Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia susceptibility (MHS) is a potentially lethal, hereditary disorder of skeletal muscle that may be triggered by inhalation anesthetics and depolarizing muscle relaxants. Defects in the gene encoding the ryanodine receptor (RYR1) localized on human chromosome 19q13.1 have been proposed to be responsible for MHS. Using a chromosome 19-specific human/hamster somatic cell hybrid mapping panel, we were able to determine that four closely linked microsatellite repeat markers bracket RYR1 with the order 19cen-D19S75-D19S191-RYR1-(D19S47, D19S190)-19ter. Application of the four markers to genetic studies of MHS showed recombination between the markers and MHS in two families, with linkage analysis apparently excluding the MHS locus from the RYR1 region of 19q13.1. These results therefore support the recent observations of genetic heterogeneity in MHS.
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PMID:High-resolution physical mapping of four microsatellite repeat markers near the RYR1 locus on chromosome 19q13.1 and apparent exclusion of the MHS locus from this region in two malignant hyperthermia susceptible families. 142 2

The halothane-caffeine contracture test is presently the most well-established method for identification of malignant hyperthermia susceptibility (MHS) or non-susceptibility (MHN). However, 10-20% of the patients tested are classified as equivocal (MHE), i.e. their susceptibility remains uncertain. A genetic disorder of the calcium releasing ryanodine receptor has been postulated recently. Therefore, 12 patients were tested in addition to the protocol of the European Malignant Hyperthermia Group (EMHG) for dose- and time-dependent contracture after ryanodine application. In this study, contracture of 0.2g appeared significantly earlier in MHS patients (17.5 +/- 1.7 min; n = 5) during cumulative ryanodine exposition (0.4-0.8-1.6-10.0 mumol/l) than in MHN (38.2 +/- 5.4 min; n = 5). A significant difference between MHS (10.0 +/- 1.7 min; n = 6) and MHN (19.8 +/- 0.6 min; n = 3) was also seen after bolus application of ryanodine (10.0 mumol/l). One patient classified as MHE according to the EMHG protocol, manifested as MHN after the ryanodine contracture test. This study supports previous work suggesting the ryanodine contracture test as an improvement in the in-vitro diagnosis of MH susceptibility.
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PMID:[Ryanodine-induced contractures for the diagnosis of malignant hyperthermia susceptibility]. 178 6

Halothane, in a dose-dependent manner, induced the release of intracellular Ca2+ in hepatocytes prepared from swine. The magnitude of the release induced by halothane was greater for hepatocytes prepared from animals susceptible to malignant hyperthermia (MH) than for those from normal swine. Two different methods were used to ascertain the release of Ca2+ induced by halothane: 1) the release of 45Ca2+ from nonmitochondrial stores of saponin-permeabilized hepatocytes was measured; and 2) changes in luminescence from intact hepatocytes loaded with the Ca2(+)-sensitive photoprotein aequorin were recorded. It was also observed that, although 1,4,5-inositol trisphosphate (IP3), guanosine-5-triphosphate, and arachidonic acid all induced a significant release of 45Ca2+ from permeabilized swine hepatocytes, only the quantities of 45Ca2+ released by IP3 were significantly greater for the hepatocytes prepared from the animals susceptible to MH. These data indicate an abnormal Ca2+ homeostasis in hepatocytes isolated from swine susceptible to MH, which supports the hypothesis that membrane systems from multiple organs may be affected in this genetic disorder.
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PMID:Enhanced mobilization of intracellular Ca2+ induced by halothane in hepatocytes isolated from swine susceptible to malignant hyperthermia. 200 Oct 32

Malignant hyperthermia occurs in man and pigs as a hereditary disorder notably as a complication of halothane-induced anaesthesia. It involves an abnormality in the metabolism of Ca2+. A search was made for abnormalities of calcium-binding proteins. Troponin C from normal pig muscle was found to differ in 2 of 159 amino acids from rabbit Tn C and 3 from man. No differences between normal and abnormal pig muscle were found. Two-dimensional electrophoresis of red cell calmodulin from normal and abnormal pigs also failed to demonstrate a difference.
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PMID:Malignant hyperthermia in pigs: a search for abnormalities in Ca2+ binding proteins. 682 63

The purpose of this study was to gain new insights in the role of succinylcholine in the initiation of malignant hyperthermia (MH). The intravenous (i.v.) administration of succinylcholine (2.0 mg/kg) induced fasciculations and masseter spasm in both normal swine and those susceptible to MH. However, the amplitudes and durations of generalized fasciculations were significantly greater in the susceptible animals that subsequently developed a fulminant episode of MH: succinylcholine induced not only tachycardia, hyperthermia, contractures, and increases in PaCO2 and lactate, all classic indicators of an episode, but also an initial severe hypotension. The mean arterial pressure in these swine decreased from 115 +/- 6 mm Hg to 60 +/- 12 mm Hg (mean +/- SD), 1 min after the administration of succinylcholine. Normal swine developed neither cardiovascular effects nor altered metabolism in response to succinylcholine. The pretreatment of animals with a nondepolarizing muscle relaxant (pancuronium 0.1 mg/kg) minimized fasciculations induced by succinylcholine, but did not prevent the hypotension nor episodes of MH in the susceptible swine. In the pretreated and untreated susceptible swine, dantrolene was an equally effective treatment. Plasma catecholamine levels after succinylcholine administration were increased only in the susceptible swine without the pancuronium pretreatment. We concluded that the effects of succinylcholine on skeletal muscle and/or on other tissues play a significant role in the initiation of a MH episode in swine with this genetic disorder, and that these effects are not dependent on an abnormal sensitivity for succinylcholine-induced skeletal muscle fasciculations in these animals.
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PMID:Response to succinylcholine in porcine malignant hyperthermia. 801 Apr 26

