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) and nemaline myopathy (NM) are congenital myopathies for which differential diagnosis is often based on the presence either of cores or rods. Missense mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in some families with CCD. Mutations in the alpha-tropomyosin and alpha-actin genes have been associated with most dominant forms of NM. Analysis of the RYR1 cDNA in a French family identified a novel Y4796C mutation that lies in the C-terminal channel-forming domain of the RyR1 protein. This mutation was linked not only to a severe and penetrant form of CCD, but also to the presence of rods in the muscle fibres and to the malignant hyperthermia susceptibility (MHS) phenotype. The Y4796C mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. Expression of the mutant RYR1 cDNA produced channels with increased caffeine sensitivity and a significantly reduced maximal level of Ca(2+) release. Single-cell Ca(2+) analysis showed that the resting cytoplasmic level was increased by 60% in cells expressing the mutant channel. These data support the view that the rate of Ca(2+) leakage is increased in the mutant channel. The resulting chronic elevation in myoplasmic concentration is likely to be responsible for the severe expression of the disease. Haplotyping analysis indicated that the mutation arose as a neomutation in the proband. This first report of a neomutation in the RYR1 gene has strong implications for genetic linkage studies of MHS or CCD, two diseases characterized by a genetic heterogeneity.
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PMID:An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. 1106 19

Central core disease (CCD) is an autosomal dominant congenital myopathy. Diagnosis is based on the presence of cores in skeletal muscles. CCD has been linked to the gene encoding the ryanodine receptor (RYR1) and is considered to be an allelic disease of malignant hyperthermia susceptibility. However, the report of a recessive form of transmission together with a variable clinical presentation has raised the question of the genetic heterogeneity of the disease. Analyzing a panel of 34 families exclusively recruited on the basis of both clinically and morphologically expressed CCD, 12 different mutations of the C-terminal domain of RYR1 have been identified in 16 unrelated families. Morphological analysis of the patients' muscles showed different aspects of cores, all of them associated with mutations in the C-terminal region of RYR1. Furthermore, we characterized the presence of neomutations in the RyR1 gene in four families. This indicates that neomutations into the RyR1 gene are not a rare event and must be taken into account for genetic studies of families that present with congenital myopathies type 'central core disease'. Three mutations led to the deletion in frame of amino acids. This is the first report of amino acid deletions in RYR1 associated with CCD. According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1.
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PMID:Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. 1170 45

Mutations in the ryanodine receptor type 1 (RYR1) gene are associated with Malignant Hyperthermia (MH) and Central Core Disease (CCD). We report here on the molecular analysis of the RYR1 gene in Italian families referred as potential cases of MH or in patients with CCD or multicore/minicore myopathy. Of a total of 20 individuals with mutations in the RYR1 gene, 14 were part of a group of 47 MH susceptible (MHS) patients, 4 of 34 individuals diagnosed as MH equivocal (MHE), and 2 were patients diagnosed with minicore myopathy and CCD, respectively. Mutations were found to segregate with the MHS or MHE phenotype within the families of the probands. A discordance between phenotype and genotype was observed in a family where a mutation detected in an MHS proband was also found in the father who had been diagnosed MH normal (MHN) at the IVCT. In addition to known mutations, seven novel mutations were found, five of which occurred in exons encoding the C-terminal region of RYR1. These results indicate that the C-terminal region of RYR1 represents an additional hot spot for mutations in patients with MH, similar to what has been reported for patients with CCD.
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PMID:Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region. 1220 34

Central core disease (CCD) is a congenital disorder of skeletal muscle that is characterised histologically by typical central cores in type 1 skeletal muscle fibres. This disease is associated with malignant hyperthermia susceptibility and has been linked to the gene of skeletal muscle ryanodine receptor RYR1. In this study, we present a family with the spontaneous occurrence of the RYR1 Ile2453Thr mutation. Affected individuals were diagnosed as susceptible to malignant hyperthermia in the in vitro contracture test (IVCT) and showed histological signs of CCD. Myotubes were derived from the index patient. The calcium homeostasis in response to the ryanodine receptor agonist 4-chloro-m-cresol (4CmC) was investigated by calcium imaging using the Ca(2+)-sensitive fluorescent probe FURA 2. In the myotubes derived from the mutation carrier, the EC(50) of 4CmC was reduced to 94 micro as compared to 201 microM in a control group of 16 individuals non-susceptible to malignant hyperthermia. In the myotubes of the non-affected family members, the EC(50) was found within the same range as that of the control group. The reduction of EC(50) indicates a facilitated calcium release from sarcoplasmic reticulum in the myotubes of the index patient suggesting that the RYR1 Ile2453Thr mutation is pathogenic for the malignant hyperthermia susceptibility and CCD of the two affected individuals.
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PMID:The Ile2453Thr mutation in the ryanodine receptor gene 1 is associated with facilitated calcium release from sarcoplasmic reticulum by 4-chloro-m-cresol in human myotubes. 1281 58

