Sodium Channelopathies in Human and Animal Models of Epilepsy and Neurodevelopmental Disorders

Excerpt

The genes SCN1A, SCN2A, and SCN8A encode the voltage-gated sodium channel (VGSC) α-subunits Nav1.1, Nav1.2, and Nav1.6, respectively. Dravet syndrome is eat the severe end of the disease spectrum caused by SCN1A variants, and Nav1.1 haploinsufficiency in parvalbumin-positive inhibitory neurons has been proposed as a primary cause for the disease. Nav1.2 is predominantly expressed in excitatory neurons in neocortex and hippocampus. SCN2A is the gene with the largest number of de novo variants in patients with autism spectrum disorder and/or intellectual disability, and those are mainly truncations. SCN2A variants also appear in patients with epileptic encephalopathies, but those are mostly missense. Variants of SCN8A have been reported in a number of patients with variable epilepsies. Gain-of-function missense variants are the most common in SCN8A developmental and epileptic encephalopathy associated with motor manifestations such as ataxia and choreoathetosis in the most severe cases. SCN1B encodes the non-pore-forming VGSCβ1 and β1B subunits, which are multifunctional channel regulatory molecules expressed in excitatory and inhibitory neurons. SCN1B variants are reported in patients with epilepsies of multiple etiologies. In vitro and animal model studies have provided critical insights into pathological mechanisms of the diseases caused by genetic variation in these genes.