain information about the coverage of dependents, what services will require a co-pay, and the circumstances under which your employer can change or terminate a health benefits plan. Save the SPD and all other health plan brochures and documents, along with memos or correspondence from your employer relating to health benefits. 5. Assess your benefit coverage as your family status changes. Marriage, divorce, childbirth or adoption, and the death of a spouse are all life events that may signal a need to change your health benefits. You, your spouse and dependent children may be eligible for a special enrollment period under provisions of the Health Insurance Portability and Accountability Act (HIPAA). Even without life-changing events, the information provided by your employer should tell you how you can change benefits or switch plans, if more than one plan is offered. If your spouse's employer also offers a health benefits package, consider coordinating both plans for maximum coverage. 6. Changing jobs and other life events can affect your family’s health benefits. Under the Consolidated Omnibus Budget Reconciliation Act (COBRA), you, your covered spouse, and your dependent children may be eligible to purchase extended health coverage under your employer's plan if you lose your job, change employers, get divorced, or upon occurrence of certain other events. Coverage can range from 18 to 36 months depending on your situation. COBRA applies to most employers with 20 or more workers and requires your plan to notify you of your rights. Most plans require eligible individuals to make their COBRA election within 60 days of the plan's notice. Be sure to follow up with your plan sponsor if you don't receive notice, and make sure you respond within the allotted time.

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7. HIPAA can also help if you are changing jobs, particularly if you have a medical condition. HIPAA generally limits pre-existing condition exclusions to a maximum of 12 months (18 months for late enrollees). HIPAA also requires this maximum period to be reduced by the length of time you had prior “creditable coverage.” You should receive a certificate documenting your prior creditable coverage from your old plan when coverage ends. 8. Plan for retirement. Before you retire, find out what health benefits, if any, extend to you and your spouse during your retirement years. Consult with your employer's human resources office, your union, the plan administrator, and check your SPD. Make sure there is no conflicting information among these sources about the benefits your family will receive or the circumstances under which they can change or be eliminated. With this information in hand, you can make other important choices, like finding out if you are eligible for Medicare and Medigap insurance coverage. 9. Know how to file an appeal if a health benefits claim is denied. Understand how your plan handles grievances and where to make appeals of the plan's decisions. Keep records and copies of correspondence. Check your health benefits package and your SPD to determine who is responsible for handling problems with benefit claims. Contact PWBA for customer service assistance if you are unable to obtain a response to your complaint. 10. You can take steps to improve the quality of the healthcare and the health benefits your family receives. Look for and use things like Quality Reports and Accreditation Reports whenever you can. Quality reports may contain consumer ratings -- how satisfied consumers are with the doctors in their plan, for instance-- and clinical performance measures -- how well a healthcare organization prevents and treats illness. Accreditation reports provide information on how accredited organizations meet national standards, and often include clinical performance measures. Look for these quality measures whenever possible. Consult “Your Guide to Choosing Quality Health Care” on the Internet at www.ahcpr.gov/consumer.

Medicaid Illness strikes both rich and poor families. For low-income families, Medicaid is available to defer the costs of treatment. In the following pages, you will learn the basics about Medicaid as well as useful contact information on how to find more in-depth information.

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Medicaid is a joint federal and state program that helps pay medical costs for some people with low incomes and limited resources. Medicaid programs vary from state to state. You can find more information about Medicaid on the HCFA.gov Web site at http://www.hcfa.gov/medicaid/medicaid.htm.

NORD’s Medication Assistance Programs Finally, the National Organization for Rare Disorders, Inc. (NORD) administers medication programs sponsored by humanitarian-minded pharmaceutical and biotechnology companies to help uninsured or underinsured individuals secure life-saving or life-sustaining drugs.59 NORD programs ensure that certain vital drugs are available “to those families whose income is too high to qualify for Medicaid but too low to pay for their prescribed medications.” The program has standards for fairness, equity, and unbiased eligibility. It currently covers some 14 programs for nine pharmaceutical companies. NORD also offers early access programs for investigational new drugs (IND) under the approved “Treatment INDs” programs of the Food and Drug Administration (FDA). In these programs, a limited number of individuals can receive investigational drugs that have yet to be approved by the FDA. These programs are generally designed for rare medical conditions. For more information, visit www.rarediseases.org.

