Malignant Hyperthermia and Central Core Disease

Abstract

Abstract Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder triggered by certain types of anaesthetic agents. Genetic and biochemical evidence show that defects in the skeletal muscle ryanodine receptor calcium release channel account for most cases of MH and the related myopathy central core disease (CCD). Analysis of mutant receptors shows that these disorders are largely explained by abnormalities in ryanodine receptor‐mediated calcium release and have identified three distinct classes of channel defects. Most MH and mild CCD mutations make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat. A second class of mutations, which are rarer make the channel significantly deficient in calcium release in response to depolarisation in muscle and are essentially excitation–contraction uncoupling type mutations. The third class of mutation which are also rare have been associated with recessive multimini core disease (MmD) and core myopathy and lead to a decrease in the stability of the RyR1 complex causing partial depletion of RyR1 channels expressed in skeletal muscle. Key Concepts: Malignant hyperthermia is a pharmacogenetic disorder triggered by anaesthetics and manifests as a rapid increase in body temperature and metabolism accompanied by contracture of skeletal muscles. Central core disease is closely associated with malignant hyperthermia and presents as muscle weakness at infancy and the presence of cores in muscle fibres. The ryanodine receptor is the central channel in skeletal muscle responsible for release of calcium from the sarcoplasmic reticulum into the myoplasm. The ryanodine receptor is physically coupled to the dihydropyridine receptor. The latter is located in the t‐tubules and is a voltage‐gated calcium release channel. Depolarisation of the t‐tubular membrane causes a conformational change in the dihydropyridine receptor which interlocks with the ryanodine receptor to open its calcium release channel. The released calcium cause muscle contraction. Human and animal genetics have shown that mutations in the ryanodine receptor account for most cases of malignant hyperthermia and central core disease whereas mutations in the alpha channel of the dihydropyridine receptor account for a small number of malignant hyperthermia cases. The ryanodine receptor mutations causing malignant hyperthermia and central core disease fall into three classes. The first class of mutations are most common and make the ryanodine receptor hypersensitive to drug stimulation and in some instances heat. The second class of mutations make the channel significantly deficient in calcium release in response to depolarisation. The third class of mutation lead to a decrease in the stability of the RyR1 complex.