The Neuroscience of Autism Spectrum Disorders

Joseph D. Buxbaum, Patrick R. Hof

• Publisher: Academic Press
• Year: 2012
• Print ISBN: 9780123919243
• eBook ISBN: 9780123919304
• Topic: Medicine
• Subtopic: Neurology

Autism is no longer considered a rare disease, and the Center for Disease Control now estimates that upwards of 730, 000 children in the US struggle with this isolating brain disorder. New research is leading to greater understanding of and ability to treat the disorder at an earlier age. It is hoped that further genetic and imaging studies will lead to biologically based diagnostic techniques that could help speed detection and allow early, more effective intervention.Edited by two leaders in the field, this volume offers a current survey and synthesis of the most important findings of the neuroscience behind autism of the past 20 years. With chapters authored by experts in each topic, the volume explores etiology, neuropathology, imaging, and pathways/models. Offering a broad background of ASDs with a unique focus on neurobiology, the volume offers more than the others on the market with a strictly clinical focus or a single authored perspective that fails to offer expert, comprehensive coverage. Researchers and graduate students alike with an interest in developmental disorders and autism will benefit, as will autism specialists across psychology and medicine looking to expand their expertise.- Uniquely explores ASDs from a neurobiological angle, looking to uncover the molecular/cellular basis rather than to merely catalog the commonly used behavioral interventions- Comprehensive coverage synthesizes widely dispersed research, serving as one-stop shopping for neurodevelopmental disorder researchers and autism specialists- Edited work with chapters authored by leaders in the field around the globe – the broadest, most expert coverage available

Section II

Etiology of Autism Spectrum Disorders

Joseph D. Buxbaum

Chapter 2.1 Etiological Heterogeneity in Autism Spectrum Disorders

Chapter 2.2 Copy Number Variation in Autism Spectrum Disorders

Chapter 2.3 Common Genetic Variants in Autism Spectrum Disorders

Chapter 2.4 Next-Generation Sequencing For Gene and Pathway Discovery and Analysis in Autism Spectrum Disorders

Chapter 2.5 Mitochondria and Autism Spectrum Disorders

Chapter 2.6 Parental and Perinatal Risk Factors for Autism

Chapter 2.7 The Environment in Autism Spectrum Disorders

Chapter 2.8 Hormonal Influences in Typical Development

Chapter 2.9 Immune Abnormalities and Autism Spectrum Disorders

There have been eight twin studies in autism spectrum disorders (ASD) and all show increased concordance between monozygotic twins, compared to dizygotic twins. These findings are strong evidence for an important role for genetics in ASD ‘ACE’ modeling, which derives its name from an attempt to divide risk into three components, termed A (additive genetics), C (common twin environment), and E (unique twin environment), gives estimates of heritability amongst the highest in psychiatry when applied to these twin studies. Additional family studies also provide strong support for a genetic risk for ASD. Genes and their gene products provide a molecular window into disease pathogenesis, are readily translated into model systems, and are ideal targets for drug development.

There is also evidence from the twin studies for what has been called ‘environmental’ risk for ASD. ACE modeling was established years ago, before other mechanisms were considered in detail, and it is important to understand that the historical titles associated with each category (broadly ‘genetic’ and ‘environmental’) are imprecise, with ‘genetic’ including things in addition to germline genetic changes, and ‘environment’ covering things including genetic and non-genetic factors. For example, in modern epidemiology one can consider de novo germline mutation, epigenetics, somatic mutation, epistatic interactions between loci, stochastic phenomena – including random X chromosome inactivation, monoallelic expression of some genes, mitochondrial effects, parent-of-origin effects, gene–environment interaction and gene–environment correlation, maternal/fetal effects, and likely additional mechanisms. Where each of these mechanisms fall in ACE modeling is not always well studied, but suffice to say that many of these mechanisms will fall into ‘genetic’ or ‘environmental’ categories. In short, what proportion of positive values for A, C or E reflect some of these other mechanisms cannot be determined from ACE modelling, and the field is only now beginning to grapple with some of these mechanisms, as represented in several of the chapters in this section.

In spite of the etiological complexity of ASD, there have been enormous efforts in genetic and environmental risk factor discovery with significant successes in identifying high-risk ASD genes and loci (Betancur and Coleman) and high-risk ASD copy number variants (Marshall, Lionel, and Scherer).

There has been considerably less success in identifying common single nucleotide polymorphisms (SNPs) in ASD (Anney), although sample sizes are very small compared to other complex disorders such as schizophrenia, and the ASD studies are underpowered for realistic effect sizes. Given the estimates of the large number of ASD genes and loci (many hundreds), methods of massively parallel (next-generation) sequencing will likely be an important means for gene discovery in ASD, with some important results already emerging (Cai and Buxbaum).

Some of the additional risk for ASD can be encompassed by mitochondrial effects (Naviaux), prenatal and perinatal risk factors (Sandin, Kolevzon, Levine, Hultman, and Reichenberg), and other environmental influences (Lyall, Schmidt, and Hertz-Picciotto). In addition, some of the genetic and non-genetic risk can be mediated by hormonal influences (Auyeung and Baron-Cohen) and immune abnormalities (Eloi, Heuer, and Van de Water).

While not exhaustive as to potential processes that can contribute to ASD risk, this section provides an up-to-date survey of recent findings in ASD risk and mediators of ASD risk. The role of the nuclear genome in ASD has been validated through ongoing gene discovery. In addition, the contributions of other risk factors and mediators of risk are supported by a growing body of evidence. The next few years promises to bring an explosion of discovery in the etiology of ASD.

