Mark L. Batshaw, M.D. Nancy J. Roizen, M.D. Louis Pellegrino, M.D. Children with Disabilities 8th EDITION --- PAUL H BROOKES PUBLISHING C? Paul H. Brookes Publishing Co. Post Office Box 10624 Baltimore, Maryland 21285-0624 USA www.brookespublishing.com Copyright © 2019 by Paul H. Brookes Publishing Co., Inc. All rights reserved. Previous edition copyright © 2013. “Paul H. Brookes Publishing Co.” is a registered trademark of Sheridan Books, Inc., Chelsea, Michigan. Illustrations, as listed, copyright © 2013 by Mark L. Batshaw. All rights reserved. Figures 1.1, 1.2, 1.4–1.12, 1.14, 3.3, 5.3, 5.4, 5.6, 6.4, 6.6, 7.1, 7.2, 7.4, 7.5, 7.6, 7.8, 8.2a, 8.2c, 8.3–8.6, 8.9–8.11, 12.1, 12.4, 13.1, 15.1, 16.1, 16.2, 21.6 (drawings only), 21.7, 21.12, 21.15, 21.17, 21.18, 22.2–22.4, 25.1–25.3, 25.6, 29.1, 29.3, 29.4, 29.6, 29.9, 29.10, 32.3, and 35.1. Illustrations, as listed, copyright © Lynn Reynolds. All rights reserved. Figures 3.4, 3.7, 9.1, 25.5, 29.5, 29.8, and 29.11. Illustrations, as listed, copyright © by Catherine Twomey. All rights reserved. Figures 3.2, 6.1, 6.2, 7.3, 7.7, and 32.2. Appendix C, Commonly Used Medications, which appears in the back matter and in the book’s online materials, provides information about numerous drugs frequently used to treat children with disabilities. This appendix is in no way meant to substitute for a physician’s advice or expert opinion; readers should consult a medical practitioner if they are interested in more information. The publisher and the authors have made every effort to ensure that all of the information and instructions given in this book are accurate and safe, but they cannot accept liability for any resulting injury, damage, or loss to either person or property, whether direct or consequential and however it occurs. Medical advice should only be provided under the direction of a qualified health care professional. The vignettes presented in this book are composite accounts that do not represent the lives or experiences of specific individuals, and no Library of Congress Cataloging-in-Publication Data Library of Congress Cataloging-in-Publication Data Names: Batshaw, Mark L., 1945- editor. | Roizen, Nancy J., editor. | Pellegrino, Louis, editor. Title: Children with disabilities / edited by Mark L. Batshaw, M.D., Nancy J. Roizen, M.D., and Louis Pellegrino, M.D. Description: Eighth edition. | Baltimore : Paul H. Brookes Publishing Co., [2019] | Includes bibliographical references and index. Identifiers: LCCN 2018048552 (print) | LCCN 2018059190 (ebook) | ISBN 9781681253213 (epub) | ISBN 9781681253220 (pdf) | ISBN 9781681253206 (hardcover) Subjects: LCSH: Developmental disabilities. | Developmentally disabled children—Care. | Children with disabilities—Care. Classification: LCC RJ135 (ebook) | LCC RJ135 .B38 2019 (print) | DDC 618.92/8588—dc23 implications should be inferred. In all instances, names and identifying details have been changed to protect confidentiality. Purchasers of Children with Disabilities, Eighth Edition, are granted permission to download, print, and photocopy the Online Companion Materials for educational purposes. In addition, purchasers are granted permission to download Appendices A–D and the letters from Andrew Batshaw for research and professional purposes. PowerPoint presentations, illustrations, extended case studies, a test bank, and sample syllabi are also available for faculty. All Online Companion Materials are available at http://downloads.brookespublishing. com/children-with-disabilities-8e. This content may not be reproduced to generate revenue for any program or individual. Photocopies may only be made from the original content. Unauthorized use beyond this privilege may be prosecutable under federal law. You will see the LC record available at https://lccn.loc.gov/2018048552 British Library Cataloguing in Publication data are available from the British Library. 2023 2022 2021 2020 2019 Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- Contents About the Online Companion Materials. xiii About the Online Companion Materials for Faculty. xv About the Editors. xvii Contributors. xix A Personal Note to the Reader. xxv Preface. xxvii Acknowledgments. xxx Letters from Andrew Batshaw. xxxi # I As Life Begins 1 The Genetics Underlying Developmental Disabilities Mark L. Batshaw, Eyby Leon, and Monisha S. Kisling 3 Genetic Disorders 4 Chromosomes 4 Cell Division and Its Disorders 5 Genes and Their Disorders 8 Epigenetics 17 Genetic Testing 17 Environmental Influences on Heredity 19 Genetic Therapies 20 2 Environmental Exposures Shruti N. Tewar 23 A Historical Perspective 24 The Developing Brain and Toxic Exposure 24 Timing of Vulnerability to Environmental Toxins 25 Specific Neurotoxicants 25 --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ How Is Newborn Screening Done? ..... 58 What Should Be Done When a Child Has a Positive Newborn Screen? ..... 59 What Happens to Children with Confirmed Disease? ..... 59 What Is the Risk of Developmental Disability in Children with Confirmed Disease? ..... 60 How Can Screening Fail? ..... 60 The Past, Present, and Future of Newborn Screening ..... 61 5 Premature and Small-for-Dates Infants Khodayar Rais-Bahrami and Billie Lou Short ..... 65 Definitions of Prematurity and Low Birth Weight ..... 66 Incidence of Preterm Births ..... 67 Causes of Premature Birth ..... 67 Complications of Prematurity ..... 69 Medical and Developmental Care of Low Birth Weight Infants ..... 75 Survival of Low Birth Weight Infants ..... 76 Care After Discharge from the Hospital ..... 76 Early Intervention Programs ..... 77 Ne --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Contents vii 10 Nutrition Lina Diaz-Calderon, Virginia Gebus, and Laurie S. Conklin. 159 Typical Growth During Childhood. 160 Nutritional Guidelines. 161 Nutritional Issues in Children with Developmental Disabilities. 161 Medical Nutritional Therapy. 165 Special Nutritional Concerns in Children with Disabilities. 167 Nutrition within Complementary Health Approaches. 170 III Developmental Assessment 11 Child Development Louis Pellegrino. 177 Defining Child Development. 178 Theoretical Perspectives on Development. 179 Developmental Milestones. 181 Development and Adaptation: Trends and Key Milestones. 183 Distinguishing Typical and Atypical Development. 194 12 Diagnosing Developmental Disabilities Scott M. Myers. 199 Developmental Principles. 200 Atypical Patterns of Development. 201 Diagnostic --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ 16 Inborn Errors of Metabolism *Nicholas Ah Mew, Erin MacLeod, and Mark L. Batshaw* ..... 285 Types of Inborn Errors of Metabolism ..... 286 Mechanism of Brain Damage ..... 291 Associated Disabilities ..... 291 Diagnostic Testing ..... 291 Newborn Screening ..... 292 Therapeutic Approaches ..... 292 Outcome ..... 297 17 Speech and Language Disorders *Barbara L. Ekelman and Barbara A. Lewis* ..... 301 Definitions, Descriptions, and Classifications ..... 302 Prevalence and Epidemiology ..... 307 Etiology ..... 309 Assessment and Diagnosis ..... 311 Treatment, Management, and Intervention ..... 312 Outcomes ..... 313 18 Autism Spectrum Disorder *Deborah Potvin and Allison B. Ratto --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Contents ix Assessment Procedures ..... 408 Intervention Strategies ..... 409 Outcome ..... 414 21 Cerebral Palsy Tara L. Johnson, Eric M. Chin, and Alexander H. Hoon ..... 423 What Is Cerebral Palsy? ..... 424 What Causes Cerebral Palsy? ..... 424 Epidemiology ..... 426 Risk Factors ..... 426 Diagnosis ..... 427 Subtypes of Cerebral Palsy ..... 434 Establishing the Etiology of Cerebral Palsy ..... 436 Associated Impairments in Cerebral Palsy ..... 436 Comprehensive Management for Individuals with Cerebral Palsy ..... 437 Advocacy and Awareness ..... 449 Future Directions ..... 449 22 Epilepsy Tesfaye Getaneh Zelleke, Devi Frances T. Dep x Contents 26 Deaf/Hard of Hearing Plus *Susan E. Wiley* ..... 541 Definitions, Descriptions, and Classifications ..... 542 Prevalence and Epidemiology ..... 542 Causes and Associations with Specific Developmental Disabilities ..... 545 Diagnosis and Clinical Manifestations ..... 546 Monitoring, Screening, and Evaluation ..... 549 Treatment, Management, and Interventions ..... 549 Outcomes ..... 549 27 Behavioral and Psychiatric Disorders *Adelaide S. Robb and Gabrielle Sky Cardwell* ..... 555 Prevalence of Psychiatric Disorders Among Children with Developmental Disabilities ..... 556 Causes of Psychiatric Disorders in Developmental Disabilities ..... 557 Psychiatric Disorders of Childhood and Adolescence ..... 558 Vulnerability ..... 567 Evaluation ..... 567 Treatment ..... 568 2 --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Components of Part C of IDEA: The Infants and Toddlers with Disabilities Program . . . 640 Outcomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ xii Contents Effects on the Child with a Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . --- Preface One of the first questions asked about a subsequent edition of a textbook is, “What’s new?” The challenge of determining what to revise, what to add, and, in some cases, what to delete is always significant in preparing a new edition in a field that is changing as rapidly as developmental disabilities. Since the publication of the seventh edition in 2013, advances in the fields of neuroscience and genetics have greatly enhanced our understanding of the brain and inheritance. This creates opportunities for treatments previously not thought possible for some children with developmental disabilities. Genomic sequencing is now used routinely (and sometimes recreationally), gene therapy is being used to correct birth defects, and the brain can be probed to correct birth defects, and the brain can be probed noninvasively by functional imaging techniques. The need to examine and explain this advanced knowledge and its significance for children with disabilities has necessitated an increase in the depth and breadth of the subjects covered in the book. Yet, although the book is now more expansive and has several new chapters, we have worked hard to ensure that it retains its clarity and cohesion. Its mission continues to be to provide the individual working with and caring for children with disabilities the necessary background to understand different disabilities and their treatments, thereby enabling affected children to reach their full potential. THE AUDIENCE THE AUDIENCE Since it was originally published, Children with Disabilities has been used by students in a wide range of disciplines as a medical textbook addressing the impact of disabilities on child development and function. It has also served as a professional reference for special educators, general educators, physical therapists, occupational therapists, speech-language pathologists, psychologists, child-life specialists, social workers, pediatric residents and medical students, psychiatrists, neurologists, pediatric nurses and nurse practitioners, advocates, and other practitioners who provide care for children with disabilities. Finally, as a family resource, parents, grand- One of the first questions asked about a subsequent edi-have used the book. They have found useful information of a textbook is, “What’s new?” The challenge of tion on the medical and rehabilitative aspects of care for cases, what to delete is always significant in preparing a new edition in a field that is changing as rapidly as a new edition in a field that is changing as rapidly as FEATURES FOR THE READER developmental disabilities. Since the publication of the seventh edition in 2013, advances in the fields of neuro-We have been told that the strengths of previous ediscience and genetics have greatly enhanced our under-tions of this book have been the accessible writing standing of the brain and inheritance. This creates style, the clear illustrations, and the up-to-date inforopportunities for treatments previously not thought mation and references. We have dedicated our efforts possible for some children with developmental disabil-to retaining these strengths and building on them with ities. Genomic sequencing is now used routinely (and the addition of new features to highlight the applicasometimes recreationally), gene therapy is being used tion of content to evidence-based practice. Some of the to correct birth defects, and the brain can be probed features you will find in the eighth edition include the following. The need to examine and explain this advanced • Learning goals: Each chapter begins with learning knowledge and its significance for children with disoutcomes to orient you to the key content of that abilities has necessitated an increase in the depth abilities has necessitated an increase in the depth particular chapter. and breadth of the subjects covered in the book. Yet, although the book is now more expansive and has sev-• Thought questions: Questions have been crafted to eral new chapters, we have worked hard to ensure that “prime” the reader for what he or she should be ational examples to help bring alive the conditions ground to understand different disabilities and their and issues discussed in the chapter. treatments, thereby enabling affected children to reach • Key terms: As key medical terms pertaining to a specific chapter are introduced in the text, they appear in boldface type at their first use; definitions for disabilities on child development and function. It has you to more easily understand and remember the also served as a professional reference for special educa-material you are reading. tors, general educators, physical therapists, occupational • Summary: Each chapter closes with a final section therapists, speech-language pathologists, psychologists, that in a bulleted list summarizes its key elements child-life specialists, social workers, pediatric residents and provides you with an abstract of the covered and medical students, psychiatrists, neurologists, pedi- xxvii --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ xxviii Preface and relevant, although classic research is often still relevant and included. • Interdisciplinary boxes: New to this edition, chapters include special boxes that summarize the role of specific disciplines relevant to the chapter’s content. This feature emphasizes the interprofessional nature of caring for children with developmental nature of caring for children with developmental disabilities. • Evidence-based practice boxes: This new feature acknowledges the importance of evidence-based practice by summarizing the results of current research relevant to the topic and providing a “takeaway message” so readers can apply the informa- away message” so readers can apply the information to practice. • Appendices: In addition to the Glossary, there are two other helpful appendices: 1) Syndromes and Inborn Errors of Metabolism, a mini-reference of pertinent information on inherited disorders causing developmental disabilities, and 2) Commonly Used Medications, to describe indications and side effects of medications often prescribed for children effects of medications often prescribed for children with disabilities. • Web site: We have created a web site specific for Children with Disabilities that has additional content, including the following: 1) a resource directory of a wide range of national organizations, federal agencies, information sources, self-advocacy and accessibility programs, and support groups that can provide assistance to families and professionals; 2) a bank of 250 test questions for instructors; and 3) study questions and extension activities for every chapter. This content will be continuously include review articles, reports of study findings, through educational, medical, and scientific advances CONTENT include review articles, reports of study findings, through educational, medical, and scientific advances research discoveries, and other key references that since 2013. can help you find additional information. We have Seven new chapters have been added, including can help you find additional information. We have Seven new chapters have been added, including tried to keep the majority of the references within the following. 