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 Kunz; Holger 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

doi:10.1212/WNL.0000000000200660

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

Filadelfia

Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

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 V3.2 in the regulation of brain excitability.

Originalsprog	Engelsk
Sider (fra-til)	e2046-e2059
Antal sider	14
Tidsskrift	Neurology
Vol/bind	98
Udgave nummer	20
DOI	https://doi.org/10.1212/WNL.0000000000200660
Status	Udgivet - 17 maj 2022

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10.1212/WNL.0000000000200660

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Schwarz, N., Seiffert, S., Pendziwiat, M., Rademacher, A. V., Brünger, T., Hedrich, U. B. S., Augustijn, P. B., Baier, H., Bayat, A., Bisulli, F., Buono, R. J., Zeev, B. B., Doyle, M. G., Guerrini, R., Heimer, G., Iacomino, M., Kearney, H., Klein, K-M., Kousiappa, I., ... Weber, Y. (2022). Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants. Neurology, 98(20), e2046-e2059. https://doi.org/10.1212/WNL.0000000000200660

@article{f952ea8f606f4491b6c3de50e249ebdf,

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

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 V3.2 in the regulation of brain excitability. ",

keywords = "Epilepsy, Generalized/genetics, Epilepsy/genetics, Humans, Phenotype, Seizures/genetics, Shaw Potassium Channels/genetics, Whole Exome Sequencing",

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

note = "Copyright {\textcopyright} 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2022",

month = may,

day = "17",

doi = "10.1212/WNL.0000000000200660",

language = "English",

volume = "98",

pages = "e2046--e2059",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "20",

}

Schwarz, N, Seiffert, S, Pendziwiat, M, Rademacher, AV, Brünger, T, Hedrich, UBS, Augustijn, PB, Baier, H, Bayat, A, Bisulli, F, Buono, RJ, Zeev, BB, Doyle, MG, Guerrini, R, Heimer, G, Iacomino, M, Kearney, H, Klein, K-M, Kousiappa, I, Kunz, WS, Lerche, H, Licchetta, L, Lohmann, E, Minardi, R, McDonald, M, Montgomery, S, Mulahasanovic, L, Oegema, R, Ortal, B, Papakostas, SS, Ragona, F, Granata, T, Reif, PS, Rosenow, F, Rothschild, A, Scudieri, P, Striano, P, Tinuper, P, Tanteles, GA, Vetro, A, Zahnert, F, Goldberg, EM, Zara, F, Lal, D, May, P, Muhle, H, Helbig, I & Weber, Y 2022, 'Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.', Neurology, bind 98, nr. 20, s. e2046-e2059. https://doi.org/10.1212/WNL.0000000000200660

TY - JOUR

T1 - Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

AU - Schwarz, Niklas

AU - Seiffert, Simone

AU - Pendziwiat, Manuela

AU - Rademacher, Annika Verena

AU - Brünger, Tobias

AU - Hedrich, Ulrike B S

AU - Augustijn, Paul B

AU - Baier, Hartmut

AU - Bayat, Allan

AU - Bisulli, Francesca

AU - Buono, Russell J

AU - Zeev, Bruria Ben

AU - Doyle, Michael G

AU - Guerrini, Renzo

AU - Heimer, Gali

AU - Iacomino, Michele

AU - Kearney, Hugh

AU - Klein, Karl-Martin

AU - Kousiappa, Ioanna

AU - Kunz, Wolfram S

AU - Lerche, Holger

AU - Licchetta, Laura

AU - Lohmann, Ebba

AU - Minardi, Raffaella

AU - McDonald, Marie

AU - Montgomery, Sarah

AU - Mulahasanovic, Lejla

AU - Oegema, Renske

AU - Ortal, Barel

AU - Papakostas, Savvas S

AU - Ragona, Francesca

AU - Granata, Tiziana

AU - Reif, Philipp S

AU - Rosenow, Felix

AU - Rothschild, Annick

AU - Scudieri, Paolo

AU - Striano, Pasquale

AU - Tinuper, Paolo

AU - Tanteles, George A

AU - Vetro, Annalisa

AU - Zahnert, Felix

AU - Goldberg, Ethan M

AU - Zara, Federico

AU - Lal, Dennis

AU - May, Patrick

AU - Muhle, Hiltrud

AU - Helbig, Ingo

AU - Weber, Yvonne

PY - 2022/5/17

Y1 - 2022/5/17

N2 - 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.

AB - 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.

KW - Epilepsy, Generalized/genetics

KW - Epilepsy/genetics

KW - Humans

KW - Phenotype

KW - Seizures/genetics

KW - Shaw Potassium Channels/genetics

KW - Whole Exome Sequencing

U2 - 10.1212/WNL.0000000000200660

DO - 10.1212/WNL.0000000000200660

M3 - Article

C2 - 35314505

SN - 0028-3878

VL - 98

SP - e2046-e2059

JO - Neurology

JF - Neurology

IS - 20

ER -

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

Abstract

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