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)

The ryanodine receptor (RYR1) gene is responsible for some forms of malignant hyperthermia and has been localized to 19q13.1. Central core disease is a genetic myopathy that is genetically linked to RYR1. We have identified an overlapping set of cosmid and YAC clones that spans more than 800 kb and includes the RYR1 gene (approximately 205 kb). Cosmids from this region were identified by screening three chromosome 19 cosmid libraries (11-fold coverage) with six subclones representing the entire RYR1 cDNA. Genomic sequences from positive cosmids were then used as probes to identify additional cosmids. A minimally overlapping set of 23 cosmids was assembled into two contigs on the basis of restriction fragment analysis and hybridization data. Three YAC clones were isolated by screening a human YAC library with selected cosmid inserts. Overlaps among these YACs and the cosmid contigs were determined by hybridizing YAC Alu-PCR products to cosmid DNAs. The YACs bridged the gap between the cosmid contigs and extended the contig on both sides. Fluorescence in situ hybridization experiments positioned the RYR1 contig between GPI, MAG, and D19S191 on the proximal side and D19S190, CYP2A, CYP2F, SNRPA, BCKDHA, and other markers on the distal side. The 800-kb contig of cloned reagents will facilitate the detailed characterization of the RYR1 gene and other loci that may be closely related to central core disease.
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PMID:A cosmid and yeast artificial chromosome contig containing the complete ryanodine receptor (RYR1) gene. 840 83

Central core disease (CCO) is an autosomal dominant myopathy clinically distinct from malignant hyperthermia (MHS). In a large kindred in which the gene for CCO is segregating, two-point linkage analysis gave a maximum lod score, between the central core disease locus (CCO) and the ryanodine receptor locus (RYR1), of 11.8, with no recombination. Mutation within RYR1 is responsible for MHS, and RYR1 is also a candidate locus for CCO. A combination of physical mapping using a radiation-induced human-hamster hybrid panel and of multipoint linkage analysis using the Centre d'Etude du Polymorphisme Humain families established the marker order and sex-average map distances (in centimorgans) on the background map as D19S75-(5.2)-D19S9-(3.4)-D19S191-(2.2)-RYR1-(1.7)-D19S190-(1.6)-D19S47-(2.0)- CYP2B. Recombination was observed between CCO and the markers flanking RYR1. These linkage data are consistent with the hypothesis that CCO and RYR1 are allelic. The most likely position for CCO is near RYR1, with a multipoint lod score of 11.4, in 19q13.1 between D19S191 and D19S190, within the same interval as MHS (RYR1).
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PMID:Refined genetic localization for central core disease. 843 Jul

We report two boys aged 4 and 10 months who suffered cardiac arrests after induction of anaesthesia. Both infants had no personal or family history of myopathy. In both cases anaesthesia was induced by inhalation with halothane and N2O/O2 (70/30). To facilitate tracheal intubation both were given succinylcholine after the administration of atropine. The 4-month-old developed muscle rigidity and cardiac arrest occurred immediately after tracheal intubation. Resuscitation was unsuccessful. Laboratory findings during resuscitation showed elevated serum potassium levels of more than 10 mmol/l and serum creatine phosphokinase 17.700 IU/l. Histopathologic examination of the skeletal muscle revealed congenital muscular dystrophy. In the older boy no muscle contractures were noted after administration of succinylcholine. He developed bradycardia that progressed to asystole 15 min after induction of anaesthesia. After 1 h of resuscitation a sinus rhythm could be established. The boy developed myoglobinuria and his serum creatine phosphokinase reached a maximum level of 45,000 IU/l on the 2nd day. The child survived and made a complete recovery. Two months later a muscle biopsy taken from the quadriceps showed marked muscular dystrophy. Duchenne's muscular dystrophy could be excluded. The most likely underlying reasons for these complications are discussed: anaesthesia-induced acute rhabdomyolysis or malignant hyperthermia.
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PMID:[Anesthetic-induced heart arrest. A case report of 2 infants with previously unrecognized muscular dystrophy]. 844 72

