SCN1A

SCN1A is a human gene that encodes the alpha subunit Nav1.1 of voltage-gated sodium channels. The gene is located on chromosome 2q24.3. The Nav1.1 protein comprises four homologous domains (DI–DIV), each with six transmembrane segments; the S4 segments act as voltage sensors and the channel mediates rapid sodium influx necessary for the initiation and propagation of action potentials. In the brain, Nav1.1 is predominantly expressed in inhibitory GABAergic interneurons, especially in the cortex and hippocampus, where it contributes to the regulation of neuronal excitability and network synchronization.

Pathogenic variants in SCN1A are a major cause of epilepsy. Most disease-associated mutations reduce Nav1.1 function (loss-of-function) and lead to haploinsufficiency, resulting in decreased inhibitory interneuron activity and consequent network hyperexcitability. The best-known disorder is Dravet syndrome (severe myoclonic epilepsy of infancy), often presenting with febrile seizures in infancy and evolving into treatment-resistant epilepsy with developmental impairment. Generalized epilepsy with febrile seizures plus (GEFS+) is another well-described phenotype. Some mutations with altered gating or gain-of-function effects have been linked to familial hemiplegic migraine type 3.

Inheritance is usually de novo, but inherited and familial cases occur with variable expressivity and penetrance. Diagnosis relies on clinical evaluation corroborated by genetic testing, typically SCN1A sequencing or epilepsy gene panels. Management is individualized; many sodium channel–blocking antiepileptic drugs can worsen Dravet syndrome, whereas valproate, clobazam, stiripentol (often with valproate and clobazam), topiramate, and dietary therapies such as the ketogenic diet are commonly used. Early diagnosis and comprehensive care improve long-term outcomes, though prognosis varies with syndrome severity.