The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.Autism spectrum disorder (ASD) is a syndrome characterized by a triad of core deficits: disturbances in social behavior, atypical verbal and nonverbal communication, and restricted interests that can be accompanied by repetitive behavior. The clinical diagnosis, which includes individuals with any one of a spectrum of neurodevelopmental conditions (including autism, Rett syndrome, pervasive developmental disorder-not otherwise specified, and Asperger syndrome), is made in 1 of every 150 individuals and is four times more prevalent in boys than girls (1). While ASD is among the most heritable psychiatric disorders defined in the Diagnostic and statistical manual of mental disorders (4th edition) (2), it is not a static or simple disorder with fixed effects on a circumscribed age. Instead, equally fundamental facets of pathology emerge at different points of maturation of the child. Moreover, the disorder does not result in immutable social and cognitive deficits, but rather the core symptoms typically change over time and to different degrees. Co-occurring medical conditions (sleep problems, epilepsy, and gastrointestinal symptoms) and psychiatric disturbances (anxiety, obsessive-compulsive disorder, and aggression) are common and can appear at different ages in children on the spectrum.Contemporary hypotheses of the causes of ASD often include experience-dependent processes through which atypical gene-by-environment (G X E) interactions yield pathophysiology in later emerging systems that underlie social and communication competencies. The later emergence of symptoms is consistent with the concept that developmental differentiation, whether at the cellular, circuit, or systems level, occurs from the bottom up; behavior develops from basic sensory and perceptual systems that feed into higher integration centers (3-5). Impairments in initial basic processes become expressed in ever more complex systems, with the population heterogeneity of the clinical features of ASD expected to increase from infancy to childhood and through adolescence. However, it is not clear whether the factors that contribute to the developmental diversification and phenotypic heterogeneity of...

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…Autism spectrum disorders (ASDs) are a complex and diverse group of disorders, which can be caused by different factors such as gene mutations, epigenetics, and environmental factors (reviewed in van de Lagemaat and Grant, 2010). Over the past years, evidence is emerging that the PI3K/ mTOR signaling pathway is frequently linked to autism, via both inherited and exogenous mechanisms, suggesting that dysregulated PI3K/mTOR signaling might be a common mechanism in many ASDs (reviewed in Levitt and Campbell, 2009). The observation that PI3K/mTOR signaling in FXS is dysregulated Gross et al, 2010;Sharma et al, 2010) might therefore provide another interesting link between FXS and autism.…”

Nicotinic Acetylcholine Receptor Alterations in Autism Spectrum Disorders – Biomarkers and Therapeutic Targets

“…There is also a paucity of biomarkers for autism. Both genetic and environmental factors are thought to contribute to autism susceptibility (Courchesne, 2007;Geschwind, 2009;Südhof, 2008;Ramocki & Zoghbi, 2008), but because only some of the genetic factors have been identified unequivocally thus far (Cook & Scherer, 2008;Levitt & Campbell, 2009), finding effective treatments that target the underlying causes of ASD remains a major challenge. Identifying endophenotypes and biomarkers for complex and heterogeneous disorders such as ASD are important not only to elucidate their etiologies, but also to identify suitable biochemical molecules and pathways to target the treatment of core deficits.…”

Autoimmune Disorder and Autism

“…Copy number variation (CNV) analysis is a newer molecular cytogenetic approach, aiming to detect the insertion or deletion of DNA fragments typically larger than 50 kb [61]. However, extreme caution must be paid when interpreting CNV analysis since it is very dependent on the specific methods employed, which may partly account for the low replicability among studies [62]. Differing from cytogenetics, linkage studies trace genetic loci that are transmitted with autism in the families of affected individuals.…”