SCN8A – Benign Familial Infantile Epilepsy

SCN8A encodes the voltage-gated sodium channel NaV1.6, which is critical for action potential initiation and propagation in central neurons. Heterozygous missense variants in SCN8A have been identified in families with benign familial infantile epilepsy (BFIE), an autosomal dominant disorder characterized by afebrile focal or generalized tonic-clonic seizures beginning in infancy, normal interictal EEG, and normal cognitive development.

1. Clinical Validity

The gene–disease relationship is categorized as Moderate. This determination is based on segregation of heterozygous missense variants in four independent families (18 affected individuals across one Korean family and three unrelated pedigrees) with consistent co-segregation and phenotype (PMID:29263050, PMID:26677014).

2. Genetic Evidence

Inheritance is autosomal dominant. Segregation analysis demonstrated 18 affected relatives carrying heterozygous SCN8A variants ([PMID:29263050], [PMID:26677014]). Two causative missense changes have been reported: c.4427G>A (p.Gly1476Asp) in a Korean family and the recurrent c.4447G>A (p.Glu1483Lys) in three families. Both variants alter highly conserved residues and were absent from population databases. No loss-of-function or splice variants have been implicated in BFIE to date.

3. Functional / Experimental Evidence

Functional data specific to BFIE are limited to in silico pathogenicity predictions. No targeted electrophysiological or cellular assays have been reported for the BFIE-associated variants. However, clinical response to sodium channel blockers in affected individuals supports a channel dysfunction mechanism.

4. Conflicting Evidence

No studies to date have refuted the association between SCN8A missense variants and BFIE. The same variants have not been observed in unaffected controls or associated with alternative phenotypes in these families.

5. Integration & Clinical Utility

Heterozygous SCN8A missense variants causing NaV1.6 dysfunction underlie a distinct, benign infantile epilepsy syndrome with normal neurodevelopment. Diagnostic exome sequencing should include SCN8A in panels for infantile seizures without cognitive impairment. Identification of pathogenic variants can guide use of sodium channel blockers and inform prognosis.

Key Take-home: SCN8A testing is clinically informative for infants with afebrile seizures and normal development, enabling precise diagnosis and targeted therapy.

References

• Annals of clinical and laboratory science • 2017 • A Novel Inherited Mutation of SCN8A in a Korean Family with Benign Familial Infantile Epilepsy Using Diagnostic Exome Sequencing. PMID:29263050
• Annals of neurology • 2016 • Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. PMID:26677014

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