5 years of the book’s publication so they are recent • Chapter 7: The Senses: The World We See, Hear, and and relevant, although classic research is often still and relevant, although classic research is often still Feel ters include special boxes that summarize the role • Chapter 28: Sleep Disorders of specific disciplines relevant to the chapter’s con- • Chapter 11: Child Development Interdisciplinary boxes: New to this edition, chap- of specific disciplines relevant to the chapter’s con- • Chapter 30: Interdisciplinary Education and Practice tent. This feature emphasizes the interprofessional nature of caring for children with developmental • Chapter 38: Pharmacological Therapy • Chapter 42: Racial and Ethnic Disparities Evidence-based practice boxes: This new feature The new chapters focus on recently gained knowledge acknowledges the importance of evidence-based that is transforming our understanding of the causes practice by summarizing the results of current organized to help guide readers through the breadth of content. Each part is detailed next. Appendices: In addition to the Glossary, there are Part I: The book starts with a section titled As Life two other helpful appendices: 1) Syndromes and Begins, which addresses what happens before, dur- Inborn Errors of Metabolism, a mini-reference of ing, and/or shortly after birth to cause a child to be pertinent information on inherited disorders caus-at increased risk for a developmental disability. The ing developmental disabilities, and 2) Commonly concepts and consequences of genetics, environmen- Used Medications, to describe indications and side tal influences, prenatal diagnosis, newborn screening, effects of medications often prescribed for children neonatal complication, and prematurity are explained. Used Medications, to describe indications and side tal influences, prenatal diagnosis, newborn screening, effects of medications often prescribed for children neonatal complication, and prematurity are explained. Part II: The next section of the book, The Child’s Body: Physiology, covers embryonic and fetal devel- Web site: We have created a web site specific for opment, the sensory systems, the brain and central Children with Disabilities that has additional content, nervous system, muscles, bones and nerves, and the including the following: 1) a resource directory of a gastrointestinal tract—how they develop and work, wide range of national organizations, federal agen- new topics that demand our attention. All chapters lepsy, acquired brain injury, and chronic diseases with have been substantially revised, and many have been related developmental disabilities. rewritten to include an expanded focus on the psy-Part V: The fifth section addresses Associated Dischosocial, rehabilitative, and educational interven-abilities, those disorders that occur more commonly in 2) a bank of 250 test questions for instructors; and ties, assessing physical disabilities, and neurocognitive study questions and extension activities for and behavioral assessment. every chapter. This content will be continuously Part IV: As its title implies, the fourth section, Developmental Disabilities, provides comprehensive descriptions of the major developmental disabilities and genetic syndromes that cause disabilities. This section includes chapters on intellectual disability, Down In developing this eighth edition, we have aimed for a syndrome and fragile x syndrome, inborn errors of balance between consistency with the text that many metabolism, speech and language disorders, autism of you have come to know so well and appreciate in spectrum disorder, attention-deficit/hyperactivity disits previous editions and innovation in exploring the order, specific learning disabilities, cerebral palsy, epinew topics that demand our attention. All chapters lepsy, acquired brain injury, and chronic diseases with --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Preface xxix include discussions on visual deficits, hearing impairment, behavioral/mental health issues, sleep disorders ment, behavioral/mental health issues, sleep disorders and feeding disorders. Part VI: The sixth section focuses on Interventions. It contains chapters on interdisciplinary care, early intervention and special education services, (re)habilitative services, oral health care, behavioral therapy, assistive technology, family assistance, medication, assistive technology, family assistance, medication, and complementary health approaches. Part VII: The final section is directed at Outcomes. This section concentrates on transition to adulthood, the effect of health care systems on outcomes, and health care disparities and their effect on outcomes in THE CONTRIBUTORS AND REVIEW PROCESS For contributors to this edition, we chose educators, physicians, dentists, psychologists, social workers, genetic counselors, occupational and physical therapists, speech-language pathologists, and other health care professionals who are experts in the areas they write about. Many are colleagues from Children’s National Medical Center in Washington, D.C. Each chapter in the book has undergone editing at Paul H. Brookes Publishing Co. to ensure consistency in style and accessibility of content. Once the initial drafts were completed, each chapter was sent for peer review by major clinical and academic leaders in the field and was revised according to their input. A FEW NOTES ABOUT TERMINOLOGY AND STYLE As is the case with any book of this scope, the edi- include discussions on visual deficits, hearing impair-particular words and the presentation style of informament, behavioral/mental health issues, sleep disorders tion. We would like to share with you some of the deci- sions we have made for this book. Part VI: The sixth section focuses on Interventions. • Categories of intellectual disability: This book uses It contains chapters on interdisciplinary care, early the American Psychiatric Association’s categories intervention and special education services, (re)habiliaccording to the term intellectual disability (i.e., mild, tative services, oral health care, behavioral therapy, moderate, severe, profound) when discussing mediassistive technology, family assistance, medication, cal diagnosis and treatment, and uses the categories that the American Association on Intellectual and Part VII: The final section is directed at Outcomes. Developmental Disabilities (formerly the American This section concentrates on transition to adulthood, Association on Mental Retardation) established in the effect of health care systems on outcomes, and 1992 (i.e., requiring limited, intermittent, extensive, health care disparities and their effect on outcomes in or pervasive support) when discussing educational and other interventions, thus emphasizing the capabilities rather than the impairments of individ- capabilities rather than the impairments of individuals with intellectual disability. • “Typical” versus “normal”: Recognizing diversity and the fact that no one type of person or lifestyle For contributors to this edition, we chose educators, is inherently “normal,” we have chosen to refer to physicians, dentists, psychologists, social workers, the general population of children as “typical” or genetic counselors, occupational and physical thera- “typically developing,” meaning that they follow pists, speech-language pathologists, and other health “typically developing,” meaning that they follow pists, speech-language pathologists, and other health the natural continuum of development. care professionals who are experts in the areas they write about. Many are colleagues from Children’s • Person-first language: We have tried to preserve the National Medical Center in Washington, D.C. Each dignity and personhood of all individuals with chapter in the book has undergone editing at Paul H. disabilities by consistently using person-first lan- Brookes Publishing Co. to ensure consistency in style guage, speaking, for example, of “a child with cereand accessibility of content. Once the initial drafts were bral palsy,” instead of “a cerebral palsied child.” In completed, each chapter was sent for peer review by this way, we are able to emphasize the person, not major clinical and academic leaders in the field and was this way, we are able to emphasize the person, not major clinical and academic leaders in the field and was define him or her by the condition. As you read this eighth edition of Children with Disabilities, we hope you will find that the text continues to address the frequently asked question, “Why this child?” and to provide the medical background you need to care for children with developmental As is the case with any book of this scope, the edi- --- CHAPTER The Genetics Underlying 1 Developmental Disabilities Mark L. Batshaw, Eyby Leon, and Monisha S. Kisling Upon completion of this chapter, the reader will Upon completion of this chapter, the reader will ■■ Know about the human genome and its implication for the origins of ■■ Know about the human genome and its implication for the origins of developmental disabilities ■■ Be able to explain how errors in cell division can cause genetic syndromes ■■ Know about Mendelian inheritance ■■ Recognize the importance of mutations and genetic variation ■■ Understand the ways that genes can be affected by the environment in which ■■ Understand the ways that genes can be affected by the environment in which they reside, i.e., epigenetics ■■ Know about genetic testing for the origins of developmental disability Whether we have brown or blue eyes is determined by genes passed on to us from our parents. Other traits, such as height and weight, are affected by genes and by our environment both before and after birth. In a similar manner, genes alone or in combination with environmental factors can place children at increased risk for many developmental disorders, including birth defects such as meningomyelocoele (spina bifida). In the case of meningomyelocoele, a maternal nutritional deficiency of folic acid can markedly increase the risk of the genetic disorder. Disorders associated with developmental disabilities have a spectrum of genetic and environmental origins. Some disorders are purely genetic, such as Tay-Sachs disease (a progressive neurologic disorder) and result from a defect in a single gene, while others like Down syndrome (see Chap- Whether we have brown or blue eyes is determined by extra chromosome containing hundreds of genes exists. genes passed on to us from our parents. Other traits, Other developmental disorders result from purely such as height and weight, are affected by genes and environmental exposures, including prenatal viral by our environment both before and after birth. In a infections such as cytomegalovirus and teratogenic similar manner, genes alone or in combination with agents like alcohol and thalidomide (see Chapter 2). environmental factors can place children at increased There are also conditions in which genes are affected risk for many developmental disorders, including birth by their environment, leading to epigenetic disorders --- 4 Batshaw, Leon, and Kisling that manipulate or use an understanding of the child’s genome to improve an outcome. It is important to understand that while these disorders are individually rare, genetic alterations underlie almost half of developmental disabilities. Medical treatment is increasingly available for a number of these disorders, though often at great cost. ■ ■ ■ CASE STUDY Katy developed typically until she was 2 years old, when she started to have episodes of vomiting and lethargy after high-protein meals. Her parents became very concerned because their older son, Andrew, had died in infancy after an episode of lethargy and seizures was followed by coma, although no specific diagnosis had been made. After extensive testing by a genetic specialist, Katy was discovered to have a specific mutation or error in the gene that codes for ornithine transcarbamylase (OTC), an enzyme that prevents the accumulation of toxic ammonia in the body and brain. The OTC gene is located on the X chromosome; since girls have two X chromosomes, when one X has the mutation, there is a second normal copy to mitigate the defect. As a result, girls are less likely to be affected by X-linked disorders than boys, and, when affected, they generally have less severe symptoms. After Katy was diagnosed with OTC deficiency, her specialist tested DNA that was extracted before Andrew’s death and found that he too carried this mutation. Katy was placed on a low-protein diet and given a medicine to provide an alternate pathway to rid the body of ammonia, and she has done well. Now age 7, she appears to have a mild nonverbal learning disability resulting from her prior metabolic crises; if Katy had been left untreated, she would probably not be alive. Thought Questions: How often do we miss a genetic diagnosis as a cause of developmental disabilities? Could earlier diagnosis and left untreated, she would probably not be alive. she started to have episodes of vomiting and lethargy after high-protein meals. Her parents became very concerned because their older son, Andrew, had died in Figure 1.1. An idealized cell. The genes within chromosomes direct the creation of a product on the ribosomes. The product is then packaged in the Golgi infancy after an episode of lethargy and seizures was followed by coma, although no specific diagnosis had been made. After extensive testing by a genetic specialist, Katy was discovered to have a specific mutation or genes (units of heredity) in each chromosome. There error in the gene that codes for ornithine transcarbamyare 23 pairs of chromosomes and about 20,000 proteinlase (OTC), an enzyme that prevents the accumulation coding genes that collectively make up the human of toxic ammonia in the body and brain. The OTC gene genome. These genes are responsible for our physical is located on the X chromosome; since girls have two attributes and for the biological functioning of our bod- X chromosomes, when one X has the mutation, there is ies. Under the direction