Personalized treatment with retigabine for pharmacoresistant epilepsy arising from a pathogenic variant in the KCNQ2 selectivity filter

Objective. Mutations in the KCNQ2 gene, encoding the voltage-gated potassium channel, Kv7.2, cause neonatal epilepsies. The potassium channel opener, retigabine, may improve epilepsy control in cases with loss-of-function mutations, but exacerbate seizures in cases with gain-of-function mutations. Our aim was to describe a patient with a KCNQ2 mutation within the K⁺-selectivity fi lter and illustrate how electrophysiological analysis helped us to implement personalized treatment. Methods. Medical history of a patient with severe neonatal epileptic encephalopathy was recorded. Diagnosis was reached by whole-exome-sequencing. The pathogenic variant was expressed in Chinese hamster ovary cells, and patch-clamp studies were performed, directing therapy. Results. A seven-year-old male presented with neonatal seizures, progressing to hundreds of seizures/day without developmental milestones. Whole-exome sequencing revealed a pathogenic variant, p.Gly281Arg, in the KCNQ2 gene, located within the ion selectivity fi lter of the pore, predicted to cause loss-of-function of Kv7.2, not affected by retigabine. Patch-clamp analysis revealed no current with the mutant homomer and reduced current with heterotetramer (KCNQ2^WT/KCNQ2^G281R/KCNQ3^WT) channels, consistent with a dominant-negative effect. Addition of 5 m M retigabine did not produce a current with the mutant homomer, but increased current with the heterotetramer (V₅₀:−30.4 mV vs. −51.3 mV). Following these results, retigabine at 15 mg/kg was administered off-label, prompting a 90% seizure reduction. Drug withdrawal, imposed by revocation of marketing authorisation for retigabine, caused 50% increase in seizure burden. Significance. Retigabine may be used for precision therapy in patients with KCNQ2-related epilepsy due to loss-of-function variants. It is imperative to reintroduce safe marketing of retigabine for selected patients as personalized treatment.