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Published online before print December 31, 2008, doi:10.1212/01.wnl.0000342387.65477.46)
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Received July 23, 2008
Accepted November 12, 2008

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

E. Matthews MRCP, R. Labrum PhD, M. G. Sweeney BSc, R. Sud PhD, A. Haworth MSc, P. F. Chinnery FRCP, G. Meola MD, S. Schorge PhD, D. M. Kullmann FRCP, M. B. Davis PhD, and M. G. Hanna FRCP*

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.


* To whom correspondence should be addressed. E-mail: 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.


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S. C. Cannon
Getting a charge out of periodic paralysis?
Neurology, May 5, 2009; 72(18): 1540 - 1541.
[Full Text] [PDF]

Correspondence:

Read all Correspondence

Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis
Robert L. Ruff, et al.
Neurology Online, 22 Jul 2009 [Full text]
Reply from the authors
Stephanie Schorge, et al.
Neurology Online, 22 Jul 2009 [Full text]
Reply from the Editorialist
Stephen C. Cannon
Neurology Online, 22 Jul 2009 [Full text]

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