Genetic Epilepsy with Febrile Seizures Plus (GEFS+)
• MedGen: C1858673 | OMIM: 604403
• History: defined by Scheffer and Berkovic (1997) as an autosomal dominantly inherited familial epilepsy spectrum; a few years later sodium-channel genes, including SCN1A, were subsequently implicated (~2000). “G” updated from “Generalized” to “Genetic” (2020).
• Core Features: familial epilepsy in which febrile seizures begin in infancy/early childhood and persist beyond age 6 (FS+), co-occur with afebrile seizures. Cognition is often normal, but severity varies within families.
• Inheritance: autosomal dominant with incomplete penetrance and variable expressivity
• Prevalence: population prevalence isn’t well-defined, but within SCN1A-positive cohorts, approximately 5 – 10% of patients present with a GEFS+ phenotype.
Dravet Syndrome (DS)
• MedGen: C0751122 | OMIM: 607208
• History: described as severe myoclonic epilepsy of infancy (SMEI) in 1978 by Dr. Charlotte Dravet; renamed Dravet syndrome (1989). SCN1Avariants linked to DS (2001). DS classified as a developmental and epileptic encephalopathy (2017).
• Core Features: onset at 2 -15 months with prolonged febrile and afebrile hemiclonic or generalized convulsive seizures, evolving into a polymorphic, medication-resistant epilepsy with developmental slowing/regression and motor/behavioral comorbidities; SUDEP risk is elevated.
• Inheritance: autosomal dominant, most often de novovariants; parental mosaicism accounts for a minority of cases, and rare non-mosaic inherited cases have also been reported, typically from mildly affected parents.
• Prevalence: 1:15,000 – 1:40,900 live births; SCN1A variants major genetic cause (80 – 95%)
Familial Hemiplegic Migraine, Type 3 (FHM3)
• MedGen: C1864987 | OMIM: 609634
• History: SCN1A variants linked to FHM3 (2005), extending spectrum beyond epilepsy.
• Core Features: familial migraine with aura that includes reversible hemiparesis; attacks may be prolonged and can be triggered by minor head trauma; seizures occur in some families.
• Inheritance: autosomal dominant
• Prevalence: FHM3 is very rare (0.01%) and SCN1A variants account for a minority of cases compared with CACNA1Aand ATP1A2variants
Developmental and Epileptic Encephalopathy 6B (DEE6B)
• MedGen: C5543353 | OMIM: 619317
• History: SCN1A variants linked to distinct neonatal encephalopathy (2014 – 2017).
• Core Features: onset <3 months with refractory seizures, hyperkinetic movement disorder, and profound developmental impairment
• Inheritance: autosomal dominant, typically de novo variants
• Prevalence: extremely rare; case reports
SCN1A