孤独症的遗传学

DOI: 10.1542/peds.113.5.e472 2004;113;e472-e486 Pediatrics Rebecca Muhle, Stephanie V. Trentacoste and Isabelle Rapin The Genetics of Autism http://www.pediatrics.org/cgi/content/full/113/5/e472 located on the World Wide Web at: The online version of this article, along with updated information and services, is rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk publication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly by on July 6, 2009 www.pediatrics.orgDownloaded from REVIEW ARTICLE The Genetics of Autism Rebecca Muhle, BA*; Stephanie V. Trentacoste, BA*; and Isabelle Rapin, MD‡ ABSTRACT. Autism is a complex, behaviorally de- fined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric preva- lence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new en- vironmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive develop- mental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and Interna- tional Classification of Diseases, Tenth Revision. Except for Rett syndrome—attributable in most affected indi- viduals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene—the other PDD subtypes (autistic disor- der, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published be- tween 1961 and 2003 yields convincing evidence for mul- tiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, ter- atogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the mea- sles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/non- genetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytoge- netic abnormalities, and single-gene defects (eg, tuber- ous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that “idiopathic” autism is a herita- ble disorder. Epidemiologic studies report an ASD prev- alence of �3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the con- tribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is �2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic au- tism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to ge- netic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that in- cluded communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause “idiopathic” autism but that epigenetic factors and exposure to envi- ronmental modifiers may contribute to variable expres- sion of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual’s genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identify- ing genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in popula- tions of multiplex families (families with >1 affected family member); 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive con- tribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest in- teractions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31- q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a “chromosome 15 pheno- type” was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22- q33 and the GABAA receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the seroto- nin transporter gene (5-HTT) on 17q11-q12 are more fre- quent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more chil- dren with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in From the *Class of 2004, Albert Einstein College of Medicine, Bronx, New York; and ‡Saul R. Korey Department of Neurology, Department of Pedi- atrics, and Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, New York. Received for publication Aug 27, 2002; accepted Dec 1, 2003. Ms Muhle and Ms Trentacoste contributed equally to this work. Address correspondence to Isabelle Rapin, MD, Albert Einstein College of Medicine, K 807, 1300 Morris Park Ave, Bronx NY 10461. E-mail: rapin@aecom.yu.edu PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- emy of Pediatrics. e472 PEDIATRICS Vol. 113 No. 5 May 2004 http://www.pediatrics.org/cgi/content/full/113/5/e472 by on July 6, 2009 www.pediatrics.orgDownloaded from high-functioning children with a normal appearance and IQ and moderate social and language impairments. Ge- netic counseling justifies testing, but until autism genes are identified and their functions are understood, prena- tal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormali- ties. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogene- sis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elu- cidating the influences of their products on brain devel- opment and physiology. Pediatrics 2004;113:e472–e486. URL: http://www.pediatrics.org/cgi/content/full/113/ 5/e472; autism, genetic, chromosome, review. ABBREVIATIONS. ASD, autistic spectrum disorder; PDD, perva- sive developmental disorder; MMR, measles-mumps-rubella; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; ICD-10, International Classification of Diseases Tenth Revi- sion; TSC, tuberous sclerosis complex; FXS, fragile X syndrome; AS, Angelman syndrome; PWS, Prader-Willi syndrome; MZ, monozygotic; DZ, dizygotic; LD, linkage disequilibrium; GABA, �-amino butyric acid; IMGSAC, International Molecular Genetic Study of Autism Consortium; MLS, multipoint logarithm of the odds score; DBH, dopamine � hydroxylase; Hox, homeobox; OT, oxytocin. Autism, also known as autistic spectrum dis-order (ASD) or pervasive developmentaldisorder (PDD), is