of the genes, the products that a second normal copy to mitigate the defect. As a result, are needed for the organism’s development and funcgirls are less likely to be affected by X-linked disorders tions, such as waste disposal and the release of energy, than boys, and, when affected, they generally have less are made in the cytoplasm. The nucleus contains the severe symptoms. After Katy was diagnosed with OTC blueprint for the organism’s growth and development, deficiency, her specialist tested DNA that was extracted and the cytoplasm manufactures the products needed before Andrew’s death and found that he too carried this (Figure 1.1). The red blood cell differs insofar as it does CHROMOSOMES not have a nucleus. The nucleus houses chromosomes, structures that contain the genetic code—DNA (deoxy-Each organism has a fixed number of chromosomes are divided into two compartments: a central, enclosed of genetic defects. core—the nucleus—and an outer area—the cytoplasm (Figure 1.1). The red blood cell differs insofar as it does deficiency, her specialist tested DNA that was extracted and the cytoplasm manufactures the products needed before Andrew’s death and found that he too carried this to complete the task. mutation. Katy was placed on a low-protein diet and When there is a defect within this system, the given a medicine to provide an alternate pathway to rid result may be a genetic disorder, often causing developthe body of ammonia, and she has done well. Now age 7, mental disabilities. These disorders take many forms. she appears to have a mild nonverbal learning disability They include the addition of an entire chromosome in resulting from her prior metabolic crises; if Katy had been each cell (e.g., Down syndrome), the loss of an entire chromosome in each cell (e.g., Turner syndrome), and the loss or deletion of a significant portion of a chromosome (e.g., Cri-du-chat syndrome). There can also be a microdeletion of a number of closely spaced or How often do we miss a genetic diagnosis as a cause contiguous genes within a chromosome (e.g., chromoof developmental disabilities? Could earlier diagnosis and some 22q11.2 deletion syndrome, also called velocardiofacial syndrome [VCFS]). Microdeletions may have varied expression depending on stochastic (randomly determined) and environmental processes, as well as on genetic effects, with these factors potentially acting The human body is composed of approximately 100 tril-alone or in combination (Bertini et al., 2017). Finally, lion cells. There are many cell types: nerve cells, muscle there can be a defect within a single gene (e.g., phenylcells, white blood cells, liver cells and skin cells, to name ketonuria) or altered expression of the gene (e.g., Rett a few. All cells, with the exception of the red blood cell, syndrome). This chapter discusses each of these types --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ there are normally 46 chromosomes. Each chromosome contains many genes, but some chromosomes have more (e.g., 500–800 gene loci in chromosomes 1, 19, and X) and others have fewer (50–120 in chromosomes 13, 18, 21, and Y). The 46 chromosomes are organized into 23 pairs. Typically, one chromosome in each pair comes from the mother and the other from the father. Egg and sperm cells, unlike all other human cells, each contains only 23 chromosomes. During conception, these germ cells (i.e., sperm and eggs) fuse to produce a fertilized egg with the full complement of produce a fertilized egg with the full complement of 46 chromosomes. Among the 23 pairs of chromosomes, 22 are termed autosomes. The 23rd pair consists of the X and Y chromosomes and are called the sex chromosomes. The Y chromosome, which is involved in male sex determination and development, is one-third to one-half the size of the X chromosome, has a different shape, and has far fewer genes. Two X chromosomes determine the child to be female; an X and a Y chromosome deter- mine the child to be male. CELL DIVISION AND ITS DISORDERS Cells have the ability to divide into daughter cells that contain genetic information that is identical to the information from the parent cell. The prenatal development of a human being is accomplished through cell division, differentiation into different cell types, and movement of cells to different locations in the body. There are two kinds of cell division: mitosis and meiosis. In mitosis, or nonreductive division, 2 daughter cells, each containing 46 chromosomes, are formed from 1 parent cell. In meiosis, or reductive division, 4 daughter cells, each containing only 23 chromosomes, are formed from 1 parent cell. Although mitosis occurs in all cells, meiosis takes place only in the germ cells. body’s capacity to recover after medical events, such as strokes, or from traumatic injuries. One of the primary differences between mitosis and meiosis can be seen during the first of the two meiotic divisions. During this cell division, the corresponding chromosomes line up beside each other in pairs (e.g., both copies of chromosome 1 line up there are normally 46 chromosomes. Each chromo-and may “cross over,” exchanging genetic material. some contains many genes, but some chromosomes This adds variability. Although this crossing over (or have more (e.g., 500–800 gene loci in chromosomes recombination) of the chromosomes may result in dis- 1, 19, and X) and others have fewer (50–120 in chro-orders (e.g., deletions), it also allows for the mutual mosomes 13, 18, 21, and Y). The 46 chromosomes are transfer of genetic information, reducing the chance organized into 23 pairs. Typically, one chromosome in that siblings end up as exact copies (clones) of each each pair comes from the mother and the other from other. Some of the variability among siblings can also the father. Egg and sperm cells, unlike all other human be attributed to the random assortment of maternal cells, each contains only 23 chromosomes. During con-and paternal chromosomes during the first of the two cells, each contains only 23 chromosomes. During con-and paternal chromosomes during the first of the two ception, these germ cells (i.e., sperm and eggs) fuse to meiotic divisions. produce a fertilized egg with the full complement of Throughout the life span of the male, meiosis of the immature sperm produces spermatocytes with Among the 23 pairs of chromosomes, 22 are termed 23 chromosomes each. These cells will lose most of autosomes. The 23rd pair consists of the X and Y chro-their cytoplasm, sprout tails, and become mature mosomes and are called the sex chromosomes. The sperm. This process is termed spermatogenesis. In Y chromosome, which is involved in male sex deter-the female, meiosis forms oocytes that will ultimately mination and development, is one-third to one-half the become mature eggs in a process called oogenesis. By size of the X chromosome, has a different shape, and the time a girl is born, her body has produced all of the has far fewer genes. Two X chromosomes determine approximately 2 million eggs she will ever have. size of the X chromosome, has a different shape, and the time a girl is born, her body has produced all of the has far fewer genes. Two X chromosomes determine approximately 2 million eggs she will ever have. the child to be female; an X and a Y chromosome deter-A number of events that adversely affect a child’s development can occur during meiosis. When chromosomes divide unequally, a process known as nondisjunction occurs; as a result, 1 daughter egg or sperm contains 24 chromosomes and the other 22 Cells have the ability to divide into daughter cells that chromosomes. Meiotic nondisjunction, particularly in contain genetic information that is identical to the oogenesis, is the most common mutational mechanism information from the parent cell. The prenatal develop-in humans responsible for chromosomally atypical ment of a human being is accomplished through cell fetuses. Usually, these cells do not survive, but occadivision, differentiation into different cell types, and sionally they do and can lead to the child being born movement of cells to different locations in the body. with too many chromosomes (e.g., Down syndrome) There are two kinds of cell division: mitosis and mei-or too few (e.g., Turner syndrome). Notably, the most osis. In mitosis, or nonreductive division, 2 daughter commonly found trisomy in miscarriages is trisomy cells, each containing 46 chromosomes, are formed 16, and embryos with trisomy 16 are never carried from 1 parent cell. In meiosis, or reductive division, 4 to term (Nussbaum, McInnes, & Willard, 2016). The daughter cells, each containing only 23 chromosomes, chromosome 16 contains so many genes important for are formed from 1 parent cell. Although mitosis occurs normal development that its disruption is incompatible with life. Conversely, trisomies 13, 18, and 21 are The ability of cells to continue to undergo mito-the most commonly observed full trisomies at birth sis throughout the life span is essential for proper (Mai et al., 2013). However, even in these conditions, bodily functioning. Cells divide at different rates, how-the vast majority of embryos with the defect do not Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- 6 Batshaw, Leon, and Kisling Chromosomal Gain: Down Syndrome Chromosomal Gain: Down Syndrome The most frequent chromosomal abnormality is unequal division of non-sex chromosomes, and the most common clinical consequence is trisomy 21, or Down syndrome (Nussbaum, McInnes, & Willard, 2016; also see Chapter 15). Nondisjunction can occur during either mitosis or meiosis but is more common in meiosis (Figure 1.2). When nondisjunction occurs during the first meiotic division, both copies of chromosome 21 end up in one cell. Instead of an equal distribution of chromosomes among cells (23 each), 1 daughter cell receives 24 chromosomes and the other receives only 22. The cell containing 22 chromosomes is unable to survive. However, the egg (or sperm) with 24  chromosomes occasionally can survive. After fertilization with a sperm (or egg) containing 23 chromosomes, the resulting embryo contains 3 copies of chromosome 21, or trisomy 21. The child will be born with 47 rather than 46 chromosomes in each cell and with 47 rather than 46 chromosomes in each cell and will thus have Down syndrome (Figure 1.3). The majority of individuals with Down syndrome (approximately 95%) have trisomy 21. This trisomy results from nondisjunction during meiosis in oogenesis in 90% of the cases and from nondisjunction during spermatogenesis in 10% (Nussbaum, McInnes, & Willard, 2016). This disparity is partially due to the increased rate of autosomal nondisjunction in egg production, but also to the lack of viability of sperm with an extra chromosome 21. Another 3%–4% of individuals is unable to survive. However, the egg (or sperm) with chromosomes occasionally can survive. After fer- Figure 1.3. Karyotype of a boy with Down syndrome (47, XY). Note that the mosomes, the resulting embryo contains 3 copies of chromosome 21, or trisomy 21. The child will be born with 47 rather than 46 chromosomes in each cell and acquire Down syndrome as a result of translocation (discussed later) and 1%–2% acquire it from mosaicism The majority of individuals with Down syndrome (some cells being affected and others not; this is also (approximately 95%) have trisomy 21. This trisomy results from nondisjunction during meiosis in oogenesis in 90% of the cases and from nondisjunction during spermatogenesis in 10% (Nussbaum, McInnes, & Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ The Genetics Underlying Developmental Disabilities to be miscarried (Hook & Warburton, 2014). Females with Turner syndrome (1 in every 5,000 live births) have a single X chromosome and no second X or Y chromosome, for a total of 45, rather than 46, chromosomes. In contrast to Down syndrome, 80% of individuals with monosomy X conditions are affected by meiotic errors in sperm production; these children usually receive an X chromosome from their mothers but no sex chromo- X chromosome from their mothers but no sex chromosome from their fathers. Girls with Turner syndrome typically have short stature, a webbed neck, a broad “shield-like” chest with widely spaced nipples, and nonfunctional ovaries. Twenty percent have obstruction of the left side of the heart, most commonly caused by a coarctation of the aorta. Unlike children with Down syndrome, most girls with Turner syndrome develop typically. They do, however, have visual–perceptual impairments that predispose them to develop nonverbal learning disabilities (Table 1.1; Hong & Reiss, 2014). Human growth hormone injections have been effective in increasing height in girls with Turner syndrome, and estrogen supplementation can lead to the emergence of secondary sexual characteristics; however, these girls remain Mosaicism In mosaicism, cells in the same individual have different genetic makeups (Nussbaum, McInnes, & Willard, 2016). For example, a child with the mosaic form of Down syndrome may have trisomy 21 in skin cells but not in blood cells. or the individual may have trisomy 21 in some, but not all, brain cells. Children with mosaicism often appear as though they have a particular condition (in this example, Down syndrome); however, the physical/organ and cognitive impairments may be less severe. Usually mosaicism occurs when some cells in a trisomy conception lose the extra chromosome via nondisjunction during mitosis. Mosaicism also can occur if some cells lose a chromosome after a normal conception (e.g., some cells lose an X chromosome in mosaic Turner syndrome). Mosaicism is present in only 5%–10% of all children with chromosomal abnormalities. Mosaicism Translocations to be miscarried (Hook & Warburton, 2014). Females Translocations with Turner syndrome (1 in every 5,000 live births) have A relatively common dysfunction in cell division, a single X chromosome and no second X or Y chromotranslocation can occur during mitosis and meiosome, for a total of 45, rather than 46, chromosomes. In sis when the chromosomes break and then exchange contrast to Down syndrome, 80% of individuals with parts with other chromosomes. Translocation involves monosomy X conditions are affected by meiotic errors the transfer of a portion of one chromosome to a comin sperm production; these children usually receive an pletely different chromosome. For example, a portion X chromosome from their mothers but no sex chromoof chromosome 21 might attach itself to chromosome 14 ( Figure 1.4). If this occurs during meiosis, 1 daughter Girls with Turner syndrome typically have short cell will then have 23 chromosomes but will have both a stature, a webbed neck, a broad “shield-like” chest chromosome 21 and a chromosome 14/21 translocation. with widely spaced nipples, and nonfunctional ova- Fertilization of this egg, by a sperm with a cell containries. Twenty percent have obstruction of the left side of ing the normal complement of 23 chromosomes, will the heart, most commonly caused by a coarctation of result in a child with 46 chromosomes. This includes the aorta. Unlike children with Down syndrome, most two copies of