Abstract / Summary
Pathogenic variants in SCN1A are associated with a broad and overlapping spectrum of epilepsies, ranging from febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+) to severe developmental and epileptic encephalopathies (DEEs), most notably Dravet syndrome. SCN1A encodes the voltage-gated sodium channel α-subunit Nav1.1, which has a critical role in inhibitory interneurons. In classical loss-of-function-associated Dravet syndrome, reduced Nav1.1 function contributes to impaired inhibitory neuronal excitability and network hyperexcitability. However, SCN1A-related disorders are mechanistically heterogeneous, with gain-of-function or mixed-function pathogenic variants being associated with clinically distinct phenotypes, including early-onset DEE and familial hemiplegic migraine type 3 (FHM3). This narrative review integrates functional variant classification with genotype–function–phenotype relationships, clinical diagnosis, and phenotype-specific treatment considerations. Particular emphasis is placed on early molecular testing, careful variant interpretation, and the distinction between chronic sodium-channel-blocker avoidance in classical loss-of-function-associated Dravet syndrome and potential mechanism-informed treatment strategies for selected gain-of-function phenotypes. We also summarize emerging SCN1A-targeted approaches, including antisense oligonucleotide therapy, gene activation, and interneuron-targeted gene replacement. A clearer understanding of variant-specific mechanisms and longitudinal clinical features may improve diagnostic precision, individualized management, and the development of disease-modifying therapies for SCN1A-related epilepsies.