Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group.

Survival from a malignant hyperthermia (MH) crisis is highly dependent on early recognition and prompt action. MH crises are very rare and an increasing use of total i.v.

The role of CACNA1S in predisposition to malignant hyperthermia.

Background: Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the alpha1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK.

Genetic variation in RYR1 and malignant hyperthermia phenotypes.

Background: Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype.

Methods: The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH.

A RYR1 mutation associated with recessive congenital myopathy and dominant malignant hyperthermia in Asian families.

In this study we present 3 families with malignant hyperthermia (MH), all of Indian subcontinent descent. One individual from each of these families was fully sequenced for RYR1 and presented with the non-synonymous change c.11315G>A/p.

Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility.

Background: Tissue-specific monoallelic silencing of the RYR1 gene has been proposed as an explanation for variable penetrance of dominant RYR1 mutations in malignant hyperthermia (MH). We examined the hypothesis that monoallelic silencing could explain the inheritance of an MH discordant phenotype in some instances.

Methods: We analysed parent-offspring transmission data from MH kindreds to assess whether there was any deviation from the expected autosomal dominant Mendelian inheritance pattern.

Analysis of RYR1 haplotype profile in patients with malignant hyperthermia.

This study represents a new approach to characterising patients at risk of malignant hyperthermia (MH) through the use of a recently published method for identifying high-risk haplotypes in candidate genes. We present analysis based upon the largest standardised and genotyped database of MH patients worldwide. We used unphased RYR1 SNP data directly to (1) assess RYR1 haplotype frequency differences between susceptible cases and control groups and (2) analyse population-based association via clustering of RYR1 haplotypes based on disease risk.

Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia.

Background: In normal resting muscle, cytosolic Mg(2+) exerts a potent inhibitory influence on the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR1). Impaired Mg(2+)-regulation of RyR1 has been proposed as a causal factor in malignant hyperthermia (MH). The aim of this study was to compare the effects of cytosolic Mg(2+) on SR Ca(2+) release induced by halothane or sevoflurane in normal (MHN) and MH susceptible (MHS) human skeletal muscle fibres.

Mutation analysis of two patients with hypokalemic periodic paralysis and suspected malignant hyperthermia.

Hypokalemic periodic paralysis (HypoPP) and malignant hyperthermia (MH) are autosomal-dominant genetically heterogeneous ion channelopathies. MH has been described in patients with HypoPP, suggesting a potential link between these disorders. However, a common genetic determinant has not been described.

Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy.

Central core disease and malignant hyperthermia (MH) are both associated with mutations in the RYR1 gene. We report the anaesthetic management of one such patient presenting for coronary artery bypass grafting. Her medication included aspirin 75 mg, atorvastatin 20 mg, isosorbide mononitrate 60 mg, atenolol 25 mg and glyceryl trinitrite sublingual spray as required.

Multicentre evaluation of in vitro contracture testing with bolus administration of 4-chloro-m-cresol for diagnosis of malignant hyperthermia susceptibility.

Background And Objective: The in vitro contracture test with halothane and caffeine is the gold standard for the diagnosis of susceptibility to malignant hyperthermia (MH). However, the sensitivity of the in vitro contracture test is between 97 and 99% and its specificity is 78-94% with the consequence that false-negative as well as false-positive test results are possible. 4-Chloro-m-cresol is potentially a more specific test drug for the in vitro contracture test than halothane or caffeine.

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes.

Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH.

No evidence of mutations in the CACNA1S gene in the UK malignant hyperthermia population.

Background: Malignant hyperthermia (MH) is an inherited, potentially fatal, pharmocogenetic disorder triggered by certain anaesthetic agents. In light of the reported genetic heterogeneity for the disorder and the recent introduction of DNA testing guidelines for the trait, we have assessed the role of the CACNA1S gene in MH susceptibility in UK patients. Linkage to this locus has previously been demonstrated in several European MH families.

