Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/20732
Title: Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
Authors: 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;Jan-Kamsteeg, Eric;Paciorkowski, Alex R;King, Mary D;Cross, J Helen;Poduri, Annapurna;Mefford, Heather C;Scheffer, Ingrid E;Haack, Tobias B;McCullagh, Gary;Millichap, John J;Carvill, Gemma L;Clayton-Smith, Jill;Maher, Eamonn R;Raymond, F Lucy;Kurian, Manju A
Affiliation: Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9NT, UK
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK
Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
Division of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
Epilepsy Center, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK
NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge CB2 0QQ UK
Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA
GeneDx, Gaithersburg, MD 20877, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Clinical Neurophysiology, Great Ormond Street Hospital, London WC1N 3JH, UK
Clinical Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
Division of Genetics and Molecular Medicine, King's College, London WC2R 2LS, UK
Department of General Paediatrics, Birmingham Children's Hospital, Birmingham B4 6NH, UK
Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham B4 6NH, UK
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK
Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands
Department of Neurology, Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA
Department of Neurology and Clinical Neurophysiology, Children's University Hospital, Temple Street, Dublin DO1 YC67, Ireland
Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA
Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Florey Institute and Murdoch Institute of Neuroscience and Mental Health, Parkville, 3052, VIC, Australia
Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, 3052, VIC, Australia
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen 72706, Germany
Department of Neurology, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK
DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
UK10K, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals, NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK
Issue Date: 10-Apr-2019
EDate: 2019-04-10
Citation: American journal of human genetics 2019; online first: 10 April
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 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/20732
DOI: 10.1016/j.ajhg.2019.03.005
ORCID: 0000-0002-2311-2174
PubMed URL: 30982612
Type: Journal Article
Subjects: CACNA1B
developmental and epileptic encephalopathy (DEE)
epilepsy
epilepsy-dyskinesia
Appears in Collections:Journal articles

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