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De novo  mutations of the voltage-gated sodium channel gene  SCN8A  have recently been recognized as a cause of epileptic encephalopathy, which is characterized by refractory seizures with developmental delay and cognitive disability. We previously described the heterozygous  SCN8A  missense mutation p.Asn1768Asp in a child with epileptic encephalopathy that included seizures, ataxia, and sudden unexpected death in epilepsy (SUDEP). The mutation results in increased persistent sodium current and hyperactivity of transfected neurons. We have characterized a knock-in mouse model expressing this dominant gain-of-function mutation to investigate the pathology of the altered channel  in vivo . The mutant channel protein is stable  in vivo . Heterozygous  Scn8a N1768D/+   mice exhibit seizures and SUDEP, confirming the causality of the  de novo  mutation in the proband. Using video/EEG analysis, we detect ictal discharges that coincide with convulsive seizures and myoclonic jerks. Prior to seizure onset, heterozygous mutants are not defective in motor learning or fear conditioning, but do exhibit mild impairment of motor coordination and social discrimination. Homozygous mutant mice exhibit earlier seizure onset than heterozygotes and more rapid progression to death. Analysis of the intermediate phenotype of functionally hemizygous  Scn8a N1768D/−   mice indicates that severity is increased by a double dose of mutant protein and reduced by the presence of wild-type protein.  Scn8a N1768D   mutant mice provide a model of epileptic encephalopathy that will be valuable for studying the  in vivo  effects of hyperactive Na v 1.6 and the response to therapeutic interventions.

Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy