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)

A member of a family which was known to be susceptible to malignant hyperpyrexia, who was identified as a carrier by the presence of an elevated serum creatine-phosphokinase, has been investigated further. Muscle was examined biochemically, and the study included the sarcoplasmic ATPase-activity, actinomycin, Mg2+ ATPase activity, ATP, phosphocreatine and glucose-6-phosphate. In addition, the calcium uptake by the sarcoplasmic reticulum was studied. The histochemical analysis of the muscle revealed the presence of a new fibre type characterised by a dense rim of ATPase activity, which gives the impression of a 'picture-frame'. Ultramicroscopic study revealed changes in the mitochondria and areas of myofibrillar disruption with swelling of the sarcoplasmic reticulum.
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PMID:'Picture frame' fibres in a carrier of the trait for malignant hyperpyrexia. 0 Jul 95

This communication presents evidence in support of a neuropathic basis for the myopathy associated with malignant hyperpyrexia (MH). Muscle from MH susceptible individuals showed a reduced calcium uptake by the sarcoplasmic reticulum. There was a reduced concentration of phosphocreatine and ATP and an increased concentration of glucose-6-phosphate in these muscle samples.
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PMID:Morphological and biochemical defects in muscles of human carriers of the malignant hyperthermia syndrome. 12 80

Thirteen of 31 Belgian Landrace pigs developed malignant hyperthermia (MH) after breathing halothane. A short period of exercise 1 h before the administration of the triggering agent increased the incidence of the syndrome to 100% in eight similar pigs. Clinical symptoms were more marked and developed more rapidly in the exercised pigs. All the reacting pigs became typically acidotic, developed rigor and died. Serum Na+, K+, Ca2+, c.p.k., l.d.h. and protein concentrations were increased to a variable extent during the reaction and there was an increase in p.c.v. also. No hyperglycaemia was detected in pigs which were rested before receiving halothane. Four of the eight exercised pigs became markedly hyperglycaemic and plasma noradrenaline increased to higher values. Phosphocreatine and ATP decreased to low values and lactate increased in the muscles of all pigs which reacted. At the time of death, muscle glycogen had decreased significantly in the rested, but not in the exercised, MH pigs.
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PMID:Malignant hyperthermia in Belgian Landrace pigs rested or exercised before exposure to halothane. 97 90

In vivo muscle 31P nuclear magnetic resonance spectroscopy was performed on 12 homozygous halothane-nonsensitive female pigs and 13 female pigs heterozygous with respect to the halothane gene. Fifteen female pigs of a third line, consisting of heterozygotes and halothane-nonsensitive homozygotes, were also available. Body weight ranged from 12 to 18 kg. Mean decrease in phosphocreatine concentration in the biceps femoris of anesthetized pigs was significantly lower for heterozygous vs homozygous pigs (3.46% vs 5.94%, P less than 0.01) after 40 minutes of halothane exposure (3%; oxygen flow, 3 L/min). Also, a statistically significant difference, with respect to the initial (7.21 vs 7.11, P less than 0.008) and end muscle pH values (7.18 vs 7.06, P less than 0.0002), was observed for homozygous vs heterozygous pigs. By means of canonical discriminant analysis, it was possible to distinguish nonsensitive homozygotes from heterozygotes (P less than 0.0001). When applying this classification method to pigs of the same strain, 2 populations (nonsensitive homozygotes, heterozygotes) emerged, with a proportion of pigs corresponding to the expected value on the basis of breeding records. In contrast to the phenotypic expression of muscular rigidity related to the malignant hyperthermia syndrome, the expression of metabolic variables (phosphocreatine, pH) was shown to be dominant.
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PMID:Identification of halothane gene carriers by use of in vivo 31P nuclear magnetic resonance spectroscopy in pigs. 834 46

