Abstract
The genetic and phenotypic heterogeneity of autism spectrum disorders (ASD) presents a substantial challenge for diagnosis, classification, research, and treatment. Investigations into the underlying molecular etiology of ASD have often yielded mixed and at times opposing findings. Defining the molecular and biochemical underpinnings of heterogeneity in ASD is crucial to our understanding of the pathophysiological development of the disorder, and has the potential to assist in diagnosis and the rational design of clinical trials. In this review, we propose that genetically diverse forms of ASD may be usefully parsed into entities resulting from converse patterns of growth regulation at the molecular level, which lead to the correlates of general synaptic and neural overgrowth or undergrowth. Abnormal brain growth during development is a characteristic feature that has been observed both in children with autism and in mouse models of autism. We review evidence from syndromic and non-syndromic ASD to suggest that entities currently classified as autism may fundamentally differ by underlying pro- or anti-growth abnormalities in key biochemical pathways, giving rise to either excessive or reduced synaptic connectivity in affected brain regions. We posit that this classification strategy has the potential not only to aid research efforts, but also to ultimately facilitate early diagnosis and direct appropriate therapeutic interventions.
Highlights
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders frequently characterized by impairments in social interactions, difficulties with language and communication, and the presence of repetitive, perseverative behaviors (Abrahams and Geschwind, 2008; Zoghbi and Bear, 2012)
Another line of evidence pointing to upregulated brainderived neurotrophic factor (BDNF) signaling in Fragile X syndrome (FXS) comes from recent studies demonstrating aberrant increases in matrix metalloprotease-9 (MMP9) levels in brains of FXS patients and Fmr1 KO mice (Gkogkas et al, 2014)
Based on the aforementioned phenotypes resulting from mutations in the Tuberous sclerosis (TSC) tumor suppressor, we propose that autism spectrum disorders (ASD) patients with TSC loss-of-function represent an example characterized by neuronal overgrowth phenotypes
Summary
Defining the molecular and biochemical underpinnings of heterogeneity in ASD is crucial to our understanding of the pathophysiological development of the disorder, and has the potential to assist in diagnosis and the rational design of clinical trials. We review evidence from syndromic and non-syndromic ASD to suggest that entities currently classified as autism may fundamentally differ by underlying pro- or anti-growth abnormalities in key biochemical pathways, giving rise to either excessive or reduced synaptic connectivity in affected brain regions. We posit that this classification strategy has the potential to aid research efforts, and to facilitate early diagnosis and direct appropriate therapeutic interventions
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