of great concern to the practicing pediatrician. The US Department of De- velopmental Services reported a 556% increase in the prevalence of autism from 1991 to 1997,1 a rate that is higher than the prevalence rates reported for other pediatric disorders such as spina bifida, cancer, and Down syndrome.2 Likely explanations for this aston- ishing increase include the inclusion of broader cri- teria for the diagnosis of ASD and physicians’ in- creased awareness of ASD symptoms.3 Although the media have focused attention on the measles- mumps-rubella (MMR) vaccine and, more recently, mercury poisoning as potential causes of autism, epidemiologic studies to date have shown no correl- ative associations.4,5 Greater public awareness of autism has led to increased funding for autism re- search, yet the cause of ASD remains largely un- known because of the complex behavioral pheno- types and multigenic etiology of this disorder.6 According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM- IV-TR)7 and International Classification of Diseases, Tenth Revision (ICD-10)8 classifications, autism is characterized by impairments in 3 behavioral do- mains: 1) social interaction; 2) language, communi- cation, and imaginative play; and 3) range of inter- ests and activities.7 Assignment to 1 of 5 subtypes is based on the number and distribution of endorsed behavioral descriptors in each of the domains, as well as on the age at onset. The 5 DSM-IV PDD subtypes are 1) autistic disorder (classic autism), 2) Asperger disorder (language development at the ex- pected age, no mental retardation), 3) disintegrative disorder (behavioral, cognitive, and language regres- sion between ages 2 and 10 years after entirely nor- mal early development, including language), 4) PDD not otherwise specified (individuals who have autis- tic features and do not fit any of the other subtypes), and 5) Rett disorder (a genetic disorder of postnatal brain development, caused by a single-gene defect predominantly affecting girls). The highly variable cognitive manifestations of the ASDs range from a nonverbal child with severe men- tal retardation and self-injury9 to a high-functioning college student with an above-average IQ despite impaired language use and inadequate social skills.10 Mental retardation thus is not a defining criterion for autism (albeit certain cognitive abilities are charac- teristically affected), but the mean distribution of IQs is lower than average,11 and the likelihood of retar- dation increases with more widespread brain dys- function.12 Mental retardation is itself a behaviorally defined disorder of complex human abilities with many genetic and nongenetic causes. The more se- vere the retardation, the more likely the underlying brain dysfunction will affect the widely distributed networks responsible for sociability, language, and cognitive flexibility. Like mental retardation, autism is a behaviorally defined syndrome with a wide variety of both ge- netic and nongenetic causes. With the exception of Rett syndrome, which is caused in the majority of cases by de novo mutations or microdeletions of the methyl-CpG-binding protein 2 (MeCP2) gene on Xq28,13 there is no current evidence that the other DSM-IV subtypes of autism are linked to any partic- ular genetic or nongenetic disorder. Therefore, when we refer in this article to autism, we are referring to the entire spectrum of behaviorally defined autism with the exception of Rett syndrome. Current evi- dence indicates that multiple genetic factors are the causative determinants of the majority of cases of autism.14 METHODS We performed a comprehensive search of Medline using the terms “autism,” “autistic,” “gene,” “genome,” ”genomic,“ ”ge- netic,“ ”chromosome,“ ”chromosomal,“ and ”loci“ in various combinations. These queries returned �500 citations. We re- viewed papers published between 1961 and 2003, focusing on scientific articles published between 1995 and 2003. After study of these papers, we performed additional searches to examine spe- cific topics (eg, ”autism, oxytocin“) not included in the initial set. We also reviewed 2 current definitive textbooks concerned with autism: Cohen and Volkmar15 and Gillberg and Coleman.9 RESULTS Defined Nongenetic and Genetic Medical Conditions Associated With Autism Autism has been linked to a wide variety of pre- natal and postnatal insults but predominantly in in- dividual case reports or short series. In the aggregate, they account for only a small percentage of cases.9,16 Obstetric complications (eg, an increased incidence of uterine bleeding) have often been blamed for au- tism17 despite that many studies show no significant http://www.pediatrics.org/cgi/content/full/113/5/e472 e473 by on July 6, 2009 www.pediatrics.orgDownloaded from causal relationship.18,19 Intrauterine exposure to the teratogenic drugs thalidomide and valproate have been implicated as the cause of autism in a few affected children.20,21 Mean levels of some of the neuropeptides substance P, vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, and neurotrophin nerve growth factor, the concentration of all of which is under genetic control, were elevated in