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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 is a rare disease triggered by succinylcholine and the volatile anesthetic agents in genetically predisposed individuals. Recent studies have implicated an abnormality in the calcium release channel of the sarcoplasmic reticulum in skeletal muscle as the likely etiology. Genetic studies have narrowed the search for the chromosomal abnormality to human chromosome 19. Although the mortality from this disorder has dramatically decreased in the past decade due to the discovery of dantrolene, elective diagnosis of the disorder is only now appearing on the horizon.
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PMID:Malignant hyperthermia. 134 75

1. In malignant hyperthermia susceptible muscle fibers, the calmodulin antagonist, W-7 (10 microM), evoked contractures and potentiated halothene (3%) induced contracture. No effect was seen at 0.1 or 1.0 microM) W-7. 2. Dantrolene sodium (6 microM) prevented and reversed W-7 induced contracture: nifedipine did not. 3. In chemically skinned fibers, 10 microM, 1.0 microM, and 0.1 microM W-7 released 100%, 30%, and 10% of stored calcium respectively, and the effect of 10 microM W-7 was irreversible in that the SR was unable to re-sequestor calcium after exposure to the drug. 4. The release of calcium by W-7 was not prevented by exogenously added calmodulin (3 microM), nor mimicked by mastoparan (10 microM). 5. Calcium release by W-7 appears to be independent of calmodulin inhibition.
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PMID:W-7, a calmodulin antagonist, and contracture of malignant hyperthermia susceptible skeletal muscle. 135 16

Two cDNA probes for the porcine calcium release channel gene (CRC) were used in restriction fragment length polymorphism (RFLP) analysis in an attempt to develop genetic markers linked to the malignant hyperthermia (stress susceptibility) gene (HAL). Three TaqI RFLPs, denoted CRC1-CRC3, each composed of two alleles, were detected. RFLPs were also detected with MspI and PvuII, but the MspI RFLP correlated completely with CRC3 in this material and the PvuII RFLP could not be scored reliably due to a minute size difference between the two allelic fragments. The autosomal codominant inheritance of these RFLP loci was confirmed by family analyses. Significant evidence for genetic linkage between the CRC1/CRC3 loci and the A1BG locus in the HAL linkage group confirmed a previous assignment of the CRC gene to chromosome 6 in the pig.
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PMID:Multiple restriction fragment length polymorphisms in the porcine calcium release channel gene (CRC): assignment to the halothane (HAL) linkage group. 135 20

Malignant hyperthermia (MH) is a rare clinical syndrome characterized by hypermetabolism and triggered by specific anesthetic agents. The mechanism of this abnormal reaction is due to uncontrolled calcium flux in the skeletal muscles resulting in a variable clinical syndrome of muscle rigidity, respiratory and metabolic acidosis, and elevation of temperature. The specific genetic defect underlying this condition has not been identified in humans, though in susceptible swine a mutation of the gene for the ryanodine receptor, a large protein which comprises the calcium channel in the sarcoplasmic reticulum, has been identified recently. Inheritance in humans appears to be autosomal dominant with variable penetrance. Patients with MH rarely have physical or laboratory signs of muscle disease. However, scattered case reports and investigations of individuals with known myopathies and other muscle related problems, such as acute rhabdomyolysis or idiopathic persistently elevated creatine kinase, suggest a possible association of MH with a variety of neuromuscular diseases and stress syndromes. This association is very strong in the case of central core disease (CCD) where it is supported by clinical and laboratory evidence, including the proximity of the CCD gene to the ryanodine receptor gene on chromosome 19. A variety of other diseases have been implicated and can be classified as possibly associated (King-Denborough syndrome, Duchenne muscular dystrophy) or unlikely to be associated (myotonia congenita, sudden infant death syndrome, limb girdle dystrophy, neuroleptic malignant syndrome, etc.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Malignant hyperthermia and neuromuscular disease. 148 40

