Implication of genetic-dependent stage in the development of SCN8A-associated epilepsy: a case report

The SCN8A gene encodes the voltage-gated sodium channel Na_V1.6, which is essential for neuronal excitability and action potential propagation. SCN8A variants are associated with a broad clinical spectrum, ranging from self-limiting syndromes to developmental and epileptic encephalopathies. Here, we identified a novel de novo heterozygous SCN8A variant (c.791 T > C/p.Val264Ala) in a 19-year-old female patient. This variant was absent in gnomAD and was predicted to be damaging by multiple in silico tools. According to the American College of Medical Genetics and Genomics guidelines, the variant was evaluated as "likely pathogenic." The patient presented with frequent cluster seizures characterized by early onset, remission in childhood, and recurrence in adolescence. The electroencephalograph revealed multifocal epileptiform discharges. The patient was diagnosed with developmental and epileptic encephalopathy. Treatment with sodium channel blockers (oxcarbazepine and lamotrigine) achieved seizure control, a clinical response that suggests a potential gain-of-function effect of the variant. The brain temporal expression of SCN8A gradually increases after birth with a peak during infancy, declines through childhood, and rises significantly in adolescence, explaining the development of the patient's clinical course. This study contributes to the genotype-phenotype correlation of SCN8A-related diseases and highlights the implication of genetic-dependent expression (stage) in clinical assessment.