Multiple interacting gene products may influence susceptibility to malignant hyperthermia.

Malignant hyperthermia (MH) is a potentially lethal disorder triggered in susceptible individuals on exposure to common anaesthetic agents. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. MH is an autosomal dominant, genetically heterogeneous trait.

Segregation of malignant hyperthermia, central core disease and chromosome 19 markers.

Malignant hyperthermia (MH) is an autosomal dominant disorder presenting under general anaesthesia. It is occasionally associated with a myopathy, central core disease (CCD), named after its predominant histochemical characteristic. The penetration of CCD is variable, but typically affected individuals show delayed motor milestones in infancy and remain physically compromised.

Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families.

Malignant hyperthermia (MH) is an autosomal dominant genetic condition that presents in susceptible people undergoing general anaesthesia. The clinical disorder is a major cause of anaesthetic morbidity and mortality. The UK Malignant Hyperthermia Group has performed genetic linkage analysis on 20 large, well defined malignant hyperthermia families, using hypervariable markers on chromosome 19q13.

In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group.

Background: Determination of sensitivity and specificity of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility using the European MH Group (EMHG) protocol has been performed in some laboratories but only on a small sample from the combined EMHG. Thus, the purpose of the present study was to determine combined EMHG sensitivity and specificity of the test.

Methods: Results of IVCT of patients with previous fulminant MH and normal, low-risk subjects (controls) were collected from 22 centres of the EMHG.

The G1021A substitution in the RYR1 gene does not cosegregate with malignant hyperthermia susceptibility in a British pedigree.

A single base change in the RYR1 gene encoding the skeletal muscle ryanodine receptor (calcium-sensitive calcium-release channel of the sarcoplasmic reticulum), resulting in the substitution of G1021 by A, has been proposed to underlie malignant-hyperthermia (MH) susceptibility in as many as 10% of cases in the European population. As part of our mutation-screening program in MH-susceptible (MHS) individuals, we have investigated this substitution in individuals from 151 unrelated British MHS families and have detected G1021A heterozygotes in 7 families. This mutation was not found in 156 unrelated MH-negative (MHN) individuals.

An analysis of the predictive probability of the in vitro contracture test for determining susceptibility to malignant hyperthermia.

An objective estimate of the likelihood of correct designation of malignant hyperthermia (MH) susceptibility from in vitro contracture test (IVCT) results is essential if genetic linkage studies of MH are to be more informative. The aim of this study was to generate and test statistical models that could be used to predict the probability of susceptibility of an individual to MH from the results of their IVCTs. Logistic regression of the IVCT results of an index group of 50 patients (age range 9-73 years; MH susceptible [MHS], n = 13; MH normal [MHN], n = 32; MH equivocal [MHE], n = 5) who were either at low risk of MH or were proband cases were used to generate models to predict probability of MH susceptibility.

The effects of benzamil on in vitro contracture responses of human skeletal muscle to halothane.

1. Inhibition of sodium-calcium exchange using 100 microM benzamil caused contracture development of in vitro skeletal muscle samples from humans susceptible to malignant hyperthermia, but not of samples from normal individuals. 2.

Genetic mapping of the beta 1- and gamma-subunits of the human skeletal muscle L-type voltage-dependent calcium channel on chromosome 17q and exclusion as candidate genes for malignant hyperthermia susceptibility.

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder of skeletal muscle which manifests as a life-threatening hypermetabolic crisis triggered by commonly-used inhalation anaesthetics and depolarizing muscle relaxants. Defects in the ryanodine receptor (RYR1) protein have been proposed to underly MHS, but significant genetic heterogeneity in MHS has recently been demonstrated. In order to investigate the potential roles played by other skeletal muscle calcium channels in MHS, we isolated cosmids containing the gene encoding the beta 1-subunit of skeletal muscle L-type voltage-dependent calcium channel (CACNLB1).