Malignant hyperthermia (MH) is a rare myopathy inducing severe accident when carriers are exposed to triggering agents. MH susceptibility (MHS) is assessed by pharmacological tests performed on muscle strips. Exertional heat stroke (EHS) is a severe accident occurring during long and strenuous exercise. It has been observed that numerous EHS patients are susceptible to MH according to pharmacological tests. Because most of those EHS-MHS subjects were soldiers, we hypothesize that military duty could select subjects with infraclinical myopathy and therefore would increase the MHS:EHS subject ratio.
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PMID:On the nature of the link between malignant hyperthermia and exertional heatstroke. 856 50

Malignant hyperthermia is a seemingly rare genetic myopathy. Hypermetabolic crisis accompanied by a rise in body temperature to as high as 44 degrees C is its hallmark. Malignant hyperthermia is usually triggered by potent inhalational anesthetics and/or depolarizing muscle relaxants. Because of the extraordinary risk of death in patients who are at risk, otologists may be reluctant to operate on these patients. Seven such patients were referred to the Section of Otology, Neurotology, and Skull Base Surgery and the UCLA Malignant Hyperthermia Center Following first episodes of malignant hyperthermia or with a strong family history of malignant hyperthermia for anesthetic and surgical management. They were anesthetized with nitrous oxide, barbiturates, opiates, tranquilizers, and nondepolarizing muscle relaxants. The patients were not treated prophylactically with dantrolene. Cardiac monitoring, end-tidal PC02, and rectal temperatures were followed. All seven patients had a vastus lateralis muscle biopsy performed and subsequent caffeine/halothane contracture studies completed. The contracture study was positive in six of the seven patients studied. No anesthetic or surgical complications were encountered. This study demonstrates that patients at risk of developing malignant hyperthermia crisis can have otologic surgical procedures performed safely while undergoing appropriately selected general anesthesia.
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PMID:Malignant hyperthermia in the otology patient: the UCLA experience. 857 42

Seven out of eight piglets which were susceptible to malignant hyperthermia (MHS) died when subjected to a heat challenge which was well tolerated by controls. The piglets which succumbed developed the classical clinical and biochemical changes of malignant hyperthermia before they died. These results show that overheating alone can trigger malignant hyperthermia in susceptible animals. Because the biochemical basis of malignant hyperthermia is similar in both humans and pigs, these observations suggest that overheating can also trigger malignant hyperthermia in humans. The susceptibility to overheating in malignant hyperthermia susceptible humans and animals probably explains why the myopathy which predisposes to this condition has also been reported to predispose to heat-stroke and the sudden infant death syndrome. In view of this, particular care to prevent overheating should be taken in infants of parents who are susceptible to malignant hyperthermia.
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PMID:Overheating alone can trigger malignant hyperthermia in piglets. 897 28

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder and is one of the major causes of death resulting from anaesthesia. MH is currently diagnosed by the in vitro contracture test performed on a muscle biopsy. Genetic linkage analysis on an Irish MH pedigree showed that when the thresholds for the standardised European protocol for MHS diagnosis was applied, linkage between the MHS phenotype and the RYR1 locus was excluded. When we raised the threshold values for assignment of MHS status and assumed MHN diagnosis in subjects where this threshold was not attained, tight linkage between MHS and RYR1 markers was observed, suggesting that MHS is linked to the RYR1 locus in this pedigree. Confirmation of these results was borne out by the fact that all of the MHS patients in the pedigree exceeding the raised threshold carried the known MHS Gly341Arg RYR1 mutation. The results obtained could be explained (1) by false positive diagnosis of MHS in the recombinant subjects, (2) by the presence of a mutation in a predisposing gene other than RYR1, or (3) by the presence of mild subclinical myopathies. The implications of these results for heterogeneity studies is discussed.
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PMID:Diagnosis of malignant hyperthermia: a comparison of the in vitro contracture test with the molecular genetic diagnosis in a large pedigree. 882 43

