Chapter 3 - Molecular aspects of malignant hyperthermia and central core disease

Abstract

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. MH reactions are triggered by the use of non-halogenated anesthetics such as ether, ethylene, and cyclopropane; and halogenated anesthetics such as halothane, isoflurane, enflurane, and sevoflurane. The chapter describes the clinical presentation, treatment, diagnosis of susceptibility, sensitivity and specificity of IVCT, and inheritance and penetrance of malignant hyperthermia. The only major disorder that consistently exhibits a MHS phenotype is central core disease (CCD). Both MH and CCD are primarily disorders of calcium regulation abnormalities in skeletal muscle. Molecular genetic linkage studies implicate the ryanodine receptor gene (RYR1) in more than 50% MH cases and in all CCD cases tested. This suggests that MH is a very heterogeneous disorder. The screening of MH and CCD has identified mutation in RYR1 gene. Functional characterization of several MH susceptible and CCD mutations in cultured cells has provided insights into molecular etiology of these disorders. The phenotype outcomes seen in MHS and CCD reflects the effect of RYR1 mutations on the size of the releasable calcium stores in muscle, the resting calcium concentrations, and the level of compensation achieved with respect to maintenance of calcium homeostasis. The chapter describes the ryanodine receptor, exogeneous RYR1 modulator binding sites, functional expression of the RYR1 cDNA, and expression and functional analysis of RYR1 mutants. The chapter discusses the construction of an alternative model for the two related disorders MH and CCD.