De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Deciphering Developmental Disorders Study

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Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume103
Issue number5
Pages (from-to)666-678
ISSN0002-9297
DOIs
Publication statusPublished - 1. Nov 2018

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Contracture
S 6
R-Type Calcium Channels
Hyperkinesis
Muscle Hypotonia
Movement Disorders
Electroencephalography
Central Nervous System
Pharmaceutical Preparations

Keywords

  • Adolescent
  • Adult
  • Calcium Channels, R-Type/genetics
  • Cation Transport Proteins/genetics
  • Child
  • Child, Preschool
  • Contracture/genetics
  • Dyskinesias/genetics
  • Epilepsy/genetics
  • Female
  • Genetic Variation/genetics
  • Humans
  • Infant
  • Male
  • Megalencephaly/genetics
  • Neurodevelopmental Disorders/genetics
  • Spasms, Infantile/genetics

Cite this

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title = "De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias",
abstract = "Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.",
keywords = "Adolescent, Adult, Calcium Channels, R-Type/genetics, Cation Transport Proteins/genetics, Child, Child, Preschool, Contracture/genetics, Dyskinesias/genetics, Epilepsy/genetics, Female, Genetic Variation/genetics, Humans, Infant, Male, Megalencephaly/genetics, Neurodevelopmental Disorders/genetics, Spasms, Infantile/genetics",
author = "Helbig, {Katherine L} and Lauerer, {Robert J} and Bahr, {Jacqueline C} and Souza, {Ivana A} and Myers, {Candace T} and Bet{\"u}l Uysal and Niklas Schwarz and Gandini, {Maria A} and Sun Huang and Boris Keren and Cyril Mignot and Alexandra Afenjar and {Billette de Villemeur}, Thierry and Delphine H{\'e}ron and Caroline Nava and St{\'e}phanie Valence and Julien Buratti and Fagerberg, {Christina R} and Soerensen, {Kristina P} and Maria Kibaek and Erik-Jan Kamsteeg and Koolen, {David A} and Boudewijn Gunning and Schelhaas, {H Jurgen} and Kruer, {Michael C} and Jordana Fox and Somayeh Bakhtiari and Randa Jarrar and Sergio Padilla-Lopez and Kristin Lindstrom and Jin, {Sheng Chih} and Xue Zeng and Kaya Bilguvar and Antigone Papavasileiou and Qinghe Xin and Changlian Zhu and Katja Boysen and Filippo Vairo and Lanpher, {Brendan C} and Klee, {Eric W} and Jan-Mendelt Tillema and Payne, {Eric T} and Cousin, {Margot A} and Kruisselbrink, {Teresa M} and Wick, {Myra J} and Joshua Baker and Eric Haan and Nicholas Smith and Corbett, {Mark A} and MacLennan, {Alastair H} and {Deciphering Developmental Disorders Study}",
note = "Copyright {\circledC} 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "11",
day = "1",
doi = "10.1016/j.ajhg.2018.09.006",
language = "English",
volume = "103",
pages = "666--678",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",

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De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. / Deciphering Developmental Disorders Study.

In: American Journal of Human Genetics, Vol. 103, No. 5, 01.11.2018, p. 666-678.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

AU - Helbig, Katherine L

AU - Lauerer, Robert J

AU - Bahr, Jacqueline C

AU - Souza, Ivana A

AU - Myers, Candace T

AU - Uysal, Betül

AU - Schwarz, Niklas

AU - Gandini, Maria A

AU - Huang, Sun

AU - Keren, Boris

AU - Mignot, Cyril

AU - Afenjar, Alexandra

AU - Billette de Villemeur, Thierry

AU - Héron, Delphine

AU - Nava, Caroline

AU - Valence, Stéphanie

AU - Buratti, Julien

AU - Fagerberg, Christina R

AU - Soerensen, Kristina P

AU - Kibaek, Maria

AU - Kamsteeg, Erik-Jan

AU - Koolen, David A

AU - Gunning, Boudewijn

AU - Schelhaas, H Jurgen

AU - Kruer, Michael C

AU - Fox, Jordana

AU - Bakhtiari, Somayeh

AU - Jarrar, Randa

AU - Padilla-Lopez, Sergio

AU - Lindstrom, Kristin

AU - Jin, Sheng Chih

AU - Zeng, Xue

AU - Bilguvar, Kaya

AU - Papavasileiou, Antigone

AU - Xin, Qinghe

AU - Zhu, Changlian

AU - Boysen, Katja

AU - Vairo, Filippo

AU - Lanpher, Brendan C

AU - Klee, Eric W

AU - Tillema, Jan-Mendelt

AU - Payne, Eric T

AU - Cousin, Margot A

AU - Kruisselbrink, Teresa M

AU - Wick, Myra J

AU - Baker, Joshua

AU - Haan, Eric

AU - Smith, Nicholas

AU - Corbett, Mark A

AU - MacLennan, Alastair H

AU - Deciphering Developmental Disorders Study

N1 - Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

AB - Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

KW - Adolescent

KW - Adult

KW - Calcium Channels, R-Type/genetics

KW - Cation Transport Proteins/genetics

KW - Child

KW - Child, Preschool

KW - Contracture/genetics

KW - Dyskinesias/genetics

KW - Epilepsy/genetics

KW - Female

KW - Genetic Variation/genetics

KW - Humans

KW - Infant

KW - Male

KW - Megalencephaly/genetics

KW - Neurodevelopmental Disorders/genetics

KW - Spasms, Infantile/genetics

U2 - 10.1016/j.ajhg.2018.09.006

DO - 10.1016/j.ajhg.2018.09.006

M3 - Journal article

C2 - 30343943

VL - 103

SP - 666

EP - 678

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -