Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024591 (malignant hyperthermia)
 2,353 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.
 ...
PMID:RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. 1212 89

Advances in physiology and molecular genetics have promoted greater understanding of the various clinical manifestations of muscle disorders. For example, myotonia or profound weakness may be observed in sodium channel disease (e.g., paramyotonia congenita or hyperkalemic periodic paralysis), depending on the specific channel defect or with slight changes in membrane potential. Observed effects of anesthetic techniques have been essential to elucidating the primary muscular nature of myotonia. Commonly used anesthetic medications have potentially lethal (e.g., MH) or serious (e.g., myotonic dystrophy) adverse effects. Conversely, lidocaine or propofol may have therapeutic benefit for patients with skeletal muscle sodium channel disorders. Additional investigation is required to improve our understanding of how age, gender, or other factors determine the phenotypic expression of malignant hyperthermia. Future research holds the promise for more accurate pre-anesthetic identification of persons with heritable myopathies, especially those who are asymptomatic. Enhanced awareness of multiple organ system involvement in myotonic dystrophy is essential for planning perioperative care. Patients with periodic paralysis require that we know factors that incite or inhibit the development of their attacks. Advances in bench research and detailed clinical studies will further improve our ability to provide optimal care for patients with muscle disorders.
 ...
PMID:Malignant hyperthermia and myotonic disorders. 1229 10

Changes in intracellular Ca2+-concentration play an important role in the excitation-contraction-relaxation cycle of skeletal muscle. In this review we describe various inheritable muscle diseases to highlight the role of Ca2+-regulatory mechanisms. Upon excitation the ryanodine receptor releases Ca2+ in the cytosol. During and after contraction the sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) pumps Ca2+ back in the SR resulting in relaxation. An abnormal change in the intracellular Ca2+-concentration results in defective muscle contraction and/or relaxation, which is the cause of various muscle diseases. Malignant hyperthermia (MH) and central core disease (CCD) are both caused by mutations in the ryanodine receptor but show different clinical phenotypes. In MH an acute increase of Ca2+ results in excessive muscle contraction causing rigidity, while in CCD a chronic rise of cytosolic Ca2+ is seen, leading to mitochondrial damage, disorganization of myofibrils and muscle weakness. In Brody disease and also in mitochondrial myopathies, SERCA functions sub optimal causing a prolonged physiological Ca2+-elevation leading to slowing of relaxation. Defective actin-myosin interactions, as in nemaline myopathy and also in mitochondrial myopathies due to ATP-shortage, cause Ca2+-hyposensitivity and slowness of contraction. Information of Ca2+-kinetics in these inherited muscular diseases improves our understanding of the role of calcium in the physiology and pathophysiology of the skeletal muscle cell.
 ...
PMID:Calcium regulation and muscle disease. 1236 86

We report on two boys aged 2 and 6 years-old respectively with dysmorphic face, ptosis, down-slanting palpebral fissures, hypertelorism, epicanthic folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, palmar simian line, pectus excavatum, winging of the scapulae, lumbar lordosis and mild thoracic scoliosis who present congenital hypotonia, slightly delayed motor development, diffuse joint hyperextensibility and mild proximal weakness. The muscle biopsy revealed minimal but identifiable changes represented by size fiber variability, type I fiber predominance and atrophy, perimysial fibrous infiltration and some disarray of the intermyofibrillary network. These cases correspond to the first Brazilian reports of the King-Denborough syndrome and our objective is increasing the awareness of this disorder as these patients are predisposed to developing malignant hyperthermia.
 ...
PMID:King-Denborough Syndrome: report of two Brazilian cases. 1236 41

Oculopharyngodistal-myopathy (OPDM) is an autosomal dominant, heredofamilial myopathy accompanied with slowly progressive ptosis and extraocular palsy, and weakness of the masseter, facial, and bulbar muscles, as well as distal involvement of the limbs starting around 40 years of age or later. A 54-year-old female with OPDM underwent resection of the uterus for uterus body cancer. We speculated the patient might be at the risk of aspiration pneumonia, prolonged respiratory depression, and malignant hyperthermia, and chose spinal and epidural anesthesia. The operation was performed successfully and the patient was discharged uneventfully.
 ...
PMID:[Anesthetic management of a patient with oculopharyngodistal-myopathy]. 1264 70

Multi-minicore disease (MmD) is a congenital non-progressive or slowly progressive myopathy associated with multifocal degeneration of muscle fibers. Obstetric management for patients with MmD has not been described previously. A 25-year-old primigravida with a history of muscular weakness from birth was diagnosed with MmD and found to be susceptible to malignant hyperthermia (MH) by muscle biopsy at 28 weeks of gestation. Pregnancy proceeded uneventfully and she had a successful vaginal delivery under sufficient preparation for the possible occurrence of MH. Pregnant women who exhibit myopathic symptoms from childhood should consult an anesthesiologist prior to delivery.
 ...
PMID:Multi-minicore disease with susceptibility to malignant hyperthermia in pregnancy. 1505 93

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.
 ...
PMID:Central core disease due to recessive mutations in RYR1 gene: is it more common than described? 1722 26

Central core myopathy is a nonprogressive or only slowly progressive congenital muscle disease. In most cases, symptoms begin in childhood, but rare cases with adult onset are described. Regardless of its high variability, the clinical hallmarks are diffuse muscle weakness and the development of multiple bone deformities and contractures. Skeletal muscle biopsy is of high diagnostic significance. Due to a potential association with malignant hyperthermia, early diagnosis is of great importance. A curative treatment is not currently known. Here we discuss aetiology, pathogenesis, clinical features, diagnosis, differential diagnosis, therapeutic strategies, and prognosis of central core myopathy based on a clinical example with an atypical onset of symptoms in adulthood.
 ...
PMID:[Central core myopathy: a juvenile and adult disease]. 1723 22

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channel.
 ...
PMID:Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. 1748 90

Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.
 ...
PMID:Central core disease. 1750 18


<< Previous 1 2 3 4 5 6 7 8 Next >>