2019 - Functional consequences of a KCNT1 variant associated with status dystonicus and early‐onset infantile encephalopathy
SyncroPatch 384PE (a predeccessor model of the SyncroPatch 384i) publication in Annals of Clinical and Translational Neurology (2019)
Gertler T.S., Thompson C.H., Vanoye C.G., Millichap J.J., George Jr A.L.
Annals of Clinical and Translational Neurology (2019) doi: org/10.1002/acn3.50847
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 KNa1.1 channel to investigate the molecular mechanisms responsible for this disorder.
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.
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.
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.