Malignant Hyperthermia and Central Core Disease

The recorded history of malignant hyperthermia (MH) began in 1900, when several, often fatal, cases of unexpected fever and “convulsions” during anesthesia in the operating room were reported. It was not until Denborough and colleagues (1961) reported 10 cases in a single Australian family, however, that it was realized that MH is inherited as an autosomal dominant abnormality. In 1966 it was discovered that pigs afflicted with porcine stress syndrome also develop MH reactions that are virtually identical to human MH, providing an excellent experimental model for MH. By 1970 the site of the primary defect could be assigned to skeletal muscle rather than brain. Muscle fascicles from MH-susceptible (MHS) patients were shown to be more sensitive than normal to the contracture-inducing properties of caffeine and halothane, providing the basis for the caffeine/halothane contracture test for MH susceptibility. In a landmark paper, Harrison (1975) showed that dantrolene sodium is an effective antidote, reversing the symptoms of an MH reaction. In the early 1980s the Ca2+-release channel of skeletal muscle sarcoplasmic reticulum from both humans and swine was shown to be hypersensitive to Ca2+-, caffeine-, and halothane-induced channel opening. Subsequent genetic analysis has shown that abnormalities in the Ca2+-release channel of skeletal muscle sarcoplasmic reticulum (the ryanodine receptor, OMIM 180901) are linked to MH in a large proportion of MH families