Epileptic Encephalopathy Mutation Displays a Loss-of-Function Phenotype and Distinct Insensitivity to Valproate.

Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform () have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the - curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.