Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Deciphering Developmental Disorders Study; UK10K Consortium; NIHR BioResource; Michael A. Simpson; Elena Prigmore; Philip Jones; Ruth Armstrong; Chris Bennett; Jonathan Berg; Birgitta Bernhard; Nicola Cooper; Helen Cox; Frances Flinter; Andrew Fry; Harinder Gill; Emma Gray; Victoria Harrison; Melita Irving; Dragana Josifova; Caroline Langman; Shehla Mohammed; David Moore; Helen Murphy; Jonathan Roberts; Marc Tischkowitz; Michael Wright; Patrick Bolton; Gerome Breen; Gail Clement; David Collier; Sarah Curran; Peter Ellis; David Evans; Deborah Hart; Tim Hubbard; Pirro Hysi; Yalda Jamshidi; Genevieve Lachance; Margarida Lopes; Peter McGuffin; Sarah Metrustry; Alireza Moayyeri; Alexandros Onoufriadis; Jeremy R. Parr; Lydia Quaye; Sally I. Sharp; Kerrin Small; Olivera Spasic-Boskovic; Elizabeth Stevens; Ana Valdes; James T.R. Walters; Yu Wang; David Bennett; John R. Bradley; John Davis; Ania Koziell; Rajiv Machado; Michael Richards; Kenneth Smith; Laura Southgate; Ellen Thomas; Richard Trembath; Catherine Williamson; Patrick Yong

doi:10.1016/j.ajhg.2019.03.005

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Deciphering Developmental Disorders Study, UK10K Consortium, NIHR BioResource, Michael A. Simpson, Elena Prigmore, Philip Jones, Ruth Armstrong, Chris Bennett, Jonathan Berg, Birgitta Bernhard, Nicola Cooper, Helen Cox, Frances Flinter, Andrew Fry, Harinder Gill, Emma Gray, Victoria Harrison, Melita Irving, Dragana Josifova, Caroline LangmanShehla Mohammed, David Moore, Helen Murphy, Jonathan Roberts, Marc Tischkowitz, Michael Wright, Patrick Bolton, Gerome Breen, Gail Clement, David Collier, Sarah Curran, Peter Ellis, David Evans, Deborah Hart, Tim Hubbard, Pirro Hysi, Yalda Jamshidi, Genevieve Lachance, Margarida Lopes, Peter McGuffin, Sarah Metrustry, Alireza Moayyeri, Alexandros Onoufriadis, Jeremy R. Parr, Lydia Quaye, Sally I. Sharp, Kerrin Small, Olivera Spasic-Boskovic, Elizabeth Stevens, Ana Valdes, James T.R. Walters, Yu Wang, David Bennett, John R. Bradley, John Davis, Ania Koziell, Rajiv Machado, Michael Richards, Kenneth Smith, Laura Southgate, Ellen Thomas, Richard Trembath, Catherine Williamson, Patrick Yong

Research output: Contribution to journal › Article › peer-review

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Abstract

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca _v 2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca ²⁺ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca _v 2.2 in normal human neurodevelopment.

Original language	English
Pages (from-to)	948-956
Number of pages	9
Journal	American Journal of Human Genetics
Volume	104
Issue number	5
Early online date	11 Apr 2019
DOIs	https://doi.org/10.1016/j.ajhg.2019.03.005
Publication status	Published - 2 May 2019

Keywords

CACNA1B
developmental and epileptic encephalopathy (DEE)
epilepsy
epilepsy-dyskinesia

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10.1016/j.ajhg.2019.03.005

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Deciphering Developmental Disorders Study, UK10K Consortium, NIHR BioResource, Simpson, M. A., Prigmore, E., Jones, P., Armstrong, R., Bennett, C., Berg, J., Bernhard, B., Cooper, N., Cox, H., Flinter, F., Fry, A., Gill, H., Gray, E., Harrison, V., Irving, M., Josifova, D., ... Yong, P. (2019). Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. American Journal of Human Genetics, 104(5), 948-956. https://doi.org/10.1016/j.ajhg.2019.03.005

@article{73531a8872cc4567b1ee54b997b0774d,

title = "Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia",

abstract = " The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca v 2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca 2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca v 2.2 in normal human neurodevelopment. ",

keywords = "CACNA1B, developmental and epileptic encephalopathy (DEE), epilepsy, epilepsy-dyskinesia",