chromosome 21, one chromosome 14/21, girls with Turner syndrome develop typically. They and one chromosome 14. This child will have Down do, however, have visual–perceptual impairments that syndrome because of the functional trisomy 21 caused predispose them to develop nonverbal learning dis- Behavior abilities (Table 1.1; Hong & Reiss, 2014). Human growth hormone injections have been effective in increasing height in girls with Turner syndrome, and estrogen Deletions supplementation can lead to the emergence of secondary sexual characteristics; however, these girls remain Another somewhat common dysfunction in cell division is deletion. Here, part, but not all, of a chromosome is lost. Chromosomal deletions occur in two forms: visible deletions and microdeletions. Those that are large enough to be seen through the microscope are called visible deletions. Those that are so small that they can In mosaicism, cells in the same individual have differonly be detected at the molecular level are called microent genetic makeups (Nussbaum, McInnes, & Willard, deletions and can be identified by a test called chromo- 2016). For example, a child with the mosaic form of somal microarray. | Intellectual function | Typical but 5-10 points below siblings; verbal IQ＞performance IQ | | --- | --- | | Visual spatial | Deficits in spatial orientation | | Math | Difficulties with calculation | | Executive function | Impairment in attention, processing speed, working memory,cognitive flexibility,and planning | | Social | Impairments in face recognition and social reciprocity | | Behavior | Overall risk of attention-deficit/hyperactivity disorder and dyscalculia;equivocal evidence for autism | Source: Hong and Reiss (2014). Excerpted from Children with Disabilities, 8th Edition Edited by Mark trisomy conception lose the extra chromosome via nondisjunction during mitosis. Mosaicism also can occur if some cells lose a chromosome after a normal conception (e.g., some cells lose an X chromosome in mosaic Turner Figure 1.4. Translocation. During prophase of meiosis in a parent, there may be a transfer of a portion of one chromosome to another. In this figure, the long syndrome). Mosaicism is present in only 5%–10% of all arm of chromosome 21 is translocated to chromosome 14, and the residual --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ 8 Batshaw, Leon, and Kisling Cri-du-chat (“cat cry”) syndrome is an example of a visible chromosomal deletion in which a portion of the short arm of chromosome 5 is lost. Cri-du-chat syndrome affects approximately 1 in 50,000 children, causing microcephaly and an unusual facial appear- causing microcephaly and an unusual facial appearance with a round face, widely spaced eyes, epicanthal folds, and low-set ears. Children with the syndrome have a high-pitched cry and intellectual disability have a high-pitched cry and intellectual disability (Cerruti Mainardi, 2006). Examples of microdeletion syndromes (also called contiguous gene syndromes because they involve the deletion of a number of adjacent genes) include Smith-Magenis syndrome, Williams syndrome, and VCFS (Weischenfeldt, Symmons, Spitz, & Korbel, 2013). Smith-Magenis is caused by a microdeletion in the short arm of chromosome 17, Williams syndrome by a deletion in the long arm of chromosome 7, and VCFS by a deletion in the long arm of chromosome 22. Children with Smith-Magenis syndrome have feeding difficulties, hypotonia, distinctive facial features, selfinjurious behavior, and intellectual disability. Children with Williams syndrome likewise have intellectual disability with a distinctive facial appearance, but they also have cardiac defects and a unique cognitive profile with apparent expressive language skills beyond what would be expected based on their cognitive abilities. Children with VCFS syndrome may have a cleft palate, a congenital heart defect, a characteristic facial appearance, and/or a nonverbal learning disability. Cognitive problems are often present, and many affected children satisfy the criteria for a diagnosis of autism. GENES AND THEIR DISORDERS satisfy the criteria for a diagnosis of autism. GENES AND THEIR DISORDERS The underlying problem with the previously mentioned Frequency of Chromosomal Abnormalities In total, approximately 25% of eggs and 3%–4% of sperm have an extra or missing chromosome, and an additional 1% and 5%, respectively, have a structural chromosomal abnormality (Hassold, Hall, & Hunt, 2007). As a result, 10%–15% of all conceptions have a chromosomal abnormality. Somewhat more than 50% of these abnormalities are trisomies, 20% are monosomies, and 15% are triploidies (69 chromosomes). The remaining chromosomal abnormalities are composed of structural abnormalities and tetraploidies (92 chromosomes). It may therefore seem surprising that more children are not born with chromosomal abnormalities. The explanation is that more than 95% of fetuses with chromosomal abnormalities do not survive to term. In fact, many are lost very early in gestation, even before a pregnancy may be recognized. Cri-du-chat (“cat cry”) syndrome is an example too few genes resulting from extra or missing chromoof a visible chromosomal deletion in which a portion somal material. Genetic disorders can also result from of the short arm of chromosome 5 is lost. Cri-du-chat an abnormality in a single gene. As noted above, there syndrome affects approximately 1 in 50,000 children, are about 20,000 genes in the human genome. This is causing microcephaly and an unusual facial appear-quite remarkable given that the fruit fly has approxiance with a round face, widely spaced eyes, epicanthal mately 13,000 genes, the round worm 19,000 genes, and folds, and low-set ears. Children with the syndrome a simple plant 26,000 genes. It was previously thought have a high-pitched cry and intellectual disability that each gene regulated the production of a single protein. Now it is known that the situation is much more Examples of microdeletion syndromes (also complex; single genes in humans code for multiple procontiguous gene syndromes because they teins, giving humans the combinational diversity that involve the deletion of a number of adjacent genes) lower organisms lack. Humans can produce approxiinclude Smith-Magenis syndrome, Williams syndrome, mately 100,000 proteins from less than one-quarter of and VCFS (Weischenfeldt, Symmons, Spitz, & Korbel, that many genes. However, it must be acknowledged 2013). Smith-Magenis is caused by a microdeletion in that the chimp shares 99% of the human genome. Havthe short arm of chromosome 17, Williams syndrome ing now examined the genome of innumerable organby a deletion in the long arm of chromosome 7, and isms, the minimum number of genes necessary for life VCFS by a deletion in the long arm of chromosome 22. appears to be approximately 300; all living organisms by a deletion in the long arm of chromosome 7, and isms, the minimum number of genes necessary for life VCFS by a deletion in the long arm of chromosome 22. appears to be approximately 300; all living organisms Children with Smith-Magenis syndrome have feeding share these same 300 genes. difficulties, hypotonia, distinctive facial features, self-The mechanism by which genes act as blueprints injurious behavior, and intellectual disability. Children for producing specific proteins needed for body funcwith Williams syndrome likewise have intellectual tions is as follows. Genes are composed of various disability with a distinctive facial appearance, but they lengths of DNA that, together with intervening DNA also have cardiac defects and a unique cognitive profile sequences, form chromosomes. DNA is formed as a with apparent expressive language skills beyond what double helix, a structure that resembles a twisted ladwould be expected based on their cognitive abilities. der (Figure 1.5). The sides of the ladder are composed of Children with VCFS syndrome may have a cleft palate, sugar and phosphate molecules, whereas the “rungs” a congenital heart defect, a characteristic facial appear-are made up of four chemicals called nucleotide bases: ance, and/or a nonverbal learning disability. Cognitive cytosine (C), guanine (G), adenine (A), and thymine problems are often present, and many affected children (T). Pairs of nucleotide bases interlock to form each rung: cytosine bonds with guanine, and adenine bonds with thymine. The sequence of nucleotide bases on a segment of DNA (spelled out by the four-letter alphabet C, G, A, T) make up an individual’s genetic code. In total, approximately 25% of eggs and 3%–4% of sperm Individual genes range in size, containing from 1,500 have an extra or missing chromosome, and an additional to more than 2 million nucleotide–base pairs. Overall, 1% and 5%, respectively, have a structural chromosomal there are approximately 3.3 billion base pairs in the abnormality (Hassold, Hall, & Hunt, 2007). As a result, human genome, but only about 1% encode genes that 10%–15% of all conceptions have a chromosomal abnor-serve as a blueprint for protein production. It should mality. Somewhat more than 50% of these abnormalities also be noted that all genes are not “turned on” or Figure 1.5. Deoxyribonucleic acid (DNA). Four nucleotides (C, cytosine; G, guanine; A, adenosine; T, thymine) form the genetic code. On the mRNA mol The underlying problem with the previously mentioned ecule, uracil (U) substitutes for thymine. The DNA unzips to transcribe its mes-- --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ life (e.g., the fetal hemoglobin gene), and it is hoped that some are never expressed (e.g., oncogenes, which have the potential to cause cancer). The turning on and off of genes usually follows a carefully developmentally regulated process, but it can also be influenced by the environment. Regulation of gene expression plays a particularly important role during fetal development; as a result, problems involving gene expression during fetal development can be particularly devastating. The way gene expression is regulated involves a number of structural changes to the DNA and its architecture without altering the actual nucleotide sequence of the DNA. This process is termed epigenetics and is a cause of a number of genetic syndromes that are associated with developmental disabilities. Transcription The production of a specific protein begins when the DNA comprising that gene unwinds and the two strands (the sides of the ladder) unzip to expose the genetic code (Jorde, Carey, & Bamshad, 2015). The exposed DNA sequence then serves as a template for the formation, or transcription (the writing out), of a similar nucleotide sequence called messenger ribonucleic acid (mRNA; Figure 1.6). In all RNA, the nucleotides are the same as in DNA except that uracil (U) substitutes for thymine (T). In most genes, coding regions (exons) are interrupted by noncoding regions (introns). During transcription, the entire gene is copied into a pre-mRNA, which includes exons and introns. During the process of RNA splicing, introns are removed and exons are joined to form a contiguous coding sequence. Figure 1.6. A summary of the steps leading from gene to protein formation. Transcription of the DNA (gene) onto mRNA occurs in the cell nucleus. The mRNA is then transported to the cytoplasm, where translation into protein life (e.g., the fetal hemoglobin gene), and it is hoped that exons is called the exome. As might be expected, errors some are never expressed (e.g., oncogenes, which have or mutations may occur during transcription; however, the potential to cause cancer). The turning on and off a proofreading enzyme generally catches and repairs of genes usually follows a carefully developmentally these errors. If not corrected, however, transcription regulated process, but it can also be influenced by the errors can lead to the production of a disordered pro- as a result, problems involving gene expression during fetal development can be particularly devastating. The Translation way gene expression is regulated involves a number Once transcribed, the single-stranded mRNA detaches of structural changes to the DNA and its architecture and the double-stranded DNA zips back together. without altering the actual nucleotide sequence of the The mRNA then moves out of the nucleus into the DNA. This process is termed epigenetics and is a cause cytoplasm, where it provides instructions for the proof a number of genetic syndromes that are associated duction of a protein, a process termed translation ( Figure 1.7). The mRNA attaches itself to a ribosome. The ribosome moves along the mRNA strand, reading the message in three-letter “words,” or codons, such as GCU, CUA, and UAG. Most of these triplets code for The production of a specific protein begins when the specific amino acids, the building blocks of proteins. DNA comprising that gene unwinds and the two As these triplets are read, another type of RNA, transstrands (the sides of the ladder) unzip to expose the fer RNA (tRNA), carries the requisite amino acids to genetic code (Jorde, Carey, & Bamshad, 2015). The particularly important role during fetal development; as a result, problems involving gene expression during Figure 1.7. Translation of mRNA into protein. The ribosome moves along the A summary of the steps leading from gene to protein formation. mRNA strand assembling a growing polypeptide chain using tRNA–amino acid Transcription of the DNA (gene) onto mRNA occurs in the cell nucleus. The complexes. In this example, it has already assembled six amino acids (phenymRNA is then transported to the cytoplasm, where translation into protein alanine [Phe], arginine [Arg], histidine [His], cystine [Cys], threonine [Thr], and --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Batshaw, Leon, and Kisling Certain triplets, termed stop codons, instruct the ribosome to terminate the sequence by indicating that all of the correct amino acids are in place to form the com- of the correct amino acids are in place to form the complete protein, for example, thyroid hormone. Once the protein is complete, the mRNA, ribosome, and protein separate. The protein is released into the cytoplasm and is either used by the cytoplasm or prepared for secretion into the bloodstream. If the protein is to be secreted, it is transferred to the Golgi apparatus (Figure 1.1), which packages it in a form that can be released through the cell membrane and carried Mutations Mutations An abnormality at any step in the transcription or translation process can cause the body to produce a structurally abnormal protein, reduced amounts of a protein, or no protein at all. When the error occurs in the gene itself, thus disrupting the subsequent steps, that mistake is termed a mutation. The likelihood of mutations occurring increases with the size of the gene. In sperm cells, the point mutation rate also increases with paternal age. Although most mutations occur spontaneously, they can be induced by radiation, toxins, and viruses. Once they occur, mutations become part of a person’s genetic code. If they are present in the germline, they can be passed on from one generation to the next. Point Mutations The