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Correlating phenotype and genotype in the periodic paralyses

T. M. Miller, MD, PhD, M. R. Dias da Silva, MD, PhD, H. A. Miller, BS, H. Kwiecinski, MD, PhD, J. R. Mendell, MD, R. Tawil, MD, P. McManis, MD, R. C. Griggs, MD, C. Angelini, MD, S. Servidei, MD, J. Petajan, MD, PhD, M. C. Dalakas, MD, L. P.W. Ranum, PhD, Y. H. Fu, PhD and L. J. Ptáek, MD

From the Department of Neurology (Drs. T.M. Miller, Dias da Silva, Fu, and Ptáek, and H.A. Miller), University of California San Francisco; Department of Neurology (Dr. Kwiecinski), Medical Academy of Warsaw, Poland; Department of Neurology (Dr. Mendell), Ohio State University School of Medicine, Columbus; Department of Neurology (Drs. Tawil and Griggs), University of Rochester, NY; Department of Neurology (Dr. McManis), University of Sydney, Australia; Department of Neurology (Dr. Angelini), University of Padova, Italy; Institute of Neurology (Dr. Servidei), Catholic University, Rome, Italy; Department of Neurology (Dr. Petajan), University of Utah, SR210 Medical Center, Salt Lake City; Neuromuscular Diseases Section (Dr. Dalakas), National Institute of Neurologic Diseases and Stroke, National Institutes of Health, Bethesda, MD; and Department of Genetics (Dr. Ranum), Cell Biology and Development and the Institute of Human Genetics, University of Minnesota, Minneapolis.

Address correspondence and reprint requests to Dr. Louis J. Ptáek, University of California, San Francisco, Department of Neurology, Box 2922, 19B Mission Bay, Room 548, 1550 4th Street, San Francisco, CA 94143-2922; e-mail: ptacek{at}itsa.ucsf.edu

Background: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease.

Objective: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease.

Methods: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations.

Results: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide.

Conclusions: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Received February 24, 2004. Accepted in final form June 8, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the November 9 issue to find the title link for this article.

Presented in part as a poster at the annual meeting of the American Academy of Neurology; San Francisco, CA; April 2004.

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Attacks of immobility caused by diet or exercise? The mystery of periodic paralyses

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