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 of muscle (CCD; MIM 117000) is a rare inheritable myopathy that is frequently found in association with susceptibility to malignant hyperthermia (MHS). This observation has prompted us to perform a linkage study in CCD families using various chromosome 19q probes that are linked to the MHS locus and map close to the ryanodine receptor gene (RYR1), a strong MHS candidate gene. Our genetic linkage data support a location of the CCD gene on proximal 19q13.1 and thus suggest that CCD and MHS may be allelic.
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PMID:Evidence for linkage of the central core disease locus to the proximal long arm of human chromosome 19. 188 18

Findings in 13 patients with central core disease are reported and compared with 62 patients from the literature. Patients with central core disease show wide variation in the clinical spectrum of muscle involvement. Some will have no symptoms and be completely normal on examination, many will show mild to moderate weakness, and a small number will be severely affected. Muscle atrophy is a frequent finding, but progression of muscle weakness is rare and occurs only slowly. Musculoskeletal deformities, including kyphoscoliosis, congenital hip dislocation, feet deformities, and joint contractures, are often seen but generally do not alter the natural history of the disease. Surgical treatment may be required for some of these abnormalities. No relationship appears to exist between the degree of muscle weakness and the presence or type of musculoskeletal deformities. Cardiac abnormalities have rarely been reported in association with central core disease. Mitral valve prolapse was noted in 3 of our patients and 2 others had cardiac arrhythmias. Central core disease and susceptibility to malignant hyperthermia was present in all 11 patients we studied (2 patients with central core disease did not have studies for malignant hyperthermia). These 11 patients came from 4 families. All patients with central core disease should be considered at risk for malignant hyperthermia unless in-vitro contracture tests show that the particular patient is free of the trait.
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PMID:Central core disease. Clinical features in 13 patients. 362 47

Central Core Disease (CCD) is a myopathy closely linked to malignant hyperthermia (MH) susceptibility. We present a family with a girl suffering from CCD. Due to the CCD diagnosis, all available relatives were investigated for MH-susceptibility. No other family member has CCD. In vitro contracture tests revealed that several relatives are MH-susceptible. Thus our results suggest that healthy members of families with CCD could be at risk for being malignant hyperthermia susceptible.
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PMID:Malignant hyperthermia susceptibility without central core disease (CCD) in a family where CCD is diagnosed. 776 91

Recent findings on the ryanodine receptor of vertebrates, a Ca-release channel protein for the caffeine- and ryanodine-sensitive Ca pools, are reviewed in this article. Three distinct genes, i.e., ryr1, ryr2, and ryr3, express different isoforms in specific locations: Ryr1 in skeletal muscle and Purkinje cells of cerebellum; Ryr2 in cardiac muscle and brain, especially cerebellum; Ryr3 in skeletal muscle of nonmammalian vertebrates, the corpus striatum, and limbic cortex of brain, smooth muscles, and the other cells in vertebrates. While only one isoform (Ryr1) is expressed in mammalian skeletal muscles, two isoforms (alpha- and beta-isoforms expressed by ryr1 and ryr3, respectively) are found in nonmammalian vertebrate skeletal muscles. Although the coexistence of two isoforms may merely be related to differentiation and specialization, the biological significance remains to be clarified. Ryanodine receptors in vertebrate skeletal muscles are believed to mediate two different modes of Ca release: Ca(2+)-induced Ca release and action potential-induced Ca release. All results obtained so far with any isoform of ryanodine receptor are related to Ca(2+)-induced Ca release and show very similar characteristics. Ca(2+)-induced Ca release, however, cannot be the underlying mechanism of Ca release on skeletal muscle activation. Susceptibility of the ryanodine receptor's ryanodine-binding activity to modification by physical factors, such as osmolality of the medium, might be related to action potential-induced Ca release. A hypothesis of molecular interaction in view of the plunger model of action potential-induced Ca release is discussed, suggesting that the model could be compatible with Ryr1 and Ryr3, but incompatible with Ryr2. The functional relevance of ryanodine receptor isoforms, especially Ryr3, in brain also remains to be clarified. Among ryr1 gene-related diseases, malignant hyperthermia was the first to be identified; however, there is still the possibility of involvement of the other genes. Central core disease has been added to the list recently. A molecular approach for the diagnosis and treatment of diseases is now in progress.
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PMID:Role of ryanodine receptors. 800 96

Central core disease (CCD) is a morphologically distinct, autosomal dominant myopathy with variable clinical features. A close association with malignant hyperthermia (MH) has been identified. Since MH and CCD genes have been linked to the skeletal muscle ryanodine receptor (RYR1) gene, cDNA sequence analysis was used to search for a causal RYR1 mutation in a CCD individual. The only amino acid substitution found was an Arg2434His mutation, resulting from the substitution of A for G7301. This mutation was linked to CCD with a lod score of 4.8 at a recombinant fraction of 0.0 in 16 informative meioses in a 130 member family, suggesting a causal relationship to CCD.
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PMID:A mutation in the human ryanodine receptor gene associated with central core disease. 822 Apr 22

Central core disease (CCD) of muscle is an inherited myopathy which is closely associated with malignant hyperthermia (MH) in humans. CCD has recently been shown to be tightly linked to the ryanodine receptor gene (RYR1) and mutations in this gene are known to be present in MH. Mutation screening of RYR1 has led to the identification of two previously undescribed mutations in different CCD pedigrees. One of these mutations was also detected in an unrelated MH pedigree whose members are asymptomatic of CCD. The data suggest a model to explain how a single mutation may result in two apparently distinct clinical phenotypes.
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PMID:Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. 822 Apr 23

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

The preoperative evaluation of the enzymatic level concerning the functioning of the neuromuscular system, is of particular importance. The diseases of these regions may lead to Malignant Hyperthermia (MH) in the course of general anaesthesia. The authors illustrate the case of a young asymptomatic patient with constantly high levels of CPK, who was later affected by Central Core Disease (CCD), a rare hereditary slow progressing myopathy strictly related to MH. The authors suggest tat preoperative CPK levels, though not predictive of a patient to develop MH, can allow identification of patients affected by clinically silent myopathies. This can also acquire legal importance in case of clinical MH manifestation.
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PMID:[Muscular enzyme level disorders and a malignant hyperthermia susceptability test: postoperative study of a patient with elevated CPK]. 965 90

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation-contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility.
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PMID:Ryanodine receptor mutations in malignant hyperthermia and central core disease. 1079 Feb 2


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