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 speci fic gene defects in the skeletal muscle ryanodine receptor. We have st udied the frequency of occurrence of the C1840T mutation, analogous to the porcine mutation, and three mutations associated both with centra l core disease (G7301A, C1209G). We investigated skeletal muscle speci mens from up to 137 patients testing negative and 101 patients testing positive for MH susceptibility by the North American MH Group protoco l. The presence or absence of the mutations was determined by polymera se chain reaction and restriction enzyme digestion. The frequencies of occurrence of the C1840T and C487T mutations were 2% and 1%, respecti vely, in MH-positive subjects and were the only two mutations identifi ed. One subject with central core disease did not have any of the thre e mutations examined associated with this disorder. Therefore, the por cine and central core disease-associated mutations examined in the rya nodine receptor account for a small proportion (approximately 3%) of M H-positive diagnoses. The mutations examined did not occur in any of t he 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 rigidi ty) in two subjects with the C1840T ryr1 mutation, including 18 uneven tful anaesthetics in one, suggests that either additional modulating f actors must contribute to the syndrome or the presence of the C1840T m utation is nota causative factor in MH.