Susceptibility to Malignant Hyperthermia.

KUN Katholieke Universiteit Nijmegen, 11 november 2004
Promotor : Sengers, R.C.A. Co-promotor : Gielen, M.J.M.
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In this thesis the author studied the diagnostic procedures for susceptibility to malignant hyperthermia (MH), with special emphasis upon refining the biological diagnostic test and improving protocols and guidelines for investigation of MH susceptibility. MH is a pharmacogenetic disease of skeletal muscle which is mainly of concern during and following anaesthesia. Abnormalities in the calcium release channel of skeletal muscle sarcoplasmic reticulum, the ryanodine receptor, have been implicated as the central factor in the cause of the MH syndrome. The in vitro muscle contracture test (IVCT) is the standard test to establish an individual's risk of susceptibility to MH. The diagnostic sensitivity of 99.0% and the accompanying specificity of 93.6% of the standard halothane-caffeine IVCT have been determined in a joint European study. Sevoflurane, a potent inhalational anaesthetic agent that is structurally similar to halothane, has been able to trigger an abnormal contracture in human muscle in vitro. The IVCT is invasive, time consuming and it is a technically demanding test that requires expertise. Cultured skeletal muscle cells, obtained by percutaneous needle biopsies may well be applied in diagnostic tests for MH susceptibility since the dose-dependant Ca2+ response in cultured muscle cells of MH-susceptible individuals is significantly different from that of control individuals after exposure to halothane. Because MH displays a high level of locus heterogeneity, it is not feasible to diagnose MH susceptibility, and, more specifically, to exclude MH risk, on the basis of a simple genetic test alone. Clinical practitioners and geneticists of the European MH Group have agreed on guidelines for the detection of MH susceptibility using molecular genetic techniques. Evaluation of the diagnostic procedure in 4 European MH investigation units helped to gain an insight into the need for further standardisation and quality assurance for the diagnosis of MH.