Genetic effects on the variability of the halothane and caffeine muscle contracture tests.

BACKGROUND

The spectrum of the clinical presentation of malignant hyperthermia (MH) and the results of recent linkage studies suggest that there is a degree of heterogeneity in MH susceptibility. In the current study, we analyzed in vitro muscle contracture tests from members of large families with MH to evaluate if the results of these tests could be related to genetic influences.

METHODS

Forty-seven subjects from four families with an MH-related death and with at least five clinically 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 to supramaximal electrical stimulation among the families.

RESULTS

Clinical MH susceptibility was confirmed in 36 individuals, and 11 individuals were diagnosed as MH-negative. In MH-susceptible individuals, muscle contractures to the 2% halothane challenge were significantly higher in family 1 (n = 15; 16.2 +/- 2.9 mN, mean +/- standard error of the 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 contractures 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 the halothane challenge in family 2 (P < 0.01) and to the caffeine challenge 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 provide evidence for genetic influences on the variability of this test procedure. However, it is not known if the observed differences are caused by heterogeneity of the MH gene mutation(s) or by other genetic factors that might modify muscle contractures in vitro.