Defective phosphoinositide metabolism in autism

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Autism disorders are a spectrum of diseases and include individuals who are nonverbal and have IQs below 40 on one end of the spectrum and high‐functioning individuals who can have above‐average intellectual capabilities in certain domains but are impaired in social interaction and communication skills on the other end of the spectrum (Lord and Bishop, 2015). The underlying neurobiology of autism spectrum disorders seems to reflect this phenotypic variety; many genetic and functional studies have suggested that the molecular mechanisms underlying autism spectrum disorders are complex and as heterogeneous as the disease phenotype (De Rubeis and Buxbaum, 2015). Nonetheless, evidence is emerging that defects in certain cellular pathways are overrepresented and might be shared among different forms of autism (Cusco et al., 2009; Pinto et al., 2014; Sanders et al., 2015). Such pathways may be potential therapeutic targets with broader applicability, in particular if specific drugs for components of these pathways already exist. Recent studies have suggested that defects in lipid kinases and phosphatases regulating phosphoinositides and their phosphorylated derivatives are such a shared pathological mechanism in autism spectrum disorders and other neurodevelopmental diseases. This review describes and critically assesses recent findings of altered phosphoinositide metabolism in autism and related disorders, outlines the implications for the development of novel therapeutic strategies, and discusses the challenges the field is facing to translate these findings successfully into treatment options.
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