Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia

Urwyler, Albert; Deufel, Thomas; McCarthy, Tommie V.; West, Sarah P.

doi:10.1093/bja/86.2.283

Cited by 230 publications

(120 citation statements)

References 22 publications

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“…It has proven to be especially useful in early diagnosis of children and patients who cannot undergo the caffeine-halothane contracture test (CHCT) for MH susceptibility because CHCT requires an invasive muscle biopsy. 19 relatives of the chosen individuals (a total of 116 individuals) subsequently consented to enrol in the study (Table 1).…”

Section: Résumémentioning

confidence: 99%

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder that is manifested on exposure of susceptible individuals to halogenated anesthetics or succinylcholine. Since MH is associated primarily with mutations in the ryanodine receptor type 1 (RYR1) gene, the purpose of this study was to determine the distribution and frequency of MH causative RyR1 mutations in the Canadian MH susceptible (MHS) population. Methods In this study, we screened a representative cohort of 36 unrelated Canadian MHS individuals for RYR1 mutations by sequencing complete RYR1 transcripts and selected regions of CACNA1S transcripts. We then analyzed the correlation between caffeine-halothane contracture test (CHCT) results and RYR1 genotypes within MH families. Results Eighty-six percent of patients had at least one RyR1 mutation (31 out of 36), five of which were unrelated individuals who were double-variant carriers. Fifteen of the 27 mutations identified in RYR1 were novel. Eight novel mutations, involving highly conserved amino acid residues, were predicted to be causal. Two of the mutations co-segregated with the MHS phenotype within two large independent families (a total of 79 individuals). Fourteen percent of MHS individuals (five out of 36) carried neither RYR1 nor known CACNA1S mutations. Conclusions The distribution and frequency of MH causative RyR1 mutations in the Canadian MHS population are close to those of European MHS populations. Novel mutations described in this study will contribute to the worldwide pool of MH-associated mutations in the RYR1 gene, ultimately increasing the value of MH genetic diagnostic testing. RésuméObjectif L'hyperthermie maligne (HM) est une maladie pharmacoge´ne´tique he´re´ditaire dominante autosomique qui se manifeste lors de l'exposition des personnes susceptibles a`des anesthe´siques haloge´ne´s ou à la succinylcholine. E´tant donne´que l'HM est principalement associe´e aux mutations au niveau du ge`ne des re´cepteurs de ryanodine de type 1 (RYR1), l'objectif de cette e´tude e´tait de de´terminer la distribution et la fre´quence des mutations RyR1 causant une HM chez la population canadienne susceptible a`l'HM (SHM). Méthode Dans cette e´tude, nous avons examine´une cohorte repre´sentative de 36 personnes canadiennes SHM This article is accompanied by an editorial. Please see Can J Anesth 2011; 58: 6.

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Section: Résumémentioning

confidence: 99%

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Kraeva

Riazi

Loke

et al. 2011

Can J Anesth/J Can Anesth

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“…14 -16 Following 10 years of genetic research and investigation of MH-susceptible families as a European consortium, a stage has now been reached where genetic screening for the condition can be offered in a limited capacity. 17 Genetic testing guidelines have been recently published by the EMHG to enable DNA diagnosis of MH in supplementation to the IVCT method of patient screening in MH families. In summary, genetic testing using certain mutations in the RYR1 gene demonstrated to be 'causative' of MH through in vitro biochemical assays, 18,19 or through linkage analysis with markers flanking the RYR1 locus is now feasible.…”

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confidence: 99%

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Robinson

Anetseder

Brancadoro³

et al. 2003

Eur J Hum Genet

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Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to B30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive

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“…If a proband is diagnosed MHS in IVCT and genetic analyzes reveals a known MHS mutation then mutation analysis can be used for making the MHS diagnosis in relatives. However mutation analysis can never be used for excluding MHS (1).…”

mentioning

confidence: 99%

Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility

Islander

Ørding

Bendixen

et al. 2002

Acta Anaesthesiol Scand

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Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility.Islander, Gunilla; Ording, H; Bendixen, D; Ranklev Twetman, EvaPublished in: Acta Anaesthesiologica Scandinavica DOI: 10.1034/j.1399-6576.2002.460914.x Published: 2002 Link to publication Citation for published version (APA): Islander, G., Ording, H., Bendixen, D., & Ranklev Twetman, E. (2002). Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility. Acta Anaesthesiologica Scandinavica, 46(9), 1144 -1149 . DOI: 10.1034 /j.1399 -6576.2002 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, DenmarkBackground: The in vitro contracture test (IVCT) is the golden standard to diagnose malignant hyperthermia susceptibility (MHS). A high reproducibility is important for a high validity of a test. Methods: We have therefore analyzed IVCT in 838 patients, investigated in two laboratories. Each halothane and caffeine test was performed in two muscle strips. The test results were analyzed with respect to reproducibility of abnormal outcomes within pairs of tested muscle strips and size of contractures, thresholds and quality criteria. The patients were tested according to the European Malignant Hyperthermia Group protocol (EMHG). To fulfill quality criteria in the EMHG protocol the twitch height should be 10 mN (1 g) or more. For the caffeine test a minimum contracture of 50 mN (5 g) or more at 32 mmol l ª1 caffeine could be used as an alternative quality criterion Results: There was better reproducibility with larger contractures. The correlation between size of contractures and fraction of muscle strips with abnormal contractures was 0.77 or larger. Contractures Ͻ 5 mN (0.5 g) were reproducible in less than half

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Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia

Cited by 230 publications

References 22 publications

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

Reproducibility of in vitro contracture test results in patients tested for malignant hyperthermia susceptibility

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