Additional Resources In addition to the references already listed in this chapter, you may need more information on health insurance, hospitals, or the healthcare system in general. The NIH has set up an excellent guidance Web site that addresses these and other issues. Topics include:60 ·

Health Insurance: http://www.nlm.nih.gov/medlineplus/healthinsurance.html

·

Health Statistics: http://www.nlm.nih.gov/medlineplus/healthstatistics.html

·

HMO and Managed Care: http://www.nlm.nih.gov/medlineplus/managedcare.html

·

Hospice Care: http://www.nlm.nih.gov/medlineplus/hospicecare.html

Adapted from NORD: http://www.rarediseases.org/cgibin/nord/progserv#patient?id=rPIzL9oD&mv_pc=30. 60 You can access this information at: http://www.nlm.nih.gov/medlineplus/healthsystem.html. 59

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·

Medicaid: http://www.nlm.nih.gov/medlineplus/medicaid.html

·

Medicare: http://www.nlm.nih.gov/medlineplus/medicare.html

·

Nursing Homes and Long-term Care: http://www.nlm.nih.gov/medlineplus/nursinghomes.html

·

Patient's Rights, Confidentiality, Informed Consent, Ombudsman Programs, Privacy and Patient Issues: http://www.nlm.nih.gov/medlineplus/patientissues.html

·

Veteran's Health, Persian Gulf War, Gulf War Syndrome, Agent Orange: http://www.nlm.nih.gov/medlineplus/veteranshealth.html

Vocabulary Builder Athetosis: A derangement marked by ceaseless occurrence of slow, sinuous, writhing movements, especially severe in the hands, and performed involuntarily; it may occur after hemiplegia, and is then known as posthemiplegic chorea. Called also mobile spasm. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU]

Online Glossaries 197

ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries and glossaries. The National Library of Medicine has compiled the following list of online dictionaries: ·

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

·

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

·

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

·

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

·

On-line Medical Dictionary (CancerWEB): http://www.graylab.ac.uk/omd/

·

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

·

Terms and Definitions (Office of Rare Diseases): http://rarediseases.info.nih.gov/ord/glossary_a-e.html

Beyond these, MEDLINEplus contains a very user-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia Web site address is http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a) and drkoop.com (http://www.drkoop.com/). Topics of interest can be researched by using keywords before continuing elsewhere, as these basic definitions and concepts will be useful in more advanced areas of research. You may choose to print various pages specifically relating to phenylketonuria and keep them on file. The NIH, in particular, suggests that parents of children with phenylketonuria visit the following Web sites in the ADAM Medical Encyclopedia:

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·

Basic Guidelines for Phenylketonuria Phenylketonuria Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001166.htm PKU Web site: http://www.nlm.nih.gov/medlineplus/ency/article/001166.htm

·

Signs & Symptoms for Phenylketonuria Athetosis Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003197.htm Hyperactivity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003256.htm Microcephaly Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003272.htm Rashes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Seizures Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003200.htm Skin rashes Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003220.htm Spasticity Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003297.htm

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·

Diagnostics and Tests for Phenylketonuria Enzyme assay Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003332.htm Phenylalanine Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003362.htm PK Web site: http://www.nlm.nih.gov/medlineplus/ency/article/003357.htm

·

Nutrition for Phenylketonuria Protein Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002467.htm

·

Background Topics for Phenylketonuria Amino acids Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002222.htm Central nervous system Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002311.htm Enzyme Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002353.htm Melanin Web site: http://www.nlm.nih.gov/medlineplus/ency/article/002256.htm

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Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries and glossaries: ·

