SCN1A Overview
• Locus/Structure: 2q24.3 cluster (with SCN2A/SCN3A); 26 coding exons spanning ~100 kb
• Protein: Nav1.1 -subunit (four homolgous domains, six transmembrane segments (S) in each domain; S4 in each domain are voltage sensors and S5/S6 + P-loops in each domain together form the ion-conducting pore)
• Neurobiology: Nav1.1 is expressed in all brain neurons, but enriched in GABAergic interneurons (including parvalbumin-positive fast-spiking cells) and is critical for reliable inhibitory firing.
• Mechanisms: most epilepsy-associated variants are monoallelic loss-of-function (LOF) leading to Nav1.1 haploinsufficiency, interneuron hypoexcitability, and network disinhibition; a subset of variants are monoallelic gain-of-function (GOF) missense changes that increase persistent sodium current or shift gating/voltage-dependence and underlie very early-infantile DEE and hemiplegic migraine.
• Testing: since phenotypes overlap, multigene epilepsy panels or whole exome/genome sequencing with copy number variant (CNV) analysis are preferred over single-gene tests.
Genetic Epilepsy with Febrile Seizures Plus (GEFS+)
• Variants: usually monoallelic missense with milder LOF or mixed effects
• Pathophysiology: reduced Nav1.1 function in inhibitory interneurons resulting in network hyperexcitability, often manifesting as fever-provoked seizures in early life.
Dravet Syndrome (DS)
• Variants: predominantly LOF (truncating/splice/missense, often in voltage-sensor or pore regions) resulting in Nav1.1 haploinsufficiency and network disinhibition. CNVs (exonic/whole-gene deletions) contribute to a minority of cases.
• Pathophysiology: Nav1.1 haploinsufficiency in inhibitory interneurons results in network disinhibition and thermosensitive seizure susceptibility. Over time, secondary network and structural changes emerge.
Familial Hemiplegic Migraine, Type 3 (FHM3)
• Variants: missense GOF changes that alter Nav1.1 gating and increase persistent current
• Pathophysiology: enhanced cortical excitability lowers the threshold for cortical spreading depression (migraine aura)
Developmental and Epileptic Encephalopathy 6B (DEE6B)
• Variants: often de novo missense GOF changes clustering around inactivation and gating domains, this results in variants with increased persistent current or shifts in activation/inactivation
• Pathophysiology: biophysical assays demonstrate GOF variants within neonatal period can result in interneuron depolarization block, resulting in network hyperexcitability.
SCN1A