Malignant hyperthermia: characterization of erythrocyte membranes from individuals at risk.

Structural and functional characteristics of erythrocytes and isolated erythrocyte membranes from known malignant hyperthermia (MH) carriers have been examined in the hope of deriving some information concerning the underlying molecular basis of this genetic abnormality, which may represent a state of generalized membrane involvement. The increase in erythrocyte osmotic fragility which has previously been noted in porcine MH was found not to apply to the human disorder and there was evidence that in some individuals at risk osmotic fragility was in fact reduced. Although no alteration in erythrocyte membrane phospholipid profiles was detected, membrane cholesterol levels were reduced in all three definite carriers examined as well as in approximately half of the possible MH carriers investigated. No evidence for associated changes in membrane protein sulfhydryl group latency or in temperature-dependent perturbations of membrane fluidity using a stearic acid spin probe could be detected. Finally, since alterations at the level of skeletal muscle membrane -Ca++ interaction have been implicated in the pathogenesis of MH, we have examined in detail the influence of temperature on the Ca++-stimulated components of the Mg++-dependent ATPase of erythrocyte membranes from known MH carriers but no evidence of any abnormality could be found. Since MH carriers detection based solely on measurements of plasma creatine phosphokinase elevations may yield equivocal results, a decrease in erythrocyte membrane cholesterol content may provide a convenient means of identifying such individuals at risk.

Erythrocyte membrane enzyme abnormalities in two hereditary disorders of muscle.

Enzymatic properties of erythrocyte membranes in Duchenne muscular dystrophy (DMD) and malignant hyperthermia (MH), two genetically determined abnormalities of skeletal muscle, were examined. Acetylcholinesterase (AChE) and ATPase activities were chosen for investigation since alterations in these enzymes have been demonstrated in animal models of dystrophy. A significant decrease in Na+,K+-ATPase activity was noted in DMD patients and a number of possible DMD carriers, suggesting that this enzyme may provide a useful marker of the carrier state in carriers not exhibiting an elevation in plasma creatine phosphokinase activity. No abnormalities in AChE were demonstrable in any of our DMD patients, indicating that human dystrophy is biochemically distinct from certain animal models of dystrophy (e.g., dystrophic mice) where erythrocyte AChE is decreased. In contrast, evidence was found in two known MH carriers, who had normal erythrocyte ATPase activities, for the presence of an altered membrane AChE characterized by an increase in substrate affinity and a large decrease in maximal hydrolytic rate. While the exact relevance of this membrane defect, if any, to the pathogenesis of MH remains to be seen, the presence of this modified enzyme may serve to identify those individuals in a family where a positive history of MH exists who are at risk of developing a hyperthermic crisis during anesthesia.