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From the Division of Neurology (Dr. Bulman), Ottawa General Hospital, Ottawa Hospital Research Institute (Drs. Bulman and Scoggan), and the Department of Clinical Neurological Sciences (M.D. van Oene, Drs. Nicolle, Hahn, and Ebers, and L. L. Tollar), London Health Sciences Centre, London, Ontario, Canada.
Address correspondence and reprint requests to Dr. Dennis E. Bulman, Ottawa General Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6; e-mail: dbulman{at}ogh.on.ca
OBJECTIVE: To identify the cause of hypokalemic periodic paralysis (HOKPP) in a family whose disease is not caused by a mutation in the dihydropyridine-sensitive (DHP) receptor 
1-subunit gene (CACNA1S).
BACKGROUND: Hypokalemic periodic paralysis is primarily caused by mutations within CACNA1S. Genetic heterogeneity for HOKPP has been reported, but no other locus has been identified.
METHODS: Single-stranded conformational polymorphism (SSCP) analysis and PCR direct sequencing were used to screen the skeletal muscle 1-sodium channel gene (SCN4A) for a mutation in our family.
RESULTS: SSCP analysis showed an abnormally migrating conformer in exon 12. Direct sequencing of the conformer showed a guanine to adenine transition at position 2006 in the cDNA sequence; this results in an amino acid substitution of a highly conserved arginine (Arg) to histidine (His) at position 669. This sequence alteration segregated only with the affected members of the kindred and was not found in a panel of 100 DNA samples from healthy controls. The amino acid substitution alters the outermost positive charge in the membrane spanning segment DII/S4, which is involved in voltage sensing.
CONCLUSIONS: The first arginine in DII/S4 and in DIV/S4 within the skeletal muscle sodium channel and the L-type calcium channel gene CACNA1S appear to be critical for normal function. In all four cases, Arg to His mutations result in a disease phenotype. The identification of a mutation within the skeletal muscle sodium channel resulting in hypokalemic periodic paralysis represents a novel finding.
Key words: Hypokalemic periodic paralysis—SCNA4—Mutation—Family study.
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