Cenobamate in Dravet syndrome with electrophysiologically confirmed SCN1A loss-of-function variants: long-term real-world follow-up

Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy (DEE) characterized by seizures and developmental delay/regression, primarily caused by loss-of-function (LoF) variants in the SCN1A gene, which encodes the Nav1.1 sodium channel. Hyperexcitability in DS results from impaired inhibitory interneuron function. Sodium channel blockers are considered to be contraindicated particularly in the long-term treatment of patients with LoF variants in sodium channels as they may exacerbate seizures. However, we previously reported that cenobamate (CNB), an anti-seizure medication thought to be contraindicated due to its sodium channel blocking action, was effective in treating adult DS patients. These patients displayed a typical DS phenotype. Extended long-term follow-up demonstrated sustained clinical benefit of CNB treatment. To functionally characterize the previously unclassified patient-specific SCN1A variants, we conducted electrophysiological and localization studies using HEK cells expressing Nav1.1. Whole-cell patch-clamp recordings confirmed that the patient variants were LoF, ranging from markedly reduced to nearly absent peak sodium currents. Acute CNB exposure did not alter peak sodium current density under the experimental conditions used. These findings demonstrate sustained clinical benefit of CNB in adults with genetically confirmed DS carrying electrophysiologically confirmed LoF SCN1A variants and further expand the clinical experience with CNB in this patient population.