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Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
Schwarz, Niklas; Seiffert, Simone; Pendziwiat, Manuela; Rademacher, Annika Verena; Brünger, Tobias; Hedrich, Ulrike B S; Augustijn, Paul B; Baier, Hartmut; Bayat, Allan; Bisulli, Francesca; Buono, Russell J; Bruria, Ben Zeev; Doyle, Michael G; Guerrini, Renzo; Heimer, Gali; Iacomino, Michele; Kearney, Hugh; Klein, Karl Martin; Kousiappa, Ioanna; Kunz, Wolfram S; 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; Muhle, Hiltrud; Helbig, Ingo; Weber, Yvonne.
Afiliação
  • Schwarz N; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Seiffert S; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Pendziwiat M; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Rademacher AV; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Brünger T; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Hedrich UBS; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Augustijn PB; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Baier H; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Bayat A; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Bisulli F; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Buono RJ; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Bruria BZ; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Doyle MG; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Guerrini R; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Heimer G; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Iacomino M; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Kearney H; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Klein KM; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Kousiappa I; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Kunz WS; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Lerche H; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Licchetta L; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Lohmann E; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Minardi R; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • McDonald M; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Montgomery S; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Mulahasanovic L; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Oegema R; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Ortal B; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Papacostas SS; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Ragona F; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Granata T; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Reif PS; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Rosenow F; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Rothschild A; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Scudieri P; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Striano P; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Tinuper P; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Tanteles GA; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Vetro A; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Zahnert F; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Goldberg EM; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Zara F; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Lal D; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • May P; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Muhle H; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Helbig I; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
  • Weber Y; From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments
Neurology ; 98(20): e2046-e2059, 2022 05 17.
Article em En | MEDLINE | ID: mdl-35314505
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 KV3.2 in the regulation of brain excitability.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Epilepsia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Neurology Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia Generalizada / Epilepsia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Neurology Ano de publicação: 2022 Tipo de documento: Article