title: Results of contracture tests with halothane, caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations.
abstract: BACKGROUND
  More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine.
  
  
  METHODS
  Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 microm ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene.
  
  
  RESULTS
  In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene.
  
  
  CONCLUSIONS
  The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.
authors.affiliation: Department of Anesthesiology, University-Hospital Eppendorf, Hamburg, Germany.
authors.forename: Marko
authors.initials: M
authors.lastname: Fiege
authors.forename: Frank
authors.initials: F
authors.lastname: Wappler
authors.forename: Ralf
authors.initials: R
authors.lastname: Weisshorn
authors.forename: Mark
authors.initials: M
authors.lastname: Ulrich Gerbershagen
authors.forename: Markus
authors.initials: M
authors.lastname: Steinfath
authors.forename: Jochen
authors.initials: J
authors.lastname: Schulte Am Esch
mesh_terms: D000293:Adolescent; D000328:Adult; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects*; D009154:Mutation; D011446:Prospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D018685:Anesthetics, Inhalation; D000697:Central Nervous System Stimulants; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D006221:Halothane