the cord blood of children who later received a diagnosis of autism or mental retardation22; they were normal in nonautistic children with cerebral palsy, which generally results from an abnormal in- trauterine environment or peri-/postnatal insult rather than a genetic condition. Maternal factors have also been examined as potential causes of au- tism; antibodies in the sera of a mother of 2 children, one with autism and another with severe language impairment, were shown to bind to the cerebellar cells of developing fetal mice.23 There is no evidence in population surveys of any association between autism and immigrant status, socioeconomic status, or ethnicity.16 Various epidemiologic studies have reported that cerebral palsy, defined as a static motor deficit of brain origin present from early life, is present in 2.1% to 2.9% of individuals with autism and mental retar- dation.24–27 Congenital rubella infection, initially found to be highly associated with autism,28 is present in only 0.75% of recent autistic populations,24 thanks to the near eradication of rubella after the introduction of quasi-universal immunization in Western countries. Other pre- and postnatal infec- tions by organisms such as Haemophilus influenzae and cytomegalovirus can cause autism when they significantly damage the immature brain.9 In a review of several epidemiologic studies of autism, Fombonne24 found no association between autism and inflammatory bowel disease or with a live MMR vaccination. This contradicts an earlier publication by Wakefield et al.29 Large surveys that have examined the prevalence of autism before and after the initiation of widespread MMR vaccination have also failed to corroborate an association with autism4,5 but have not reassured a skeptical public of the safety of the vaccine.30 Some investigators pos- tulate that it is the mercury-based preservative thimerosal in vaccines, rather than the vaccines themselves, that poses a risk to the developing in- fant.31 This theory has also met with significant crit- icism.32 Epilepsy has the highest association with autism, reported in up to a third of individuals with an ASD by adulthood.25–27,33–35 The epilepsy may be subclin- ical, yielding an electroencephalogram that is epilep- tiform but without clinical seizures, and is particu- larly frequent in disintegrative disorder.36 Like autism, epilepsy is a disorder of the brain with mul- tiple genetic and nongenetic causes and a broad range of phenotypes. Infantile spasms are particu- larly likely to result in autism with nondevelopment of language and mental retardation, especially when the epileptiform activity involves both temporal lobes.37 An occasional nonverbal child with mental retardation, autism, and epilepsy has exhibited early bilateral hippocampal sclerosis.38,39 Behavioral symptoms of autism are frequent in tuberous sclerosis complex (TSC) and fragile X syn- drome (FXS), but these 2 disorders nevertheless ac- count for only a minority of the total cases of au- tism.40,41 Given the high rate of epilepsy in children with TSC and the association between autism and epilepsy, it is perhaps not surprising that as many as 25% of patients with TSC have autism.42,43 An auto- somally dominant neurocutaneous disorder, TSC arises from genetic mutations of either TSC1 on 9q or TSC2 on 16p and is characterized by ash-leaf depig- mented or other cutaneous manifestations and hamartomatous lesions in multiple organs. In the brain, these lesions are termed tubers, and they are thought to cause the epilepsy seen in more than three quarters of children with TSC.44,45 Furthermore, it is the haphazard distribution of these tubers, together with other metabolic changes, that influences the phenotype of TSC, giving rise in some individuals to autism or epilepsy (often infantile spasms).37 In the population of patients with autism, numerous stud- ies have quoted TSC rates of 1.1% to 1.3%,25–27,46 rates that, although low, are 30% higher than the prevalence of TSC in the general population. FXS is an X-linked genetic disorder that is signifi- cantly associated with autism and that is denoted by unusual facial features, macro-orchidism in adult- hood, and cognitive impairment of variable severity. It is caused by an increased number of trinucleotide (CGG) repeats in the gene coding for the fragile X mental retardation protein. Approximately 30% of individuals with FXS are on the autistic spec- trum.47,48 There is disagreement, however, over the degree of FXS prevalence in patients with autism. Some early studies reported little or no association between FXS and autism,24,49 whereas others found a high association50 (see41 for additional review). More recent epidemiologic studies have documented rates of FXS between 7% and 8% in populations with autism.26,33,51,52 The discrepancies regarding the prevalence of FXS among individuals with autism may reflect the limited reliability of the cytogenetic tests used in the past compared with the more sen- sitive molecular tests currently used; as such, the number of girls who receive a diagnosis of FXS has increased.6 Genetic mutations that give rise to a number of additional diagnosable