Phenotypic and genetic spectrum in Chinese children with SCN8A-related disorders

Background: Pathogenic variants in SCN8A have been demonstrated with a wide spectrum of epilepsy phenotypes, ranging from benign infantile epilepsy (BIE), to early onset developmental and epileptic encephalopathy (DEE) with moderate to severe developmental delay. In order to provide further insight on the spectrum of SCN8A-related epilepsy, we aimed to explore the clinical and genetic phenotype in Chinese children.

Methods: A cohort of fifty Chinese patients with SCN8A-related disorders was included in the retrospective study. Genetic and clinical features and treatment effect of patients were further assessed based on phenotype parameters. The pathogenicity of variants was classified using the next-generation sequencing variation study.

Results: We found 50 patients who presented with severe developmental and epileptic encephalopathy (DEE, 70%), benign infantile epilepsy (BIE, 12%), developmental encephalopathy with epilepsy (16%), and severe developmental delay without epilepsy (2%). The seizure onset age ranged from 1 day to 1 year and 11 months. After anti-seizure treatment, 28% of patients obtained seizure control. Sodium channel blockers showed good prognosis in 26% of patients with severe DEE. Oxcarbazepine (OXC) monotherapy was obviously effective in patients with BIE and developmental encephalopathy with epilepsy, most importantly, 87.5% received the anti-seizure therapy with sodium channel blockers in combination. All the variants were de novo missense with exception of one splice site variant. We reported three new variants, Asn1887Ser, Ile1605Thr, and Met1869Thr, which were associated with SCN8A-BIE.

Conclusion: The phenotypic spectrum of SCN8A-related disorders in Chinese children ranged from severe developmental delay without epilepsy to severe DEE. Three new variants were associated with SCN8A-BIE. Sodium channel blockers were effective in treating seizures for some SCN8A-related disorders however may not be relevant to the mutant location.