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

Orphanet Journal of Rare Diseases

Frank Lehmann-Horn²  Vincenzo Tegazzin⁷  Vincenzo Sorrentino⁹  Marc Snoeck^1,10  Frank Schuster⁶  Henrik Rüffert⁵  Karin Jurkat-Rott²  Stephan Johannsen⁶  James JA Heffron³  Elvira Gravino¹  Thierry Girard⁸  Sebastian Heiderich⁴  Werner Klingler² 

[1]University of Naples, Naples, Italy

[2]Rare Disease Center, University Hospital Ulm, Ulm 89081, Germany

[3]Biochemistry Department, University College Cork, Cork, Ireland

[4]Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany

[5]University of Leipzig, Helios Kliniken Leipziger Land Leipzig, Germany

[6]Department of Anesthesia and Critical Care, University of Würzburg, Würzburg, Germany

[7]Department of Anesthesia, University of Padua, Padua, Italy

[8]University of Basel, Basel, Switzerland

[9]Molecular Medicine Section, Department of Molecular and Developmental Medicine, University of Siena, via A. Moro 2, Siena 53100, Italy

[10]Department of Anesthesia, Canisius-Wilhelmina Hospital, University of Nijmegen, Nijmegen, The Netherlands

关键词: In vitro contracture test;    RyR1 mutations;    Volatile anesthetics;    Suxamethonium;    Succinylcholine;    Malignant hyperthermia;   

Others  :  863307
DOI  :  10.1186/1750-1172-9-8

 received in 2013-09-28, accepted in 2014-01-08,  发布年份 2014

【 摘 要 】

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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ release. SCh might act as an accelerant by promoting unspecific Ca²⁺ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.

【 授权许可】

   
2014 Klingler et al.; licensee BioMed Central Ltd.

【 图 表 】

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