TY - JOUR
T1 - Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia
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
AU - Deciphering Developmental Disorders Study
AU - NIHR BioResource
AU - UK10K Consortium
AU - Millichap, John J.
AU - Carvill, Gemma L.
AU - Clayton-Smith, Jill
AU - Maher, Eamonn R.
AU - Raymond, F Lucy
AU - Kurian, Manju A
AU - Study group members AMC, null
N1 - Copyright © 2019 American Society of Human Genetics. All rights reserved.
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064910539&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30982612
U2 - https://doi.org/10.1016/j.ajhg.2019.03.005
DO - https://doi.org/10.1016/j.ajhg.2019.03.005
M3 - Article
C2 - 30982612
SN - 0002-9297
VL - 104
SP - 948
EP - 956
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -