DNA from seven unrelated patients with hyperkalemic periodic paralysis (HYPP) was examined for mutations in the adult skeletal muscle sodium channel gene (SCN4A) known to be genetically linked to the disorder. Single-strand conformation polymorphism analysis revealed aberrant bands that were unique to three of these seven patients. All three had prominent fixed muscle weakness, while the remaining four did not. Sequencing the aberrant bands demonstrated the same C to T transition in all three unrelated patients, predicting substitution of a highly conserved threonine residue with a methionine in a membranespanning segment of this sodium channel protein. The observation of a distinct mutation that cosegregates with HYPP in two families and appears as a de novo mutation in a third establishes SCN4A as the HYPP gene. Furthermore, this mutation is associated with a form of HYPP in which fixed muscle weakness is seen. fntroduction

The periodic paralyses include several conditions in which episodes of limb weakness occur spontaneously or are provoked by various stimuli including changes in plasma potassium, muscle cooling, and muscle activity. Some patients with these paralyses also exhibit myotonia, a form of abnormal electrical activity consisting of repetitive action potentials on electromyography associated with delayed relaxation of muscle after voluntary contraction or mec~ hanical stimulation (Griggs, 1977). A disabling feature of several of these periodic paralytic disorders is a progressive, fixed, interattack weakness. The factors responsible for this fixed weakness in certain patients are not known. In vitro electrophysiologic studies have suggested that sodium channel (NaCh) genes are excellent candidates for thesite of the defect in these autosomal dominant disor-