Autism Spectrum Disorders

M. Créteil, P. Paris

• Verlag: S. Karger
• Jahr: 2015
• ISBN:
  9783318026023
• Thema: Medicine
• Thema: Psychiatry & Mental Health

Accurate and exhaustive, this book provides a wide overview of the current knowledge on phenotypes, mechanisms and treatment of autism spectrum disorders. It covers topics on diagnostic issues, comorbid conditions and therapeutic strategies along with a detailed discussion on the actual understanding of the pathophysiology of autism disorders. More specifically, this book reviews in detail the current knowledge on the comorbidity between mental and medical disorders, describes abnormal cognitive and social development and gives a thorough overview on genetic as well as brain imaging abnormalities observed in autism spectrum disorders. In addition, the current literature on environmental risk factors which may provide an explanation for the increased prevalence of autism is being described. The last chapter gives an extensive review of early detection and early therapeutic interventions encompassing psycho-social and pharmacological strategies. Each chapter is easy to read and gives the reader access to the most important information on each topic covered. This book provides innovative reading material for medical students, psychologists, researchers and clinicians who need accurate information on the best available diagnostic and therapeutic strategies as well as on up-to-date research data.

Leboyer M, Chaste P (eds): Autism Spectrum Disorders. Phenotypes, Mechanisms and Treatments.
Key Issues Ment Health. Basel, Karger, 2015, vol 180, pp 113-134 (DOI: 10.1159/000363611)

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Environmental Factors and Autism Spectrum Disorder

Antonio M. Persico^{a, b} · Sara Merelli^b

^aUnit of Child and Adolescent Neuropsychiatry, Laboratory of Molecular Psychiatry and Neurogenetics, Campus Bio-Medico University, Rome, and ^bMafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy

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Abstract

Multiple observations indicate that environmental and epigenetic factors play an important role in the emergence of autism spectrum disorders (ASD). Growing ASD incidence rates, the incomplete penetrance of many rare variants linked to autism, and increased exposure to environmental contaminants all strongly support the role of gene × environment interactions in a substantial fraction of autistic patients. Within this framework, genetically susceptible individuals exposed to detrimental environmental factors at critical times during neurodevelopment might undergo disrupted brain morphogenesis, neuronal connectivity, and synaptic functioning consequently yielding ASD. Several teratogenic drugs and prenatal viral infections are able to cause autism in humans, as supported by case reports, cohort studies, and animal models. Moreover, recent studies have shown that some newly identified potential neurotoxicants may negatively affect developmental trajectories, leading to altered cognitive, attentive, behavioral, and motor performances, as well as to systemic abnormalities frequently seen in autistic individuals. A variety of mechanisms are potentially involved, ranging from oxidative and inflammatory brain damage to altered gene expression and impaired signal transduction. More research is needed to thoroughly investigate the effects of these compounds on neurodevelopment, to validate their involvement specifically in ASD, to study gene × environment interactions in potentially susceptible individuals, and to plan targeted prevention strategies.

© 2015 S. Karger AG, Basel

In the last two decades, epidemiological studies have shown a progressive increase in the number of autism spectrum disorder (ASD) diagnoses, with the most recent statistics released by the Centers for Disease Control and Prevention (CDC) attesting its incidence rate at 1/68 newborn children [1]. Increased awareness in the medical community, improved detection, and broadening of the diagnostic criteria for ASD have certainly contributed to this trend, but a real increase in incidence is also likely [2, 3]. Genetic factors are thought to strongly contribute to the development of ASD, which can stem from copy number variants or disruptive point mutations in autosomes, in the X chromosome, or, very rarely, in mitochondrial DNA [4]. Nevertheless, it is now becoming evident that environmental factors may also play an important role in the emergence of ASD, especially by acting upon a genetically vulnerable background (table 1). An environmental factor is defined as a nongenetic, toxic, infectious, or immune factor which is thought to contribute to the disorder [5]. The role of environmental factors in neuropsychiatry has garnered renewed attention after initial observations of the behavioral effects of prenatal exposure to neurotoxic substances proven to alter brain maturation and produce a nonspecific array of neurodevelopmental deficits [6]. During critical periods or ‘time windows of susceptibility’, the developing brain is thus particularly sensitive to the effects of environmental factors in a way that has no counterpart in the adult brain [6]. In particular, these different time windows correspond to the timing of when neuronal proliferation, migration, differentiation, maturation (i.e. neurite sprouting and pruning), synaptogenesis, and activity-dependent synaptic remodeling can be permanently modulated by early exposure to environmental factors through epigenetic mechanisms. This scenario is highly compatible with recent ‘multiple-hit’ models of autism pathogenesis [7-9], whereby a complex mix of genetic variants creates a highly individualized spectrum of sensitivities to the detrimental effects of environmental factors. In addition, genetics and epigenetics both contribute to the great phenotypic heterogeneity that characterizes ASD. In this chapter, we shall first examine the environmental factors whose etiological role in autism has been conclusively demonstrated; we shall then explore the most recently identified environmental factors, with suggestive evidence pointing toward their potential role in ASD.