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

·

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

·

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

·

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

Glossary 201

PHENYLKETONURIA GLOSSARY The following is a complete glossary of terms used in this sourcebook. The definitions are derived from official public sources including the National Institutes of Health [NIH] and the European Union [EU]. After this glossary, we list a number of additional hardbound and electronic glossaries and dictionaries that you may wish to consult. Acrodermatitis: Inflammation involving the skin of the extremities, especially the hands and feet. Several forms are known, some idiopathic and some hereditary. The infantile form is called Gianotti-Crosti syndrome. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH]

Aetiology: Study of the causes of disease. [EU] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Ammonia: Ammonia. A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Athetosis: A derangement marked by ceaseless occurrence of slow, sinuous, writhing movements, especially severe in the hands, and performed involuntarily; it may occur after hemiplegia, and is then known as posthemiplegic chorea. Called also mobile spasm. [EU] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Benign: Not malignant; not recurrent; favourable for recovery. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU]

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Bleomycin: A complex of related glycopeptide antibiotics from Streptomyces verticillus consisting of bleomycin A2 and B2. It inhibits DNA metabolism and is used as an antineoplastic, especially for solid tumors. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU]

Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, poly- and heterosaccharides. [EU] Cardiovascular: Pertaining to the heart and blood vessels. [EU] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU]

Cervical: Pertaining to the neck, or to the neck of any organ or structure. [EU] Cholecystitis: Inflammation of the gallbladder. [EU] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Chronic: Persisting over a long period of time. [EU] Cirrhosis: Liver disease characterized pathologically by loss of the normal microscopic lobular architecture, with fibrosis and nodular regeneration. The term is sometimes used to refer to chronic interstitial inflammation of any organ. [EU] Colorectal: Pertaining to or affecting the colon and rectum. [EU] Contamination: The soiling or pollution by inferior material, as by the introduction of organisms into a wound, or sewage into a stream. [EU] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Criterion: A standard by which something may be judged. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH]

Glossary 203

Diurnal: Occurring during the day. [EU] Dyskinesia: Impairment of the power of voluntary movement, resulting in fragmentary or incomplete movements. [EU] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eczema: A pruritic papulovesicular dermatitis occurring as a reaction to many endogenous and exogenous agents, characterized in the acute stage by erythema, edema associated with a serous exudate between the cells of the epidermis (spongiosis) and an inflammatory infiltrate in the dermis, oozing and vesiculation, and crusting and scaling; and in the more chronic stages by lichenification or thickening or both, signs of excoriations, and hyperpigmentation or hypopigmentation or both. Atopic dermatitis is the most common type of dermatitis. Called also eczematous dermatitis. [EU] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH] Enzyme: A protein molecule that catalyses chemical reactions of other substances without itself being destroyed or altered upon completion of the reactions. Enzymes are classified according to the recommendations of the Nomenclature Committee of the International Union of Biochemistry. Each enzyme is assigned a recommended name and an Enzyme Commission (EC) number. They are divided into six main groups; oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Fibrosis: The formation of fibrous tissue; fibroid or fibrous degeneration [EU] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Gastrointestinal: Pertaining to or communicating with the stomach and intestine, as a gastrointestinal fistula. [EU] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Gingivitis: Inflammation of the gingivae. Gingivitis associated with bony changes is referred to as periodontitis. Called also oulitis and ulitis. [EU] Hepatitis: Inflammation of the liver. [EU] Heterozygote: An individual having different alleles at one or more loci in homologous chromosome segments. [NIH] Histamine:

