Publication Date
4-1-2023
Journal
Annals of Clinical and Translational Neurology
DOI
10.1002/acn3.51742
PMID
36793218
PMCID
PMC10109319
PubMedCentral® Posted Date
2-15-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, 4-Aminopyridine, Gain of Function Mutation, Mutation, Epilepsy, Epilepsy, Generalized, Kv1.1 Potassium Channel
Abstract
Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage‐gated K+ channel subunit KV1.1. So far, loss‐of‐function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain‐of‐function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4‐aminopyridine. Clinical use of 4‐aminopyridine was associated with reduced seizure burden, enabled simplification of co‐medication and prevented rehospitalization.
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