In vitro contracture testing for the diagnosis of malignant hyperthermia susceptibility

Abstract: Malignant hyperthermia (MH) susceptibility is a rare inherited muscular disorder, which may cause a lethal increase in metabolism during anaesthesia with certain commonly used anaesthetic. Susceptible individuals are without any signs or symptoms. It is important to identify individuals at risk, since the MH reaction is preventable. Susceptibility to MH is diagnosed with an in vitro contracture test (IVCT) performed on viable skeletal muscle. The muscle is exposed to halothane/caffeine in an organ bath. An increase in baseline tension >=0.2g is abnormal. There have been few thorough validations of the IVCT and false diagnoses do occur, which make genetic research difficult. We have investigated 1) the reliability of a negative diagnosis, 2) the inheritance pattern suggested by IVCT and 3) the validation the IVCT results in 706 patients in 175 families. Fourteen patients diagnosed MH negative revealed no signs of MH when exposed to anaesthetics known to cause MH. Judged from outcome of IVCT in 101 families, there is more than one mode of inheritance. The IVCT was validated with comparisons within and between laboratories, between different types of tests and within and between monozygotic twins. We found that increase in baseline tension exceeding 0.5g were almost always reproducible within and between laboratories, between different types of tests and within and between monozygotic twins. Our conclusions are that 1. There are no indications of false negative diagnoses. 2. There could be more than one mode of inheritance. 3. For scientific purposes when a high specificity is needed the threshold could be increased to 0.5g. However the clinical diagnostic cut off limits should be unchanged.