Central core disease and malignant hyperthermia (MH) are both associated with mutations in the RYR1 gene. We report the anaesthetic management of one such patient presenting for coronary artery bypass grafting. Her medication included aspirin 75 mg, atorvastatin 20 mg, isosorbide mononitrate 60 mg, atenolol 25 mg and glyceryl trinitrite sublingual spray as required. The use of aprotinin, statins and moderate hypothermia in patients with central core disease and known susceptibility to MH has not been documented.
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PMID:Anaesthetic management of coronary artery bypass grafting in a patient with central core disease and susceptibility to malignant hyperthermia on statin therapy. 1457 Aug 2

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.
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PMID:Central core disease: clinical, pathological, and genetic features. 1467 Jul 67

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

The skeletal muscle ryanodine receptor is an intracellular calcium release channel which plays a central role in excitation contraction coupling. At least 80 mutations have been identified in the gene encoding the skeletal muscle ryanodine receptor and linked to several neuromuscular disorders, whose common feature appears to be a dysregulation of calcium homeostasis. A decade of research into the functional consequences of how these mutations affect the functional properties of the ryanodine receptor and their impact on disease, have significantly advanced our understanding of Malignant Hyperthermia, Central Core Disease and Multiminicore Disease. This review gives an overview of the important findings in the field of calcium homeostasis in skeletal muscle and describes how mutations in the ryanodine receptor gene might affect the function of this intracellular calcium release channel and lead to neuromuscular disorders.
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PMID:Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. 1608 90

Central core disease (CCD) and malignant hyperthermia (MH) are skeletal muscle disorders that are linked to mutations in the gene that encodes the type 1 ryanodine receptor (RYR1). The RYR1 ion channel plays a central role in excitation-contraction (EC) coupling by releasing Ca(2+) from an internal store. Pathogenic CCD mutations in RYR1 result in changes in the magnitude of Ca(2+) release during EC coupling. CCD has recently been linked to two novel deletions (c.12640_12648delCGCCAGTTC [p.Arg4214_Phe4216del] and c.14779_14784delGTCATC [p.Val4927_Ile4928del]) in the C-terminal region of RYR1. To determine the phenotypic consequences of these mutations and extend our understanding of the pathogenic mechanisms that underlie CCD, we determined functional effects on Ca(2+) release channel activity of analogous deletions (p.Arg4215_Phe4217del and p.Val4926_Ile4927del) engineered into rabbit RYR1 following expression in RYR1-null (dyspedic) myotubes and HEK293 cells. In addition, we assessed effects of the p.Arg4214 Phe4216del mutation on RYR1 function in lymphoblastoid cells obtained from CCD patients heterozygous for the mutation. Here we report that both deletions significantly reduce Ca(2+) release following RYR1 activation, but by different mechanisms. While the p.Arg4214_Phe4216del deletion promotes Ca(2+) depletion from intracellular stores by exhibiting a classic "leaky channel" behavior, the p.Val4927_Ile4928del deletion reduces Ca(2+) release by disrupting Ca(2+) gating and eliminating Ca(2+) permeation through the open channel.
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PMID:Two central core disease (CCD) deletions in the C-terminal region of RYR1 alter muscle excitation-contraction (EC) coupling by distinct mechanisms. 1695 53

Central core disease (CCD) is an autosomal-dominant congenital myopathy, with muscle weakness and malignant hyperthermia (MH) susceptibility. We identified two of nine Brazilian CCD families carrying two mutations in the RYR1 gene. The heterozygous parents were clinically asymptomatic, and patients were mildly affected, differing from the few autosomal-recessive cases described previously. Recessive inheritance in CCD may therefore be more common than previously appreciated, which has important implications for genetic counseling and MH prevention in affected families.
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PMID:Central core disease due to recessive mutations in RYR1 gene: is it more common than described? 1722 26


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