Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

GORMAN, KM, MEYER, E, GROZEVA, D, SPINELLI, E, MCTAGUE, A, SANCHIS-JUAN, A, CARSS, KJ, BRYANT, E, REICH, A, SCHNEIDER, AL, PRESSLER, RM, SIMPSON, MA, DEBELLE, GD, WASSMER, E, MORTON, J, SIECIECHOWICZ, D, JAN-KAMSTEEG, E, PACIORKOWSKI, AR, KING, MD, CROSS, JH, PODURI, A, MEFFORD, HC, SCHEFFER, IE, HAACK, TB, MCCULLAGH, G, MCRAE, JF, CLAYTON, S, FITZGERALD, TW, KAPLANIS, J, PRIGMORE, E, RAJAN, D, SIFRIM, A, AITKEN, S, AKAWI, N, ALVI, M, AMBRIDGE, K, BARRETT, DM, BAYZETINOVA, T, JONES, P, JONES, WD, KING, D, KRISHNAPPA, N, MASON, LE, SINGH, T, TIVEY, AR, AHMED, M, ANJUM, U, ARCHER, H, ARMSTRONG, R, AWADA, J, BALASUBRAMANIAN, M, BANKA, S, BARALLE, D, BARNICOAT, A, BATSTONE, P, BATY, D, BENNETT, C, BERG, J, BERNHARD, B, BEVAN, AP, BITNER-GLINDZICZ, M, BLAIR, E, BLYTH, M, BOHANNA, D, BOURDON, L, BOURN, D, BRADLEY, L, BRADY, A, BRENT, S, BREWER, C, BRUNSTROM, K, BUNYAN, DJ, BURN, J, CANHAM, N, CASTLE, B, CHANDLER, K, CHATZIMICHALI, E, CILLIERS, D, CLARKE, A, CLASPER, S, CLAYTON-SMITH, J, CLOWES, V, COATES, A, COLE, T, COLGIU, I, COLLINS, A, COLLINSON, MN, CONNELL, F, COOPER, N, COX, H, CRESSWELL, L, CROSS, G, CROW, Y, D'ALESSANDRO, M, DABIR, T, DAVIDSON, R, DAVIES, S, DE VRIES, D, DEAN, J, DESHPANDE, C and CROOKS, Lucy (2019). Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia. American Journal of Human Genetics, 104 (5), 948-956.

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Official URL: https://www.sciencedirect.com/science/article/pii/...
Link to published version:: https://doi.org/10.1016/j.ajhg.2019.03.005
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Abstract

© 2019 American Society of Human Genetics 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.

Item Type: Article
Uncontrolled Keywords: CACNA1B; developmental and epileptic encephalopathy (DEE); epilepsy; epilepsy-dyskinesia; Adolescent; Calcium; Calcium Channels, N-Type; Child; Child, Preschool; Dyskinesias; Epilepsy; Female; Humans; Infant; Loss of Heterozygosity; Male; Mutation; Pedigree; Synaptic Transmission; Deciphering Developmental Disorders Study; UK10K Consortium; NIHR BioResource; Humans; Epilepsy; Dyskinesias; Calcium; Calcium Channels, N-Type; Pedigree; Synaptic Transmission; Mutation; Loss of Heterozygosity; Adolescent; Child; Child, Preschool; Infant; Female; Male; Genetics & Heredity; 06 Biological Sciences; 11 Medical and Health Sciences
Identification Number: https://doi.org/10.1016/j.ajhg.2019.03.005
Page Range: 948-956
SWORD Depositor: Symplectic Elements
Depositing User: Symplectic Elements
Date Deposited: 21 May 2021 14:51
Last Modified: 21 May 2021 15:00
URI: http://shura.shu.ac.uk/id/eprint/27895

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