Hyperkalemic periodic paralysis: rapid molecular diagnosis and relationship of genotype to phenotype in 12 families.

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 Met1592Val 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.