Table 1. Elements that support the role of gene × environment interactions in the etiology of ASD

Increased ASD incidence rate

Increased exposure to environmental contaminants/drugs

Decreased heritability estimates

Low percentage of cases entirely attributable to a known genetic cause

Evidence for early exposure-related ASD development

Evidence for exposure-related DNA epigenetic and signal transduction alterations

High phenotypic variability with regard to behavioral and neuroanatomical ASD-related features

Documented Environmental Factors Involved in Autism Spectrum Disorders

Some environmental factors have been shown to significantly enhance the risk of developing autism, to the point that at least in a limited number of patients they can be regarded as ‘the primary cause’ of the disease [6, 7]; these agents include teratogenic drugs, i.e. valproic acid, misoprostol, and thalidomide, as well as prenatal rubella and cytomegalovirus (CMV) infections (table 2). Evidence for their causal role comes from case reports, patient cohort studies, and epidemiological and neuroanatomical investigations, as well as from animal models.

Table 2. Documented environmental factors in ASD

Teratogenic Drugs: Sodium Valproate, Thalidomide, and Misoprostol

Prenatal exposure to antiepileptic drugs (AED), i.e. phenytoin, sodium valproate (VPA), and carbamazepine, can cause ‘fetal anticonvulsant syndrome’, a condition characterized by dysmorphic craniofacial features associated with limb, heart, and genitourinary defects and developmental delay to a variable degree. This syndrome can most clearly encompass autistic symptoms following prenatal exposure to VPA, whereas this may occur less consistently with phenytoin and carbamazepine, although polydrug therapy has also been frequently reported. Multiple studies have examined the relationship between prenatal AED exposure and autism. Firstly, a population-based study found the ASD incidence following prenatal exposure to AED to be 4.6% for all AED collectively, 9% when looking at VPA exposure alone, and 11.7% for VPA in polydrug therapy [10]; secondly, a perspective cohort study found that 12 and 15% of children prenatally exposed to monotherapy or polytherapy with VPA, respectively, were diagnosed with a neurodevelopmental disorder (ASD, attention deficit/hyperactivity disorder, or dyspraxia, with ASD being the most frequent diagnosis), with a 6- and 10-fold increase in ASD risk compared to controls and carbamazepine- or lamotrigine-exposed children [11]; thirdly, the largest population-based study to date confirmed a significant increase in autism risk among children prenatally exposed to VPA, even after adjusting for parental psychiatric disease and epilepsy, with adjusted hazard ratios (aHR) of 2.9 and 5.2% for ASD and childhood autism, respectively [12]. Differently from idiopathic autism, the male-to-female ratio in VPA-exposed autistic children is close to 1; autistic features are mostly associated with speech delay, mild motor delays, and minor and major malformations in the absence of severe cognitive impairment or regression (i.e. loss of acquired skills). Suggested mechanisms of the teratogenic effects of VPA include folic acid deficiency, oxidative stress, and most strongly epigenetic abnormalities produced through inhibition of histone deacetylase [13]. VPA acts as an antimetabolite to folic acid, interfering with its use and therefore mimicking folic acid deficiency, which in turn leads to disrupted gene expression, oxidative stress, and alterations in protein synthesis. Since maternal supplementation with folic acid during pregnancy seems to protect against the development of idiopathic autism in the offspring [14], conversely this mechanism may contribute to the enhancement of autism risk. Nevertheless, the teratogenic effect of VPA is believed to be mainly exerted through inhibition of histone deacetylase [15]; the persistent acetylation of histones and demethylation of cytosines at the promoters of neurodevelopmentally relevant genes is predicted to produce dysregulation in excess of their gene expression. In accordance with this prediction, valproic acid does increase the expression of several neurally relevant genes involved in neurodevelopment, such as WNT, FZD-5, GFRA-2, and GATA-3 [15, 16]. Furthermore, VPA reduces the expression of serotoninergic genes, delaying the differentiation of serotoninergic neurons and resulting in enhanced growth and an abnormal distribution of serotoninergic terminals [17]. Mouse models of early VPA exposure have shown that neuroanatomical anomalies primarily include abnormal cerebellar cytoarchitectonics and brainstem nuclei formation [18, 19]. Especially interesting because of its clear parallel with human autism is the local hyperconnectivity present in the neocortex of rats exposed prenatally on embryonic day 11.5 to VPA, as well as diminished numbers of putative synaptic contacts between layer-5 pyramidal neurons [20]....