Chapter 2.1

Etiological Heterogeneity in Autism Spectrum Disorders
Role of Rare Variants

Catalina Betancur^∗ and Mary Coleman^†

^∗INSERM U952, CNRS UMR 7224 and Pierre and Marie Curie, Paris, France

^†Foundation for Autism Research, Sarasota, FL, USA

Outline

Introduction

Genetic Disorders Strongly Associated with ASD

Genetic Overlap between ASD and Intellectual Disability

Genetic Overlap between ASD and Epilepsy

Metabolic Disorders Associated with ASD

Other Examples of Etiological Subgroups Associated with ASD

Myriad Biological Pathways

Conclusion

Introduction

Autism spectrum disorders (ASD) encompass a group of behaviorally defined developmental disabilities characterized by marked clinical and etiological heterogeneity. ASD can be associated with intellectual disability (ID) of varying degrees (∼70%), epilepsy (∼30%), and dysmorphic features and congenital malformations (∼20%) (Coleman and Gillberg, 2012). ASD can thus be considered syndromic (i.e., associated with dysmorphic, neuromuscular, metabolic or other distinctive clinical features, including structural brain abnormalities) or nonsyndromic, similar to the division of ID into syndromic and nonsyndromic forms (Gecz et al., 2009).¹

The genetic architecture of ASD is highly heterogeneous (Abrahams and Geschwind, 2008; Betancur, 2011; State, 2010). About 20% of individuals have an identified genetic etiology. Cytogenetically visible chromosomal aberrations have been reported in ∼5% of cases, involving many different loci on all chromosomes. The most frequent abnormalities are maternally derived 15q11–q13 duplications, involving the imprinted Prader–Willi/Angelman region and detected in ∼1%. ASD, can also be due to mutations of numerous single- genes involved in autosomal dominant, autosomal recessive and X-linked disorders. The most common single gene defect identified in ASD is fragile X syndrome (FMR1), present in ∼2% of cases (Kielinen et al., 2004) (Chapter 4.5). Other monogenic disorders described in ASD include tuberous sclerosis (TSC1, TSC2) (Chapter 4.8), Angelman syndrome (UBE3A), Rett syndrome (MECP2) (Chapter 4.6), and PTEN mutations in patients with macrocephaly and autism (Chapter 4.8). Rare mutations have been identified in multiple synaptic genes, including NLGN3, NLGN4X (Jamain et al., 2003), SHANK3 (Durand et al., 2007), and SHANK2 (Berkel et al., 2010; Pinto et al., 2010) (Chapter 4.7). Recent genome-wide microarray studies in large ASD samples have highlighted the important contribution of rare submicroscopic deletions and duplications, called copy number variation (CNV), to the etiology of ASD, including de novo events in 5–10% of cases (Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011; Sebat et al., 2007) (Chapter 2.2). Most recently, the first whole-exome sequencing studies in ASD have shown an increased rate of rare de novo point mutations and confirmed a high degree of locus heterogeneity (Neale et al., 2012; O’Roak et al., 2011; 2012; Sanders et al., 2012) (Chapter 2.4).

The constantly increasing number of distinct, individually rare genetic causes of ASD and the substantial contribution of de novo events indicates that the genetic architecture of ASD resembles that of ID, with hundreds of genetic and genomic disorders involved, each accounting for a very small fraction of cases. In fact, all the known genetic causes of ASD are also causes of ID, indicating that these two neurodevelopmental disorders share common genetic bases.

We recently performed an exhaustive review of all the genetic and genomic disorders reported in subjects with ASD or autistic behavior, and identified 103 disease genes and 44 recurrent genomic imbalances (Betancur, 2011), and the numbers have continued to grow. These findings are in stark contrast to a persisting claim among the autism research community that we know very little about the etiology of autism, and that there are only a modest number of autism loci known. Here, rather than listing all the genetic and genomic disorders involved in ASD, we review what we can learn about the profound etiological heterogeneity underlying ASD.

The most obvious conclusion we can draw is that, when examined from an etiological perspective, ASD is not a single disease entity but a behavioral manifestation of many hundreds of single-gene and genomic disorders. In addition, it is emerging that de novo variants are an important part of the architecture of ASD, consistent with purifying selection against deleterious genetic variants of major effect. One of the most important observations is that there is considerable overlap in high-risk genes and loci for ASD, ID, and epilepsy. Similarly, many of the rare recurrent CNVs identified recently have been found to confer risk for a broad range of neurological and psychiatric phenotypes, including not only ID, ASD, and epilepsy, but also schizophrenia and attention deficit/hyperactivity disorder (ADHD). This highlights how disruption of core neurodevelopmental processes can give rise to a wide range of clinical manifestations, and that greater attention should be placed on the neurobiological processes of brain development and function rather than on the precise behavioral manifestation. Finally, we show how some of the genes implicate specific pathways, subcellular organelles, or systems in the pathophysiology of ASD, which can lead to biological and neurobiological insights into disease mechanisms.

Genetic Disorders Strongly Associated with ASD

Table 2.1.1 shows genetic and genomic disorders in which ASD is a common manifestation. For some of these disorders, ASD is among the clinical hallmarks, including Phelan-McDermid syndrome (22q13 deletion syndrome/SHANK3 mutations), maternal 15q11–q13 duplications, Rett syndrome (MECP2) and MECP2 duplication syndrome, fragile X syndrome (FMR1), tuberous sclerosis (TSC1, TSC2), adenylosuccinate lyase deficiency (ADSL), Timothy syndrome (CACNA1C), cortical dysplasia-focal epilepsy syndrome (CNTNAP2), Smith–Lemli–Opitz syndro...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Introduction
• Section I: Autism Spectrum Disorders
• Section II: Etiology of Autism Spectrum Disorders
• Section III: Brain Imaging and Neuropathology of Autism Spectrum Disorders
• Section IV: Model Systems and Pathways in Autism Spectrum Disorders
• Index