A genetic disorder of the calcium releasing ryanodine receptor has recently been postulated in malignant hyperthermia (MH) and ryanodine-induced contractures differ between subjects who are malignant hyperthermia susceptible (MHS) and non-susceptible (MHN). We tested 39 patients from 26 families for MH, using the procedure of the European Malignant Hyperthermia Group. A ryanodine contracture test was performed by both cumulative (0.4-10.0 mumol litre-1 every 3 min) and bolus (10.0 mumol litre-1) application. Contracture with cumulative ryanodine application started significantly earlier in MHS (9.6 (SEM 0.5) min) than in MHN patients (24.6 (1.3) min). A significant difference in start of contracture between MHS (4.8 (0.6) min) and MHN (14.5 (0.6) min) patients occurred also after bolus application of ryanodine. The ryanodine contracture test seems to be a potentially specific in vitro diagnostic test for MH.
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PMID:Accelerated contractures after administration of ryanodine to skeletal muscle of malignant hyperthermia susceptible patients. 812

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 19q13.1, including the candidate MH gene RYR1, the gene coding for the skeletal muscle ryanodine receptor protein. The results were analysed using LINKAGE to perform two point and multipoint lod scores, then HOMOG to calculate levels of heterogeneity. The results clearly showed genetic heterogeneity between MH families; nine of the families gave results entirely consistent with linkage to the region around RYR1 while the same region was clearly excluded in three families. In the remaining eight MHS families there were single recombinant events between RYR1 and MH susceptibility. HOMOG analysis was of little added benefit in determining the likelihood of linkage to RYR1 in these families. This confirmation of the presence of heterogeneity in the UK MH population, along with the possibility of the presence of two MH genes in some pedigrees, indicates that it would be premature and potentially dangerous to offer diagnosis of MH by DNA based methods at this time.
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PMID:Genetic heterogeneity and HOMOG analysis in British malignant hyperthermia families. 954 Nov 2

Fatal destruction of skeletal muscle coincident with exposure to specific drugs used during anethesia has been recognized as a potentially heritable disorder for more than 30 years. Variable expressivity and incomplete penetrance of the clinical malignant hyperthermia phenotype, together with inherent drawbacks of the in-vitro contracture test confounded efforts to discover the underlying pathogenesis until the application of molecular genetic techniques. On the basis of linkage analysis and mapping of positional candidate genes, mutant alleles at loci on chromosomes 1q, (dihydropyridine-sensitive L-type calcium channel-A1S); 3q, 5p, 7q (dihydropyridine-sensitive L-type calcium channel-LA2), and 19q (ryanodine receptor) are now believed to account for up to 50% of human malignant hyperthermia susceptibility. Although inconsistent genotype-phenotype correlations and doubts regarding the causality of each mutant allele persist, the definition of malignant hyperthermia and relevance of molecular genetic data to the problems of family counseling, population screening, and improved resolution of the malignant hyperthermia phenotype must now be appraised in view of significant locus and allelic genetic heterogeneity.
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PMID:The anesthetic myopathies and malignant hyperthermias. 984 96

Malignant hyperthermia (MH) is a rare genetic condition which may manifest for the first time during anaesthesia associated with a routine surgical procedure. Characterised initially by muscle rigidity, increased body temperature and metabolic acidosis, the syndrome may prove fatal unless prompt, effective treatment is administered. The sudden development of MH constitutes a medical emergency; hence it is essential that theatre practitioners are knowledgeable about the presenting symptoms and management of the condition.
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PMID:Malignant hyperthermia. 1617 7

Malignant hyperthermia (MH) susceptibility is a genetic disorder of skeletal muscle associated with mutations in the ryanodine receptor isoform 1 (RyR1) of sarcoplasmic reticulum (SR). In MH-susceptible skeletal fibers, RyR1-mediated Ca(2+) release is highly sensitive to activation by the volatile anesthetic halothane. Indeed, studies with isolated RyR1 channels (using simple Cs(+) solutions) found that halothane selectively affects mutated but not wild-type RyR1 function. However, studies in skeletal fibers indicate that halothane can also activate wild-type RyR1-mediated Ca(2+) release. We hypothesized that endogenous RyR1 agonists (ATP, lumenal Ca(2+)) may increase RyR1 sensitivity to halothane. Consequently, we studied how these agonists affect halothane action on rabbit skeletal RyR1 reconstituted into planar lipid bilayers. We found that cytosolic ATP is required for halothane-induced activation of the skeletal RyR1. Unlike RyR1, cardiac RyR2 (much less sensitive to ATP) responded to halothane even in the absence of this agonist. ATP-dependent halothane activation of RyR1 was enhanced by cytosolic Ca(2+) (channel agonist) and counteracted by Mg(2+) (channel inhibitor). Dantrolene, a muscle relaxant used to treat MH episodes, did not affect RyR1 or RyR2 basal activity and did not interfere with halothane-induced activation. Studies with skeletal SR microsomes confirmed that halothane-induced RyR1-mediated SR Ca(2+) release is enhanced by high ATP-low Mg(2+) in the cytosol and by increased SR Ca(2+) load. Thus, physiological or pathological processes that induce changes in cellular levels of these modulators could affect RyR1 sensitivity to halothane in skeletal fibers, including the outcome of halothane-induced contracture tests used to diagnose MH susceptibility.
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PMID:Halothane modulation of skeletal muscle ryanodine receptors: dependence on Ca2+, Mg2+, and ATP. 1830 28


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