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A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia

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Abstract

Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.

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References

  1. Jen JC, Graves TD, Hess EJ et al (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130(Pt 10):2484–2493

    Article  CAS  PubMed  Google Scholar 

  2. Graves TD, Cha YH, Hahn AF et al (2014) Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation. Brain 137(Pt 4):1009–1018

    Article  PubMed  PubMed Central  Google Scholar 

  3. Browne DL, Gancher ST, Nutt JG et al (1994) Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet 8(2):136–140

    Article  CAS  PubMed  Google Scholar 

  4. Brownstein CA, Beggs AH, Rodan L et al (2016) Clinical heterogeneity associated with KCNA1 mutations include cataplexy and nonataxic presentations. Neurogenetics 17(1):11–16

    Article  CAS  PubMed  Google Scholar 

  5. Tomlinson SE, Rajakulendran S, Tan SV et al (2013) Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1. J Neurol Neurosurg Psychiatry 84(10):1107–1112

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zuberi SM, Eunson LH, Spauschus A et al (1999) A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 122(Pt 5):817–825

    Article  PubMed  Google Scholar 

  7. Demos MK, Macri V, Farrell K et al (2009) A novel KCNA1 mutation associated with global delay and persistent cerebellar dysfunction. Mov Disord 24(5):778–782

    Article  PubMed  Google Scholar 

  8. D’Adamo MC, Gallenmuller C, Servettini I et al (2014) Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene. Front Physiol 5:525

    PubMed  Google Scholar 

  9. Klein A, Boltshauser E, Jen J, Baloh RW (2004) Episodic ataxia type 1 with distal weakness: a novel manifestation of a potassium channelopathy. Neuropediatrics 35(2):147–149

    Article  CAS  PubMed  Google Scholar 

  10. Larach MG, Gronert GA, Allen GC et al (2010) Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 110(2):498–507

    Article  PubMed  Google Scholar 

  11. Zerr P, Adelman JP, Maylie J (1998) Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. J Neurosci 18(8):2842–2848

    CAS  PubMed  Google Scholar 

  12. Friederich P, Benzenberg D, Trellakis S, Urban BW (2001) Interaction of volatile anesthetics with human Kv channels in relation to clinical concentrations. Anesthesiology 95(4):954–958

    Article  CAS  PubMed  Google Scholar 

  13. Zhou L, Zhang CL, Messing A, Chiu SY (1998) Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J Neurosci 18(18):7200–7215

    CAS  PubMed  Google Scholar 

Download references

Author contributions

TAM—took care of the patients, was responsible for the study concept and design, acquisition of data, analysis and interpretation, and wrote the first draft of the manuscript.

AM, MGH, and RM—were responsible for the electrophysiological studies and contributed Fig. 2.

HM—contributed clinical data and Fig. 1.

SR and NK—were responsible for the clinical and genetic evaluations of malignant hyperthermia for the patients.

AEL—contributed clinical data and data analysis.

GY—took care of the patients, was responsible for the study concept and design, acquisition of data, analysis and interpretation, and overall supervision of the study.

All authors critically revised the manuscript for important intellectual content.

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Authors and Affiliations

  1. Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University Health Network, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada

    Tiago A. Mestre & Anthony E. Lang

  2. Parkinson’s Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

    Tiago A. Mestre

  3. MRC Centre for Neuromuscular Disease, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BT, UK

    Andreea Manole, Michael G. Hanna & Roope Männikkö

  4. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

    Heather MacDonald & Grace Yoon

  5. Malignant Hyperthermia Investigation Unit, Toronto General Hospital, Department of Anesthesia, University of Toronto, Toronto, ON, Canada

    Sheila Riazi & Natalia Kraeva

  6. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada

    Grace Yoon

Authors
  1. Tiago A. Mestre
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  2. Andreea Manole
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  3. Heather MacDonald
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  4. Sheila Riazi
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  5. Natalia Kraeva
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  6. Michael G. Hanna
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  7. Anthony E. Lang
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  8. Roope Männikkö
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  9. Grace Yoon
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Corresponding authors

Correspondence to Roope Männikkö or Grace Yoon.

Ethics declarations

Competing interests

None relevant to this study. Dr. Lang reports personal fees from AbbVie, personal fees from Acorda, personal fees from Avanir Pharmaceuticals, personal fees from Biogen Idec, personal fees from Bristol-Myers Squibb, personal fees from Merck, personal fees from Cipla, and personal fees from Intekrin. Dr. Hanna has acted as a UCL consultant for Novartis.

Funding

AM, MGH, and RM are supported by the UCLH Biomedical Research Centre.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Mestre, T.A., Manole, A., MacDonald, H. et al. A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia. Neurogenetics 17, 245–249 (2016). https://doi.org/10.1007/s10048-016-0486-0

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  • DOI: https://doi.org/10.1007/s10048-016-0486-0

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