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)

"Central core disease" (CCD) is a rare disease of infancy and childhood and represents the prototypic member of a group of muscular disorders known as "congenital, benign (non progressive) myopathies". It is very uncommon to diagnose cases affected by CCD in youth and adulthood. The disease is mainly familial with a dominant autosomal pattern of inheritance, but sporadic cases are known to occur. The candidate gene has been localized on chromosome 19q13.1, and is allelic with RYR-1 ("ryanodine receptor" [calcium release channel gene]), the gene responsible of the susceptibility to malignant hyperthermia. In some familial cases of CCD a susceptibility to malignant hyperthermia was also recognized. The diagnosis is only made based on muscular biopsy, which documents some peculiar morphological abnormalities, i.e. focal losses of oxidative enzyme activities, exclusively in type I muscular fibres. The basis for the loss of such activities is represented by an almost total absence of mitochondria and sarcoplasmic reticulum in those focal regions of muscle fibres. Cores may be "structured" and "unstructured" based on the reactivity with myosin ATPases, which ultrastructurally means preservation or destruction of myofilaments. Both structured and unstructured cores qualify this disease in the same way. The authors have observed two cases of CCD in patients in their non infantile age. Both diagnoses were accomplished by means of muscular biopsy, and the results of their studies in both cases are herein presented and discussed.
Pathologica 1999 Dec
PMID:[Central core disease. Report of 2 cases in adults]. 1078 39

In this review, potential roles for the endogenous sphingolipid, sphingosine, and its derivatives are described for muscle cells. Sphingosine modulates the function of important calcium channels in muscle, including the ryanodine receptor (RyR) calcium release channel of the sarcoplasmic reticulum (SR). Sphingosine blocks calcium release through the SR ryanodine receptor and reduces the activity of single skeletal muscle RyR channels reconstituted into planar lipid bilayers. Sphingosine-blocked calcium release is coincident with the inhibitory effects of sphingosine on [3H]ryanodine binding to the RyR. The sphingomyelin signal transduction pathway has also been identified in both skeletal and cardiac muscle. A neutral form of sphingomyelinase (nSMase) enzyme has been localized to the junctional transverse tubule membrane. The high turnover of the SMase is responsible for the production of ceramide and sphingosine. HPLC analyses indicate that significant resting levels of sphingosine are present in muscle tissue. A model of excitation-contraction coupling is presented suggesting a potential role for this endogenous sphingolipid in normal muscle function. Putative roles for sphingolipid mediators in skeletal muscle dysfunction are also discussed. We hypothesize that sphingosine plays important roles in malignant hyperthermia and during the development of muscle fatigue.
Ital J Neurol Sci 1999 Dec
PMID:The role of sphingolipids in the control of skeletal muscle function: a review. 1093 63

The authors submit the case-history of a 29-year-old man, followed up on account of liver steatosis with a toxic-nutritional etiology who developed, after previous increased physical exertion and alcohol abuse, fever associated with major muscular weakness. Gradually he developed an amental delirious state which was evaluated as suspect delirium tremens. Fever of 40-41 degrees C continued, the patient developed muscular rigidity, tremor and hypotension. After intubation during which succinylcholine was administered, the patient's condition deteriorated further with a rise of temperature and muscular rigidity. The patient developed acute renal failure with anuria and the necessity of repeated haemodialyses and severe acidosis of the mixed type on account of which he was intubated and switched to artificial ventilation. According to the case-history clinical and laboratory picture of the disease (extremely high creatine kinase activity, hyperkalaemia, acidosis, hepatorenal failure) malignant hyperthermia was suspected. After a single intravenous injection of sodium dantrolene, 2.5 mg/kg, the temperature dropped and within 24 hours the patient was afebrile. Gradually the acidosis improved, the blood pressure became stabilized and artificial ventilation was no longer used. The patient was discharged after 34 days in hospital in a state of cardiopulmonary compensation with mild polyuria but without signs of retention of nitrogenous substances with sideropenic anaemia and marginal creatine kinase and lactate dehydrogenase values. Within one month after discharge the laboratory values reached normal levels and only slight muscular weakness and greater fatiguability persisted.
Vnitr Lek 1999 Dec
PMID:[An attack of malignant hyperthermia caused by a combination of the effects of succinylcholine, increased physical exertion and alcohol abuse]. 1095 47

