GENETIC-EFFECTS ON THE VARIABILITY OF THE HALOTHANE AND CAFFEINE MUSCLE CONTRACTURE TESTS

Background: The spectrum of the clinical presentation of malignant hyp erthermia (MH) and the results of recent linkage studies suggest that there is a degree of heterogeneity in MH susceptibility. In the curren t study, we analyzed in vitro muscle contracture tests from members of large families with MH to evaluate if the results of these tests coul d be related to genetic influences. Methods: Forty-seven subjects from four families with an MH-related death and with at least five clinica lly MH-susceptible individuals per family, as diagnosed by an in vitro muscle contracture test according to the protocol of the European MH Group, were included in the current analysis. We compared the strength of muscle contractures to challenges of halothane, caffeine, or both and the effect of these two drugs on twitch potentiation in response t o supramaximal electrical stimulation among the families. Results: Cli nical MH susceptibility was confirmed in 36 individuals, and 11 indivi duals were diagnosed as MH-negative. In MH-susceptible individuals, mu scle contractures to the 2% halothane challenge were significantly hig her in family 1 (n = 15; 16.2 +/- 2.9 mN, mean +/- standard error of t he mean) and in family 4 (n = 5; 16.4 +/- 5 mN) than in family 2 (n = 9; 5.8 +/- 1.5 mN) or family 3 (n = 7; 6.0 +/- 1.1 mN). Muscle contrac tures to the caffeine challenge (2 mM) were significantly increased in family 1 (7.3 +/- 1.4 mN) compared with those in family 3 (1.3 +/- 1. 0 mN). In addition, we found a dose-dependent twitch potentiation to t he halothane challenge in family 2 (P < 0.01) and to the caffeine chal lenge in families 2 (P < 0.001) and 3 (P < 0.01), whereas there was no twitch potentiation in families 1 and 4. Conclusions: The differences of in vitro muscle contracture tests among several families with MH p rovide evidence for genetic influences on the variability of this test procedure. However, it is not known if the observed differences are c aused by heterogeneity of the MH gene mutation(s) or by other genetic factors that might modify muscle contractures in vitro.