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Am J Hum Genet. 2019 May 2;104(5):948-956. doi: 10.1016/j.ajhg.2019.03.005. Epub 2019 Apr 11.

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

Collaborators (747)

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, Devlin G, Dixit A, Dobbie A, Donaldson A, Donnai D, Donnelly D, Donnelly C, Douglas A, Douzgou S, Duncan A, Eason J, Ellard S, Ellis I, Elmslie F, Evans K, Everest S, Fendick T, Fisher R, Flinter F, Foulds N, Fry A, Fryer A, Gardiner C, Gaunt L, Ghali N, Gibbons R, Gill H, Goodship J, Goudie D, Gray E, Green A, Greene P, Greenhalgh L, Gribble S, Harrison R, Harrison L, Harrison V, Hawkins R, He L, Hellens S, Henderson A, Hewitt S, Hildyard L, Hobson E, Holden S, Holder M, Holder S, Hollingsworth G, Homfray T, Humphreys M, Hurst J, Hutton B, Ingram S, Irving M, Islam L, Jackson A, Jarvis J, Jenkins L, Johnson D, Jones E, Josifova D, Joss S, Kaemba B, Kazembe S, Kelsell R, Kerr B, Kingston H, Kini U, Kinning E, Kirby G, Kirk C, Kivuva E, Kraus A, Kumar D, Kumar VKA, Lachlan K, Lam W, Lampe A, Langman C, Lees M, Lim D, Longman C, Lowther G, Lynch SA, Magee A, Maher E, Male A, Mansour S, Marks K, Martin K, Maye U, McCann E, McConnell V, McEntagart M, McGowan R, McKay K, McKee S, McMullan DJ, McNerlan S, McWilliam C, Mehta S, Metcalfe K, Middleton A, Miedzybrodzka Z, Miles E, Mohammed S, Montgomery T, Moore D, Morgan S, Morton J, Mugalaasi H, Murday V, Murphy H, Naik S, Nemeth A, Nevitt L, Newbury-Ecob R, Norman A, O'Shea R, Ogilvie C, Ong KR, Park SM, Parker MJ, Patel C, Paterson J, Payne S, Perrett D, Phipps J, Pilz DT, Pollard M, Pottinger C, Poulton J, Pratt N, Prescott K, Price S, Pridham A, Procter A, Purnell H, Quarrell O, Ragge N, Rahbari R, Randall J, Rankin J, Raymond L, Rice D, Robert L, Roberts E, Roberts J, Roberts P, Roberts G, Ross A, Rosser E, Saggar A, Samant S, Sampson J, Sandford R, Sarkar A, Schweiger S, Scott R, Scurr I, Selby A, Seller A, Sequeira C, Shannon N, Sharif S, Shaw-Smith C, Shearing E, Shears D, Sheridan E, Simonic I, Singzon R, Skitt Z, Smith A, Smith K, Smithson S, Sneddon L, Splitt M, Squires M, Stewart F, Stewart H, Straub V, Suri M, Sutton V, Swaminathan GJ, Sweeney E, Tatton-Brown K, Taylor C, Taylor R, Tein M, Temple IK, Thomson J, Tischkowitz M, Tomkins S, Torokwa A, Treacy B, Turner C, Turnpenny P, Tysoe C, Vandersteen A, Varghese V, Vasudevan P, Vijayarangakannan P, Vogt J, Wakeling E, Wallwark S, Waters J, Weber A, Wellesley D, Whiteford M, Widaa S, Wilcox S, Wilkinson E, Williams D, Williams N, Wilson L, Woods G, Wragg C, Wright M, Yates L, Yau M, Nellåker C, Parker M, Firth HV, Wright CF, FitzPatrick DR, Barrett JC, Hurles ME, Al Turki S, Anderson C, Anney R, Antony D, Artigas MS, Ayub M, Balasubramaniam S, Barrett JC, Barroso I, Beales P, Bentham J, Bhattacharya S, Birney E, Blackwood D, Bobrow M, Bochukova E, Bolton P, Bounds R, Boustred C, Breen G, Calissano M, Carss K, Chatterjee K, Chen L, Ciampi A, Cirak S, Clapham P, Clement G, Coates G, Collier D, Cosgrove C, Cox T, Craddock N, Crooks L, Curran S, Curtis D, Daly A, Day-Williams A, Day INM, Down T, Du Y, Dunham I, Edkins S, Ellis P, Evans D, Faroogi S, Fatemifar G, Fitzpatrick DR, Flicek P, Flyod J, Foley AR, Franklin CS, Futema M, Gallagher L, Geihs M, Geschwind D, Griffin H, Grozeva D, Guo X, Guo X, Gurling H, Hart D, Hendricks A, Holmans P, Howie B, Huang L, Hubbard T, Humphries SE, Hurles ME, Hysi P, Jackson DK, Jamshidi Y, Jing T, Joyce C, Kaye J, Keane T, Keogh J, Kemp J, Kennedy K, Kolb-Kokocinski A, Lachance G, Langford C, Lawson D, Lee I, Lek M, Liang J, Lin H, Li R, Li Y, Liu R, Lönnqvist J, Lopes M, Iotchkova V, MacArthur D, Marchini J, Maslen J, Massimo M, Mathieson I, Marenne G, McGuffin P, McIntosh A, McKechanie AG, McQuillin A, Metrustry S, Mitchison H, Moayyeri A, Morris J, Muntoni F, Northstone K, O'Donnovan M, Onoufriadis A, O'Rahilly S, Oualkacha K, Owen MJ, Palotie A, Panoutsopoulou K, Parker V, Parr JR, Paternoster L, Paunio T, Payne F, Pietilainen O, Plagnol V, Quaye L, Quail MA, Raymond L, Rehnström K, Ring S, Ritchie GRS, Roberts N, Savage DB, Scambler P, Schiffels S, Schmidts M, Schoenmakers N, Semple RK, Serra E, Sharp SI, Shin SY, Skuse D, Small K, Southam L, Spasic-Boskovic O, St Clair D, Stalker J, Stevens E, St Pourcian B, Sun J, Suvisaari J, Tachmazidou I, Tobin MD, Valdes A, Van Kogelenberg M, Vijayarangakannan P, Visscher PM, Wain LV, Walters JTR, Wang G, Wang J, Wang Y, Ward K, Wheeler E, Whyte T, Williams H, Williamson KA, Wilson C, Wong K, Xu C, Yang J, Zhang F, Zhang P, Aitman T, Alachkar H, Ali S, Allen L, Allsup D, Ambegaonkar G, Anderson J, Antrobus R, Armstrong R, Arno G, Arumugakani G, Ashford S, Astle W, Attwood A, Austin S, Bacchelli C, Bakchoul T, Bariana TK, Baxendale H, Bennett D, Bethune C, Bibi S, Bitner-Glindzicz M, Bleda M, Boggard H, Bolton-Maggs P, Booth C, Bradley JR, Brady A, Brown M, Browning M, Bryson C, Burns S, Calleja P, Canham N, Carmichael J, Carss K, Caulfield M, Chalmers E, Chandra A, Chinnery P, Chitre M, Church C, Clement E, Clements-Brod N, Clowes V, Coghlan G, Collins P, Cooper N, Creaser-Myers A, DaCosta R, Daugherty L, Davies S, Davis J, De Vries M, Deegan P, Deevi SVV, Deshpande C, Devlin L, Dewhurst E, Doffinger R, Dormand N, Drewe E, Edgar D, Egner W, Erber WN, Erwood M, Everington T, Favier R, Firth H, Fletcher D, Flinter F, Fox JC, Frary A, Freson K, Furie B, Furnell A, Gale D, Gardham A, Gattens M, Ghali N, Ghataorhe PK, Ghurye R, Gibbs S, Gilmour K, Gissen P, Goddard S, Gomez K, Gordins P, Gräf S, Greene D, Greenhalgh A, Greinacher A, Grigoriadou S, Grozeva D, Hackett S, Hadinnapola C, Hague R, Haimel M, Halmagyi C, Hammerton T, Hart D, Hayman G, Heemskerk JWM, Henderson R, Hensiek A, Henskens Y, Herwadkar A, Holden S, Holder M, Holder S, Hu F, Huissoon A, Humbert M, Hurst J, James R, Jolles S, Josifova D, Kazmi R, Keeling D, Kelleher P, Kelly AM, Kennedy F, Kiely D, Kingston N, Koziell A, Krishnakumar D, Kuijpers TW, Kumararatne D, Kurian M, Laffan MA, Lambert MP, Allen HL, Lawrie A, Lear S, Lees M, Lentaigne C, Liesner R, Linger R, Longhurst H, Lorenzo L, Machado R, Mackenzie R, MacLaren R, Maher E, Maimaris J, Mangles S, Manson A, Mapeta R, Markus HS, Martin J, Masati L, Mathias M, Matser V, Maw A, McDermott E, McJannet C, Meacham S, Meehan S, Megy K, Mehta S, Michaelides M, Millar CM, Moledina S, Moore A, Morrell N, Mumford A, Murng S, Murphy E, Nejentsev S, Noorani S, Nurden P, Oksenhendler E, Ouwehand WH, Papadia S, Park SM, Parker A, Pasi J, Patch C, Paterson J, Payne J, Peacock A, Peerlinck K, Penkett CJ, Pepke-Zaba J, Perry DJ, Pollock V, Polwarth G, Ponsford M, Qasim W, Quinti I, Rankin S, Rankin J, Raymond FL, Rehnstrom K, Reid E, Rhodes CJ, Richards M, Richardson S, Richter A, Roberts I, Rondina M, Rosser E, Roughley C, Rue-Albrecht K, Samarghitean C, Sanchis-Juan A, Sandford R, Santra S, Sargur R, Savic S, Schulman S, Schulze H, Scott R, Scully M, Seneviratne S, Sewell C, Shamardina O, Shipley D, Simeoni I, Sivapalaratnam S, Smith K, Sohal A, Southgate L, Staines S, Staples E, Stauss H, Stein P, Stephens J, Stirrups K, Stock S, Suntharalingam J, Tait RC, Talks K, Tan Y, Thachil J, Thaventhiran J, Thomas E, Thomas M, Thompson D, Thrasher A, Tischkowitz M, Titterton C, Toh CH, Toshner M, Treacy C, Trembath R, Tuna S, Turek W, Turro E, Van Geet C, Veltman M, Vogt J, von Ziegenweldt J, Vonk Noordegraaf A, Wakeling E, Wanjiku I, Warner TQ, Wassmer E, Watkins H, Webster A, Welch S, Westbury S, Wharton J, Whitehorn D, Wilkins M, Willcocks L, Williamson C, Woods G, Wort J, Yeatman N, Yong P, Young T, Yu P.

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.

KEYWORDS:

CACNA1B; developmental and epileptic encephalopathy (DEE); epilepsy; epilepsy-dyskinesia

PMID:
30982612
PMCID:
PMC6507039
[Available on 2019-11-02]
DOI:
10.1016/j.ajhg.2019.03.005

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