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. The underlying feature of MH is a hypersensitivity of the calcium release machinery of the sarcoplasmic reticulum, and in many cases this is a result of point mutations in the skeletal muscle ryanodine receptor calcium release channel (RYR1). RYR1 is mainly expressed in skeletal muscle, but a recent report demonstrated the existence of this isoform in human B-lymphocytes. As B-cells can produce a number of cytokines, including endogenous pyrogens, we investigated whether some of the symptoms seen during MH could be related to the involvement of the immune system. Our results show that (i) Epstein-Barr virus-immortalized B-cells from MH-susceptible individuals carrying the V2168M RYR1 gene mutation were more sensitive to the RYR activator 4-chloro-m-cresol and (ii) their peripheral blood leukocytes produce more interleukin (IL)-1beta after treatment with the RYR activators caffeine and 4-chloro-m-cresol, compared with cells from healthy controls. Our result demonstrate that RYR1-mediated calcium signaling is involved in release of IL-1beta from B-lymphocytes and suggest that some of the symptoms seen during an MH episode may be due to IL-1beta production.
J Biol Chem 2001 Dec 21
PMID:B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators. 1167 62

The skeletal muscle ryanodine receptor gene (RYR1; OMIM 180901) on chromosome 19q13.1 encodes the skeletal muscle calcium release channel. To date, more than 25 missense mutations have been identified in RYR1 and are associated with central core disease (CCD; OMIM 117000) and/or the malignant hyperthermia susceptibility phenotype (MHS1; OMIM 145600). The majority of RYR1 mutations are clustered in the N-terminal hydrophilic domain of the protein. Only four mutations have been identified so far in the highly conserved C-terminal region encoding the luminal/transmembrane domain of the protein which forms the ion pore. Three of these mutations have been found to segregate with pure or mixed forms of CCD. We have screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients, diagnosed clinically and/or histologically as having CCD. We have identified five missense mutations (four of them novel) in 13 index patients. The mutations cluster in exons 101 and 102 and replace amino acids which are conserved in all known vertebrate RYR genes. In order to study the functional effect of these mutations, we have immortalized B-lymphocytes from some of the patients and studied their [Ca(2+)](i) homeostasis. We show that lymphoblasts carrying the newly identified RYR1 mutations exhibit: (i) a release of calcium from intracellular stores in the absence of any pharmacological activators of RYR; (ii) significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and (iii) a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. Our data suggest the C-terminal domain of RYR1 as a hot spot for mutations leading to the CCD phenotype. If the functional alterations of mutated RYR channels observed in lymphoblastoid cells are also present in skeletal muscles this could explain the predominant symptom of CCD, i.e. chronic muscle weakness. Finally, the study of calcium homeostasis in lymphoblastoid cells naturally expressing RYR1 mutations offers a novel non-invasive approach to gain insights into the pathogenesis of MH and CCD.
Hum Mol Genet 2001 Dec 01
PMID:Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. 1174 31

Recently, a variety of ion channel defects have been identified as the biological basis of certain familial epilepsies, paroxysmal movement disorders, myopathies and some degenerative disorders of central nervous system. Ion channel defects were mainly caused by genetic and autoimmune mechanisms. Here, we reviewed several channelopathies including spinocerebellar ataxia type 6, familial hemiplegic migraine, episodic ataxia type 2, familial hypokalemic periodic paralysis, congenital myotonia, malignant hyperthermia, epilepsy, Gitelman syndrome and Lambert-Eaton syndrome.
Rinsho Shinkeigaku 2001 Dec
PMID:[Channelopathy]. 1223 44