A point mutation in the human gene for the skeletal muscle calcium release channel (ryanodine receptor [RYR1]) correlates with inheritance of malignant hyperthermia in a family of Northern European descent. The substitution of thymine for cytosine at position 1840 of the RYR1 transcript results in a cysteine-for-arginine substitution at position 614 (R614C) of the amino acid sequence. The mutation was absent in 59 normal individuals from the general population, in 61 additional unrelated malignant hyperthermia-susceptible patients, and in 18 patients with malignant hyperthermia associated with other inherited or congenital diseases. Together with reports of an equivalent mutation in six susceptible pig strains and an identical mutation in one other human pedigree, these findings suggest that the cysteine-for-arginine mutation represents a shared calcium release channel pathogenesis between porcine malignant hyperthermia and a subset of mutations responsible for the human malignant hyperthermia syndrome.
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PMID:A cysteine-for-arginine substitution (R614C) in the human skeletal muscle calcium release channel cosegregates with malignant hyperthermia. 151 Feb 67

The sarcoplasmic reticulum (SR) controls uptake and release of Ca2+ in muscle. Little information is available regarding the effect of volatile anesthetics on Ca2+ release from SR isolated from normal skeletal muscle, even though an abnormality of Ca2+ handling is implicated in malignant hyperthermia. In this study we used a Ca2+ electrode to monitor continuously the release of Ca2+ from SR and the effect of volatile anesthetics on this process. We found that halothane, enflurane, and isoflurane at 0.6, 0.7, and 0.8 vol%, respectively, each increased the velocity of Ca2+ leakage by at least 150% when compared to control. Ruthenium red, a blocker of the SR Ca(2+)-release channel, was shown to have no effect on the velocity of Ca2+ leakage. Halothane and isoflurane both shortened the time at which Ca2+ leakage began (T) in a dose-dependent fashion. Halothane at 4.8 vol% decreased T from 293 +/- 21 s to 149 +/- 20 s. Isoflurane (4.8 vol%) decreased T to 203 +/- 16 s, and enflurane at 5 vol% had little effect, decreasing T to 259 +/- 19 s. We noted a marked stimulation in the ATPase activity of the SR by all three volatile anesthetics. Halothane at 0.63 vol%, isoflurane at 0.42 vol%, and enflurane at 0.62 vol% each increased ATPase activity by at least 300%. We conclude that the stimulation of the velocity of Ca2+ leakage by the volatile anesthetics is related to the more rapid depletion of ATP, but that the shortening of the onset of Ca2+ leakage is a independent phenomenon with a markedly different dose dependence.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Halothane, enflurane, and isoflurane stimulate calcium leakage from rabbit sarcoplasmic reticulum. 153 95

A defect in the skeletal muscle sarcoplasmic reticulum (SR) calcium release channel of malignant hyperthermia-susceptible (MHS) pigs greatly enhances SR calcium release in pigs homozygous for the malignant hyperthermia (MH) gene. In pigs heterozygous at this locus, rates of calcium release from isolated SR stimulated by Ca2+, ATP, or caffeine are intermediate to those of both MHS and normal SR [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. In this study bundles of intact muscle cells dissected from pigs of various genotypes were used to examine the effects of the MH gene on contractile responses to caffeine (direct stimulation of the SR) or to surface membrane (sarcolemma) depolarization (i.e., stimulation by way of the steps in excitation-contraction coupling). The caffeine threshold for contractures in the heterozygous muscles (5 mM) was intermediate to both types of homozygous muscles (2 mM for MHS and 10 mM for normal) as is the case with direct stimulation of calcium release from SR vesicles [Mickelson et al. Am. J. Physiol. 257 (Cell Physiol. 26): C787-C794, 1989]. Sarcolemmal depolarization was elicited by electrical stimuli or elevated extracellular potassium. Control twitch tension for MHS and heterozygous muscles did not differ and was significantly greater in both than in homozygous normal muscles. Potassium-induced contractures were significantly larger in MHS and heterozygous than in normal muscles. Thus, in heterozygous muscles, force production via sarcolemmal depolarization (twitches and potassium contractures) was enhanced as much as in homozygous MHS muscles. This could be the result of feedback from abnormal SR calcium channels producing altered (enhanced) transverse tubule to SR signal transduction.
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PMID:Excitation-contraction coupling in pigs heterozygous for malignant hyperthermia. 153 30

