XXIVth Annual Meeting of the European Malignant Hyperthermia Group. Mainz, Germany. May 19–21, 2005.
The XXIVth Annual Meeting of the European Malignant Hyperthermia Group took place May 19–21, 2005, in Mainz, Germany. Research was presented from nine European countries, including Bulgaria and the new European Union members, Hungary, Latvia, and Poland, as well as from Japan, New Zealand, Canada, and the United States. There were three guest lectures by professors Richard Ellis, M.D. (President of the European Malignant Hyperthermia Group), Wilfred Nix, M.D. (Department of Neurology, University of Mainz, Germany), and Philip M. Hopkins, M.D. (Department of Anesthesia, University of Leeds, United Kingdom), and several short reports on clinical aspects of malignant hyperthermia (MH), central core disease (CCD), the in vitro contracture test and alternative diagnostic approaches for MH susceptibility, and the genetics of MH. Most interesting were the reports of ryanodine receptor genetics.
Analysis of the entire ryanodine receptor gene type 1 (RYR1 ) coding region in Switzerland and Japan confirmed a previous study of 30 patients from the United States in that many novel sequence variants were found outside the three much-studied “hot spots.”RYR1 mutations were found in only 40% of Swiss MH-susceptible families when the genetic examination was restricted to the three hot spots. However, RYR1 sequence variants were found in 27 of 36 MH-susceptible patients when the entire coding region of RYR1 was examined. Six of these were previously described mutations, and 21 were new findings of unknown significance (novel mutations). Similarly, 6 known and 22 novel sequence variants were found in a sample of 34 Japanese MH-susceptible individuals when the entire coding region was examined. The functional effects of all of these novel variants have not been determined. Of the 392 sequence variants reported in RYR1 to date, 67 are associated with MH susceptibility, 18 are associated with both MH and CCD, and 30 are associated with CCD only. However, only 23 have been shown to decrease the threshold for calcium release in a biologic system and meet the other criteria necessary to designate the genetic change causative of MH.
The sensitivity of a genetic test of MH susceptibility is difficult to define without consideration of patient characteristics. A multicenter study from Grenoble, Marseille, Lille, and Paris, France; Toronto, Canada; and Padua, Italy, reported clinical, molecular, pharmacologic, histologic, and functional data from 179 families. In those with a diagnosis of MH susceptibility by contracture testing, 60% had mutations in 1 of the 32 RYR1 exons examined by denaturing high-performance liquid chromatography and sequencing. In only 20% of the 50 individuals who did not have contracture testing but were studied after a clinical MH event were RYR1 mutations identified. In contrast, causative mutations were identified in 12 of 14 patients in a series from North America that looked for 17 RYR1 mutations in 11 exons. Ten of these 14 patients also had positive contracture tests. Four were not tested by contracture test for clinical reasons. Persistent myopathic symptoms were present in 4 cases, including the 2 patients in whom RYR1 mutation was not found.
Examination of a limited number of exons can produce misleading results. Two RYR1 mutations were found in 6 of 179 families. In a different study, 8 families had two and 2 families had three RYR1 variants. Two very common RYR1 mutations in Europe and North America, Gly341Arg and Arg614Cys, are rare in Japan. A discordance of 6% between MH-susceptible status by contracture testing and mutation analysis was reported again. Therefore, both positive and negative results of a genetic test of MH susceptibility must be interpreted carefully.
Genetic confirmation of CCD was reported by the clinical diagnostic laboratory in Leeds, England. Before performing such a test, the clinical and histologic evidence supporting the diagnosis of CCD is evaluated. In 30 such cases, RYR1 exons 95 and 100–104 contained sequence variants in 30%. Of these, 70% were novel. A sequence variant in these exons does not automatically indicate that the patient is susceptible to MH. MH susceptibility should be evaluated by contracture testing in such cases. The absence of mutations in exons 95 or 100–104 of RYR1 does not rule out CCD, because there are six other known loci for the histologic and clinical diagnosis of CCD.
A new mutation, Ile4138Thr, was found in a woman who had masseter spasm followed by several days of muscle pain after succinylcholine administration for cesarian delivery without exposure to inhalation anesthetics. Contracture test results in this proband and two other relatives were positive. Histologic findings of CCD were present in these MH-susceptible individuals, and there was a reduction in the EC50 for 4 chloro-m-cresol and halothane on calcium flux in their myotubes. MH-negative relatives, by contracture testing, had normal histology and normal RYR1 . More cases of suspected MH should be evaluated by all of these methods.
Data supporting revised recommendation for postoperative treatment of MH-susceptible patients from New Zealand was presented. Presumed MH-susceptible patients had nontriggering anesthetics as day surgery patients. In the total of 72 patients, 39 were diagnosed with MH susceptibility with positive contracture tests, and 3 were diagnosed by DNA analysis. Propofol, narcotics, antiemetics, and nonsteroidal antiinflammatory drugs were given. Capnography and other noninvasive monitoring were used. The average anesthetic duration was 45 min. After 60 min in the postanesthesia care unit, patients went to a second-stage recovery area for 90 min before discharge home. Some children went home sooner after tympanostomy tube placement. The next day, 68% of cases were contacted. There were no reports of postoperative fever or muscle pain. Pain at the incision and nausea were commonly reported.
Also noteworthy is the demonstration from Wurzburg, Germany, that sevoflurane cannot be substituted for halothane in in vitro contracture testing. This group continues to work on the microdialysis measurement of intramuscular metabolism after local injection of RYR1 agonists halothane and caffeine as a less invasive test to diagnose MH.
The next meeting of this group will be in Riga, Latvia.
§University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. bwb@pitt.edu
