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Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

From MRC Centre for Neuromuscular Diseases (E.M., D.M.K., M.G.H.), Neurogenetic Unit (R.L., M.G.S., R.S., A.H., M.B.D.), Department of Molecular Neuroscience (E.M., M.G.H.), and Department of Clinical and Experimental Epilepsy (S.S., D.M.K.), UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London; Mitochondrial Research Group (P.C.), Newcastle University, Newcastle upon Tyne, UK; and Department of Neurology (G.M.), University of Milan, Italy.

Address correspondence and reprint requests to Prof Hanna, Medical Research Council Centre for Neuromuscular Diseases, Department of Molecular Neuroscience, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK m.hanna{at}ion.ucl.ac.uk

Background: Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined.

Methods: We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis.

Results: We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S).

Conclusions: All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.

Abbreviations: HypoPP = hypokalemic periodic paralysis.

Supplemental data at www.neurology.org

Editorial, page 1540

e-Pub ahead of print on December 31, 2008, at www.neurology.org.

Supported by the Medical Research Council UK through an MRC Centre grant (G0601943) and by the National Center for Research Resources (Grant No. 5U54 RR019498-05) through the NIH-Consortium for Clinical Investigation of Neurologic Channelopathies and through the Brain Research Trust. This work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science.

Disclosure: The authors report no disclosures.

Received July 23, 2008. Accepted in final form November 12, 2008.

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