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 journalArticlepeer-review

44 Citations (Scopus)


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
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
Early online date11 Apr 2019
Publication statusPublished - 2 May 2019


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


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