1H-Imidazole-4-ethanamine. A depressor amine derived by

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enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Hydroxylation: Hydroxylate, to introduce hydroxyl into (a compound or radical) usually by replacement of hydrogen. [EU] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hypertension: Persistently high arterial blood pressure. Various criteria for its threshold have been suggested, ranging from 140 mm. Hg systolic and 90 mm. Hg diastolic to as high as 200 mm. Hg systolic and 110 mm. Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). [EU] Hyperthyroidism: 1. excessive functional activity of the thyroid gland. 2. the abnormal condition resulting from hyperthyroidism marked by increased metabolic rate, enlargement of the thyroid gland, rapid heart rate, high blood pressure, and various secondary symptoms. [EU] Hypothyroidism: Deficiency of thyroid activity. In adults, it is most common in women and is characterized by decrease in basal metabolic rate, tiredness and lethargy, sensitivity to cold, and menstrual disturbances. If untreated, it progresses to full-blown myxoedema. In infants, severe hypothyroidism leads to cretinism. In juveniles, the manifestations are intermediate, with less severe mental and developmental retardation and only mild symptoms of the adult form. When due to pituitary deficiency of thyrotropin secretion it is called secondary hypothyroidism. [EU] Hypotonia: A condition of diminished tone of the skeletal muscles; diminished resistance of muscles to passive stretching. [EU] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulindependent diabetes mellitus. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH]

Iontophoresis: Therapeutic introduction of ions of soluble salts into tissues by means of electric current. In medical literature it is commonly used to indicate the process of increasing the penetration of drugs into surface tissues by the application of electric current. It has nothing to do with ion

Glossary 205

exchange, air ionization nor phonophoresis, none of which requires current. [NIH]

Isoleucine: An essential branched-chain amino acid found in many proteins. It is an isomer of leucine. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels. [NIH] Jaundice: A clinical manifestation of hyperbilirubinemia, consisting of deposition of bile pigments in the skin, resulting in a yellowish staining of the skin and mucous membranes. [NIH] Lesion: Any pathological or traumatic discontinuity of tissue or loss of function of a part. [EU] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Mammary: Pertaining to the mamma, or breast. [EU] Mammography: Radiographic examination of the breast. [NIH] Membrane: A thin layer of tissue which covers a surface, lines a cavity or divides a space or organ. [EU] Metabolite: process. [EU]

Any substance produced by metabolism or by a metabolic

Microorganism: A microscopic organism; those of medical interest include bacteria, viruses, fungi and protozoa. [EU] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Myeloma: A tumour composed of cells of the type normally found in the bone marrow. [EU] Neonatal: Pertaining to the first four weeks after birth. [EU] Neural: 1. pertaining to a nerve or to the nerves. 2. situated in the region of the spinal axis, as the neutral arch. [EU] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite

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or inhibit the target cell. Among the many substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nifedipine: A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. The use of nifedipine as a tocolytic is being investigated. [NIH] Overdose: 1. to administer an excessive dose. 2. an excessive dose. [EU] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU] Parathyroid: 1. situated beside the thyroid gland. 2. one of the parathyroid glands. 3. a sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Pathologic: 1. indicative of or caused by a morbid condition. 2. pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Perinatal: Pertaining to or occurring in the period shortly before and after birth; variously defined as beginning with completion of the twentieth to twenty-eighth week of gestation and ending 7 to 28 days after birth. [EU] Peroxidase: A hemeprotein from leukocytes. Deficiency of this enzyme leads to a hereditary disorder coupled with disseminated moniliasis. It catalyzes the conversion of a donor and peroxide to an oxidized donor and water. EC 1.11.1.7. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of YEASTS. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phenytoin: An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of

Glossary 207

therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Porphyria: A pathological state in man and some lower animals that is often due to genetic factors, is characterized by abnormalities of porphyrin metabolism, and results in the excretion of large quantities of porphyrins in the urine and in extreme sensitivity to light. [EU] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Preclinical: Before a disease becomes clinically recognizable. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Progeria: An abnormal congenital condition characterized by premature aging in children, where all the changes of cell senescence occur. It is manifested by premature greying, hair loss, hearing loss, cataracts, arthritis,osteoporosis, diabetes mellitus, atrophy of subcutaneous fat, skeletal hypoplasia, and accelerated atherosclerosis. Many affected individuals develop malignant tumors, especially sarcomas. [NIH] Prostaglandins: A group of compounds derived from unsaturated 20carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH]

