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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 948-956 |
| Number of pages | 9 |
| Journal | American journal of human genetics |
| Volume | 104 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2 2019 |
Funding
We thank our patients and their families for participating in this study. MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas’ National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship). We thank our patients and their families for participating in this study. MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust , Great Ormond Street Children's Hospital Charity , and Rosetrees Trust . E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity . K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital , the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre . K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases . The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003 ), a parallel funding partnership between the Wellcome Trust and the Department of Health , and the Wellcome Trust Sanger Institute (grant number WT098051 ). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre . J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre , an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve . I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship). A.R. is an employee of GeneDx, a wholly owned subsidiary of OPKO Health. I.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia and Xenon Pharmaceuticals; editorial boards of the Annals of Neurology, Neurology and Epileptic Disorders; might accrue future revenue on pending patent WO61/010176 (filed in 2008) for Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, BioMarin, Eisai, and Transgenomics; has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; and receives or has received research support from the National Health and Medical Research Council of Australia, National Institutes of Health, Australian Research Council, Health Research Council of New Zealand, CURE, and March of Dimes. J.J.M. reports honoraria as an editor from the American Academy of Neurology; royalties from Up-To-Date and BMJ Best Practice, honoraria for speaking for Invitae, BioMarin, Greenwich, Sunovion, and Mallinkrodt; consulting for Esai, Xenon, and Ionis; research grants from UCB, NIH, and Citizens United for Research in Epilepsy; all of these are outside of the current work. All other authors declare no competing interests .
Keywords
- CACNA1B
- developmental and epileptic encephalopathy (DEE)
- epilepsy
- epilepsy-dyskinesia
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)