Hereditary Muscle Channelopathies

Abstract

A combination of electrophysiological and molecular genetic studies has resulted in the discovery of certain skeletal muscle disorders caused by pathologically functioning ion channels. The group of thus defined hereditary “muscle channelopathies” comprises congenital myasthenic syndromes, nondystrophic myotonias, dyskalemic periodic paralyses, central core myopathy and multiminicore myopathy, as well as malignant hyperthermia. Many muscle channelopathies are benign disorders, but muscle hypermetabolism resulting in muscle stiffness and hyperthermia as in an event of malignant hyperthermia can be life-threatening. In addition, forms of familial periodic paralysis can be severe when they produce serious dyskalemia that disturbs cardiac excitation conduction. The hypokalemia is most pronounced in thyrotoxic periodic paralysis. Some of the periodic paralyses are associated with a progressive permanent weakness. The weakness is explained by strongly depolarized, inexcitable muscle fibers that accumulate sodium and water. Drugs that repolarize the fiber membrane can restore muscle strength and may prevent progression. Expression studies of putative mutations have become standard in supporting the disease-causing nature of mutations. Not all variants detected by genetic analysis may be causative for a clinical dysfunction; they may be just a functional polymorphism. These problems are addressed and a more critical evaluation of the underlying genetic data is proposed.