SCN2A – Benign Familial Infantile Epilepsy

SCN2A is associated with autosomal dominant benign familial infantile epilepsy (BFIE) (MONDO:0017615), a self-limited seizure disorder presenting with focal, afebrile partial seizures between 3 and 9 months of age and remission by 12 months. Clinical suspicion is raised in families with multiple affected infants exhibiting secondarily generalized seizures and normal development between episodes. Genetic heterogeneity at BFIE loci includes PRRT2, KCNQ2/3 and SCN2A, the latter encoding the neuronal sodium channel NaV1.2 (SCN2A, benign familial infantile epilepsy).

In a cohort of 68 BFIE families, targeted sequencing identified SCN2A mutations in 5 unrelated kindreds (7.4%) (PMID:29215089). Earlier, SCN2A variants were detected in 8 families with benign familial neonatal-infantile seizures, underscoring overlap with BFIE (PMID:15048894). Affected individuals uniformly carry heterozygous missense or intronic SCN2A changes, confirming autosomal dominant inheritance. Segregation has been observed in at least 5 additional affected relatives across these families.

The BFIE‐associated SCN2A spectrum comprises primarily missense substitutions and rare deep‐intronic variants. No recurrent founder alleles have been reported. One representative variant is c.2874G>T (p.Met958Ile), detected in a BFIE proband and absent from population controls. Additional intronic hits (e.g., c.697+158G>A) suggest noncoding contributions remain to be characterized.

Functional studies of related SCN2A mutations in benign familial neonatal-infantile seizures demonstrate mixed biophysical defects. Patch-clamp recordings of R1319Q, L1330F and L1563V reveal altered voltage‐dependence of activation/inactivation and reduced cell surface expression, yielding net loss-of-function via haploinsufficiency (PMID:18479388). These membrane trafficking and gating deficits concord with a mild, self‐limited epilepsy phenotype.

Overall, genetic and experimental concordance supports a haploinsufficiency mechanism for SCN2A in BFIE. Although additional genes and loci modulate susceptibility, SCN2A testing yields a definitive diagnosis in a subset of families and informs prognosis—virtually all cases remit by 1 year. SCN2A analysis should be included in infantile epilepsy panels to guide genetic counseling and management.

Key Take-home: Autosomal dominant SCN2A mutations underlie a self-limited, infancy-onset epilepsy with favorable outcome, and genetic testing can confirm BFIE, refine recurrence risk, and direct family counseling.

References

• Annals of neurology • 2004 • Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. PMID:15048894
• Journal of human genetics • 2018 • Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort. PMID:29215089
• Epilepsia • 2008 • Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures. PMID:18479388

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