Genetics and Genomics of Neurobehavioral Disorders

427 Pages·2003·1.967 MB·English

by  Gene S. Fisch (auth.), Gene S. Fisch PhD (eds.)

Genetics and Genomics
of Neurobehavioral Disorders
C
ontemporary
C
linical
Series Editors:
N Ralph Lydic and
euroscience
Helen A. Baghdoyan
Genetics and Genomics of Neurobehavioral Disorders
edited by Gene S. Fisch, 2003
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edited by Shobha Malviya, Norah N. Naughton, and Kevin K.
Tremper, 2003
Neural Mechanisms of Anesthesia, edited by Joseph F. Antognini,
Earl E. Carstens, and Douglas E. Raines, 2002
Glutamate and Addiction
edited by Barbara Herman, 2002
Molecular Mechanisms of Neurodegenerative Diseases
edited by Marie-Françoise Chesselet, 2000
Contemporary Clinical Neuroscience
Genetics and Genomics
of Neurobehavioral
Disorders
Edited by
Gene S. Fisch
Department of Epidemiology and Public Health
and the Child Study Center
Yale University School of Medicine
New Haven, CT
Springer Science+Business Media, LLC
© 2003 Springer Science+Business Media New York
Originally published by Humana Press Inc in 2003
Softcover reprint of the hardcover 1st edition 2003
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Library of Congress Cataloging-in-Publication Data
Genetics and genomics of neurobehavioral disorders / edited by Gene S. Fisch.
p. cm. -- (Contemporary clinical neuroscience)
Includes bibliographical references and index.
ISBN 978-1-61737-322-0 ISBN 978-1-59259-353-8 (eBook)
DOI 10.1007/978-1-59259-353-8
1. Neurobehavioral disorders--Genetic aspects. I. Fisch, Gene S. II. Series.
RC455.4.G4 G493 2003
616.8’0442--dc21
2002068944
Preface
Although it seems clichéd to say so, we live in a time of great discovery.
With the remarkable advances in molecular genetics and genomics, and the
Human Genome Project essentially completed, the feasibility of establishing
meaningful genotype–phenotype correlations for complex human neurobehavioral
disorders is within our reach.
In recent years, molecular geneticists have cloned, among others, genes
producing Huntington’s disease, spinal cerebellar ataxia, myotonic dystrophy,
the fragile X syndrome (FXS), FRAXE (the “other” fragile X disorder),
α-thalassemia mental retardation (ATR-X syndrome), neurofibromatosis
types 1 and 2, tuberous sclerosis 1 and 2, and Rett syndrome. Researchers
have also identified many of the genes in regions containing microdeletions
that are associated with other neurobehavioral disorders, e.g., Prader–Willi/
Angelman syndromes, Williams syndrome, and velo-cardio-facial syndrome
(del22q11). Other genes associated with nonsyndromal X-linked mental
retardation (MRX) have also been identified.
At the phenotypic end of these disorders, the development, refinement,
and standardization of psychometric, clinical, and neuropsychological
instruments have led to greater precision in the quantitative assessment and
evaluation of cognition deficits and behavioral dysfunction. Among other
neuroimaging techniques, functional magnetic resonance imaging (fMRI) now
permits noninvasive access to brain function during the performance of various
cognitive tasks. The development of animal models to emulate cognitive–
behavioral features associated with many human genetic mutations, e.g.,
α-calcium-calmodulin kinase II, FXS, and Rett syndrome, also permit us to
examine neurobiological and neurophysiological functions, as well as
neuroanatomical structures that could not have been previously investigated.
The time has come to weave the various molecular genetic, genomic,
neurophysiological, and neurobehavioral threads together into a cohesive fabric
of human genes, brain, and behavior. The goal of Genetics and Genomics of
Neurobehavioral Disorders is to provide the reader with a clear and
comprehensive account of how genetic abnormalities, neurobiology, and
neuropsychology work in concert to manifest cognitive–behavioral dysfunction.
To achieve our objective, we have divided Genetics and Genomics of
Neurobehavioral Disorders into four distinct parts. In the first we present an
v
vi Preface
introduction and overview of neurobehavioral disorders. Chapter 1 introduces
neurobehavioral disorders from an historical prospective. Chapter 2 considers the
neuroanatomical aspects of neurogenetic disorders, and Chapter 3 examines
animal model strategies to investigate cognitive–behavioral deficits. The fourth
chapter discusses the utility of examining behavioral phenotypes to investigate
the pathway between genes and behavior.
