To refine the spectrum of SCN1A-epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize anti-seizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients.
Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole-cell patch-clamp experiments were performed for three representative SCN1A pathogenic variants.
Nine of the sixteen probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the sixteen probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies (FE) with mild or no intellectual disability. Sodium-channel-blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found thirteen SCN1A missense variants, eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature.
The boundaries of SCN1A-disorders are wide and still expanding. In our cohort, more than 50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and non-familial, focal epilepsies. Alternative, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium-channel-blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate ASM.