Malignant hyperthermia (MH) is an uncommon, life-threatening, acute pharmacogenetic disorder of the skeletal muscle cell. It manifests in susceptible individuals as a hypermetabolic response on exposure to halogenated volatile anaesthetics and depolarizing muscle relaxants. There may also be a relationship between susceptibility to MH, heat stroke and exercise-induced rhabdomyolysis. The pathophysiology of the crisis involves an uncontrolled release of cytoplasmic free calcium from the sarcoplasmic reticulum leading to activation of energy-producing biochemical pathways. Organ system failure and rhabdomyolysis may occur as a result of high fever, hyperkalaemia and acidosis. The ryanodine receptor, the calcium-release channel of the sarcoplasmic reticulum, is the primary locus for malignant hypothermia susceptibility. Multiple mutations in the gene for the ryanodine receptor protein are causative. Other genes may also be involved. A classical fulminant crisis presents with a rising end-tidal carbon dioxide, skeletal muscle rigidity, tachycardia, hyperthermia and acidosis. Mortality may be as high as 70% if the syndrome is not recognized and treated. Immediate discontinuation of triggering agents, oxygenation, and correction of acidosis and electrolyte abnormalities, cooling and dantrolene are essential for treatment of the syndrome. Thanks to clinical and research investigations, widespread education and the introduction of dantrolene sodium, the mortality from MH is less than 5%. This chapter provides an overview and an update of MH.
Best Pract Res Clin Anaesthesiol 2003 Dec
PMID:Malignant hyperthermia. 1466 55

Central core disease (CCD) is a dominantly inherited congenital myopathy allelic to malignant hyperthermia (MH) caused by mutations in the RYR1 gene on chromosome 19q13.1. Eleven individuals with RYR1 mutations are described. Four index cases showed features consistent with a congenital myopathy (hypotonia, delayed motor milestones, and skeletal abnormalities including congenital hip dislocation and scoliosis). All four cases and subsequently seven other family members were found to possess novel mutations in the RYR1 gene. The degree of disability varied from one clinically normal individual, to another who had never achieved independent ambulation (the only patient with a de novo mutation). Four cases showed a mild reduction in vital capacity, repeated nocturnal polysomnography showed hypoxaemia in one case. A variety of muscle biopsy features were found; central cores were absent in the youngest case, and the biopsy specimens from two others were more suggestive of mini-core myopathy. In all cases missense mutations in exons 101, 102, and 103 of the RYR1 gene on were found. Future laboratory diagnosis of suspected cases and family members will be less invasive and more accurate with DNA analysis. Clinicians, especially paediatricians and orthopaedic surgeons, should be aware of this disorder because of the potential risk of MH.
Arch Dis Child 2003 Dec
PMID:Central core disease: clinical, pathological, and genetic features. 1467 Jul 67

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.
Am J Forensic Med Pathol 2004 Dec
PMID:Pathologic findings in malignant hyperthermia: a case report and review of literature. 1557 23

Malignant hyperthermia (MH) is an operative emergency associated with general anesthesia. Early diagnosis and prompt treatment are the keynotes in management of MH. Dantrolene is the only specific drug and all of the institutions where general anesthesia is a daily routine should have a stockpile of this drug for the rare occurrence of MH. Nonetheless, the enormous expenditure on stockpile and 3-year validity make a large reserve of the drug to forestall MH, a disorder of rare occurrence, seems disputable, especially in small hospitals where general anesthesia is seldom practiced. We herein report two cases of MH with excellent response to small doses of dantrolene and then discuss the way of practicable management and debate on the question of whether fewer stock of dantrolene is an alternative way for hospitals of smaller scale.
Acta Anaesthesiol Taiwan 2004 Dec
PMID:Malignant hyperthermia with excellent response to small dose of dantrolene. 1567 36


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