Trends in Neurosciences
INMED/TINS special issueSearching for ways out of the autism maze: genetic, epigenetic and environmental clues
Introduction
Autistic disorder was first described by the psychiatrist Leo Kanner in 1943 [1] and is diagnosed on the basis of three behaviorally altered domains: social deficits, impaired language and communication, and stereotyped and repetitive behaviors [2]. Beyond this unifying definition lies extreme clinical heterogeneity, ranging from debilitating impairments to mild personality traits. Hence autism is not a single disease entity, but rather a complex phenotype encompassing either multiple ‘autistic disorders’ or a continuum of autistic-like traits and behaviors defined as ‘autism spectrum disorder’ (ASD), which includes autistic disorder (Kanner's ‘autism’), childhood disintegrative disorder, pervasive development disorder not otherwise specified (PDD-NOS, or ‘atypical autism’) and Asperger syndrome. The dramatic rise in ASD incidence from 2–5 to 15–60 per 10 000 children during the past two decades can be explained largely by the use of broader diagnostic criteria and increased attention by the medical community 3, 4. The limits of an exclusively genetic etiology, and the possible contributions of environmental and epigenetic factors to increased ASD incidence (Box 1), are highlighted by, among other evidence, the dramatic behavioral and neuroanatomical differences displayed by genetically identical monozygotic twins discordant for an ‘autism’ diagnosis [5]. Furthermore, in only ∼10% of the affected individuals is autism ‘syndromic’ – that is, secondary to a known genetic disorder [6] such as chromosomal rearrangement (e.g. duplication of 15q), fragile X syndrome, tuberous sclerosis and neurofibromatosis, or secondary to exposure to identified teratological agents (Box 1). This highlights the current limitations of genetic diagnostic protocols routinely employed in clinical settings. For the vast majority of patients, the origin of ‘non-syndromic’, ‘primary’ or ‘idiopathic’ autism remains unknown.
Altered neurodevelopment is widely recognized as the underlying neuropathological cause of ASD. The CNS of individuals with autism might process information by activating neural networks distinct from those employed by non-autistic individuals, particularly for socially relevant stimuli 7, 8. The neuroanatomical substrates of this altered information processing appear as heterogeneous as clinical manifestations and etiological underpinnings. The few post-mortem studies of autistic brains performed to date suffer from methodological limitations including diagnostic heterogeneity and small sample sizes; they typically describe brains of older individuals, who are likely to display chronic adaptive changes at least as much as primary developmental pathology, and in some instances the studies might not have employed the most up-to-date techniques. Nonetheless, they have uncovered various neurodevelopmental alterations, encompassing many aspects of CNS formation, such as reduced programmed cell death and/or increased cell proliferation, altered cell migration with disrupted cortical and subcortical cytoarchitectonics, abnormal cell differentiation with reduced neuronal size, and altered synaptogenesis 9, 10. These anomalies might explain the unbalanced local versus long-distance and inhibitory versus excitatory connectivity that is likely to underlie altered social-information processing in autism 11, 12. However, this anatomical heterogeneity has undoubtedly hindered the discovery of etiological factors in ASD and has prompted researchers to seek new insights through genetic approaches.
Family and twin studies have conclusively described autism as the ‘most genetic’ neuropsychiatric disorder, with concordance rates of 82–92% in monozygotic twins compared with 1–10% in dizygotic twins, sibling recurrence risk at 2–3%, and heritability estimates of >90% 6, 13. However, three different levels of complexity have emerged in recent years, namely a high degree of genetic heterogeneity (i.e. different contributing genes in different patients), a polygenic or oligogenic mode of inheritance in most cases (i.e. many susceptibility-conferring gene variants at different loci are required for an individual to develop the disease), and the presence of significant gene–gene and gene–environment interactions. To date, genome scans, linkage and association studies, chromosomal rearrangement analyses and mutation screenings have identified: (i) genomic regions likely to contain autism susceptibility loci on human chromosomes 1q, 2q, 5q, 6q, 7q, 13q, 15q, 17q, 22q, Xp and Xq; (ii) genes whose mutations represent a rare cause of ‘non-syndromic’ autism (NLGN3 and NLGN4) or yield ‘syndromic’ autism (FMR1, TSC1, TSC2, NF1 and MECP2); and (iii) candidate vulnerability genes, with potential common variants enhancing risk but not causing autism per se (Table 1).
Within the framework of this clinical, neuroanatomical and genetic heterogeneity, the study of simple monogenic forms of the disease (i.e. one gene, one disease), although relatively uncommon, can powerfully improve our understanding of the underlying causal processes. At the same time, genetic and functional studies of vulnerability genes can provide the genetic, neuroanatomical and neurobiological information necessary to delineate plausible scenarios and to design novel hypothesis-driven studies of gene–gene and gene–environment interactions.
Section snippets
Neurodevelopmental genes and autism
Figure 1 depicts proteins that have been implicated in ASD to date. All of these proteins are involved in neurodevelopment and many have roles in synaptic function. These proteins can be schematically divided into at least eight distinct ensembles (Table 1), depending on their involvement in (i) chromatin remodelling and regulation of transcription, (ii) actin cytoskeleton dynamics, (iii) synaptic scaffolding, (iv) neurotransmission, (v) second-messenger systems, (vi) apoptosis, (vii) cell
Three paths to ASD: reduced cell migration, excitatory–inhibitory imbalance and abnormal synaptogenesis
Through the evidence already summarized in this review, we can begin depicting three major pathways involved in ASD pathogenesis. The first affects cell migration, the second impinges on the glutamate–GABA equilibrium, and the third encompasses synapse formation and maintenance, as well as dendritic morphology. On one hand, the evidence surrounding the reelin pathway, in conjunction with neuropathological studies, underscores the role of altered neuronal migration in generating the aberrant
Acknowledgements
A.M.P. is supported by Telethon-Italy (grant GGP02019), the Fondation Jerome Lejeune (Paris, France), the Cure Autism Now Foundation (Los Angeles, CA USA) and the National Alliance for Autism Research (Princeton, NJ, USA). T.B. is supported by the Cure Autism Now Foundation (Los Angeles, CA, USA), Fondation France Telecom, Fondation biomédicale de la mairie de Paris, AUMOLGEN FP6 and EUSynapse FP6. We gratefully acknowledge Pat Levitt and Andrè Goffinet for helpful comments, and all the
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