The second part of the text is devoted to autosomal disorders that produce
neurobehavioral dysfunction. Chapter 5 explores the genetics and pleiotropic
phenotype of neurofibromatosis type 1. Chapter 6 is devoted to the cognitive–
behavioral phenotype in Prader–Willi syndrome and Angelman syndrome
and the genes in the deleted region that seem to affect specific functions in
PWS/AS. The seventh chapter examines tuberous sclerosis 1 and 2 and genes
recently discovered that cause these disorders. Chapter 8 investigates
the behavioral phenotype in del22q11 (velo-cardio-facial syndrome), the
psychopathology associated with the disorder, and the genes known to be
deleted from the region. In Chapter 9, Williams–Beuren syndrome and genes
in the deleted region on chromosome 7 known to be associated with the disorder
are presented. The chapter on myotonic dystrophy (Chapter 10) describes the
phenotype and the difficulties in teasing out the psychopathology associated
with the disorder from what may be produced by the mutation itself.
The third and fourth parts consider X-linked disorders in which syndromal
and nonsyndromal forms of XLMR are present. First, the nonsyndromal forms
of X-linked mental retardation are presented in Chapters 11 and 12. Chapter
11 is a comprehensive examination of all known genes that produce syndromal
and nonsyndromal XLMR (three of which are discussed in Part IV). Chapter
12 is the first comprehensive account of the genotype and phenotype in FRAXE,
the“other” fragile X mutation. In Part IV the final three chapters are devoted
to the three major syndromal forms of XLMR. In Chapter 13, α-thalassemia
mental retardation (ATR-X) syndrome is described and both gene and gene
function are reported. Chapter 14 is a comprehensive account of the fragile X
syndrome and the fragile X mutation. Chapter 15 discusses Rett syndrome, an
X-linked disorder primarily affecting females.
The editor and authors thank Martine Borghgraef, Edward Cook, Stewart
Einfeld, Jean-Pierre Fryns, Miriam Grosof, Keith Johnson, Samantha Knight,
Hans-Pieter Lipp, James MacPherson, Barbara Pober, Charles Schwartz, Roger
Stevenson, and Flora Vaccarino for reviewing the chapters, and for their many
comments and suggestions.
Gene S. Fisch
Contents
Preface.................................................................................................... v
Contributors......................................................................................... ix
PART I. INTRODUCTION AND OVERVIEW
1 The Genetics and Genomics of Neurobehavioral Disorders:
Historical Introduction and Overview
Gene S. Fisch ......................................................................................3
2 Neuroanatomical Considerations
Specific to the Study of Neurogenetics
Albert M. Galaburda and J. Eric Schmitt...................................21
3 Modeling Cognitive Disorders: From Genes to Therapies
Rui M. Costa, Ype Elgersma, and Alcino J. Silva.....................39
4 What Can the Study of Behavioral Phenotypes Teach Us
About the Pathway from Genes to Behavior?
Jonathan Flint..................................................................................69
PART II. AUTOSOMAL DISORDERS AND NEUROBEHAVIORAL DYSFUNCTION
5 The Central Nervous System in Neurofibromatosis Type 1
Nancy Ratner and Kathryn North...............................................97
6 Prader–Willi and Angelman Syndromes:
Cognitive and Behavioral Phenotypes
Elisabeth M. Dykens and Suzanne B. Cassidy........................133
7 Tuberous Sclerosis
Julian R. Sampson and Julia C. Lewis......................................159
8 Behavioral Phenotype in Velo-Cardio-Facial Syndrome
Kieran C. Murphy..........................................................................195
9 Williams–Beuren Syndrome
Mònica Bayés and Luis A. Pérez Jurado ..................................209
10 Behavioral Phenotype in Myotonic Dystrophy
(Steinert’s Disease)
Jean Steyaert..................................................................................237
vii
viii Contents
PART III. X-LINKED NONSYNDROMAL DISORDERSAND NEUROBEHAVIORAL
DYSFUNCTION
11 Genetics of X-Linked Mental Retardation
Jamel Chelly and Ben C. J. Hamel..............................................263
12 Nonsyndromal Mental Retardation Associated
with the FRAXE Fragile Site and the FMR2 Gene