most common type of mutation is a single base pair substitution (Jorde et al., 2015), also called a point mutation. Because there is redundancy in human DNA, many point mutations have no adverse consequences. Depending on where in the gene Certain triplets, termed stop codons, instruct the ribo-causing a missense mutation or a nonsense mutation some to terminate the sequence by indicating that all (Figure 1.8). A missense mutation results in a change in of the correct amino acids are in place to form the com-the triplet code that substitutes a different amino acid in the protein chain. For example, in most cases of the Once the protein is complete, the mRNA, ribo-inborn error of metabolism, phenylketonuria (PKU), a some, and protein separate. The protein is released single base substitution causes an error in the producinto the cytoplasm and is either used by the cytoplasm tion of phenylalanine hydroxylase, the enzyme necesor prepared for secretion into the bloodstream. If the sary to metabolize the amino acid phenylalanine. The protein is to be secreted, it is transferred to the Golgi result is an accumulation of phenylalanine that can apparatus (Figure 1.1), which packages it in a form that cause brain damage (see Chapter 16). In a nonsense can be released through the cell membrane and carried mutation, the single base pair substitution produces a stop codon that prematurely terminates the protein formation. In this case, no useful protein is formed. Neurofibromatosis-1 (NF1) is an example of a disorder commonly caused by a nonsense mutation. In NF1 a tumor suppressor, neurofibromin, is not formed. As a An abnormality at any step in the transcription or result, multiple benign neurofibroma tumors form on translation process can cause the body to produce a the body and in the brain. Children with NF1 also have structurally abnormal protein, reduced amounts of a a high incidence of attention-deficit/hyperactivity disprotein, or no protein at all. When the error occurs in protein, or no protein at all. When the error occurs in order (Friedman, 2014). the gene itself, thus disrupting the subsequent steps, that mistake is termed a mutation. The likelihood of Insertions and Deletions Mutations can also mutations occurring increases with the size of the gene. involve the insertion or deletion of one or more nucle- In sperm cells, the point mutation rate also increases otide bases. As one example, insertion of nucleotides with paternal age. Although most mutations occur in the fukutin gene (expressed in muscle, brain, and spontaneously, they can be induced by radiation, toxeyes) can affect its function when associated with other ins, and viruses. Once they occur, mutations become mutations and cause Fukuyama congenital muscular part of a person’s genetic code. If they are present in the dystrophy (Saito, 2012). In contrast, a common mutagermline, they can be passed on from one generation tion in another inherited muscle disease, Duchenne muscular dystrophy, usually involves a deletion in the dystrophin gene (see Chapter 9). | | Missense Mutation | | | | Nonsense Mutation | | | | Frame shift Mutation | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | DNA | AAGTTC | AGTCA | GTA CAT | CGT GCA | AAGTTC | AGTCA | GTA CAT | CGT GCA | AAGTTC | AGTCA | GTA CAT | CGT GCA | | mRNA | UUCUCA | UCA CAU | GCA | UUCUGA | UUCUGA | CAU | GCA | UUCUGA | UUCUGA | CAU | GCA | UUCUGA | | Amino acid | PheSer | HisArg | PheSer | HisArg | PheSer | HisArg | Arg | PheSer | HisArg | PheSer | HisArg | Arg | | Mutation | A forGC | | | | C forGC | | | | A inserted | | | | | DNA | AAGTTC | AGTCA | ATA TAT | CGT GCA | AAGTTC | ACTTGA | ATA TAT | CGT GCA | AAGTTC | AGTACT | TGTACA | ACGTGC | | mRNA | UUCUCA | UCA UAU | GCA | UUCUGA | UUCUGA | CAU | GCA | UUCUCA | UUCUCA | ACA | UGC | | | Amino acid | PheSer | TyrArg | PheStop codon | — | — | | | PheSer | ThrCys | | | | | *note that this is same sequence, shifted right | | | | | | | | | | | | | muscular dystrophy, usually involves a deletion in the dystrophin gene (see Chapter 9). The most common type of muta-Base additions or subtractions may also lead to a tion is a single base pair substitution (Jorde et al., 2015), frame shift in which the three-base-pair reading frame also called a point mutation. Because there is redun-is shifted. All subsequent triplets are misread, often dancy in human DNA, many point mutations have no leading to the production of a stop codon and a nonadverse consequences. Depending on where in the gene functional protein. Certain children with Tay-Sachs mutation. The shaded areas mark the point of mutation. Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ The Genetics Underlying Developmental Disabilities can affect regions of the gene that regulate transcription but that do not actually code for an amino acid. These areas are called promoter and enhancer areas. They help turn other genes on and off and are very important in the normal development of the fetus. A  mutation in a transcription gene leads to Rubinstein- Taybi syndrome, which is associated with multiple congenital malformations and severe intellectual disability (Spena, Gervasini, & Milani, 2015). Mutations in a transcription gene also may result in a normal protein being formed but at a much slower rate than usual, leading to an enzyme or other protein deficiency. An example is Cornelia de Lange syndrome, in which patients have a mutation in the NIPBL gene that codes for the developmentally important cohesin-loading protein, delangin. Affected children manifest growth delay, a dysmorphic appearance including confluent eyebrows, limb impairments, and intellectual disability. lation (Jorde et al., 2015). Selective Advantage The incidence of a genetic disease in a population depends on the difference between the rate of mutation production and that of mutation removal. Typically, genetic diseases enter populations through mutation errors. Natural selection, the process by which individuals with a selective advantage survive and pass on their genes, works to remove these errors. For instance, because individuals with sickle cell disease (an autosomal recessive inherited blood disorder) historically have had a decreased life span, the gene that causes this disorder would have been expected to be removed from the gene pool over time. Sometimes natural selection, however, favors the individual who is a carrier of one copy of a mutated recessive gene. In the case of sickle cell disease, unaffected carriers (called heterozygotes) who appear clinically healthy actually have minor differences in their hemoglobin structure that make it more resistant to a malarial parasite (López, Saravia, Gomez, Hoebeke, & Patarroyo, 2010). In Africa, where malaria is endemic, carriers of this disorder have a selective advantage. This selective advantage has maintained the sickle cell trait among Africans. Northern Europeans, for whom malaria is not an issue, rarely carry the sickle cell gene at all; this mutation has presumably died out via natural selection in this popu- Single Nucleotide Polymorphisms Despite the more than 3 billion base pairs in the genetic code, people of all races and geography share a 99.9% genetic identity (Ridley, 2006). Although this is quite can affect regions of the gene that regulate transcrip-3 million DNA sequence variations, also called single tion but that do not actually code for an amino acid. nucleotide polymorphisms (SNPs). This genetic varia- These areas are called promoter and enhancer areas. tion is the basis of evolution, but it can also contribute They help turn other genes on and off and are very to health, unique traits, or disease. One SNP involved in important in the normal development of the fetus. muscle formation, if present, makes individuals much transcription gene leads to Rubinstein-more likely to become “buff” if they weight lift; another Taybi syndrome, which is associated with multiple SNP is associated with perfect musical pitch. There congenital malformations and severe intellectual dis-is an SNP that makes individuals more susceptible to ability (Spena, Gervasini, & Milani, 2015). Mutations in adverse effects from certain medications because it leads a transcription gene also may result in a normal protein to slower metabolism of drugs by the liver. There also being formed but at a much slower rate than usual, lead-are SNPs that place people at greater risk for developing ing to an enzyme or other protein deficiency. An exam-Alzheimer’s disease and an inflammatory bowel disple is Cornelia de Lange syndrome, in which patients ease called Crohn’s disease (Uniken Venema, Voskuil, have a mutation in the NIPBL gene that codes for the Dijkstra, Weersma, & Festen, 2016). Knowledge of these developmentally important cohesin-loading protein, SNPs, as well as candidate disease genes, allows a better delangin. Affected children manifest growth delay, a understanding of certain genetic conditions, which can dysmorphic appearance including confluent eyebrows, lead to the development of novel treatments. Single-Gene (Mendelian) Disorders Single-Gene (Mendelian) Disorders Gregor Mendel (1822–1884), an Austrian monk, pio- The incidence of a genetic disease in a population neered our understanding of single-gene defects. While depends on the difference between the rate of mutation cultivating pea plants, he noted that when he bred two production and that of mutation removal. Typically, differently colored plants—yellow and green—the genetic diseases enter populations through mutation hybrid offspring all were green rather than mixed in errors. Natural selection, the process by which indicolor. Mendel concluded that the green trait was domividuals with a selective advantage survive and pass on nant, whereas the yellow trait was recessive (from the their genes, works to remove these errors. For instance, Latin word for “hidden”). However, the yellow trait because individuals with sickle cell disease (an autosometimes appeared in subsequent generations. Later, somal recessive inherited blood disorder) historically scientists determined that many human traits, includhave had a decreased life span, the gene that causes ing some birth defects, are also inherited in this fashthis disorder would have been expected to be removed ion. They are referred to as Mendelian traits. dominant, or X-linked. have a selective advantage. This selective advantage has maintained the sickle cell trait among Africans. Northern Europeans, for whom malaria is not an issue, Autosomal Recessive Disorders Among the rarely carry the sickle cell gene at all; this mutation has currently recognized Mendelian disorders, over 1,000 presumably died out via natural selection in this popu-are inherited as autosomal recessive traits (McKusick- Nathans Institute of Genetic Medicine & The National Center for Biotechnology Information, 2017). For a child to have a disorder that is autosomal recessive, he or she must carry an abnormal gene on both copies of the rel- Despite the more than 3 billion base pairs in the genetic evant chromosome. In the vast majority of cases, this code, people of all races and geography share a 99.9% means that the child receives an abnormal copy from genetic identity (Ridley, 2006). Although this is quite both parents. The one exception is uniparental disomy, remarkable, that 0.1% difference means there are about which is discussed in the next section. Excerpted from Children with Disabilities, 8th Edition Edited by Mark L. --- Table 1.2. Prevalence of genetic disorders | Disease | Appropriate prevalence | | --- | --- | | Chromosomal disorders | | | Down syndrome(trisomy 21) | 1/850 | | Klinefelter syndrome(47,XXY) | 1/600 | | Trisomy13 | 1/12,000-1/20,000 | | Trisomy18 | 1/6,000-8,000 | | Turner syndrome(45,X) | 1/2,500-1/4,000 females | | Single-gene disorders | | | Duchenne muscular dystrophy | 1/3,300 males | | Fragile X syndrome | 1/3,000-1/4,000 males;1/8,000 females | | Neurofibromatosis type I | 1/3,000 | | Phenylketonuria | 1/5,000 to 1/10,000 | | Tay-Sachs disease | 1/3,600 Ashkenazi Jews | | Mitochondrial inheritance | | | Leber hereditary optic neuropathy | Rare1/30,000-1/50,000 | | MERRF | Rare(<1/100,000) | | MELAS | Rare,unknown | MELAS Rare, unknown Sources: Nussbaum, McInnes, and Willard (2016) and Adam, Ardinger, Pagon, Wallace, Bean, Sources: Nussbaum, McInnes, and Willard (2016) and Adam, Ardinger, Pagon, Wallace, Bean, Stephens, and Amemiya (1993–2018). Key: MELAS, mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes; MERRF, Tay-Sachs disease is an example of an autosomal recessive condition. It is caused by the absence of an enzyme, hexosaminidase A, which normally metabolizes a potentially toxic product of nerve cells (Kaback & Desnick, 2011). In affected children, this product cannot be broken down and is stored in the brain, leading to progressive brain damage and early death. not be broken down and is stored in the brain, leading to progressive brain damage and early death. Alternate forms of the gene for hexosaminidase A are known to exist. The different forms of a gene, called alleles, include the normal gene, which can be symbolized by a capital “A” because it is dominant, and the mutated allele (in this example, carrying Tay-Sachs disease), which can be symbolized by the lowercase “a” because it is recessive (Figure 1.9). Upon fertilization, the embryo receives two genes for hexosaminidase A, one from the father and one from the mother. The following combinations of alleles are possible: homozygous (carrying the same allele) combinations, AA or aa, and heterozygous (carrying alternate alleles) combinations, aA or Aa. Because Tay-Sachs disease is a recessive disorder, two abnormal recessive genes (aa) are needed to produce a child who has the disease. Therefore, a child with aa would be homozygous for the Tay-Sachs mutation (i.e., have two copies of the mutated gene and manifest the disease), a child with aA or Aa would be heterozygous and a healthy carrier of the Tay-Sachs mutation, and a child with AA would the Tay-Sachs mutation (i.e., have two copies of the mutated gene and manifest the disease), a child with Figure 1.9. Inheritance of autosomal recessive disorders. Two copies of the aA or Aa would be heterozygous and a healthy carrier abnormal gene (aa) must be present to produce the disease state: A) Two carriers mating will result, on average, in 25% of the children being affected, 50% of the Tay-Sachs mutation, and a child with AA would being carriers, and 25% noncarriers; B) A carrier and a noncarrier mating will Tay-Sachs disease is an example of an autosomal If two heterozygotes (carrying alternate alleles) recessive condition. It is caused by the absence of an were to have children (aA × Aa or Aa × aA), the folenzyme, hexosaminidase A, which normally metabo-lowing combinations could occur: AA, aA or Aa, or aa lizes a potentially toxic product of nerve cells (Kaback (Figure 1.9). According to the law of probability, each & Desnick, 2011). In affected children, this product can-pregnancy would carry a one in four chance of the child --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ The Genetics Underlying Developmental