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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have reported that malignant hyperthermia susceptibility is caused in some families by inherited variation in a gene located on the short arm of chromosome 19 near to, or identical with, the ryanodine receptor gene (RYR1); this is expressed in skeletal muscle as a calcium release channel of the sarcoplasm reticulum. In other families, a gene in this location is excluded, but the locations of the genes involved have not yet been defined. We have analysed DNA samples from members of three large British families in whom in vitro muscle contracture tests for malignant hyperthermia susceptibility have been carried out in accordance with the procedure recommended by the European Malignant Hyperthermia Group. The results presented here strongly suggest that the gene for malignant hyperthermia susceptibility in one or more of these three British families is located in the same region of chromosome 19q, although further work is required to decide whether or not the RYR1 gene itself is causative in these families. As genetic heterogeneity could not be excluded, we cannot yet recommend the use of DNA markers to replace in vitro contracture tests in the diagnosis of malignant hyperthermia susceptibility.
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PMID:Genetic linkage analysis of chromosome 19 markers in malignant hyperthermia. 843 38

The regulation of intracellular free calcium ions (Ca2+) in skeletal muscle at rest and during contraction depends on mechanisms such as Na(+)-Ca2+ exchangers, Ca(2+)-ATPases, and the voltage-sensitive ryanodine receptor. The susceptibility of these regulatory mechanisms to free-radical-mediated damage may be increased because of their location within the lipid membranes of sarcolemma, sarcoplasmic reticulum, and mitochondrion with resultant uncontrolled increases in myoplasmic Ca2+ concentration and cell death. The potentially fatal pharmacogenetic disorder, malignant hyperthermia (MH), is characterised by muscle rigidity, arrhythmias, lactic acidosis, and a rapid rise in body temperature. The sequence of events responsible for the MH syndrome remains uncertain, but it has been variously ascribed to faults in many of the Ca2+ regulatory mechanisms. In swine the condition is associated with a specific mutation in the ryanodine receptor, whereas in humans the syndrome is genetically heterogenous. Free-radical-mediated peroxidation of membrane lipids and proteins also results in the rapid efflux of Ca2+ from organelles, and the detection of products of free radical reactions in tissue from MH-susceptible individuals using electron spin resonance spectroscopy provides evidence for the involvement of free radicals in the MH syndrome.
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PMID:Free radicals and calcium homeostasis: relevance to malignant hyperthermia? 846 27

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Besides a mutation in the ryanodine receptor gene, an increase in inositol, 1,4,5-triphosphate (InsP3) levels could be a possible candidate for the abnormal regulation of intracellular calcium. However, the effect of InsP3 on [Ca2+]i in MH is not known. Microinjection of InsP3 increased intracellular Ca2+ in intact skeletal muscle from malignant hyperthermia susceptible swines (MHS) with a higher potency and efficacy than in muscles from nonsusceptible (MHN) swines. Omission of extracellular Ca2+ or incubation of muscle fibers with Ca2+ channel blockers did not modify the response to InsP3. However, dantrolene (50 microM) a known blocker of intracellular Ca2+ release, decreased resting intracellular Ca2+ concentration and prevented the InsP3-induced increase in intracellular Ca2+. This suggests (i) that MHS skeletal muscles exhibit a higher responsiveness to InsP3-induced release of Ca2+, which could implicate InsP3 in the pathophysiology of MH, and (ii) that the beneficial effect of dantrolene in MHS could be related to its ability to prevent the InsP3-induced release of Ca2+.
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PMID:Hypersensitive response of malignant hyperthermia-susceptible skeletal muscle to inositol 1,4,5-triphosphate induced release of calcium. 853 74

We investigated whether malignant hyperthermia (MH)-related contractile abnormalities, such as lowered contractile threshold, were expressed in MH-susceptible (MHS) immature muscles and myotubes. Muscles from neonatal piglets homozygous for Arg615 (normal) or for Cys615 (MHS) ryanodine receptor alleles, and heterozygotes were used. Intact cell bundles from piglet muscles generally were similar in contractile properties to adult muscles of the same genotype. Thresholds for K contractures in normal, heterozygous, and MHS piglet muscles (40 mmol/L, 25 mmol/L and 15 mmol/L K+, respectively) differed significantly. Cultured myotubes were subjected to a series of square pulses of varying strengths (-50 to +50 mV) and durations (25-300 ms) using whole cell patch-clamp techniques. Threshold for contraction differed significantly among the three genotypes, for example, with 300 msec pulses thresholds were -6.9 +/- 0.9, -12.4 +/- 1.6, and -22.6 +/- 2.6 mV for normal, heterozygous and MHS myotubes, respectively. Thus a significantly lower than normal threshold for contraction was expressed in MHS and heterozygous piglet muscles and myotubes. Further, these developmentally immature preparations are likely to express other differences characteristic of adult MHS muscles, and thus provide suitable preparations for clinically relevant studies of MH-related cellular abnormalities.
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PMID:Porcine malignant hyperthermia: genotype and contractile threshold of immature muscles. 853 72

