Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

Niklas Schwarz, Simone Seiffert, Manuela Pendziwiat, Annika Verena Rademacher, Tobias Brünger, Ulrike B S Hedrich, Paul B Augustijn, Hartmut Baier, Allan Bayat, Francesca Bisulli, Russell J Buono, Bruria Ben Zeev, Michael G Doyle, Renzo Guerrini, Gali Heimer, Michele Iacomino, Hugh Kearney, Karl-Martin Klein, Ioanna Kousiappa, Wolfram S KunzHolger Lerche, Laura Licchetta, Ebba Lohmann, Raffaella Minardi, Marie McDonald, Sarah Montgomery, Lejla Mulahasanovic, Renske Oegema, Barel Ortal, Savvas S Papakostas, Francesca Ragona, Tiziana Granata, Philipp S Reif, Felix Rosenow, Annick Rothschild, Paolo Scudieri, Pasquale Striano, Paolo Tinuper, George A Tanteles, Annalisa Vetro, Felix Zahnert, Ethan M Goldberg, Federico Zara, Dennis Lal, Patrick May, Hiltrud Muhle, Ingo Helbig, Yvonne Weber*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


BACKGROUND AND OBJECTIVES: 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 analyze 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, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.

DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K V3.2 in the regulation of brain excitability.

Sider (fra-til)e2046-e2059
Antal sider14
Udgave nummer20
StatusUdgivet - 17 maj 2022

Bibliografisk note

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.


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