SCN2A – Benign Familial Infantile Seizures, Type 3

SCN2A encodes the neuronal voltage-gated sodium channel NaV1.2, critical for action potential initiation in cortical excitatory neurons. Heterozygous SCN2A variants cause a spectrum of early-onset epilepsies, including benign familial infantile seizures, type 3 (MONDO:0011904; HGNC:10588). BFIS3 is characterized by afebrile, secondarily generalized seizures with onset between 2 and 7 months and remission by 12 months.

Inheritance is autosomal dominant with high penetrance. In a cohort of eight unrelated families (13 probands), six distinct missense and one deep-intronic SCN2A variants were identified; the recurrent c.3956G>A (p.Arg1319Gln) segregated in three families across multiple generations ([PMID:15048894]). An additional Madagascar pedigree confirmed autosomal dominant transmission of c.4766A>G (p.Tyr1589Cys) in two affected infants with normal development and seizure remission by 18 months ([PMID:23758435]).

The SCN2A variant spectrum in BFIS3 comprises predominantly missense changes affecting conserved pore and voltage-sensor regions, plus rare intronic alleles (e.g., c.697+158G>A). Selected variants reported include c.3956G>A (p.Arg1319Gln) and c.4766A>G (p.Tyr1589Cys).

Functional assays demonstrate that BFIS3 missense variants impair NaV1.2 gating and cell-surface expression, yielding net loss-of-function. R1319Q, L1330F, and L1563V channels exhibit mixed defects in activation/inactivation and reduced membrane localization consistent with diminished sodium currents ([PMID:18479388]). Dynamic action potential clamp further distinguishes minimal gain-of-function in L1563V, correlating with the benign phenotype ([PMID:29844171]).

Together, genetic segregation across eight families and concordant biophysical data establish a strong association between SCN2A and BFIS3. The autosomal dominant inheritance, recurrent variants, and consistent functional impact support pathogenicity and inform prognosis.

Key Take-home: SCN2A genetic testing is warranted in familial infantile seizures, as identification of pathogenic variants guides counseling, anticipates spontaneous remission, and may inform therapy selection.

References

• Annals of neurology • 2004 • Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. PMID:15048894
• Epilepsia • 2008 • Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. PMID:18479388
• Epilepsia • 2013 • An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na(+) current. PMID:23758435
• Proceedings of the National Academy of Sciences of the United States of America • 2018 • Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. PMID:29844171

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