Proteus: A genus of gram-negative, facultatively anaerobic, rod-shaped bacteria that occurs in the intestines of humans and a wide variety of animals, as well as in manure, soil, and polluted waters. Its species are pathogenic, causing urinary tract infections and are also considered secondary invaders, causing septic lesions at other sites of the body. [NIH]

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Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychopathology: The study of significant causes and processes in the development of mental illness. [NIH] Receptor: 1. a molecular structure within a cell or on the surface characterized by (1) selective binding of a specific substance and (2) a specific physiologic effect that accompanies the binding, e.g., cell-surface receptors for peptide hormones, neurotransmitters, antigens, complement fragments, and immunoglobulins and cytoplasmic receptors for steroid hormones. 2. a sensory nerve terminal that responds to stimuli of various kinds. [EU] Recombinant: 1. a cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Registries: The systems and processes involved in the establishment, support, management, and operation of registers, e.g., disease registers. [NIH] Riboflavin: Nutritional factor found in milk, eggs, malted barley, liver, kidney, heart, and leafy vegetables. The richest natural source is yeast. It occurs in the free form only in the retina of the eye, in whey, and in urine; its principal forms in tissues and cells are as FMN and FAD. [NIH] Schizophrenia: A severe emotional disorder of psychotic depth characteristically marked by a retreat from reality with delusion formation, hallucinations, emotional disharmony, and regressive behavior. [NIH] Sclerosis: A induration, or hardening; especially hardening of a part from inflammation and in diseases of the interstitial substance. The term is used chiefly for such a hardening of the nervous system due to hyperplasia of the connective tissue or to designate hardening of the blood vessels. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder." [NIH] Selenium: An element with the atomic symbol Se, atomic number 34, and atomic weight 78.96. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. [NIH] Serum: The clear portion of any body fluid; the clear fluid moistening serous membranes. 2. blood serum; the clear liquid that separates from blood on clotting. 3. immune serum; blood serum from an immunized animal used for passive immunization; an antiserum; antitoxin, or antivenin. [EU]

Glossary 209

Somatic: 1. pertaining to or characteristic of the soma or body. 2. pertaining to the body wall in contrast to the viscera. [EU] Spasticity: A state of hypertonicity, or increase over the normal tone of a muscle, with heightened deep tendon reflexes. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones, bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Sulfites: Inorganic salts of sulfurous acid. [NIH] Tardive: Marked by lateness, late; said of a disease in which the characteristic lesion is late in appearing. [EU] Tartrazine: An anionic, hydrophilic azo dye with an orange-yellow color used in fabrics, foods and cosmetics, and as a biological stain. [NIH] Thermoregulation: Heat regulation. [EU] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH]

Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Toxin: A poison; frequently used to refer specifically to a protein produced by some higher plants, certain animals, and pathogenic bacteria, which is highly toxic for other living organisms. Such substances are differentiated from the simple chemical poisons and the vegetable alkaloids by their high molecular weight and antigenicity. [EU] Transplantation: The grafting of tissues taken from the patient's own body or from another. [EU] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It

210 Phenylketonuria

promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

General Dictionaries and Glossaries While the above glossary is essentially complete, the dictionaries listed here cover virtually all aspects of medicine, from basic words and phrases to more advanced terms (sorted alphabetically by title; hyperlinks provide rankings, information and reviews at Amazon.com): ·

Dictionary of Medical Acronymns & Abbreviations by Stanley Jablonski (Editor), Paperback, 4th edition (2001), Lippincott Williams & Wilkins Publishers, ISBN: 1560534605, http://www.amazon.com/exec/obidos/ASIN/1560534605/icongroupinterna

·

Dictionary of Medical Terms : For the Nonmedical Person (Dictionary of Medical Terms for the Nonmedical Person, Ed 4) by Mikel A. Rothenberg, M.D, et al, Paperback - 544 pages, 4th edition (2000), Barrons Educational Series, ISBN: 0764112015, http://www.amazon.com/exec/obidos/ASIN/0764112015/icongroupinterna

