A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia.
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.
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.|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
TA
Mestre
MRC Centre for Neuromuscular Disease, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BT, UK.
Andreea
A
Manole
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
H
MacDonald
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, Department of Anesthesia, University of Toronto, Toronto, ON, Canada.
Sheila
S
Riazi
Malignant Hyperthermia Investigation Unit, Toronto General Hospital, Department of Anesthesia, University of Toronto, Toronto, ON, Canada.
Natalia
N
Kraeva
MRC Centre for Neuromuscular Disease, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BT, UK.
Michael G
MG
Hanna
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.
Anthony E
AE
Lang
MRC Centre for Neuromuscular Disease, Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, Queen Square, London, WC1N 3BT, UK. r.mannikko@ucl.ac.uk.
Roope
R
Männikkö
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. grace.yoon@utoronto.ca.|Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada. grace.yoon@utoronto.ca.
Grace
G
Yoon
D000293:Adolescent; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000235:genetics* / Q000502:physiology; D008305:Malignant Hyperthermia / Q000150:complications / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree
C496946:KCNA1 protein, human; D051662:Kv1.1 Potassium Channel
Episodic ataxia; KCNA1; Malignant hyperthermia