A comparative study of mechanical and energetic parameters of superfused muscle strips from normal pigs and malignant hyperthermia susceptible (MHS) pigs has been conducted. Phosphorus nuclear magnetic resonance spectroscopy at 80.9 MHz and mechanical measurements were used to assess muscle metabolic state. At rest, biceps femoris biopsies of MHS pigs displayed reduced phosphocreatine level, higher inorganic phosphate, and a more acidic internal pH. In normal stimulated fibers, caffeine infusion (8 or 16 mM) induced twitch potentiation and contracture while twitch tension was reduced and contracture more pronounced in malignant fibers. In normal and malignant fibers, calcium ionophore A23187 produced effects similar to those of caffeine, with the exception of twitch potentiation, which was not observed. With caffeine or A23187, the ATP level remained constant throughout the rest-stimulation-recovery protocol for normal and malignant fibers but phosphocreatine dropped to undetectable levels upon stimulation of malignant fibers. In both treatments some heterogeneity in the resonances of inorganic phosphate was observed in malignant fibers together with a more severe acidosis which might play a role in the impairment of the excitation-contraction process.
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PMID:In vitro correlation between force and energy metabolism in porcine malignant hyperthermic muscle studied by 31P NMR. 165 12

Malignant hyperthermia (MH) is a potentially fatal, anesthetic-induced syndrome. Currently, the only accurate means of diagnosing susceptibility to this syndrome is the testing of biopsied skeletal muscle for its contracture response to halothane and caffeine. A less invasive means of diagnosis is needed. The authors previously reported that MH-susceptible patients studied by in vivo phosphorus nuclear magnetic resonance (31P NMR) spectroscopy demonstrated a higher resting inorganic phosphate (Pi) to phosphocreatine (PCr) ratio in their skeletal muscle, as well as a slower postexercise recovery of PCr/Pi, when compared to normal controls. In the present blinded study, the authors compared in vivo 31P NMR determination of resting Pi/PCr and recovery rate of PCr/Pi in forearm muscles to in vitro halothane/caffeine contracture test results in 42 patients. Forty-three control subjects were studied to establish normal NMR values of resting Pi/PCr and recovery rate of PCr/Pi. Their findings were compared with those of 27 patients shown to be MH-susceptible and 15 patients MH-negative by contracture testing. The MH-susceptible group had a significantly (P less than 0.005) higher resting Pi/PCr value (0.202 +/- 0.044) than either the MH-negative (0.152 +/- 0.043) or the control (0.141 +/- 0.026) group. The MH-susceptible group also had a significantly (P less than 0.02) slower postexercise recovery rate of PCr/Pi (1.50 +/- 0.872 PCr.Pi-1.min-1) than either the MH-negative (2.11 +/- 1.07 PCr.Pi-1.min-1) or control (2.25 +/- 0.828 PCr.Pi-1.min-1) group. Twenty-six of the 27 MH-susceptible patients demonstrated abnormal NMR test results (a resting Pi/PCr greater than or equal to 0.18 or recovery rate less than 1.0 PCr.Pi-1.min-1), and 13 of the 15 MH-negative patients had normal NMR results. Although neither NMR parameter alone was diagnostically reliable, an NMR test utilizing both parameters was quite accurate. The NMR test and contracture test demonstrated an overall agreement of 93% with a copositivity of 96% and conegativity of 87%. The sensitivity and specificity of the NMR test is estimated to be 98.8% +/- 11.8% and 95.3% +/- 20.3%, respectively. The role of 31P NMR in the diagnosis of MH susceptibility and possible mechanisms underlying the observations are discussed.
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PMID:A blinded comparison of noninvasive, in vivo phosphorus nuclear magnetic resonance spectroscopy and the in vitro halothane/caffeine contracture test in the evaluation of malignant hyperthermia susceptibility. 185 40

Malignant hyperthermia (MH) is a pharmacogenetic disease in man and animals. It primarily involves skeletal muscle tissue, but other tissues might be affected to a lesser degree. Calcium homeostasis in muscle cells is upset in susceptible individuals, so that various agents and circumstances can increase the free, ionised intracellular calcium concentration to damaging levels. The primary defect is not known at present, but is believed to involve an abnormally sensitive calcium-induced calcium release mechanism. Thus small, localised increases in calcium concentration releases more calcium so that a vicious cycle is triggered. The increased calcium concentration causes multiple effects in the muscles by stimulating contraction and a hypermetabolic state, clinically observed as rigidity and fever. If demands on the homeostatic mechanisms to lower the calcium concentration become exhausted, and metabolism is insufficient to supply enough phosphocreatine and ATP, membrane potentials cannot be maintained, and permeability of the cell membranes increase. This causes loss of phosphate and H+ as well as K+ and Mg++, and later myoglobin and creatine kinase. Thereby oxidative metabolism is further impeded with formation of lactate as a result. The ensuing acidosis stimulates sympathetic innervation, resulting in tachycardia, high blood pressure, and vasoconstriction. Hyperkalemia causes arrhythmia. Dantrolene inhibits the release of calcium and can halt the process if given before depletion of the energy rich phosphates is too advanced.
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PMID:Pathophysiology of malignant hyperthermia. 269 55

