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

1. The calcium channel antagonists verapamil (100 microM) and nifedipine (100 microM) inhibited twitch response and KCl induced hypercontractility in malignant hyperpyrexia (MH)-susceptible porcine skeletal muscle. These calcium channel antagonists did not effect hypercontractility induced by 3% halothane or 2 mM caffeine. 2. The calcium channel agonist BAY K 8644 (50 microM) induced contracture in MH-susceptible muscle but did not potentiate contracture response induced by 2 mM caffeine or 3% halothane. BAY K 8644 did not increase the resting tension of control muscle or increase the sensitivity of control muscle to 4 mM caffeine, 3% halothane or 80 mM KCl. 3. The sarcoplasmic reticulum (SR) from MH-susceptible and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 4. Verapamil and diltiazem [which has been previously shown to inhibit the hypercontractility of MH-susceptible porcine muscle to caffeine, halothane and KCl (Foster and Denborough, 1989 Br. J. Anaesth. 62, 566-572)] did not effect Ca2+ uptake or Ca(2+)-dependent ATPase activities of SR longitudinal tubule membranes, from MH-susceptible or control muscle. These calcium channel antagonists did not effect Ca2+ release from terminal cisternae preparations. 5. The skeletal muscle relaxant dantrolene inhibited Ca2+ efflux and equilibrium-Ca2+ exchange associated with the terminal cisternae membrane of MH-susceptible and control skeletal muscle. 6. Calcium channel antagonists modify Ca2+ fluxes in MH-susceptible and control muscle by acting at a site distal to the SR. Calcium channel antagonists may inhibit contractile response by modifying events of excitation-contraction coupling associated with the voltage sensor molecule (dihydropyridine-receptor) of the transverse-tubule membrane, whereas dantrolene directly acts on the terminal cisternae membrane to inhibit Ca2+ efflux and equilibrium Ca2+ exchange. Different calcium channel antagonists seem to modify the voltage-sensor mechanism in different ways in MH-susceptible muscle. 7. An abnormality in the coupling mechanism of the voltage sensor-SR calcium release channel may exist in MH-susceptible muscle. This dysfunction may be an adaptation to the elevated levels of myoplasmic Ca2+ and/or the molecular defect described in the Ca2+ release channel of the SR of MH-susceptible porcine muscle. In view of these results it is unlikely that nifedipine or verapamil would be of therapeutic value for the treatment of MH.
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PMID:The effect of calcium channel antagonists and BAY K 8644 on calcium fluxes of malignant hyperpyrexia-susceptible muscle. 768 90

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle. In humans, MH is inherited in an autosomal dominant fashion; in swine, the principal model for MH, it is in a recessive fashion. Those with MH susceptibility usually are asymptomatic except in the presence of certain "triggering" anaesthetic agents such as isoflurane, enflurane and the muscle relaxant succinylcholine. Upon such exposure hypermetabolism, increased CO2 production, acidosis, muscle rigidity, rhabdomyolysis and hyperthermia occur. Untreated, death may result in 70% of patients. With prompt diagnosis and treatment with dantrolene sodium, the mortality is less than 10%. The overall incidence of MH is low (perhaps 1:50,000 anaesthetics), but it is more common in children. Children also display a paradoxical increase in jaw muscle tone to succinylcholine which often presages MH, but confusing clinically, may also be a normal response to succinylcholine. The pathophysiology of MH centres around a defect in calcium flux in skeletal muscle. A specific base pair change in the gene that codes for the ryanodine receptor calcium channel in muscle has been demonstrated in susceptible swine, but occurs rarely in humans. It is hoped that the understanding of the molecular genetics of MH will lead to a simpler diagnostic test than is currently available, and enhance our understanding of MH and its relation to other myopathies.
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PMID:An update on the malignant hyperthermia syndrome. 771 Feb 42

Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disease. The genetic incidence is estimated to be 1:10,000. In predisposed individuals, MH is triggered by volatile anaesthetics and/or depolarizing muscle relaxants by an abnormal increase of intracellular calcium concentration in skeletal muscle cells. The clinical presentation may vary from abortive MH to the fulminant MH crisis. Early diagnosis, the use of electrocardiography and capnography for anaesthetic monitoring, immediate cessation of trigger agents and dantrolene treatment are essential components of an effective MH therapy. In some MH families, a genetic alteration of the ryanodine receptor gene (a calcium channel of the sarcoplasmic reticulum) on chromosome 19 has been identified as the potential cause of MH susceptibility. Recent molecular biological findings support the view of MH being a heterogenetic disease. At present, the diagnosis in potentially MH-susceptible individuals is still made using the in vitro halothane and caffeine muscle contracture test.
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PMID:[Malignant hyperthermia]. 797 81

Malignant hyperthermia (MH) has been reported as non-existent in children less than 1 yr old, although several unconfirmed reports have been published. A case report of MH in a 6-month-old child is presented, with confirmation of MH susceptibility by in vitro contracture testing of quadriceps muscle at 13 yr old. Genetic analysis revealed a novel RYR1 mutation that substitutes arginine 2452 for tryptophan in a region of the calcium channel mutated in several other MH pedigrees.
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PMID:Malignant hyperthermia in infancy and identification of novel RYR1 mutation. 1082 4

Based on the gene-related function and molecular structure of various receptors, neurological receptor diseases were reviewed from both the immunologic and genetic perspectives. The nicotinic acetyl-choline receptor (AChR), ryanodine receptor (RyR), omega-conotoxin receptor (P/Q-type voltage-gated calcium channel), dihydropyridine receptor (L-type voltage gated calcium channel), and androgen receptor have been found to be affected by autoantibodies and/or genetic anomalies. They reflect on various neurological diseases such as myasthenia gravis, congenital myasthenic syndrome, malignant hyperthermia and central core disease, paraneoplastic myasthenic syndrome, hereditary migraine and ataxias, hypokalemic periodic paralysis, and bulbospinal muscular atrophy. The interaction of calcitonin gene-related peptide with its receptor tends to compensate the dysfunction caused by antibodies to AChR and RyR. One should look for cancers or genetic disorders in the case of the receptor disease implicated in calcium channel function. Recent advances in search for the etiology of these diseases from the standpoints of immunology and genetics have opened an avenue in understanding the functional structure of receptors and the molecular sites responsible for receptor diseases.
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PMID:[Receptor diseases in the field of neurology]. 1089 86

Individuals from a large North American population were screened for the presence of the mutation in the alpha1 subunit of the voltage-dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.
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PMID:Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. 1126 Feb 27

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease, triggered by inhalative anesthetics or depolarizing muscle relaxants in genetically predisposed individuals. Linkage analysis have revealed MH to be a heterogenetic disease with about 50% of MH families linked to the locus of the ryanodine receptor calcium channel (RYR1). We investigated the frequency of the 23 published MH linked RYR1 gene mutations in the Swiss MH population and compared our findings to the results of the in vitro contracture test (IVCT). IVCT was performed following the protocol of the European MH Group and mutation screening was done by PCR amplification of genomic DNA followed by restriction enzyme digestion or SSCP. We identified RYR1 gene mutations in 40% of unrelated MH families (19/48) with a high incidence of the mutation V2168M (27%). IVCT results revealed a significantly stronger functional effect of mutations R614C and V2168M as compared to mutations G2434R and R2458C. This is the first time that such a high incidence of RYR1 gene mutations in an MH population has been found, supporting the use of molecular genetic testing for the diagnosis of MH susceptibility in suitable families. In addition our data show that different RYR1 gene mutations are associated with different IVCT phenotypes.
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PMID:Genotype-phenotype comparison of the Swiss malignant hyperthermia population. 1166 25

Hypokalemic periodic paralysis (HypoPP) is a channel disorder caused primarily by mutations in the human skeletal muscle alpha1 subunit (CACNA1S) of the dihydropyridine-sensitive calcium channel. Molecular, clinical, and biochemical studies were aimed at establishing genotype/phenotype correlations in a large Italian family affected by a severe form of HypoPP. Whereas patients with HypoPP usually show a normal life span, in this family three male patients died young, one of them from anesthetic complications resembling malignant hyperthermia. Our patients carried the c1583G>A genetic lesion (R528H), which has been associated with a mild phenotype and with incomplete penetrance in women. Surprisingly, the R528H amino acid substitution in the family presented here correlated with an unfavorable prognosis in both male and female patients. We conclude that genetic characterization is an important requirement to alert physicians about the management of similar patients, especially when anesthesia is considered.
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PMID:Severe prognosis in a large family with hypokalemic periodic paralysis. 1254 23

