Autism spectrum disorder in the fragile X premutation state: possible mechanisms and implications

There is increasing recognition of the heterogeneity of origin of cases of autism spectrum disorder (ASD) with multiple forms of ASD having been identified over the decades. Among these, a genetic etiology can be identified in 20-40% of cases when a full genetic work-up is completed. The Fragile X premutation state (characterized by the presence of 55-200 CGG repeats in the FMR1 gene) is a relatively newly identified disease state that has since been associated with several disorders including fragile X-associated tremor ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI) and most recently, fragile X-associated neurodevelopmental disorders (FXAND) which commonly includes anxiety and depression. In addition to these associated disorders, extant literature and clinical observations have suggested an association between the premutation state and ASD. In this paper, we review the literature pertinent to this and discuss possible molecular mechanisms that may explain this association. This includes lowered levels of the FMR1 Protein (FMRP), GABA deficits, mitochondrial dysfunction and secondary genetic abnormalities that is seen in premutation carriers as well as their increased vulnerability to environmental stressors. Understanding these mechanisms can facilitate development of targeted treatment for specific sub-groups of ASD and premutation disorders in future.