Personalized treatment with retigabine for pharmacoresistant epilepsy arising from a pathogenic variant in the KCNQ2 selectivity filter. Issue 5 (16th November 2021)

• Record Type: Journal Article
• Authors: Nissenkorn, Andreea; Kornilov, Polina; Peretz, Asher; Blumkin, Lubov; Heimer, Gali; Ben‐Zeev, Bruria; Attali, Bernard
• Is Part Of: Epileptic disorders. Volume 23:Issue 5(2021)
• Page Start: 695
• Page End: 705
• Publication Date: 2021-11-16
• Subjects: antiepileptic drugs -- epileptic encephalopathy -- patch‐clamp analysis -- precision medicine -- neonatal seizures; Epilepsy -- Periodicals; 616.853
• DOI: 10.1684/epd.2021.1315
• Languages: English
• ISSNs: 1294-9361

Abstract

Abstract: 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.