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

Deciphering Developmental Disorders Study, NIHR BioResource, UK10K Consortium, Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Alex R. Paciorkowski & 5 others J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Tobias B. Haack, Gary McCullagh

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)948-956
JournalAmerican journal of human genetics
Volume104
Issue number5
DOIs
Publication statusPublished - 2019

Cite this

Deciphering Developmental Disorders Study, NIHR BioResource, UK10K Consortium, Gorman, K. M., Meyer, E., Grozeva, D., ... McCullagh, G. (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
Deciphering Developmental Disorders Study ; NIHR BioResource ; UK10K Consortium ; Gorman, Kathleen M. ; Meyer, Esther ; Grozeva, Detelina ; Spinelli, Egidio ; McTague, Amy ; Sanchis-Juan, Alba ; Carss, Keren J. ; Bryant, Emily ; Reich, Adi ; Schneider, Amy L. ; Pressler, Ronit M. ; Simpson, Michael A. ; Debelle, Geoff D. ; Wassmer, Evangeline ; Morton, Jenny ; Sieciechowicz, Diana ; Paciorkowski, Alex R. ; Cross, J. Helen ; Poduri, Annapurna ; Mefford, Heather C. ; Haack, Tobias B. ; McCullagh, Gary. / Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. In: American journal of human genetics. 2019 ; Vol. 104, No. 5. pp. 948-956.
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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.",
author = "{Deciphering Developmental Disorders Study} and {NIHR BioResource} and {UK10K Consortium} and Gorman, {Kathleen M.} and Esther Meyer and Detelina Grozeva and Egidio Spinelli and Amy McTague and Alba Sanchis-Juan and Carss, {Keren J.} and Emily Bryant and Adi Reich and Schneider, {Amy L.} and Pressler, {Ronit M.} and Simpson, {Michael A.} and Debelle, {Geoff D.} and Evangeline Wassmer and Jenny Morton and Diana Sieciechowicz and Eric Jan-Kamsteeg and Paciorkowski, {Alex R.} and King, {Mary D.} and Cross, {J. Helen} and Annapurna Poduri and Mefford, {Heather C.} and Scheffer, {Ingrid E.} and Haack, {Tobias B.} and Gary McCullagh and McRae, {Jeremy F.} and Stephen Clayton and Fitzgerald, {Tomas W.} and Joanna Kaplanis and Elena Prigmore and Diana Rajan and Alejandro Sifrim and Stuart Aitken and Nadia Akawi and Mohsan Alvi and Kirsty Ambridge and Barrett, {Daniel M.} and Tanya Bayzetinova and Philip Jones and Jones, {Wendy D.} and Daniel King and Netravathi Krishnappa and David Evans and Kuijpers, {Taco W.} and Sergey Nejentsev and Noordegraaf, {Anton Vonk}",
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Deciphering Developmental Disorders Study, NIHR BioResource, UK10K Consortium, Gorman, KM, Meyer, E, Grozeva, D, Spinelli, E, McTague, A, Sanchis-Juan, A, Carss, KJ, Bryant, E, Reich, A, Schneider, AL, Pressler, RM, Simpson, MA, Debelle, GD, Wassmer, E, Morton, J, Sieciechowicz, D, Paciorkowski, AR, Cross, JH, Poduri, A, Mefford, HC, Haack, TB & McCullagh, G 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

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. / Deciphering Developmental Disorders Study; NIHR BioResource; UK10K Consortium; Gorman, Kathleen M.; Meyer, Esther; Grozeva, Detelina; Spinelli, Egidio; McTague, Amy; Sanchis-Juan, Alba; Carss, Keren J.; Bryant, Emily; Reich, Adi; Schneider, Amy L.; Pressler, Ronit M.; Simpson, Michael A.; Debelle, Geoff D.; Wassmer, Evangeline; Morton, Jenny; Sieciechowicz, Diana; Paciorkowski, Alex R.; Cross, J. Helen; Poduri, Annapurna; Mefford, Heather C.; Haack, Tobias B.; McCullagh, Gary.

In: American journal of human genetics, Vol. 104, No. 5, 2019, p. 948-956.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

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

AU - Deciphering Developmental Disorders Study

AU - NIHR BioResource

AU - UK10K Consortium

AU - Gorman, Kathleen M.

AU - Meyer, Esther

AU - Grozeva, Detelina

AU - Spinelli, Egidio

AU - McTague, Amy

AU - Sanchis-Juan, Alba

AU - Carss, Keren J.

AU - Bryant, Emily

AU - Reich, Adi

AU - Schneider, Amy L.

AU - Pressler, Ronit M.

AU - Simpson, Michael A.

AU - Debelle, Geoff D.

AU - Wassmer, Evangeline

AU - Morton, Jenny

AU - Sieciechowicz, Diana

AU - Jan-Kamsteeg, Eric

AU - Paciorkowski, Alex R.

AU - King, Mary D.

AU - Cross, J. Helen

AU - Poduri, Annapurna

AU - Mefford, Heather C.

AU - Scheffer, Ingrid E.

AU - Haack, Tobias B.

AU - McCullagh, Gary

AU - McRae, Jeremy F.

AU - Clayton, Stephen

AU - Fitzgerald, Tomas W.

AU - Kaplanis, Joanna

AU - Prigmore, Elena

AU - Rajan, Diana

AU - Sifrim, Alejandro

AU - Aitken, Stuart

AU - Akawi, Nadia

AU - Alvi, Mohsan

AU - Ambridge, Kirsty

AU - Barrett, Daniel M.

AU - Bayzetinova, Tanya

AU - Jones, Philip

AU - Jones, Wendy D.

AU - King, Daniel

AU - Krishnappa, Netravathi

AU - Evans, David

AU - Kuijpers, Taco W.

AU - Nejentsev, Sergey

AU - Noordegraaf, Anton Vonk

PY - 2019

Y1 - 2019

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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30982612

U2 - 10.1016/j.ajhg.2019.03.005

DO - 10.1016/j.ajhg.2019.03.005

M3 - Article

VL - 104

SP - 948

EP - 956

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

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ER -

Deciphering Developmental Disorders Study, NIHR BioResource, UK10K Consortium, Gorman KM, Meyer E, Grozeva D et al. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. American journal of human genetics. 2019;104(5):948-956. https://doi.org/10.1016/j.ajhg.2019.03.005