Disabilities being a noncarrier (AA), a one in two chance of the child being a carrier (aA or Aa), and a one in four risk of the child having Tay-Sachs disease (aa). If a carrier has children with a noncarrier (aA × AA), each pregnancy carries a one in two chance of the child being a carrier (aA, Aa), a one in two chance of the child being a noncarrier (AA), and virtually no chance of the child having the disease (Figure 1.9). Siblings of affected children, even if they are carriers, are unlikely to produce children with the disease because this can only occur if they have children with another carrier, which is an unlikely occurrence in sis to provide information about whether the fetus is affected (see Chapter 3). Because it is unlikely for a carrier of a rare condition to have children with another carrier of the same disease, autosomal recessive disorders are quite rare in the general population, ranging from 1 in 2,000 to 1 in 200,000 or fewer births (McKusick-Nathans Institute of Genetic Medicine & The National Center for Biotechnology Information, 2017). When a union occurs within an extended family, also called consanguinity (e.g., cousin marriage; Figure 1.10) or when unions among ethnically, religiously, or geographically isolated populations occur, the incidence of these disorders increases markedly. Some ethnic populations have higher carrier frequency than others; for example, carrier frequency for cystic fibrosis in people of Northern European background is 1 in 28, but for Asians, the carrier frequency ground is 1 in 28, but for Asians, the carrier frequency is 1 in 118 (Ong et al., 2017). Like Tay-Sachs disease, certain other autosomal recessive disorders are caused by mutations that lead to an enzyme deficiency of some kind. In most cases, there are a number of different mutations within the gene that can produce the same disease. Because these enzyme affected children in a row or five unaffected children. In the case of Tay-Sachs disease, carrier screening is used to identify at-risk couples and prenatal diagno-Figure 1.10. A family tree illustrating the effect of consanguinity (in this case, sis to provide information about whether the fetus is a marriage between first cousins) on the risk of inheriting an autosomal recessive disorder. The chance of both parents being carriers is usually less than 1 in 300. When first cousins conceive a child, however, the chance of both Because it is unlikely for a carrier of a rare condi-parents being carriers rises to 1 in 8. The risk, then, of having an affected child Table 1.3. Comparison of autosomal recessive, autosomal dominant, and X-linked inheritance patterns tion to have children with another carrier of the same disease, autosomal recessive disorders are quite rare in the general population, ranging from 1 in 2,000 to 1 in deficiencies generally lead to biochemical abnormali- 200,000 or fewer births (McKusick-Nathans Institute of ties involving either the insufficient production of a Genetic Medicine & The National Center for Biotechneeded product or the buildup of toxic materials, develnology Information, 2017). When a union occurs within opmental disabilities or early death may result (see an extended family, also called consanguinity (e.g., Chapter 16). Autosomal recessive disorders affect males cousin marriage; Figure 1.10) or when unions among and females equally, and there tends to be clustering in ethnically, religiously, or geographically isolated popufamilies (i.e., more than one affected child per family). lations occur, the incidence of these disorders increases However, a history of the disease in past generations markedly. Some ethnic populations have higher carrier | | Autosomal recessive | Autosomal dominant | X-linked | | --- | --- | --- | --- | | Type of disorder | Enzyme deficiency | Structural abnormalities | Mixed | | Examples of disorder | Tay-Sachs disease | Achondroplasia | Fragile X syndrome | | Phenylketonuria(PKU) | Neurofibromatosis | Muscular dystrophy | | | Carrier expresses disorder | No | Yes | Sometimes | | Increased risk in other family members from intermarriage/consanguinity | Yes | No | No | rarely exists unless there has been intermarriage. frequency than others; for example, carrier frequency for cystic fibrosis in people of Northern European background is 1 in 28, but for Asians, the carrier frequency Autosomal Dominant Disorders Over 1,000 autosomal dominant disorders have been identified, Like Tay-Sachs disease, certain other autosomal the most common ones having a frequency of 1 in 200 recessive disorders are caused by mutations that lead to births (Youngblom et al., 2016). Autosomal dominant an enzyme deficiency of some kind. In most cases, there disorders are quite different from autosomal recessive are a number of different mutations within the gene that disorders in mechanism, incidence, and clinical charcan produce the same disease. Because these enzyme acteristics (Table 1.3). Because autosomal dominant --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ disorders are caused by a single abnormal allele, individuals with the genotypes Aa or aA are both affected to some degree. To better understand this, consider NF1, the neurological disorder discussed previously. Suppose a represents the normal recessive gene and A indicates the mutated dominant gene for NF1. If a person with NF1 (aA or Aa) has a child with an unaffected individual (aa), there is a one in two risk, statistically speaking, that the child will have the disorder (aA or Aa) and a one in two chance he or she will be unaffected (aa; Figure 1.11). An unaffected child will not carry the abnormal allele and therefore cannot pass it on to his or her children. abnormal allele and therefore cannot pass it on to his or her children. Autosomal dominant disorders affect men and women with equal frequency. They tend to involve physical impairments (tumors in the case of NF1) rather than enzymatic defects. In affected individuals, there is often a family history of the disease; however, approximately half of affected individuals represent a new mutation. Although individuals with a new mutation will risk passing the mutated gene to their offspring, their parents are unaffected and at no greater risk than the general population of having a second affected child. In some cases, a mutation occurs early in the development of eggs and sperm. This is called germline, or gonadal, mosaicism and is estimated to occur approximately 1.3% of the time. If gonadal mosaicism is present in a parent, theoretically two siblings can be disorders are caused by a single abnormal allele, indi-affected with the same condition and neither parent viduals with the genotypes Aa or aA are both affected appears to be affected (Rahbari et al., 2015). There can also be partial penetrance of the gene, which produces To better understand this, consider NF1, the neu-a less severe disorder (e.g., in NF1 or tuberous sclerorological disorder discussed previously. Suppose a sis), or a delayed onset form of the disease (e.g., in Hun- Figure  1.11. Inheritance of autosomal dominant disorders. Only one copy of the abnormal gene (A) must be present to produce the disease state: A) If an affected person conceives a child with an unaffected person, statistically speaking, 50% of the children will be affected and 50% will be unaffected; B) If two affected people have children, 25% of the children will be unaffected, 50% will have the disorder, and 25% will have a severe (often fatal) form of the represents the normal recessive gene and A indicates tington disease). the mutated dominant gene for NF1. If a person with NF1 (aA or Aa) has a child with an unaffected individ-X-Linked Disorders Unlike autosomal recesual (aa), there is a one in two risk, statistically speak-sive and autosomal dominant disorders, which ing, that the child will have the disorder (aA or Aa) involve genes located on the 22 non-sex chromosomes and a one in two chance he or she will be unaffected (autosomes), X-linked (previously called sex-linked) Figure 1.11). An unaffected child will not carry the disorders involve mutant genes located on the X chroabnormal allele and therefore cannot pass it on to his mosome. X-linked disorders primarily affect males (Genetics Home Reference, 2017a). The reason for this Autosomal dominant disorders affect men and is that males have only one X chromosome; therefore, women with equal frequency. They tend to involve a single dose of the abnormal gene causes disease. physical impairments (tumors in the case of NF1) rather Because females have two X chromosomes, a single than enzymatic defects. In affected individuals, there is recessive allele usually does not cause disease provided often a family history of the disease; however, approxi-there is a normal allele on the second X chromosome mately half of affected individuals represent a new (Figure 1.12). Approximately 1,000 X-linked disorders mutation. Although individuals with a new mutation have been described, including Duchenne muscular will risk passing the mutated gene to their offspring, dystrophy and hemophilia (McKusick-Nathans Institheir parents are unaffected and at no greater risk than tute of Genetic Medicine & The National Center for the general population of having a second affected Biotechnology Information, 2017). Carrier mothers in child. In some cases, a mutation occurs early in the two-thirds of the cases pass on these disorders from development of eggs and sperm. This is called germ-one generation to the next; one-third of these cases rep- disorder as a result of a double dose of the abnormal gene. unaffected and 50% will be affected. Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ progressive muscle weakness (Bushby et al., 2010a, 2010b; Suthar & Sankhyan, 2017). The disease results from a mutation in the dystrophin gene (located on the X  chromosome), the function of which is to ensure stability of the muscle cell membrane. Because the disease affects all muscles, eventually the heart muscle and the diaphragmatic muscles needed for circulation and breathing respectively are impaired. Dystrophin is also required for typical brain development and function, required for typical brain development and function, so affected boys may have cognitive impairments. In fact, approximately 10% of males with intellectual disability and l0% of females with learning disabilities are affected by X-linked conditions (Inlow & Restifo, 2004). Males are more than twice as likely to have intellectual disability than females. This finding is attributable to a combination of factors: first, X-linked disorders affect males disproportionately more than females, and second, there is an unusually large number of genes residing on the X chromosome that are critical for normal brain development, nerve cell function, learning, and memory. Up to 10% of all known genetic errors causing intellectual disability are on the X chromosome despite the X chromosome containing only 4% of the human genome. genetic errors causing intellectual disability are on the X chromosome despite the X chromosome containing only 4% of the human genome. The mechanism for passing an X-linked recessive trait to the next generation is as follows: Women who have a recessive mutation (Xa) on one of their X chromosomes and a normal allele on the other (X) are carriers of the gene (XaX). Although these women are usually clinically unaffected, they can pass on the abnormal gene to their children. Assuming the father is unaffected, each female child born to a carrier mother has a one in two chance of being a carrier (i.e., inheriting the mutant Xa allele from her mother and the normal X allele from her father; Figure 1.12). A male child (who has only one X chromosome), however, has a one in two risk of having the disorder. This occurs if he inherits the X chromosome containing the mutated gene (XaY) instead of the normal one (XY). A family tree frequently reveals that some maternal uncles and male siblings have the disease. X-linked disorders are never passed from father to son because boys inherit their Y chromosome from their father and their X chromosome from their mother. Occasionally, females are affected by X-linked al., 2010a, cell is inactivated, making every female fetus a mosaic. 2010b; Suthar & Sankhyan, 2017). The disease results This implied that some cells would contain an active from a mutation in the dystrophin gene (located on the X chromosome derived from the father, whereas othchromosome), the function of which is to ensure sta-ers would contain an active X chromosome derived bility of the muscle cell membrane. Because the disease from the mother. This “lyonization” hypothesis was affects all muscles, eventually the heart muscle and later proven to be correct. In most instances, the cells the diaphragmatic muscles needed for circulation and in a woman’s body have a fairly equal division between breathing respectively are impaired. Dystrophin is also maternally and paternally derived active X chromorequired for typical brain development and function, somes. In a small fraction of women, however, the distribution is very unequal. If the normal X chromo- In fact, approximately 10% of males with intellec-some is inactivated preferentially in cells of a carrier tual disability and l0% of females with learning dis-of an X-linked disorder, the woman will manifest the abilities are affected by X-linked conditions (Inlow & disease, although usually in a less severe form than Restifo, 2004). Males are more than twice as likely to the male. An example is OTC deficiency, the disorder have intellectual disability than females. This finding Katy had in this chapter’s opening case study (see also have intellectual disability than females. This finding Katy had in this chapter’s opening case study (see also is attributable to a combination of factors: first, X-linked Chapter 16). disorders affect males disproportionately more than The second mechanism for a female to manifest females, and second, there is an unusually large num-an X-linked disorder is if the disorder is transmitted ber of genes residing on the X chromosome that are as X-linked dominant. Although most X-linked disorcritical for normal brain development, nerve cell func-ders are recessive, a few appear to be dominant. One tion, learning, and memory. Up to 10% of all known example is Rett syndrome (Chahrour & Zoghbi, 2007; genetic errors causing intellectual disability are on the Liyanage & Rastegar, 2014; Matijevic, Knezevic, Slavica, X chromosome despite the X chromosome containing & Pavelic, 2009; Percy, 2008). It appears that in this disorder, the presence of the mutated transcription gene The mechanism for passing an X-linked reces-MECP2 on the X chromosome of a male embryo nearly sive trait to the next generation is as follows: Women always leads to lethality. When it occurs in one of the who have a recessive mutation (Xa) on one of their X chromosomes of the female, however, it is compat- X chromosomes and a normal allele on the other (X) ible with survival but results in a syndrome marked by are carriers of the gene (XaX). Although these women microcephaly, developmental