·

A Dictionary of the History of Medicine by A. Sebastian, CD-Rom edition (2001), CRC Press-Parthenon Publishers, ISBN: 185070368X, http://www.amazon.com/exec/obidos/ASIN/185070368X/icongroupinterna

·

Dorland's Illustrated Medical Dictionary (Standard Version) by Dorland, et al, Hardcover - 2088 pages, 29th edition (2000), W B Saunders Co, ISBN: 0721662544, http://www.amazon.com/exec/obidos/ASIN/0721662544/icongroupinterna

·

Dorland's Electronic Medical Dictionary by Dorland, et al, Software, 29th Book & CD-Rom edition (2000), Harcourt Health Sciences, ISBN: 0721694934, http://www.amazon.com/exec/obidos/ASIN/0721694934/icongroupinterna

·

Dorland's Pocket Medical Dictionary (Dorland's Pocket Medical Dictionary, 26th Ed) Hardcover - 912 pages, 26th edition (2001), W B Saunders Co, ISBN: 0721682812, http://www.amazon.com/exec/obidos/ASIN/0721682812/icongroupinterna /103-4193558-7304618

·

Melloni's Illustrated Medical Dictionary (Melloni's Illustrated Medical Dictionary, 4th Ed) by Melloni, Hardcover, 4th edition (2001), CRC PressParthenon Publishers, ISBN: 85070094X, http://www.amazon.com/exec/obidos/ASIN/85070094X/icongroupinterna

Glossary 211

·

Stedman's Electronic Medical Dictionary Version 5.0 (CD-ROM for Windows and Macintosh, Individual) by Stedmans, CD-ROM edition (2000), Lippincott Williams & Wilkins Publishers, ISBN: 0781726328, http://www.amazon.com/exec/obidos/ASIN/0781726328/icongroupinterna

·

Stedman's Medical Dictionary by Thomas Lathrop Stedman, Hardcover 2098 pages, 27th edition (2000), Lippincott, Williams & Wilkins, ISBN: 068340007X, http://www.amazon.com/exec/obidos/ASIN/068340007X/icongroupinterna

·

Tabers Cyclopedic Medical Dictionary (Thumb Index) by Donald Venes (Editor), et al, Hardcover - 2439 pages, 19th edition (2001), F A Davis Co, ISBN: 0803606540, http://www.amazon.com/exec/obidos/ASIN/0803606540/icongroupinterna

212 Phenylketonuria

INDEX A Acrodermatitis........................................90 Adolescence ..........17, 21, 34, 35, 59, 191 Adverse .............................11, 19, 99, 197 Aetiology..............................................143 Alleles ......................................13, 35, 193 Ammonia .........................................68, 71 Anemia ..........................................59, 119 Anorexia ................................................97 Anticonvulsant .........................93, 99, 196 Aromatic ............................35, 63, 64, 196 Assay.......................................65, 66, 189 B Benign .............................................44, 61 Biochemical .................13, 34, 69, 70, 191 Biosynthesis ........................................142 Bleomycin ................................90, 98, 192 C Capillary.................................................66 Capsules..............................................159 Carbohydrate.................................97, 158 Cardiovascular.................56, 67, 153, 195 Cerebrovascular ....................................66 Cervical..................................................59 Cholecystitis ..........................................92 Cholesterol ......67, 95, 100, 156, 158, 199 Chronic .......30, 35, 67, 85, 90, 95, 97, 98, 179, 192, 193 Cirrhosis ................................................91 Colorectal ..............................................95 Conception ................................19, 20, 22 Contamination .......................................92 Cookery .................................................86 Coronary................................................66 Criterion .................................................58 D Degenerative .......................................157 Diarrhea...............................................156 Dystrophy ..............................................90 E Eczema..................................................10 Electrophoresis......................................66 Enzyme.10, 12, 35, 38, 42, 43, 44, 62, 63, 64, 65, 68, 70, 75, 76, 101, 104, 162, 193, 196 Epidemiological .....................................59 Exogenous.........................34, 68, 74, 193 F Facial .....................................................90 Fibrosis ......................92, 97, 98, 164, 192 Fissure...................................................97

