Genetics and pathogenesis of malignant hyperthermia

Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal muscle calcium homeostasis resulting in organ and systemic failure. Susceptibility to MH, an autosomal dominant trait, may be associated with congenital myopathies, but in the majority of the cases, no clinical signs of disease are visible outside of anesthesia. For diagnosis, a functional test on skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over 50% of the families show linkage of the IVCT phenotype to the gene encoding the skeletal muscle ryanodine receptor and over 20 mutations therein have been described. At least five other loci have been defined implicating greater genetic heterogeneity than previously assumed, but so far only one further gene encoding the main subunit of the voltage-gated dihydropyridine receptor has a confirmed role in MH. As a result of extensive research on the mechanisms of excitation-contraction coupling and recent functional characterization of several disease-causing mutations in heterologous expression systems, much is known today about the molecular etiology of MH.