Malignant hyperthermia (MH) is a rare genetic myopathy that was first described as a fatal complication of general anesthesia in 1960. It is estimated to affect approximately 1 in 15,000 pediatric patients and 1 in 40,000 adult middle-aged patients. The mode of transmission is genetic: the severest form is autosomal dominant, and the less severe, autosomal recessive. Thus, both men and women can have MH, although there is a slightly higher incidence in the male pediatric population. Malignant hyperthermia is usually triggered by halogenated anesthetic agents with or without depolarizing muscle relaxants. The classic diagnostic triad consists of skeletal muscle rigidity, metabolic acidosis, and elevated body temperature. The definitive diagnosis is suspected susceptible individuals is revealed by exposing an intact muscle fiber to caffeine and halothane in varying concentrations. An abnormal contracture response is hypothesized to be the result of an increase in the release of calcium ion from the sarcoplasmic reticulum in response to neuronal stimulation leading to a hypermetabolic state. The mainstay of treatment is dantrolene, given either prophylactically in susceptible patients or immediately whenever a malignant hyperthermic episode is suspected.
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PMID:Malignant hyperthermia: a review. 156 Feb 93

Malignant hyperthermia is a rare syndrome that occurs in genetically susceptible individuals who are exposed to frequently used inhalation anesthetics. The disorder is most common in children and young adults. It is triggered through a defect in the ability of skeletal muscles to concentrate and release calcium. Signs of malignant hyperthermia include hypercarbia, muscle rigidity and tachycardia. Temperature elevation is often a late sign of the syndrome. Treatment begins with stopping all inhaled anesthetics at the earliest sign of the syndrome. The use of dantrolene has significantly reduced mortality from malignant hyperthermia. No simple screening test exists. Family members or those with a suspicious history need to be counseled and should consider muscle biopsy and testing prior to surgery.
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PMID:Malignant hyperthermia. 157 19

Malignant hyperthermia (MH) is a genetic disease characterized by hypermetabolism in skeletal muscle following a triggering stimulus and can be reversed or pretreated with dantrolene sodium. The myoplasmic free [Ca2+] was measured, using Ca2+ selective microelectrodes in vivo in the superficial fibers of the sartorius muscle of eight MH-susceptible and eight control subjects. Both groups received continuous epidural anesthesia with chloroprocaine 3%. In both the control and MH muscle fibers, the myoplasmic free [Ca2+] was measured before and after the intravenous administration of a cumulative dantrolene dose of 0.5, 1.5, and 2.5 mg/kg. The mean resting myoplasmic free [Ca2+] was 0.112 +/- 0.004 microM (mean +/- SEM n = 32) in the control and 0.485 +/- 0.022 microM (n = 33) in the MH subjects. In the MH subjects, dantrolene induced a dose-dependent reduction in myoplasmic free [Ca2+]. The 0.5-mg/kg dose reduced it to 0.326 +/- 0.017 microM (n = 22), the 1.5-mg/kg dose to 0.233 +/- 0.015 microM (n = 25), and the 2.5-mg/kg dose to 0.092 +/- 0.008 microM (n = 26). In controls, dantrolene also reduced resting myoplasmic free [Ca2+] but to a lesser extent. The 0.5-mg/kg dose reduced it to 0.096 +/- 0.004 microM (n = 22), the 1.5-mg/kg dose to 0.077 +/- 0.003 microM (n = 23), and the 2.5-mg/kg dose to 0.068 +/- 0.002 microM (n = 27). The results of the study extend our previous findings in humans and swine and demonstrate that it is possible to measure myoplasmic free [Ca2+] in vivo in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of dantrolene on myoplasmic free [Ca2+] measured in vivo in patients susceptible to malignant hyperthermia. 157 38


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