Malignant Hyperthermia and Central Core Disease

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.

Keywords: malignant hyperthermia; central core disease; exertional heat stroke; ryanodine receptor 1; calcium release; anaesthetics

Figure 1.

The three different classes of MH/CCD mutations in the RyR1 calcium release channel. In skeletal muscle, the DHPR is embedded in the transverse tubles (TT) and is physically coupled to the RyR1 protein. The RyR1 protein traverses the sarcoplasmic reticulum (SR) membrane and functions as a calcium channel that can release calcium from the SR into the myoplasm. Depolarisation of the TT membrane causes a conformational change in the DHPR that is communicated to the RyR1 channel causing it to open. MH and CCD mutations fall into three classes. Most mutations fall into the first class (I) and make the RyR1 channel hypersensitive to activating ligands/drugs such as caffeine, halothane and 4‐chloro‐m‐cresol. The second (II) rarer class of mutation results in a reduction in calcium release in response to depolarisation in muscle in mutant channels by comparison with normal channels. The third (III) class of mutation, which is also rare leads to a decrease in the stability of the RyR1 complex causing partial depletion of RyR1 channels expressed in skeletal muscle.

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Durham WJ, Wehrens XH, Sood S and Hamilton SL (2007) Diseases associated with altered ryanodine receptor activity. Subcellular Biochemistry 45: 273–321.

Endo M (2009) Calcium‐induced calcium release in skeletal muscle. Physiological Reviews 89: 1153–1176.

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Web Links

European Malignant Hyperthermia (EMH). Website of the European Malignant Hyperthermia Group. This site provides a forum for discussion between the various European MH investigation centers and also provides additional information and links relevant to the disorder. http://www.emhg.org

Malignant Hyperthermia Association of the United States (MHAUS). Links to the North American MH registry. Website for MHAUS which is the major association in the United States dedicated to the control of malignant hyperthermia. http://www.mhaus.org

Online Mendelian Inheritance in Man (OMIM). OMIM is a database catalog of human genes and genetic disorders authored and edited by Dr Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere, and developed for the World Wide Web by NCBI, the National Center for Biotechnology Information. The database contains textual information and references. It also contains copious links to MEDLINE and sequence records in the Entrez system, and links to additional related resources at NCBI and elsewhere. http://www3.ncbi.nlm.nih.gov/omim/

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McCarthy, Tommie V(Nov 2011) Malignant Hyperthermia and Central Core Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006013.pub2]