regression, intellectual are usually clinically unaffected, they can pass on disability, and autism-like behaviors. That is why vir- the abnormal gene to their children. Assuming the tually all children with Rett syndrome are girls. father is unaffected, each female child born to a carrier mother has a one in two chance of being a carrier (i.e., mother has a one in two chance of being a carrier (i.e., Mitochondrial Inheritance inheriting the mutant Xa allele from her mother and the normal X allele from her father; Figure 1.12). A male Each cell contains several hundred mitochondria in child (who has only one X chromosome), however, has its cytoplasm (Figure 1.1). Mitochondria produce the a one in two risk of having the disorder. This occurs if energy needed for cellular function through a comhe inherits the X chromosome containing the mutated plex process termed oxidative phosphorylation. It has gene (XaY) instead of the normal one (XY). A family been proposed that mitochondria were originally tree frequently reveals that some maternal uncles and independent microorganisms that invaded our bodmale siblings have the disease. X-linked disorders are ies during the process of human evolution and then never passed from father to son because boys inherit developed a symbiotic relationship with the cells in the their Y chromosome from their father and their X chro-human body. They are unique among cellular organelles (the specialized parts of a cell) in that they pos- Occasionally, females are affected by X-linked sess their own DNA, which is in a double-stranded diseases. This can occur if the woman has adverse circular pattern rather than the double-helical pattern lyonization (inactivation of one of the X chromosomes) of nuclear DNA and contains genes that are different or if the disorder is X-linked “dominant.” Regard-from those contained in nuclear DNA (Figure 1.13). ing the former mechanism, the geneticist Mary Lyon Most of the proteins necessary for mitochondrial funcquestioned why women have the same amount of X tion are coded by nuclear genes, and disorders caused chromosome–directed gene product as men instead by abnormalities in these genes are most often inherof twice as much, as would be predicted from their ited in an autosomal recessive manner. Certain mitogenetic makeup. Dr. Lyon postulated that early in chondrial functions, however, are dependent on genes embryogenesis, one of the two X chromosomes in each encoded on the mitochondrial DNA. A mutation in --- Batshaw, Leon, and Kisling Figure  1.13. Mitochondrial DNA genome. The genes code for various enzyme complexes involved in energy production in the cell. The displacement loop (D loop) is not involved in energy production. (This figure was published in Medical genetics, revised 2nd edition, by Jorde, L.B., Carey, J.C., & Bamshad, M.J., et al., p. 105, Copyright C.V. Mosby [2001]; adapted by permission.) (Key: Complex I genes [NADH dehydrogenase], Complex III genes [ubiquinol: cytochrome c oxidoreductase], tRNA genes, Complex IV genes [cytochrome c oxidase], Complex V genes [ATP synthase], ribosomal RNA a mitochondrial gene can result in defective energy production and a disease state, particularly affecting organs with high energy demands, such as the heart, skeletal muscle, and brain (Gorman, 2016). An example of a disorder with mitochondrial inheritance is mitochondrial encephalomyelopathy, lactic acidosis, and stroke-like episodes (MELAS), a progressive neurological disorder marked by episodes of stroke and dementia. Other disorders with mitochondrial inheritance can lead to blindness, deafness, or muscle weakness. There are hundreds of mitochondrial diseases, some of which have clear genetic causes, while others do not. Every cell contains many mitochondria, but not every mitochondrion may carry a given mutation. In many disorders that are inherited through the mitochondrial genome, there is great clinical variability based on the heteroplasmy or the mix of different mitochondrial genomes within a single individual. There may be significant variability among specific tissues in an individual; some organs or tissues may be affected by the Because eggs, but not sperm, contain cytoplasm, mitochondria are inherited from one’s mother. As a result, mitochondrial DNA disorders are passed on from generally unaffected mothers to their children, both male and female (Figure 1.14). Men affected by a mitochondrial disorder cannot pass the trait to their children. In some cases, a mother with significant heteroplasmy may have only mild effects of a disease but may pass on only mutated mitochondrial genomes to a child. In that case, a child would have a homoplasmic mitochondrial mutation and would have a much more severe clinical course. Trinucleotide Repeat Expansion Disorders There has been an increased recognition that copy number variability accounts for several developmental disabilities (Sansović, Ivankov, Bobinec, Kero, & Barišić, 2017). One particular type of copy number variation is the trinucleotide repeat expansion (triplet repeat disorder), which has been linked to a number of disorders that do not follow typical Mendelian inheritance. Trinucleotide repeat disorders result from problems in recombination and replication during meiosis. Certain genes have highly repetitive sequences of tri- Mitochondrial DNA genome. The genes code for various enzyme complexes involved in energy production in the cell. The displacement nucleotides. These repetitive sequences may expand loop (D loop) is not involved in energy production. (This figure was published in (or contract) in size during meiosis. Once the repetitive Medical genetics, revised 2nd edition, by Jorde, L.B., Carey, J.C., & Bamshad, M.J., et al., p. 105, Copyright C.V. Mosby [2001]; adapted by permission.) (Key: sequence reaches a certain size threshold, it may inter- Complex III genes [ubiquinol: fere with the function of the gene and lead to a clini- Complex IV genes [cyto- ribosomal RNA cally apparent disorder. The expansion length is linked to the phenotype, with the longer expansions often presenting with earlier and more severe clinical signs and genomes within a single individual. There may be significant variability among specific tissues in an indi- Figure 1.14. Mitochondrial inheritance. Because mitochondria are inherited vidual; some organs or tissues may be affected by the exclusively from the mother, defects in mitochondrial disease will be passed on senting with earlier and more severe clinical signs and symptoms. The first triplet repeat disorder discovered was a mitochondrial gene can result in defective energy fragile X syndrome, the most common inherited production and a disease state, particularly affecting cause of intellectual disability. Boys and girls with organs with high energy demands, such as the heart, fragile X syndrome have a phenotype that includes --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ The Genetics Underlying Developmental Disabilities a characteristic physical appearance, cognitive skills impairments, and impaired adaptive behaviors (Chonchaiya, Schneider, & Hagerman, 2009; Schneider, Hagerman, & Hessl, 2009; also see Chapter 15). Many affected children satisfy the criteria for the diagnosis of autism. The prevalence of fragile X syndrome (the full mutation) for males is about 1 in 3,600. The prevalence of the full mutation in females is estimated to be at least 1 in 4,000 to 1 in 6,000. Fragile X syndrome arises from an expansion of the number of cytosineguanine-guanine (CGG) trinucleotide repeats occurring within the fragile X mental retardation protein (FMR1) gene. Inheritance of the instability in CGG regions leads to expansion from the normal number of repeats (6–40) to a premutation state (50–200 repeats) or from a premutation state to full mutation (>200 repeats). The stability of the CGG repeat depends upon the length of the repeat, as well as the sex of the individual passing on the mutation. The increased risk of CGG expansion from one generation to another is a phenomenon termed anticipation. Anticipation leads to an increasingly severe clinical phenotype in successive generations. When a child is suspected of having fragile X syndrome, the diagnosis can be confirmed by detecting the number of trinucleotide repeats in FMR1 using a clinically available molecular genetic blood test (Collins et al., 2010). There is a correlation between the number of trinucleotide repeats and the severity of disease. Other trinucleotide repeat disorders include myotonic dystrophy and Huntington’s disease. tonic dystrophy and Huntington’s disease. a characteristic physical appearance, cognitive skills epigenetic function. It is interesting to note that virtually impairments, and impaired adaptive behaviors all epigenetic disorders have been found to have a high (Chonchaiya, Schneider, & Hagerman, 2009; Schneider, incidence of symptoms consistent with autism spectrum Hagerman, & Hessl, 2009; also see Chapter 15). Many disorder or other neurodevelopmental disorders (Moss affected children satisfy the criteria for the diagnosis & Howlin, 2009). In addition, the risk of epigenetic disof autism. The prevalence of fragile X syndrome (the orders has been found to be increased in pregnancies full mutation) for males is about 1 in 3,600. The prev-assisted by in vitro fertilization (Lazaraviciute, Kauser, full mutation) for males is about 1 in 3,600. The prev-assisted by in vitro fertilization (Lazaraviciute, Kauser, alence of the full mutation in females is estimated to Bhattacharya, Haggarty, & Bhattacharya, 2014). be at least 1 in 4,000 to 1 in 6,000. Fragile X syndrome According to Mendelian genetics, the phenotype, arises from an expansion of the number of cytosine-or appearance of an individual should be the same guanine-guanine (CGG) trinucleotide repeats occur-whether the given gene is inherited from the mother ring within the fragile X mental retardation protein or the father. This is not always the case, however, (FMR1) gene. Inheritance of the instability in CGG because of genomic imprinting. This is an epigenregions leads to expansion from the normal number of etic phenomenon in which the activity of the gene is repeats (6–40) to a premutation state (50–200 repeats) modified depending upon the sex of the transmitting or from a premutation state to full mutation (>200 parent (Genetics Home Reference, 2017b). Most autosorepeats). The stability of the CGG repeat depends upon mal genes are expressed in both maternal and paterthe length of the repeat, as well as the sex of the indi-nal alleles. However, imprinted genes show expression vidual passing on the mutation. The increased risk of from only one allele (the other is silenced or used dif- CGG expansion from one generation to another is a ferently), and this is determined during production phenomenon termed anticipation. Anticipation leads of the egg or sperm. Imprinting implies that the gene to an increasingly severe clinical phenotype in succes-carries a “tag” placed on it during spermatogenesis or sive generations. When a child is suspected of having oogenesis. This is most often accomplished by adding fragile X syndrome, the diagnosis can be confirmed by methyl groups to the DNA, affecting the expression of detecting the number of trinucleotide repeats in FMR1 the methylated genes. Imprinted genes are important using a clinically available molecular genetic blood test in development and differentiation, and if expression (Collins et al., 2010). There is a correlation between the from both alleles is not maintained, disturbances in variation. A number of conditions causing develop- GENETIC TESTING mental disabilities, including fragile X syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Prader-Willi Genetic tests have been developed for many of the (Collins et al., 2010). There is a correlation between the from both alleles is not maintained, disturbances in number of trinucleotide repeats and the severity of dis-development can result (Soellner et al., 2017). ease. Other trinucleotide repeat disorders include myo-The first human imprinting disorder discovered was Prader-Willi syndrome. It is caused by a paternal deletion in chromosome 15 or by maternal uniparental disomy in which both chromosome 15s come from the mother. It can also result if both copies of chromo- The diagnostic evaluation of children with intellec-some 15 are imprinted as if they came from the mother tual disability and other developmental disabilities regardless of the actual parent of origin (Conlin et al., has become increasingly complex in recent years due 2010; Driscoll, Miller, Schwartz, & Cassidy, 2017). to a number of newly recognized genetic mecha-Prader-Willi syndrome is characterized by severe nisms and the availability of sophisticated methods to hypotonia and feeding difficulties in early childhood, diagnose them. It has been appreciated that changes followed by an insatiable appetite and obesity by in gene expression can occur by mechanisms that do school age. It features significant motor and language not permanently alter the DNA sequence (Urdinguio, delays in the first 2 years of life; borderline to moderate Sanchez-Mut, & Esteller, 2009), a phenomenon termed intellectual disability; and severe behavioral problems, epigenetics. Epigenetic mechanisms are important including compulsive and hording behaviors. Many regulators of biological processes because they include affected children satisfy the criteria for the diagnosis of genome reprogramming during embryogenesis (Kumar, autism (Driscoll et al., 2017; Goldstone, Holland, Hauffa, 2008). Epigenetic modification, which is important in Hokken-Koelega, & Tauber, 2008). Other examples of developmental processes, may have long-term effects imprinted neurogenetic disorders include Angelman on learning and memory formation. Epigenetic impair-syndrome and Beckwith-Wiedemann syndrome (Dan, ments may result from dysfunction of certain enzymes, 2009; Gurrieri & Accadia, 2009; Soellner et al., 2017). genomic imprinting, and triplet repeat copy number variation. A number of conditions causing develop- --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ Batshaw, Leon, and Kisling those described in this chapter. Most tests look at single genes and are used to diagnose rare genetic disorders, such as fragile X syndrome and Duchenne muscular dystrophy. In addition, some genetic tests look at rare inherited mutations of otherwise protective genes that are responsible for some hereditary breast and ovarian cancers. An increasing number of tests are being developed to look at multiple genes that may increase or decrease a person’s risk for developing common diseases, such as cancer or diabetes. In addition, pharmacogenetic tests may be used to help identify genetic variations that influence a person’s response to medicines. Here, we will focus on genetic testing used in diagnosing causes of developmental disabilities. cines. Here, we will focus on genetic testing used in diagnosing causes of developmental disabilities. There are three types of genetic testing currently being used to detect genomic-based causes of developmental