Functional and genetic characterization of clinical malignant hyperthermia crises: A multi-centre study

Werner Klingler, Sebastian Heiderich, Thierry Girard, Elvira Gravino, James J.A. Heffron, Stephan Johannsen, Karin Jurkat-Rott, Henrik Rüffert, Frank Schuster, Marc Snoeck, Vincenzo Sorrentino, Vincenzo Tegazzin, Frank Lehmann-Horn

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Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca§ssup§2+§esup§ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. Methods. In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca§ssup§2+§esup§ release from sarcoplasmic reticulum (SR) were studied in vitro. Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca§ssup§2+§esup§ release from isolated rat SR vesicles. Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca§ssup§2+§esup§ release. SCh might act as an accelerant by promoting unspecific Ca§ssup§2+§esup§ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.

Original languageEnglish
Article number8
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - 16 Jan 2014
Externally publishedYes


  • In vitro contracture test
  • Malignant hyperthermia
  • RyR1 mutations
  • Succinylcholine
  • Suxamethonium
  • Volatile anesthetics


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