G Gastrointestinal .. 59, 74, 85, 92, 153, 193, 195 Genotype .......................... 13, 23, 35, 196 Gingivitis ............................................... 97 H Hepatitis ................................................ 91 Histamine .............................................. 92 Homogeneous ...................................... 65 Hydroxylation ........................................ 65 Hyperlipidemia ...................................... 68 Hypertension....................... 56, 58, 59, 95 Hyperthyroidism ...................... 96, 99, 194 Hypothyroidism ........... 58, 74, 84, 96, 194 Hypotonia.............................................. 39 I Immunization ................................ 76, 198 Individuality ........................................... 13 Ingestion ............................................. 159 Insulin.......................... 68, 74, 85, 96, 194 Iontophoresis ...................................... 144 Isoleucine................................ 78, 79, 144 J Jaundice................................................ 39 L Lesion ................................................. 199 M Mammary .............................................. 59 Membrane............................. 99, 143, 197 Mentors ................................................. 67 Metabolite ........................................... 159 Microorganism ...................................... 92 Molecular ... 13, 69, 75, 76, 112, 116, 118, 144, 198, 199 Mutagenesis ............................. 64, 65, 70 Myeloma ............................................... 90 N Neonatal.............................. 14, 25, 62, 90 Neural ....................................... 25, 26, 84 Neurology............................................ 145 Neurotransmitter 14, 35, 69, 99, 100, 142, 194, 196, 199 Niacin .................................................. 157 Nifedipine ................................ 97, 99, 196 O Overdose ............................................ 157 Oxidation......................................... 60, 65 P Parathyroid.............................. 96, 99, 196 Pathologic ............................... 68, 74, 192 Perinatal................................................ 59

Index 213

Peroxidase...........................................146 Phenotype .........................13, 35, 44, 196 Phenytoin...............................................97 Polymorphic.........................................162 Porphyria .........................................90, 91 Postnatal................................................65 Postprandial.........................................146 Potassium............................................158 Preclinical ..............................................30 Prenatal .................45, 57, 63, 84, 85, 162 Prevalence.....................11, 12, 13, 33, 60 Progeria .................................................90 Progressive..............39, 42, 43, 44, 80, 90 Prostate .................................................95 Proteins ...........80, 81, 156, 158, 195, 199 Proteus ..................................................92 Psychology ............................................67 Psychopathology ...................................18 R Recombinant ...................................68, 71 Registries...............................................41 Respiratory ............................................96 Rheumatoid ...........................................96 Riboflavin.............................................156 S Schizophrenia......................................162

Sclerosis ............................................. 119 Seizures ... 10, 36, 38, 40, 44, 93, 99, 196, 198 Selenium ............. 141, 142, 146, 147, 158 Serum ........... 62, 65, 68, 76, 84, 145, 198 Skeletal ................... 51, 68, 100, 194, 197 Somatic ................................... 25, 34, 191 Steroid........................................... 75, 198 Substrate............................... 65, 100, 199 Sulfites .................................................. 92 Surgical ........................................... 49, 85 T Tartrazine.............................................. 92 Thermoregulation................................ 156 Threonine........................................ 79, 80 Thyroxine ............................................ 158 Toxic ........... 13, 64, 68, 76, 157, 198, 199 Toxicity.................................................. 62 Toxin ..................................................... 36 Transplantation ..................................... 91 Tryptophan............................................ 63 Tyrosine ... 14, 24, 43, 64, 65, 71, 72, 141, 142, 145, 146, 148, 161 V Valine ...................................... 78, 79, 144

214 Phenylketonuria