Children frequently undergo muscle biopsy for the workup of hypotonia under general anaesthesia which poses unique risks in patients with undiagnosed muscle disease. Mitochondrial myopathies are a relatively newly recognized cause of myopathy and multisystem disease in both adults and children. The diagnosis is complex. In addition to causing myopathy, there are metabolic derangements present in some cases that may be life-threatening. We present three cases of children with hypotonia where the diagnosis was suspected in two patients, and confirmed in the third. The question of whether patients with mitochondrial myopathies are at increased risk for developing malignant hyperthermia is discussed.
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PMID:Mitochondrial myopathies: an unusual cause of hypotonia in infants and children. 882 50

A xenobiotic, well tolerated by the majority of treated patients, can cause serious complications in patients with individual susceptibility. Based on the hypothesis that such a phenomenon may occur in rare cases of rhabdomyolysis attributed to fenoverine (DCI), we designed a protocol to look for a genetic predisposition. Six patients were included who had previously had an episode of rhabdomyolysis after taking fenoverine. A seventh patient was added, who had only experienced myalgia without cytolysis. All patients were investigated by the following tests: 31-phosphorus nuclear magnetic resonance spectroscopy, histopathological examination of the muscle, muscle contraction tests and biochemical analysis of the muscle. All patients examined proved to have muscle abnormalities. The pathology found varied greatly from patient to patient: mitochondrial myopathy, lipid storage myopathy, sensitivity to malignant hyperthermia or disorders of oxidative metabolism. The probability of finding by chance such rare muscle disorders associated with the equally rare rhabdomyolysis attributed to fenoverine is practically zero. We conclude that there is a cause and effect link between underlying abnormalities and the muscular cytolysis attributed to fenoverine.
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PMID:Research into individual predisposition to develop acute rhabdomyolysis attributed to fenoverine. 890 30

In 1992, the Malignant Hyperthermia Association of the United States and The North American Malignant Hyperthermia Registry received reports of cardiac arrest in apparently healthy children given succinylcholine. Using data from 1990 to 1993, this study analyzes: (1) etiology of all reported pediatric arrests and (2) whether survival was associated with certain patient or treatment variables. We reviewed retrospectively all reports of pediatric (age < 18 years) arrests occurring within 24 hours of anesthesia. Etiology of arrests and presence of myopathy were determined. Twenty-five patients (92% male, median 45 months old) arrested; 23/25 (92%) were scheduled for minor surgery. Before receiving a potent inhalational anesthetic (92%) and/or succinylcholine (72%), these patients were evaluated by the anesthesiologist as being healthy with no personal or family history of myopathy. Serum potassium during arrest was measured in 18/25 (72%) patients; hyperkalemia (mean [K+] = 7.4 +/- 2.8, median 7.5 mmol/L) was detected in 13/18 (72%) patients. Postarrest resuscitations lasted a median of 42 minutes (range 10-296). Ten (40%) patients died, 1 (4%) is vegetative, and 14 (56%) returned to baseline neurologic function. A previously unrecognized Duchenne dystrophy (n = 8) or unspecified myopathy (n = 4) was diagnosed in 12 (48%) patients. Eight of these 12 patients' arrests were associated with hyperkalemia. Ten (40%) patients had no postarrest evaluation to exclude occult myopathy. No patient or treatment variables were statistically associated with survival. We conclude that, whenever possible, pediatricians should evaluate their patients (especially male infants and children) preoperatively for the presence of occult myopathy. During perianesthetic resuscitations, the pediatric advanced life support protocol should be modified to detect and treat hyperkalemia, a potentially reversible state even after prolonged resuscitation efforts. Following anesthetic deaths, pathologists should examine body fluid electrolytes and skeletal muscle for myopathy and dystrophin. If a preanesthetic creatine kinase screen for myopathy in male patients and restrictions on succinylcholine had been used, 64% of arrests and 60% of deaths might have been prevented. A formal prospective risk/benefit analysis for preventive measures is needed.
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PMID:Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. 900 42


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