GENOTYPE AND PHENOTYPE RELATIONSHIPS FOR MUTATIONS IN THE RYANODINE RECEPTOR IN PATIENTS REFERRED FOR DIAGNOSIS OF MALIGNANT HYPERTHERMIA

Anaesthesia-induced malignant hyperthermia (MH) may be caused by specific gene defects in the skeletal muscle ryanodine receptor. We have studied the frequency of occurrence of the C1840T mutation, analogous to the porcine mutation, and three mutations associated both with central core disease (G7301A, C1209G). We investigated skeletal muscle specimens from up to 137 patients testing negative and 101 patients testing positive for MH susceptibility by the North American MH Group protocol. The presence or absence of the mutations was determined by polymerase chain reaction and restriction enzyme digestion. The frequencies of occurrence of the C1840T and C487T mutations were 2% and 1%, respectively, in MH-positive subjects and were the only two mutations identified. One subject with central core disease did not have any of the three mutations examined associated with this disorder. Therefore, the porcine and central core disease-associated mutations examined in the ryanodine receptor account for a small proportion (approximately 3%) of MH-positive diagnoses. The mutations examined did not occur in any of the MH-negative patients, supporting an association between defects in the ryanodine receptor and a positive diagnosis for MH. The relatively weak response to triggering anaesthetics (only masseter muscle rigidity) in two subjects with the C1840T ryr1 mutation, including 18 uneventful anaesthetics in one, suggests that either additional modulating factors must contribute to the syndrome or the presence of the C1840T mutation is nota causative factor in MH.