31Phosphorus-NMR spectroscopy may have the potential to help in the noninvasive diagnosis of malignant hyperpyrexia (MH). Changes in the phosphate-metabolite profile of MH-susceptible (MHS) skeletal muscle occur more readily under conditions of anoxia than in control muscle. Induction of anoxia caused a rapid fall in intracellular phosphocreatine, an elevation of inorganic phosphate, and finally a diminution of ATP in MHS muscle. The onset of metabolic change was slower in control tissue. Increased oxygen consumption may occur in anoxic MHS muscle, which leads to accelerated glycolysis and a rapid fall in the intracellular high-energy phosphates. In MHS muscle an abnormality may exist in carbohydrate metabolism linked with poor resynthesis of the high-energy phosphates, which may be precipitated under anaerobic conditions. Accelerated muscle metabolism is also observed in the presence of 2 mM caffeine and 3% halothane in MHS muscle. Changes in the concentrations of metabolites could be mapped noninvasively under anoxic conditions using topical 31P-NMR.
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PMID:31P-NMR spectroscopy: the metabolic profile of malignant hyperpyrexic porcine skeletal muscle. 272 66

In earlier work on malignant hyperthermia (MH) susceptible pigs the concentration of muscle metabolites differed from that found in normal control pigs. Therefore, in the present study these metabolites were measured in human muscle biopsies to find out whether normal individuals could be discriminated from MH-susceptible persons. Analysis of skeletal muscle metabolites was performed on skeletal muscle obtained from humans (n = 68) being screened to exclude or confirm susceptibility to MH. Three groups were identified based on the reaction pattern of a skeletal muscle sample exposed in vitro to caffeine or halothane 1% plus caffeine: 1) MH susceptible (MHS; n = 19); 2) normal humans, (controls; n = 31); and 3) intermediate-reaction type (K-type:n = 18). No significant differences were found in metabolite levels of phosphocreatine (normal, MHS, and K-type: 13.20 vs. 13.74 vs. 14.42 nmol/mg wet weight, respectively), creatine (16.30 vs. 16.94 vs. 15.06 nmol/mg wet weight, respectively), adenosine triphospate (3.75 vs. 3.98 vs. 3.89 nmol/mg wet weight, respectively) and lactate (3.73 vs. 3.65 vs. 3.79 nmol/mg wet weight, respectively). It is concluded that analysis of skeletal muscle metabolites cannot be used as a screening test to confirm or exclude MH susceptibility in humans.
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PMID:Comparison of metabolites in skeletal muscle biopsies from normal humans and those susceptible to malignant hyperthermia. 378 37

The effects of an induced malignant hyperthermia (MH) crisis have been studied in the intact pig. Both physiological and biochemical changes in skeletal muscle were studied. MH was induced with 3% halothane plus a bolus injection of succinylcholine. In the prechallenge period a significant difference was observed in the concentration of certain muscle metabolites, comparing the MH-susceptible (MH+) with the non-susceptible (MH-) pigs. A lower level was measured for phosphocreatine (PCr), inosine monophosphate (IMP) and an increased level of lactate and creatine (Cr) in the susceptible pigs (MH+). The challenge caused a significant reduction of the level of PCr and adenosine in MH+ pigs, compared to the prechallenge period. After administration of dantrolene sodium, a significant decrease was measured in the level of lactate, compared to the prechallenge period as well as during the challenge. In contrast, in the control pigs no significant changes were observed in muscle metabolites, either after induction of MH or after the administration of dantrolene sodium. Enzyme activity determinations of muscle adenylate kinase and adenosine monophosphate (AMP)-deaminase did not show any difference in activity either before or during the MH crisis or after treatment with dantrolene sodium. The earliest physiological change during an induced MH crisis in our study was the rapid increase of the end-tidal CO2. Within 5 min after MH induction, end-tidal CO2 was doubled. It is concluded that the monitoring of the end-tidal CO2 is essential to diagnose MH at a very early stage.
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PMID:In vivo induced malignant hyperthermia in pigs. I. Physiological and biochemical changes and the influence of dantrolene sodium. 671 Dec 53


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