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Hyperkalemic periodic paralysis

Rapid molecular diagnosis and relationship of genotype to phenotype in 12 families

Departments of Molecular Genetics and Biochemistry, Human Genetics, and Pediatrics (W.G. Feero, Drs. Wang and Hoffman, and J. Zhou) and Neurology (Drs. Conwit, Galloway, and Wessel), University of Pittsburgh School of Medicine, Pittsburgh, PA; the Department of Microbiology (Dr. Barany), Cornell University Medical College, New York, NY; the Clinic for Pediatric Neurology and Psychiatry (Dr. Todorovic), University of Belgrade, Yugoslavia; the Neuromuscular Unit (Drs. Hausmanowa-Petrusewicz and Fidzianska), Polish Academy of Science, Warsaw, Poland; the Division of Neuromuscular Research (Dr. Arahata), National Institute of Neuroscience, Tokyo, Japan; the Department of Clinical Genetics (Dr. Wadelius), University Hospital, Uppsala, Sweden; the Division of Neurology (Dr. Marks), Alfred I. DuPont Institute, Wilmington, DE; the Division of Pediatric Neurology (Dr. Hartlage), Medical College of Georgia, Augusta, GA; and the Pediatric Clinic (Dr. Hayakawa), Hitachi General Hospital, Hitachi City, Japan.

We studied mutations of the adult voltage-gated skeletal muscle sodium channel gene in 12 families, from diverse ethnic backgrounds, with hyperkalemic periodic paralysis (HyperPP). We describe a novel procedure, using ligase chain reaction (LCR), to simultaneously identify two different point mutations (previously described) and one rare, apparently benign polymorphism that results in a nonconservative amino acid substitution. Three of 12 families showed the Metl592Val mutation, and six of 12 had the Thr704Met mutation. The mutation in three of the 12 families was not identified. In one of these three families, the disease was not linked to the adult voltage-gated sodium channel gene, suggesting the existence of a clinically similar but genetically distinct form of HyperPP. Genotype/phenotype correlations based on patient records and interviews in these families showed the variable and subjective nature of the illness, although the clinical distinctions between hyperkalemic periodic paralysis and paramyotonia congenita were reinforced by the molecular data.

Address correspondence and reprint requests to Eric P. Hoffman, BST W1211, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

Supported in part by grants from the National Institutes of Health (AR41025 to E.P.H. and GM41337 to F.B.) and the Muscular Dystrophy Association (E.P.H.). W.G.F. is supported by NIH MSTP grant 2T32GM08208-06.

Received November 6, 1992. Accepted for publication in final form December 29, 1992.

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