As indicated, an essential event for normal repolarization of an excitable membrane is the rapid inactivation of the inward sodium current. This process of rapid, complete sodium channel inactivation is impaired by the sodium channel mutations implicated in hyperkalemic periodic paralysis. The mutations cause imperfect inactivation of the channel and lead to aberrant and early reopenings. Repolarization is then incomplete, rendering the muscle cell more readily re-excited; it is this hyperexcitability that causes the myotonia of hyperkalemic periodic paralysis. The problem becomes self-reinforcing because, as the membrane fails to repolarize fully, its electrolytic inactivation becomes increasingly less effective. If this process is not aborted, the result is such excessive depolarization that the muscle cell ultimately becomes unexcitable—a state that corresponds to the paralytic phase of hyperkalemic periodic paralysis. These features are evident in hyperkalemic muscle in vitro (Cannon et al) and can be recapitulated in computer simulations of aberrant channels. Presumably, over several hours, a variety of compensatory mechanisms (e.g., activation of Na-K adenosine triphosphatase [ATPase] pumps) restores the baseline excitability of the muscle membrane.
This is the best-known form of periodic paralysis. The history of the disease is difficult to trace, but the first unmistakable account was probably that of Hartwig in 1874, followed by the accounts of Westphal (1885) and Oppenheim (1891). Goldflam (in 1895) first called attention to the remarkable vacuolization of the muscle fibers that is characteristic of the process. In 1937, Aitken and associates described the occurrence of low serum potassium during attacks of paralysis and reversal of the paralysis by the administration of potassium, thus setting the stage for subsequent differentiation from the hyperkalemic forms of periodic paralysis. For English-speaking readers, Talbott’s monograph serves as the best historical review of the subject and includes all cases that had been reported prior to 1941; the more contemporary reviews by Layzer and by Lehmann-Horn and their associates (2004) are valuable.
The usual pattern of inheritance is autosomal dominant with reduced penetrance in women (male-to-female ratio of 3 or 4:1). Fontaine and coworkers (1990, 1994) localized the mutation to a region containing the gene that encodes the alpha subunit of the calcium channel of skeletal muscle and missense mutations in the responsible gene (CACNA1S) have been identified. The subunit, which is part of the dihydropyridine receptor complex, is located in the transverse tubular system. This region is believed to act both as a voltage sensor that controls calcium release from the sarcoplasmic reticulum, thus mediating muscle excitation–contraction coupling, and as a calcium- conducting pore. How precisely the reduced calcium channel function relates to hypokalemia-induced attacks of muscle weakness is not fully known but most of the mutations affect the protein in a way that would allow a cation leak (Matthews et al). Approximately 10 percent of cases, however, are due to a mutation in the earlier discussed sodium channel, SCN4A.