Spectrum of Phenotypic, Genetic, and Functional Characteristics in Epilepsy Patients With KCNC2 Pathogenic Variants
-
Published:2022-03-21
Issue:
Volume:
Page:10.1212/WNL.0000000000200660
-
ISSN:0028-3878
-
Container-title:Neurology
-
language:en
-
Short-container-title:Neurology
Author:
Schwarz NiklasORCID, Seiffert SimoneORCID, Pendziwiat ManuelaORCID, Rademacher Annika Verena, Brünger Tobias, Hedrich Ulrike B S, Augustijn Paul B, Baier Hartmut, Bayat AllanORCID, Bisulli FrancescaORCID, Buono Russell J, Bruria Ben Zeev, Doyle Michael G, Guerrini RenzoORCID, Heimer Gali, Iacomino Michele, Kearney HughORCID, Klein Karl Martin, Kousiappa Ioanna, Kunz Wolfram SORCID, Lerche HolgerORCID, Licchetta LauraORCID, Lohmann Ebba, Minardi Raffaella, McDonald Marie, Montgomery Sarah, Mulahasanovic Leijla, Oegema RenskeORCID, Ortal Barel, Papacostas Savvas SORCID, Ragona Francesca, Granata Tiziana, Reif Phillip S, Rosenow FelixORCID, Rothschild Annick, Scudieri Paolo, Striano PasqualeORCID, Tinuper Paolo, Tanteles George AORCID, Vetro Annalisa, Zahnert FelixORCID, Goldberg Ethan M, Zara FedericoORCID, Lal Dennis, May PatrickORCID, Muhle Hiltrud, Helbig IngoORCID, Weber Yvonne
Abstract
Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Neurology (clinical)
Cited by
11 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|