Abstract
OBJECTIVE: We identified a novel de novo KCNT1 variant in a patient with early-infantile epileptic encephalopathy (EIEE) and status dystonicus, a life-threatening movement disorder. We determined the functional consequences of this variant on the encoded K(Na) 1.1 channel to investigate the molecular mechanisms responsible for this disorder. METHODS: A retrospective case review of the proband is presented. We performed manual and automated electrophysiologic analyses of the KCNT1-L437F variant expressed heterologously in Chinese hamster ovary (CHO) cells in the presence of channel activators/blockers. RESULTS: The KCNT1-L437F variant, identified in a patient with refractory EIEE and status dystonicus, confers a gain-of-function channel phenotype characterized by instantaneous, voltage-dependent activation. Channel openers do not further increase L437F channel function, suggesting maximal activation, whereas channel blockers similarly block wild-type and variant channels. We further demonstrated that KCNT1 current can be measured on a high-throughput automated electrophysiology platform with potential value for future screening of novel and repurposed pharmacotherapies. INTERPRETATION: A novel pathogenic variant in KCNT1 associated with early-onset, medication-refractory epilepsy and dystonia causes gain-of-function with rapid activation kinetics. Our findings extend the genotype-phenotype relationships of KCNT1 variants to include severe dystonia.