author = "{Deciphering Developmental Disorders Study} and {UK10K Consortium} and {NIHR BioResource} and Simpson, {Michael A.} and Elena Prigmore and Philip Jones and Ruth Armstrong and Chris Bennett and Jonathan Berg and Birgitta Bernhard and Nicola Cooper and Helen Cox and Frances Flinter and Andrew Fry and Harinder Gill and Emma Gray and Victoria Harrison and Melita Irving and Dragana Josifova and Caroline Langman and Shehla Mohammed and David Moore and Helen Murphy and Jonathan Roberts and Marc Tischkowitz and Michael Wright and Patrick Bolton and Gerome Breen and Gail Clement and David Collier and Sarah Curran and Peter Ellis and David Evans and Deborah Hart and Tim Hubbard and Pirro Hysi and Yalda Jamshidi and Genevieve Lachance and Margarida Lopes and Peter McGuffin and Sarah Metrustry and Alireza Moayyeri and Alexandros Onoufriadis and Parr, {Jeremy R.} and Lydia Quaye and Sharp, {Sally I.} and Kerrin Small and Olivera Spasic-Boskovic and Elizabeth Stevens and Ana Valdes and Walters, {James T.R.} and Yu Wang and David Bennett and Bradley, {John R.} and John Davis and Ania Koziell and Rajiv Machado and Michael Richards and Kenneth Smith and Laura Southgate and Ellen Thomas and Richard Trembath and Catherine Williamson and Patrick Yong",

year = "2019",

month = may,

day = "2",

doi = "10.1016/j.ajhg.2019.03.005",

language = "English",

volume = "104",

pages = "948--956",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Elsevier",

number = "5",

}

Deciphering Developmental Disorders Study, UK10K Consortium, NIHR BioResource, Simpson, MA , Prigmore, E, Jones, P, Armstrong, R, Bennett, C, Berg, J, Bernhard, B, Cooper, N, Cox, H, Flinter, F, Fry, A, Gill, H, Gray, E, Harrison, V, Irving, M , Josifova, D , Langman, C , Mohammed, S, Moore, D, Murphy, H, Roberts, J , Tischkowitz, M, Wright, M, Bolton, P , Breen, G , Clement, G, Collier, D, Curran, S, Ellis, P, Evans, D, Hart, D , Hubbard, T , Hysi, P , Jamshidi, Y , Lachance, G , Lopes, M , McGuffin, P , Metrustry, S , Moayyeri, A , Onoufriadis, A, Parr, JR, Quaye, L , Sharp, SI , Small, K, Spasic-Boskovic, O, Stevens, E, Valdes, A, Walters, JTR, Wang, Y, Bennett, D, Bradley, JR, Davis, J, Koziell, A , Machado, R, Richards, M, Smith, K, Southgate, L , Thomas, E , Trembath, R , Williamson, C & Yong, P 2019, 'Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia', American Journal of Human Genetics, vol. 104, no. 5, pp. 948-956. https://doi.org/10.1016/j.ajhg.2019.03.005

TY - JOUR

T1 - Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

AU - Deciphering Developmental Disorders Study

AU - UK10K Consortium

AU - NIHR BioResource

AU - Simpson, Michael A.

AU - Prigmore, Elena

AU - Jones, Philip

AU - Armstrong, Ruth

AU - Bennett, Chris

AU - Berg, Jonathan

AU - Bernhard, Birgitta

AU - Cooper, Nicola

AU - Cox, Helen

AU - Flinter, Frances

AU - Fry, Andrew

AU - Gill, Harinder

AU - Gray, Emma

AU - Harrison, Victoria

AU - Irving, Melita

AU - Josifova, Dragana

AU - Langman, Caroline

AU - Mohammed, Shehla

AU - Moore, David

AU - Murphy, Helen

AU - Roberts, Jonathan

AU - Tischkowitz, Marc

AU - Wright, Michael

AU - Bolton, Patrick

AU - Breen, Gerome

AU - Clement, Gail

AU - Collier, David

AU - Curran, Sarah

AU - Ellis, Peter

AU - Evans, David

AU - Hart, Deborah

AU - Hubbard, Tim

AU - Hysi, Pirro

AU - Jamshidi, Yalda

AU - Lachance, Genevieve

AU - Lopes, Margarida

AU - McGuffin, Peter

AU - Metrustry, Sarah

AU - Moayyeri, Alireza

AU - Onoufriadis, Alexandros

AU - Parr, Jeremy R.

AU - Quaye, Lydia

AU - Sharp, Sally I.

AU - Small, Kerrin

AU - Spasic-Boskovic, Olivera

AU - Stevens, Elizabeth

AU - Valdes, Ana

AU - Walters, James T.R.

AU - Wang, Yu

AU - Bennett, David

AU - Bradley, John R.

AU - Davis, John

AU - Koziell, Ania

AU - Machado, Rajiv

AU - Richards, Michael

AU - Smith, Kenneth

AU - Southgate, Laura

AU - Thomas, Ellen

AU - Trembath, Richard

AU - Williamson, Catherine

AU - Yong, Patrick

PY - 2019/5/2

Y1 - 2019/5/2

N2 - The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca v 2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca 2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca v 2.2 in normal human neurodevelopment.

AB - The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Ca v 2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca 2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Ca v 2.2 in normal human neurodevelopment.

KW - CACNA1B

KW - developmental and epileptic encephalopathy (DEE)

KW - epilepsy

KW - epilepsy-dyskinesia

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U2 - 10.1016/j.ajhg.2019.03.005

DO - 10.1016/j.ajhg.2019.03.005

M3 - Article

C2 - 30982612

AN - SCOPUS:85064910539

SN - 0002-9297

VL - 104

SP - 948

EP - 956

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

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