Eight mutations in the ryanodine receptor gene on human chromosome 19q13.1 have been linked to malignant hyperthermia. Although 50% of malignant hyperthermia families are not linked to the ryanodine receptor gene, only single malignant hyperthermia families have been linked to alternative loci on chromosome 7q21-22 and on chromosome 3q13.1. Problems in malignant hyperthermia linkage studies may arise from the inadequacy of the caffeine halothane contractures test for phenotypic diagnosis of malignant hyperthermia.
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PMID:Discordance between phenotype and genotype in malignant hyperthermia. 854 47

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in a small proportion of cases. We report here that one of these, the Arg163Cys substitution, does not cosegregate with MH susceptibility. Comparison of cDNA sequences encoding the skeletal muscle specific components of the dihydropyridine receptor alpha 1 subunit between MH susceptible (MHS) and MH non-susceptible (MHN) patients was made in subjects without the reported MH linked RYR1 mutations. There were no differences within the sequence encoding the II-III loop or the IS3/IS3-IS4 segment, excluding defects in these functional segments of the alpha 1 subunit as frequent causes of MH.
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PMID:Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia. 859 42

The aim of the present study was to determine the effects of 4-chloro-m-cresol (4-CmC), a preservative often added to drugs intravenously administered, on the skeletal muscle sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor. In heavy SR vesicles obtained from rabbit back muscles, 4-CmC stimulated (Ca2+)-activated [3H]ryanodine binding with an EC50 of about 100 microM. In the same concentration range, 4-CmC directly activated the isolated Ca2+ release channel reconstituted into planar lipid bilayers. The sensitivity to 4-CmC was found to be higher when applied to the luminal side of the channel suggesting binding site(s) different from those of nucleotides and caffeine. In skeletal muscle fibre bundles obtained from biopsies of patients susceptible to malignant hyperthermia, a skeletal muscle disease caused by point mutations in the ryanodine receptor, 4-CmC evoked caffeine-like contractures. Contrary to caffeine which induces contractures in millimolar concentrations, the threshold concentration for 4-CmC was 25 microM compared to 75 microM for non-mutated control fibres. Since these data strongly indicate that 4-CmC specifically activates SR Ca2+ release also in intact cell systems, this substance might become a powerful tool to investigate ryanodine receptor-mediated Ca2+ release in muscle and non-muscle tissue.
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PMID:4-Chloro-m-cresol, a potent and specific activator of the skeletal muscle ryanodine receptor. 860 29

Malignant hyperthermia susceptibility is genetically heterogeneous. The ryanodine receptor gene on the long arm of chromosome 19 represents an important candidate gene but not all families with malignant hyperthermia demonstrate ryanodine receptor mutations or linkage to this region of 19q. Linkage to chromosome 17 in the region of the adult muscle sodium channel alpha subunit gene has been suggested in some families; others are not linked to either of these loci. For most families the in vitro muscle contracture test remains the only reliable method of predicting susceptibility to malignant hyperthermia. We have performed linkage analysis in a large family group with malignant hyperthermia in which the in vitro muscle contracture test had been carried out using the procedure standardised by the European Malignant Hyperthermia Group. None of the published ryanodine receptor gene mutations associated with malignant hyperthermia susceptibility were detected in affected individuals but linkage to intragenic ryanodine receptor markers strongly suggest that this gene is involved in malignant hyperthermia susceptibility in this family. This enabled accurate predictive testing by DNA analysis in 11 untested subjects at 50% risk.
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PMID:Malignant hyperthermia--a large kindred linked to the RYR1 gene. 866 59

Single-channel recordings have indicated that ryanodine receptor (RyR1) mutation Arg615Cys of porcine malignant hyperthermia-susceptible (MHS) muscle is not directly associated with the enhanced caffeine sensitivity of MH(S) muscle [1]. In the present study, the effect of a novel activator of RyR1, 4-chlorom-cresol (4-CmC), was investigated on high-affinity [3H]ryanodine binding to porcine skeletal sarcoplasmic reticulum. The 4-CmC affinity of [3H]ryanodine binding to MHS vesicles was 2-fold higher compared to that in normal tissue. This enhanced affinity was confirmed when the effect of 4-CmC on [3H]ryanodine binding to the isolated CHAPS-solubilized MHS RyR1 was investigated. 4-CmC is, therefore, suggested to be a potent tool to distinguish between Ca2+ release from MHS and normal muscle.
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PMID:4-Chloro-m-cresol: a specific tool to distinguish between malignant hyperthermia-susceptible and normal muscle. 867 99

Laboratory confirmation of a clinical suspicion of malignant hyperthermia (MH) susceptibility by the standard in vitro contracture test remains inconclusive in patients reacting only to caffeine or halothane (called 'Equivocal') or in patients with concomitant neuromuscular disease. The detection of point mutations in the ryanodine receptor gene potentially provides additional information in these cases. The diagnostic value of the Gly341 Arg mutation in a patient reacting in vitro only to caffeine was reported previously by Quane et al. (1994). The present report describes a patient with motor neuron disease carrying the Gly341 Arg mutation, expanding the diagnostic value of this mutation to the group of patients with neuromuscular diseases.
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PMID:Malignant hyperthermia susceptibility in a patient with concomitant motor neuron disease. 890 17


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