Autosomal dominant SCN8A mutation with an unusually mild phenotype

Area of Science:

• Genetics and Neurology
• Molecular Biology

Background:

• Mutations in the SCN8A gene, encoding the Nav1.6 voltage-gated sodium channel, are linked to infantile epilepsy with cognitive impairment, specifically early onset epileptic encephalopathy (EIEE) type 13.
• SCN8A gene variants are increasingly recognized as a cause of various epilepsy syndromes.

Observation:

• A family presented with early onset focal epileptic seizures but no cognitive or neurological impairment.
• Next-generation sequencing identified a heterozygous SCN8A mutation (c.5630A>G, p.(Asn1877Ser)) in the affected infant and father.
• The identified mutation affects a conserved amino acid and is predicted to be pathogenic by in silico analysis.

Findings:

• The infant showed normal development at 16-month follow-up, and the father had no cognitive impairment at 42 years.
• This represents the second SCN8A mutation associated with benign familial infantile epilepsy.
• Seizure control was achieved using sodium channel blockers.

Implications:

• The findings suggest expanding SCN8A gene testing to infants with epilepsy but without cognitive impairment.
• The same SCN8A variant (c.5630A>G, p.(Asn1877Ser)) is also found in patients with epilepsy and developmental delay, indicating phenotypic variability.
• This variability may be influenced by other protective genetic factors.