Myoplasmic calcium homeostasis is an essential feature of skeletal muscle contraction. The calcium mobilisation complex (CMC) located at the level of the triadic junction plays a major role for the regulation of calcium fluxes between extra-cellular, cytoplasmic and intra-cellular compartments. The ryanodine receptor type I (RYR1), which is located at the level of the terminal cisternae of the sarcoplasmic reticulum is a key component of the CMC. RYR1 allow the release into the myoplasm of the intralumenal stores of calcium. RYR1 interacts with other proteins: DiHydroPyridine Receptor, triadin, calsequestrin, FKBP12, calmodulin. Malignant hyperthermia (MHS) and congenital core myopathies have been associated with a dysfunction of the CMC. MHS is an autosomic dominant pharmacogenetic disease. The MH crisis is induced by exposure of the predisposed patients to halogenated volatile anaesthetics. MHS is characterised by a genetic heterogeneity and two genes, RYR1 and CACNA1S, have been associated so far with the disease. Mutations in the RYR1 gene have been recently associated with heat stroke, a related syndrome. Central Core Disease (CCD) and Multi minicore Disease (MmD) are congenital myopathies presenting with clinical variability and characterized by the presence of specific although heterogeneous muscle histological features: the cores. Clinical boundaries between the two diseases may overlap and the specific diagnosis is often based on the nature of the cores. These diseases show genetic heterogeneity with both autosomic dominant and recessive mode of inheritance and mutations in the SEPN1, RYR1, ACTA1, TPM3 genes have been reported. Mutations associated with MHS were mainly identified into 2 regions of the N-terminal part of RYR1. Functional role of these two domains is still unclear. Mutations responsible for congenital myopathies mainly mapped to the C terminal region of RYR1 that form the transmembrane calcium channel. Functional studies of the RYR1 mutations have shown that MHS mutations were mainly associated with an alteration of the calcium fluxes in response to caffeine or halothane while CCD mutations would result in a leaky RYR1 channel or would alter the Excitation-Contraction coupling at the level of the CMC.
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PMID:[Genetic of diseases by abnormal functioning of the skeletal muscle-calcium releasing complex]. 1526 63

Malignant hyperthermia (MH) is a rare, potentially lethal disorder of skeletal muscle calcium homeostasis characterized by muscle contracture and life-threatening hypermetabolic crisis following exposure to halogenated anesthetics and depolarizing muscle relaxants. Susceptibility to MH results from mutations in calcium channel proteins that mediate excitation-contraction coupling, with the ryanodine receptor calcium release channel (RyR1) representing the major locus. The mode of inheritance appears to be autosomal dominant with variable penetrance. The authors report the death of a 60-year-old white male with a history of low back pain. He had undergone 2 back surgeries previously, the first occurring 10 years prior to his current presentation. Both previous procedures were done under generalized anesthetic with no complications. Recently, he developed stenosis and presented for fusion of vertebrae L3 and L4. The procedure was performed under general anesthetic including sevoflurane, with no intraoperative complications. The anesthesiologist noted that, near the end of the 2-hour procedure, the decedent's CO2 levels were slightly elevated. After the procedure, the decedent was extubated, the temperature probe which had been recording normal values was removed, and he was rolled from ventral to dorsal position. He immediately became hypotensive and bradycardic. Lifesaving interventions were begun. Subsequently, he went into cardiac arrest, at which time the temperature probe was reinserted into the trachea, where it read a body temperature of 109 degrees F. Malignant hyperthermia protocol was initiated, and interventions continued for over 2 hours, at which time they failed. At autopsy, the abdomen contained 1800 mL of blood, and bilateral hematomas were present in the psoas muscles. The authors present this case of clinically apparent malignant hyperthermia, discuss how to approach such a case, the gross and microscopic findings, ancillary studies, and a review of the literature.
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PMID:Pathologic findings in malignant hyperthermia: a case report and review of literature. 1557 23


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