Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants / Schwarz N.; Seiffert S.; Pendziwiat M.; Rademacher A.V.; Brunger T.; Hedrich U.B.S.; Augustijn P.B.; Baier H.; Bayat A.; Bisulli F.; Buono R.J.; Bruria B.Z.; Doyle M.G.; Guerrini R.; Heimer G.; Iacomino M.; Kearney H.; Klein K.M.; Kousiappa I.; Kunz W.S.; Lerche H.; Licchetta L.; Lohmann E.; Minardi R.; McDonald M.; Montgomery S.; Mulahasanovic L.; Oegema R.; Ortal B.; Papacostas S.S.; Ragona F.; Granata T.; Reif P.S.; Rosenow F.; Rothschild A.; Scudieri P.; Striano P.; Tinuper P.; Tanteles G.A.; Vetro A.; Zahnert F.; Goldberg E.M.; Zara F.; Lal D.; May P.; Muhle H.; Helbig I.; Weber Y.. - In: NEUROLOGY. - ISSN 0028-3878. - ELETTRONICO. - 98:20(2022), pp. E2046-E2059. [10.1212/WNL.0000000000200660]

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

Bisulli F.;Minardi R.;Tinuper P.;
2022

Abstract

Background and ObjectivesKCNC2 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.MethodsIndividuals 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.ResultsWe 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.DiscussionThese findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.
2022
Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants / Schwarz N.; Seiffert S.; Pendziwiat M.; Rademacher A.V.; Brunger T.; Hedrich U.B.S.; Augustijn P.B.; Baier H.; Bayat A.; Bisulli F.; Buono R.J.; Bruria B.Z.; Doyle M.G.; Guerrini R.; Heimer G.; Iacomino M.; Kearney H.; Klein K.M.; Kousiappa I.; Kunz W.S.; Lerche H.; Licchetta L.; Lohmann E.; Minardi R.; McDonald M.; Montgomery S.; Mulahasanovic L.; Oegema R.; Ortal B.; Papacostas S.S.; Ragona F.; Granata T.; Reif P.S.; Rosenow F.; Rothschild A.; Scudieri P.; Striano P.; Tinuper P.; Tanteles G.A.; Vetro A.; Zahnert F.; Goldberg E.M.; Zara F.; Lal D.; May P.; Muhle H.; Helbig I.; Weber Y.. - In: NEUROLOGY. - ISSN 0028-3878. - ELETTRONICO. - 98:20(2022), pp. E2046-E2059. [10.1212/WNL.0000000000200660]
Schwarz N.; Seiffert S.; Pendziwiat M.; Rademacher A.V.; Brunger T.; Hedrich U.B.S.; Augustijn P.B.; Baier H.; Bayat A.; Bisulli F.; Buono R.J.; Bruria B.Z.; Doyle M.G.; Guerrini R.; Heimer G.; Iacomino M.; Kearney H.; Klein K.M.; Kousiappa I.; Kunz W.S.; Lerche H.; Licchetta L.; Lohmann E.; Minardi R.; McDonald M.; Montgomery S.; Mulahasanovic L.; Oegema R.; Ortal B.; Papacostas S.S.; Ragona F.; Granata T.; Reif P.S.; Rosenow F.; Rothschild A.; Scudieri P.; Striano P.; Tinuper P.; Tanteles G.A.; Vetro A.; Zahnert F.; Goldberg E.M.; Zara F.; Lal D.; May P.; Muhle H.; Helbig I.; Weber Y.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/901190
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