Article published by Wiley Online Library
A recent study assesses data from a retrospective cohort of 1,018 individuals with SCN1A-related epilepsies, exploring how seizure characteristics, genetic variant type, position, and in silico scores relate to the epilepsy phenotype. Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. Pathogenic variants in SCN1A, the gene coding for the alpha-1 subunit of the voltage-gated sodium channel, are associated with a range of epilepsy syndromes from relatively mild phenotypes in the genetic epilepsy with febrile seizures plus (GEFS+) spectrum to Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. DS usually presents at approximately five–six months of age with prolonged, febrile and afebrile, hemiclonic or generalized clonic seizures. From age nine months to four years, other seizure types, including myoclonic, absence, and focal seizures, develop. Typical antiseizure medications have limited efficacy, and sodium channel blockers are associated with worse outcomes. From age two years, cognitive, behavioral, and motor development becomes significantly impaired. Epilepsies within the less severe GEFS+ spectrum also present early in life; however, cognitive development is normal. This large cohort study of patients with SCN1A variants provides evidence of associations between gene variant features and phenotype. This includes differences in age at seizure onset associated with different variant types, identification of specific regions within SCN1A associated with specific presentations, and initial status epilepticus as a predictive phenotypic marker for DS.