Sodium channelopathies in neurodevelopmental disorders

A substantial burden of neurological disease is related to mutations in three sodium channel genes: SCN1A, SCN2A and SCN8A. In this Review, Meisler and colleagues discuss the neurological disorders associated with these mutations and also the therapeutic opportunities that are being investigated as a result of these recent mechanistic insights. The voltage-gated sodium channel alpha-subunit genes comprise a highly conserved gene family. Mutations of three of these genes, SCN1A, SCN2A and SCN8A, are responsible for a significant burden of neurological disease. Recent progress in identification and functional characterization of patient variants is generating new insights and novel approaches to therapy for these devastating disorders. Here we review the basic elements of sodium channel function that are used to characterize patient variants. We summarize a large body of work using global and conditional mouse mutants to characterize the in vivo roles of these channels. We provide an overview of the neurological disorders associated with mutations of the human genes and examples of the effects of patient mutations on channel function. Finally, we highlight therapeutic interventions that are emerging from new insights into mechanisms of sodium channelopathies.