Jozef Gécz and Gene S. Fisch ......................................................289
PART IV. X-LINKED SYNDROMAL DISORDERSAND NEUROBEHAVIORAL
DYSFUNCTION
13 ATR-X Syndrome
Takahito Wada and Richard J. Gibbons..................................309
14 The Fragile X Syndrome and the Fragile X Mutation
Mark C. Hirst and Gene S. Fisch................................................335
15 Rett Syndrome: Clinical–Molecular Correlates
Alan K. Percy, Joanna Dragich, and N. Carolyn Schanen ....391
Index....................................................................................................419
Contributors
MÒNICA BAYÉS, PhD• Departament de Ciències Experimentals i de la Salut
(Genetics), Universitat Pompeu Fabra, Barcelona, Spain
SUZANNE B. CASSIDY, MD• Director, Division of Human Genetics,
Department of Pediatrics, University of California at Irvine, Orange, CA
JAMEL CHELLY, MD• Institut Cochin, Laboratoire de Génétique et de
Physiopathologie des Retards Mentaux, Paris, France
RUI M. COSTA,PhD • Departments of Neurobiology, Psychiatry, and
Psychology, and Brain Research Institute, University
of California Los Angeles, Los Angeles, CA
JOANNA DRAGICH, BS• Department of Human Genetics, University
of California Los Angeles School of Medicine, Los Angeles, CA
ELISABETH M. DYKENS,PhD • Neuropsychiatric Institute, University
of California Los Angeles, Los Angeles, CA
YPE ELGERSMA, PhD• Departments of Neurobiology, Psychiatry,
and Psychology, and Brain Research Institute, University of California
Los Angeles, Los Angeles, CA
GENE S. FISCH, PhD• Senior Research Scientist, Division of Biostatistics,
Department of Epidemiology and Public Health, and the Child Study
Center, Yale University School of Medicine, New Haven, CT
JONATHAN FLINT, MD• Wellcome Trust Centre for Human Genetics,
University of Oxford, Oxford, UK
ALBERT M. GALABURDA,MD• Emily Fisher Landau Professor of Neurology
and Neuroscience, Harvard Medical School, Beth Israel Deaconess
Medical Center, Boston, MA
JOZEF GÉCZ,PhD • Department of Cytogenetics and Molecular Genetics,
Women’s and Children’s Hospital; Department of Paediatrics, Adelaide
University, Adelaide, SA, Australia
RICHARD J. GIBBONS,DPhil, FRCP • MRC Molecular Haematology Unit,
Weatherall Institute of Molecular Medicine, University of Oxford, John
Radcliffe Hospital, Oxford, UK
BEN C. J. HAMEL,MD• Department of Human Genetics, University Medical
Centre Nijmegen, Nijmegen, The Netherlands
ix
x Contributors
MARK C. HIRST,DPhil • Molecular Genetics Section, Department
of Biological Sciences, The Open University, Milton Keynes, England
LUIS A. PÉREZ JURADO, MD,PhD • Departament de Ciències Experimentals
i de la Salut (Genetics), Universitat Pompeu Fabra, Barcelona, Spain
JULIA C. LEWIS, MRCPsych • Institute of Medical Genetics, University
of Wales College of Medicine, Cardiff, UK
KIERAN C. MURPHY, MMedSci, PhD, MRCPI, MRCPsych• Department
of Psychiatry, Royal College of Surgeons in Ireland; Education
and Research Centre, Beaumont Hospital, Dublin, Ireland
KATHRYN NORTH, MD, FRACP• Department of Paediatrics, University
of Sydney; Head, Neurogenetics Research Unit, Deputy Head, Institute
of Neuromuscular Research, The Children’s Hospital at Westmead,
Westmead, Sydney, NSW, Australia
ALAN K. PERCY,MD• Departments of Pediatrics, Neurology,
and Neurobiology, University of Alabama at Birmingham School
of Medicine, Birmingham, AL
NANCY RATNER, PhD• Department of Cell Biology, Neurobiology, and
Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH
JULIAN R. SAMPSON, DM• Institute of Medical Genetics, University of Wales
College of Medicine, Cardiff, UK
N. CAROLYN SCHANEN,MD, PhD• Head of Human Genetics Research,
Nemours Research Programs, Alfred I. duPont Hospital for Children,
Wilmington, DE
J. ERIC SCHMITT, MD• Stanford Psychiatry Neuroimaging Laboratory,
Stanford University School of Medicine, Stanford, CA
ALCINO J. SILVA, PhD• Departments of Neurobiology, Psychiatry,
and Psychology, and Brain Research Institute, University of California
Los Angeles, Los Angeles, CA
JEAN STEYAERT,MD• Department of Clinical Genetics, University
of Maastricht, Maastricht, The Netherlands; Department of Child
Psychiatry, University of Leuven, Belgium
TAKAHITO WADA,PhD • MRC Molecular Haematology Unit, Weatherall
Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK