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November 22, 2016; 87 (21) Article

Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder

Stephanie Fehr, Kingsley Wong, Richard Chin, Simon Williams, Nick de Klerk, David Forbes, Rahul Krishnaraj, John Christodoulou, Jenny Downs, Helen Leonard
First published October 21, 2016, DOI: https://doi.org/10.1212/WNL.0000000000003352
Stephanie Fehr
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Kingsley Wong
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Richard Chin
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Simon Williams
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Nick de Klerk
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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David Forbes
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Rahul Krishnaraj
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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John Christodoulou
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Jenny Downs
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Helen Leonard
From Telethon Kids Institute (S.F., K.W., N.d.K., J.D., H.L.) and the School of Paediatrics and Child Health (D.F.), The University of Western Australia, Perth; Muir Maxwell Epilepsy Centre (R.C.), Child Life and Health, The University of Edinburgh, UK; Department of Neurology and Rehabilitation (S.W.), Princess Margaret Hospital, Perth; Western Sydney Genetics Program (R.K.), The Children's Hospital at Westmead, Sydney; Department of Paediatrics (J.C.), University of Melbourne; Murdoch Childrens Research Institute (J.C.), The Royal Children's Hospital, Melbourne; and School of Physiotherapy and Exercise Science (J.D.), Curtin University, Perth, Australia.
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Citation
Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder
Stephanie Fehr, Kingsley Wong, Richard Chin, Simon Williams, Nick de Klerk, David Forbes, Rahul Krishnaraj, John Christodoulou, Jenny Downs, Helen Leonard
Neurology Nov 2016, 87 (21) 2206-2213; DOI: 10.1212/WNL.0000000000003352

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Abstract

Objective: To investigate seizure outcomes and their relationships to genotype and functional abilities in individuals with the cyclin-dependent kinase-like-5 (CDKL5) disorder.

Methods: Using the International CDKL5 Disorder Database, we identified 172 cases with a pathogenic CDKL5 mutation. We categorized individual mutations into 4 groups based on predicted structural and functional consequences. Negative binomial regression was used to model the linear association between current seizure rate and mutation group, current level of assistance required to walk 10 steps, and the highest level of expressive communication used to convey refusal or request.

Results: All but 3 (169/172) patients had a history of epilepsy. The median age at seizure onset was 6 weeks (range 1 week–1.5 years) and the median seizure rate at ascertainment was 2 per day (range 0–20 per day). After adjusting for walking ability and confounders including use or otherwise of polytherapy, seizure rate was lower in those with truncating mutations between aa172 and aa781 compared to those with no functional protein (incidence rate ratio [IRR] 0.57; 95% confidence interval [CI] 0.35–0.93). Ability to walk and use of spoken language were associated with lower rates of current seizures when compared to those with the least ability after adjusting for genotype (walking: IRR 0.62; 95% CI 0.39–0.99, communication: IRR 0.48; 95% CI 0.23–1.02). At a median age at questionnaire completion of 5 years, those previously treated with corticosteroids had more frequent seizures than those who have never been treated, whether or not there was a history of infantile spasms.

Conclusions: Epilepsy is pervasive but not mandatory for the CDKL5 disorder. Genotype and functional abilities were related to seizure frequency, which appears refractory to antiepileptic drugs.

GLOSSARY

aa=
amino acid;
AED=
antiepileptic drug;
CDKL5=
cyclin-dependent kinase-like-5;
CI=
confidence interval;
IRR=
incidence rate ratio;
VNS=
vagal nerve stimulation

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received March 28, 2016.
  • Accepted in final form August 4, 2016.
  • © 2016 American Academy of Neurology
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