Understanding Autism, From Basic Neuroscience to Treatment.pdf

Autism

From Basic Neuroscience to Treatment

Understanding

Autism

From Basic Neuroscience to Treatment

Edited by

Steven O. Moldin, Ph.D.

University of Southern California

Los Angeles, California

John L.R. Rubenstein, M.D., Ph.D.

University of California

San Francisco, California

Boca Raton London New York

CRC is an imprint of the Taylor & Francis Group,

an informa business

Understanding

This book was written by Dr. Steven O. Moldin in his private capacity, outside his professional position as

Director of the Office of Human Genetics and Genomic Resources, and Associate Director, Division of Neu-

roscience & Basic Behavioral Science, National Institute of Mental Health (NIMH), National Institutes of Health

(NIH), Bethesda, Maryland, USA. The views expressed in this book do not necessarily represent the views of

NIMH, NIH, the Department of Health and Human Services nor of the United States Government.

Published in 2006 by

CRC Press

Taylor & Francis Group

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Boca Raton, FL 33487-2742

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10987654321

International Standard Book Number-10: 0-8493-2732-6 (Hardcover)

International Standard Book Number-13: 978-0-8493-2732-2 (Hardcover)

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Library of Congress Cataloging-in-Publication Data

Understanding autism : from basic neuroscience to treatment / edited by Steven O. Moldin, John L.R.

Rubenstein.

p. ; cm.

Includes bibliographical references and index.

ISBN 0-8493-2732-6 (alk. paper)

1. Autism. I. Moldin, Steven O. II. Rubenstein, John L.R., 1955-

[DNLM: 1. Autistic Disorder--diagnosis. 2. Autistic Disorder--genetics. 3. Autistic

Disorder--therapy. WM 203.5 U546 2006]

RC553.A88U53 2006

616.85’882--dc22

2005046674

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Foreword

Autism spectrum disorders exact a serious toll on those affected, on their families,

and, as a result of behavioral problems and signiﬁcant levels of disability, on society.

Despite that toll, autism has not historically received adequate research attention. The

lack of research reﬂected a mistaken belief that autism was very rare, and there was

a lack of reliable, broadly accepted diagnostic standards, and until recently, a lack of

scientiﬁc tools with which to make progress. As attested to by this volume, all this

has changed. While we still have far to go before we possess a deep understanding of

autism that translates into highly efﬁcacious new treatments, research on autism is

moving at an increasingly rapid pace and yielding promising new results.

What factors have led to the exciting new progress in autism research that is

summarized in this text? An important contribution, without doubt, was the tireless

advocacy of the families of affected individuals, families who refused to accept the

message that there was no hope. Interest in autism was also spurred by the broad

recognition that it represented a spectrum of disorders, which in aggregate were more

common than had been believed and more costly to society ( Chapter 20 ). This new

epidemiological information ( Chapter 2 ) and indeed all of autism research were facili-

tated by improved approaches to diagnosis. Progress in phenotyping and diagnosis

( Chapter 1 ) required not only new scientiﬁc efforts, but also a willingness on the part

of many researchers to reach consensus on the assignment of individuals to the autism

spectrum and to different points along the way. All this could not have created the

stirrings of progress without the emergence of new scientiﬁc tools and approaches. Some,

like the explosion of new tools for genetics developed entirely independently of autism

research, others like social neuroscience — the investigation of the circuitry and neural

mechanisms that underlie human interaction — developed in part, as a result of the new

interest in autism. Social neuroscience itself depended on the development of increas-

ingly good tools for human neuroimaging and the broad advance made by cognitive

neuroscience in addressing the underpinnings of thought, emotion, and behavior.

It is hard to overstate both the potential signiﬁcance and also the difﬁculty of a

genetic analysis of the autism spectrum ( Chapters 3 and 4 ). Gene discovery should

provide tools for neuroscientists trying to understand the neural basis of autism, and

may provide clues to new treatments. Based on twin studies, we know that of all

risk factors, genes make the largest contribution to autism spectrum disorders. As

is well known, twin studies also reveal that genes are not fate — not all monozygotic

twin pairs with an affected member are concordant for an autism spectrum disorder.

Thus, developmental, stochastic, or environmental factors must play a role in con-

verting genetic risk into disease. Nonetheless, genes exert a powerful effect, more

powerful than for schizophrenia or bipolar disorder, for example. Despite the large

effect of genes, the search for genetic risk factors has proved extremely frustrating.

In recent years, it has been hypothesized that autism spectrum disorders —indeed,

all common neuropsychiatric phenotypes — are genetically complex. That is to say

that while genes are highly signiﬁcant in aggregate, the genetic component of risk

is comprised of many genetic loci, each making a small contribution that is therefore

difﬁcult to detect. Moreover, different combinations of genetic risk factors might

act in different populations. Without the recent genomic and genetic tools that derived

from the Human Genome Project and its many follow-on projects, it would simply

be impossible to identify risk genes involved in common neuropsychiatric disorders.

Recent maps of human genetic diversity and cost-effective tools for genotyping are

beginning to make gene hunting feasible.

If the challenges posed by genetic complexity were not enough, we are beginning

to realize that the inherited sequence of genes may not be the whole explanation for the

inﬂuence of the genome on disease risk ( Chapter 5 ). Epigenetic factors may also play a

role in autism spectrum disorders and other neuropsychiatric disorders. Epigenetic inﬂu-

ences on gene expression reﬂect the methylation of certain DNA sequences and other

mechanisms that regulate the structure of chromatin and therefore gene expression.

Epigenetic risk factors are not detected by many of the common approaches to neurop-

sychiatric genetics. While it is daunting to confront the complexity of identifying genetic,

epigenetic, developmental, and environmental factors that interact to produce autism, it

is also a hopeful sign that scientists investigating autism are incorporating sophisticated

new approaches and, at the same time, adding to them (Chapter 5).

If genetics represents one of the central “bottom-up” approaches to autism, cog-

nitive and social neuroscience represent critical “top-down” approaches. Several chapters

in this book reﬂect advances in our analysis of the cognitive ( Chapter 8 ), the emotional

( Chapter 6 ), and the social brain ( Chapter 10 ) that are producing insights into autism.

Beyond deeper understanding, the results that will emerge from these ﬁelds should

ultimately have profound practical signiﬁcance. Cognitive tests combined with neu-

roimaging should make an important contribution to phenotyping for genetics and

other more basic investigations. Right now, the heterogeneity of individuals with

autistic symptoms is a major obstacle to research. In time, these approaches, perhaps

combined with genetics, may lead to more certain clinical diagnoses, perhaps predic-

tive of treatment response. Finally, as in all disease processes, biomarkers, i.e., objec-

tively measurable correlates of disease progression, can play an important role in the

development and monitoring of treatment. Rather than relying on subjective ratings,

clinical trials of both pharmacologic and behavioral treatments, and clinical practice

might one day be able to beneﬁt from objective measures.

As reﬂected in this volume, developmental neurobiology, the creation of animal

models ( Chapter 12 ), systems neurobiology ( Chapters 7 , 9 , 11 , 13 ), and structural neuro-

imaging ( Chapter 15 ) of the human brain are also making signiﬁcant contributions to

our understanding of the autism spectrum. As a disorder of the brain that impairs higher

cognitive function, emotion, and behavioral control, autism can only be understood by

bringing many different disciplines together. While we still need a great deal of progress

in each of these areas and above all at their interfaces, the accomplishments of the past

decade, as illustrated in this book, have created a palpable sense of positive movement.

Steven E. Hyman, M.D.

Harvard University

Cambridge, Massachusetts

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