SCN1A – Malignant migrating partial seizures of infancy

SCN1A is implicated in malignant migrating partial seizures of infancy (MMPSI), a rare early-onset epileptic encephalopathy. Inheritance is autosomal dominant via de novo heterozygous variants. Two unrelated probands harbor distinct de novo SCN1A missense variants: c.5006C>A (p.Ala1669Glu) confirmed in blood and brain ([PMID:21555645]) and c.2584C>G (p.Arg862Gly) affecting the voltage sensor of domain II, alongside a de novo 11.06 Mb deletion encompassing SCN1A in a second case ([PMID:21753172]). No affected relatives have been reported, and targeted screening in small cohorts failed to identify additional pathogenic SCN1A variants ([PMID:16168594]; [PMID:24315024]).

Functional data support a loss-of-function mechanism: the p.Ala1669Glu substitution disrupts a conserved intracellular linker in domain IV, and scanning mutagenesis of adjacent IVS4–S5 loop residues abolishes fast inactivation consistent with impaired channel gating ([PMID:9422778]). These findings align with the refractory migrating seizures phenotype. SCN1A sequencing is recommended in MMPSI diagnostic work-ups.

References

• Archives of neurology • 2011 • Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. PMID:21555645
• Neurology • 2011 • De novo SCN1A mutations in migrating partial seizures of infancy. PMID:21753172
• The Journal of biological chemistry • 1998 • A critical role for the S4-S5 intracellular loop in domain IV of the sodium channel alpha-subunit in fast inactivation. PMID:9422778

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