Schwarz, Niklas ORCID: 0000-0002-4064-3073, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brunger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan ORCID: 0000-0003-4986-8006, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo ORCID: 0000-0002-7272-7079, Heimer, Gali, Iacomino, Michele ORCID: 0000-0003-4788-9719, Kearney, Hugh ORCID: 0000-0003-2320-3487, Klein, Karl Martin ORCID: 0000-0002-6654-1665, Kousiappa, Ioanna ORCID: 0000-0002-7491-5946, Kunz, Wolfram S. ORCID: 0000-0003-1113-3493, Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick ORCID: 0000-0001-8698-3770, Muhle, Hiltrud, Helbig, Ingo and Weber, Yvonne (2022). Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. Neurology, 98 (20). S. E2046 - 14. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1526-632X

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Abstract

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(V)3.2 in the regulation of brain excitability.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schwarz, NiklasUNSPECIFIEDorcid.org/0000-0002-4064-3073UNSPECIFIED
Seiffert, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pendziwiat, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rademacher, Annika VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunger, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hedrich, Ulrike B. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Augustijn, Paul B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baier, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bayat, AllanUNSPECIFIEDorcid.org/0000-0003-4986-8006UNSPECIFIED
Bisulli, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buono, Russell J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruria, Ben ZeevUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doyle, Michael G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDorcid.org/0000-0002-7272-7079UNSPECIFIED
Heimer, GaliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iacomino, MicheleUNSPECIFIEDorcid.org/0000-0003-4788-9719UNSPECIFIED
Kearney, HughUNSPECIFIEDorcid.org/0000-0003-2320-3487UNSPECIFIED
Klein, Karl MartinUNSPECIFIEDorcid.org/0000-0002-6654-1665UNSPECIFIED
Kousiappa, IoannaUNSPECIFIEDorcid.org/0000-0002-7491-5946UNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Licchetta, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohmann, EbbaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Minardi, RaffaellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McDonald, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montgomery, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mulahasanovic, LejlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oegema, RenskeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortal, BarelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papacostas, Savvas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ragona, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Granata, TizianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, Phillip S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rothschild, AnnickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scudieri, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinuper, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tanteles, George A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vetro, AnnalisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahnert, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldberg, Ethan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Muhle, HiltrudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, YvonneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-698747
DOI: 10.1212/WNL.0000000000200660
Journal or Publication Title: Neurology
Volume: 98
Number: 20
Page Range: S. E2046 - 14
Date: 2022
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 1526-632X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
K+ CHANNELS; FAST-SPIKING; INTERNEURONS; MECHANISMS; SEIZURES; FAMILYMultiple languages
Clinical NeurologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69874

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