disabilities: chromosomal microarray analysis, next-generation sequencing, and whole-exome/ genome sequencing. Chromosomal microarrays use probes to test for known DNA sequences and can iden- those described in this chapter. Most tests look at single caused by a microdeletion or microduplication, as seen genes and are used to diagnose rare genetic disorders, in Williams syndrome or chromosome 15q duplicasuch as fragile X syndrome and Duchenne muscular tion syndrome. Microarrays cannot be used to identify dystrophy. In addition, some genetic tests look at rare mutations (alterations of a single nucleotide, such as a inherited mutations of otherwise protective genes that point mutation) in a gene. In general, a chromosomal are responsible for some hereditary breast and ovar-microarray is the first-line test recommended for a ian cancers. An increasing number of tests are being child presenting with developmental delays or autism developed to look at multiple genes that may increase (see Box 1.1). The second type of genetic testing, nextor decrease a person’s risk for developing common generation sequencing, allows detection of mutations diseases, such as cancer or diabetes. In addition, phar-in single genes, such as NF1 associated with neurofimacogenetic tests may be used to help identify genetic bromatosis type 1, or CFTR, in which two mutations variations that influence a person’s response to medi-are needed to cause cystic fibrosis. The final approach cines. Here, we will focus on genetic testing used in is whole-exome/genome sequencing and may be used in a case where no genetic cause has been identified There are three types of genetic testing currently for the child’s phenotype. Whole-exome sequencing is being used to detect genomic-based causes of develop-typically utilized when a child’s clinical history is susmental disabilities: chromosomal microarray analy-picious for a genetic condition based on the presence of sis, next-generation sequencing, and whole-exome/ multiple congenital anomalies, developmental delays, genome sequencing. Chromosomal microarrays use or other undiagnosed issues. Here, exome sequencprobes to test for known DNA sequences and can iden-ing (sequencing the entire exome) can help identify BOX 1.1 EVIDENCE-BASED PRACTICE BOX 1.1 EVIDENCE-BASED PRACTICE Autism and Genetic Testing Autism spectrum disorder (ASD) is a highly variable group of neurodevelopmental conditions. There is evidence that children with ASD more commonly have medical issues and/or physical differences and dysmorphic features. Because of this high level of variability, the genetic workup may differ depending on the child’s clinical issues. Stratification of children with ASD can help to determine what type of genetic testing might be most appropriate for a patient. The general recommendation is that chromosomal microarray (CMA) is the first-line test for a child with ASD. Points to Remember ■■ CMA should still be considered the first-line test for children with autism. A medical genetics evaluation were performed. Age at diagnosis with ASD was also significantly older for this complex group. In the children with essential autism, the diagnostic yield was much lower when using both CMA and WES. ■■ CMA should still be considered the first-line test for children with autism. A medical genetics evaluation should be completed prior to ordering any genetic testing. ■■ Medical genetics evaluation might help identify patients more likely to achieve a molecular diagnosis with genetic testing; complex patients might benefit from WES if properly counseled by a medical sis with genetic testing; complex patients might benefit from WES if properly counseled by a medical geneticist and genetic counselor. ■■ Patients with complex medical issues receive later diagnoses of autism; it is important to be aware of Excerpted from Children with Disabilities, 8th Edition Edited by Mark --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ The Genetics Underlying Developmental Disabilities each gene individually. It does this by selecting the approximately 180,000 exons that constitute about 1% of the human genome (or approximately 30 million base pairs) and then sequencing the DNA using a highthroughput DNA sequencing technology. This technique has been used to identify genetic variants seen in autism. Exome sequencing, however, is only able to identify those variants found in the coding region of genes that affect protein function. It is not able to identify structural and non-coding variants associated with disease; this can be found using whole-genome sequencing. Presently, whole-genome sequencing is typically not utilized in the clinical setting due to the high costs and time associated with sequencing full genomes. In addition to these challenges, our understanding of much of our genome is still in its infancy. As our knowledge continues to grow, clinicians will be able to more accurately interpret results and provide appropriate genetic counseling for families. able to more accurately interpret results and provide appropriate genetic counseling for families. There are many other types of genetic tests available for specific disorders. For example, some inborn errors of metabolism can be identified by detecting the accumulation of specific compounds in blood, urine, or other tissue samples. Testing for methylation patterns on DNA samples detects certain epigenetic disorders. Other genetic disorders may be detected radiologically. The decision about which tests are most appropriate for a specific patient is complex, and physicians with expertise in medical genetics can help guide testing and interpret results. While some tests, such as karyotype analysis to detect large chromosome abnormalities or rearrangements (like those seen in Down syndrome and Klinefelter syndrome), are no longer commonly used during evaluation of a child with developmental delay, they may be appropriate depending on a child’s clinical presentation. For example, a girl referred for mild developmental each gene individually. It does this by selecting the delays, short stature, webbed neck, and a heart defect approximately 180,000 exons that constitute about 1% should first undergo a karyotype to evaluate for of the human genome (or approximately 30 million Turner syndrome; microarray and next-generation base pairs) and then sequencing the DNA using a high-sequencing would not be the most appropriate initial throughput DNA sequencing technology. This tech-tests for this patient. Medical geneticists and genetic nique has been used to identify genetic variants seen counselors can help determine the correct test for a in autism. Exome sequencing, however, is only able patient based on utility and cost effectiveness. They to identify those variants found in the coding region can also ensure that the patient is properly consented of genes that affect protein function. It is not able to and understands the implications of these complex identify structural and non-coding variants associated analyses (see Box 1.2). with disease; this can be found using whole-genome sequencing. Presently, whole-genome sequencing is ENVIRONMENTAL typically not utilized in the clinical setting due to the typically not utilized in the clinical setting due to the INFLUENCES ON HEREDITY high costs and time associated with sequencing full genomes. In addition to these challenges, our under-The particular genes that a person possesses deterstanding of much of our genome is still in its infancy. mine his or her genotype, and the expression of the As our knowledge continues to grow, clinicians will be genes results in the physical appearance of traits—that able to more accurately interpret results and provide is, the phenotype of the individual. For some traits and clinical disorders, however, the same genotype There are many other types of genetic tests avail-can produce quite different phenotypes depending able for specific disorders. For example, some inborn on environmental influences. In terms of traits, bright errors of metabolism can be identified by detecting parents tend to have bright children and tall parents the accumulation of specific compounds in blood, tend to have tall children; however, the interaction of urine, or other tissue samples. Testing for methylation genetics with the prenatal and postnatal environments patterns on DNA samples detects certain epigenetic allows for many possible outcomes. For example, it has disorders. Other genetic disorders may be detected been found that, as a result of an increased protein radiologically. The decision about which tests are intake during childhood, Asians who grow up in the most appropriate for a specific patient is complex, United States are significantly taller than their parand physicians with expertise in medical genetics can ents who grew up in Asia. Disorders that have both help guide testing and interpret results. While some genetic and environmental influences include diabetests, such as karyotype analysis to detect large chro-tes, meningomyelocele, cleft palate, and pyloric stenomosome abnormalities or rearrangements (like those sis (Au, Ashley-Koch, & Northrup, 2010). Considering seen in Down syndrome and Klinefelter syndrome), the example of PKU, an affected child will develop are no longer commonly used during evaluation of a intellectual disability if the PKU is not treated early child with developmental delay, they may be appro-but will have typical development if it is treated with priate depending on a child’s clinical presentation. a diet low in phenylalanine from infancy (Feillet et al., For example, a girl referred for mild developmental 2010; also see Chapter 16). What Is a Genetic Counselor? Genetic counselors are health care professionals with specialized, master’s-level training in human genetics. They are an excellent resource for both patients and providers of children with rare diseases and developmental disabilities, as they are able to explain complex genetic ideas while also providing psychosocial support. Genetic counselors can guide patients on how inherited diseases might affect them or their families, analyze family histories, and help determine what kind of genetic testing might be most appropriate for a patient. In a pediatric setting, genetic counselors work alongside medical geneticists and are often the patient’s point of contact within their team of genetic care providers. Genetic counselors also work with pregnant women, cancer patients, and people with more common conditions such as heart disease, diabetes, and Alzheimer’s disease. Genetic counselors also meet with couples planning a pregnancy to help determine BOX1.2 INTERDISCIPLINARY CARE BOX 1.2 INTERDISCIPLINARY CARE --- FOR MORE, go to https://www.brookespublishing.com/children-with-disabilities/ 20 Batshaw, Leon, and Kisling GENETIC THERAPIES ber of disorders, they represent only a fraction of all the genetic causes of developmental disabilities and their cost can be up to $500,000 per year. More recently, the concepts of exon skipping, gene therapy, and gene editing have been advanced and are in clinical trials. In exon skipping, a form of RNA splicing is used to cause cells to “skip” over faulty sections of the genetic code, leading to a truncated but still functional protein despite the genetic mutation (Kole & Krieg, 2015). The first exon skipping drug was approved in 2016 for use in a subgroup of individuals with Duchenne muscular dystrophy who have a specific mutation. In gene therapy, copies of the normal gene are infused most commonly using a virus transporter in order to “replace” the defective gene. At the writing of this edition, the only approved gene therapy drugs are for cancer and HIV, although gene therapy clinical trials for several single gene defects causing developmental disabilities are currently in process. Gene editing is a form of gene therapy in which a technology called CRISPR/Cas9 is used to cut the gene at the point of the mutation and to replace it with a corrected gene sequence. The first successful case of gene editing in an embryo in the United States was reported in 2017 (Ma et al., 2017). Researchers targeted and edited a gene associated with cardiac disease at the level of the embryo. Although gene editing technology is available, many ethical considerations exist around this type of practice. Some argue that gene editing of an embryo allows prevention of serious genetic diseases, while others express concerns around creating “designer babies” or selecting traits such as SUMMARY SUMMARY A range of approaches is being used to treat genetic • Each human cell contains a full complement of disorders. In the case of inborn errors of metabolism, genetic information encoded in genes contained in treatment has focused on either replacing the deficient 46 chromosomes. product of the defective enzyme (e.g., in thyroid hor- • The unequal division of the reproductive cells, the mone deficiency) preventing the accumulation of toxic deletion of a part of a chromosome, the mutation in material because the enzyme does not break it down or a single gene, or the modification of gene expresreplacing the defective enzyme (see Chapter 16). Pre- replacing the defective enzyme (see Chapter 16). Presion can each lead to developmental disabilities. venting accumulation of toxic metabolites often relies on dietary manipulation (e.g., PKU) or stimulation of • There are numerous genetic tests available to diag- an alternate pathway around the enzyme block (urea nose many of these genetic disorders. cycle disorders). In a few cases, enzyme replacement • Early identification may lead to improved outcome therapy is available (e.g., in Gaucher disease). Here the as a result of therapies that are now available for missing or defective enzyme is given intravenously at certain rare genetic disorders associated with develintervals to correct the metabolic defect. Bone marrow transplantation (e.g., in sickle cell disease) or liver transplantation (e.g., in OTC deficiency) has been used to correct other genetic disorders by replacing the organ correct other genetic disorders by replacing the organ ADDITIONAL RESOURCES that is producing the defective product with an organ that can produce a normal one. While these approaches National Library of Medicine (NLM): http://www to genetic disorders have improved outcomes in a num-.nlm.nih.gov ber of disorders, they represent only a fraction of all the ber of disorders, they represent only a fraction of all the Genetic Alliance: http://www.geneticalliance.org genetic causes of developmental disabilities and their Online Mendelian Inheritance in Man (OMIM): More recently, the concepts of exon skipping, gene http://www.ncbi.nlm.nih.gov/omim therapy, and gene editing have been advanced and Additional resources can be found online in are in clinical trials. In exon skipping, a form of RNA Appendix D: Childhood Disabilities Resources, Sersplicing is used to cause cells to “skip” over faulty secvices, and Organizations (see About the Online Comtions of the genetic code, leading to a truncated but still Krieg, 2015). 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