At least one form of periodic paralysis is a direct consequence of a mutation in a skeletal muscle, voltage-sensitive sodium channel--it was observed that many individual with this disease developed low serum potassium levels during paralytic episodes. Some families had hyperkalemic paralysis with serum potassium levels of 6 or 7 mEg/L during paralytic crises. In both hypokalemic and hyperkalemic paralysis one of the precipitants is a period of rest after exertion. In hypokalemic periodic paralysis carbohydrates may initiate weakness. In both hyper- and hypokalemic forms, the disorder is inherited as an autosomal dominant trait. During hypokalemic and hyperkalemic paralysis, one might respectively anticipate muscle hyperpolarization or depolarization. Has been observed a potassium-related abnormality of sodium conductance in the pathogenesis at least of the hyperkalemic form of periodic paralysis. The fact that TTX reverses the physiological defect suggested the hypothesis that the primary problem might be a mutation in a TTX-sensitive sodium channel. The protein consists of some 2000 amino acids with characteristic intracytoplasmic and extracellular domains as well a four remarkably conserved membrane spanning domains, each composed of six transmembrane of a polymorphism of the human sodium channel with hyperkalemic paralysis. When multipoint analysis was used to test for coinheritance of the disease with both Na-2 and growth hormone polymorphisms, a lod score of 7 was obtained. That is, the ratio of the probability of linkage to non-linkage is 10 million to one. When extracellular potassium is increased to 10 mM, the affected myotubes demonstrate strikingly abnormal channel behavior characterized by prolonged open times or repetitive opens throughout the voltage step. Potassium implicate as a primary factor triggering an abnormal sodium channel gating mode and, as a result, aberrant sodium current behavior. It was estimated that, for the normal channel, the probability of entering a non-inactivating mode was very low and independent of potassium. On the other hand, for the abnormal channel the probability of entering an inactive mode rises up to 5-fold with hyperkalemic. Four mutations have recently been detected in individuals with cold-sensitive paramyotenia congenital. Two of the cause amino acid substitutions within the III-IV intracytoplasmic loop. It is striking that one substitutes a valine for a glycine. An analysis of the molecular biology of each mutation should illuminate not only the disease phenotype but also biophysical properties of specific sub-regions of this muscle sodium channel.