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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 Cav2.2/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 Ca2+ 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 Cav2.2 in normal human neurodevelopment. Copyright © 2019 American Society of Human Genetics. All rights reserved.


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, Eric Jan-Kamsteeg, Alex R Paciorkowski, Mary D King, J Helen Cross, Annapurna Poduri, Heather C Mefford, Ingrid E Scheffer, Tobias B Haack, Gary McCullagh, Deciphering Developmental Disorders Study, UK10K Consortium, NIHR BioResource, John J Millichap, Gemma L Carvill, Jill Clayton-Smith, Eamonn R Maher, F Lucy Raymond, Manju A Kurian. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. American journal of human genetics. 2019 May 02;104(5):948-956

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PMID: 30982612

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