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)

A 13 year-old girl with scoliosis and central core disease is reported. She was noted to have mild psychomotor developmental delay since early infancy. Scoliosis with minimal muscle weakness was noted at about five years old. The neurological examination disclosed absent knee jerk. The spine MRI showed no significant finding. The serum CK revealed 518 U/L. The muscle biopsy obtained from the quadriceps femoris muscle showed Type 1 fiber atrophy and predominance, as is commonly seen in congenital myopathies. Under nicotinamide adenine dinucleotide dehydrogenase (NADH) and succinate dehydrogenase (SDH) stains, core structures were identified and the diagnosis of central core disease (CCD) was made. Since kyphoscoliosis usually becomes prominent as muscle weakness progresses to loss of ambulation in other myopathies, the disproportionate spinal involvement in central core disease appears to be a striking feature. We suggest that all patients with idiopathic scoliosis deserve a thorough neurological evaluation if congenital myopathies are suspected. Muscle biopsy should also be recommended for a confirmatory diagnosis even if only minimal muscle weakness present. Besides, early detection of CCD helps us to identify the population who are at a higher risk for malignant hyperthermia.
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PMID:Central core disease associated with scoliosis: report of one case. 929 32

Since venous cannulation in children has become easier and extensive experience has been gained with total intravenous anaesthesia (TIVA) in adults, the interest in TIVA for children has recently increased. An intensified sensitivity of the operating room atmosphere to contamination with volatile anaesthetic agents is another important reason to choose intravenous techniques for paediatric anaesthesia. One of the most interesting agents for TIVA in paediatric anaesthesia is propofol. The pharmacokinetic and pharmacodynamic data for modern intravenous drugs is poor. Because the interpatient variability is relatively large, pharmacokinetic data can only provide guidelines for the dosage of propofol. Propofol has a rapid and smooth onset of action and is as easy to titrate in children as in adults. Propofol can be excellently controlled. Severe haemodynamic side-effects are missing in healthy children and plasma is cleared rapidly of propofol by redistribution and metabolism. There is no evidence of significant accumulation, not even after prolonged infusion times. Because propofol has no analgetic properties it must be combined with analgetics or a regional block for all painful procedures. The combination with the ultra-short acting remifentanil is a major advantage, but requires effective analgetic concepts for painful procedures. In comparison the combination of propofol with long acting opioids abolishes some of the favourable properties of propofol. Further studies of the kinetics and dynamics of propofol and other intravenous agents are needed in paediatrics which should focus on age, maturity and severity of illness. The whole importance of the propofol-infusion syndrome has to be cleared up urgently. TIVA has an important significance in paediatric anaesthesia for diagnostic and therapeutic procedures, especially where these have to be repeated. In day-case anaesthesia TIVA has advantages for all short procedures and for ENT and ophthalmic surgery: even after prolonged infusion children have an short recovery time. There is no evidence of agitation or other behavioural disorders after TIVA with propofol in paediatric anaesthesia. Propofol has anti-emetic properties. TIVA with propofol can be combined with regional anaesthesia advantageously to provide long-lasting analgesia after surgery. TIVA with propofol has been used successfully for sedation of spontaneously breathing children for MRI and CT and other procedures with open airways like bronchoscopy or endoscopy. Propofol facilitates endotracheal intubation without the use of muscle relaxants. Of course, in malignant hyperthermia TIVA will continue to be the technique of choice. Nothing is known about awareness under TIVA in paediatric patients. TIVA must be considered by comparison with the volatile agents. The use of ultra-short acting agents may cause problems such as awareness, vagal response, involuntary movements and in some cases slow recovery after prolonged infusion of propofol. But it is not known exactly how often this happens during paediatric anaesthesia. With TIVA an effective postoperative analgesia must be provided. Newer administration techniques such as the target-controlled infusions or closed-loop control systems are under development and will help to minimise the potential risk of overdosage with TIVA in paediatrics. At the present TIVA is an interesting and practicable alternative to volatile anaesthesia for pre-school and school children. TIVA with propofol in infants younger than 1 year old requires extensive experience with TIVA in older children and with the handling of this special age group and should be undertaken with maximum precautionary measures.
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PMID:[Total intravenous anesthesia. On the way to standard practice in pediatrics]. 1450 2

Malignant hyperthermia (MH) is a potentially fatal disease triggered by general anaesthesia. Four cases of compartment syndrome complicating MH have been reported. We report here a case of transient talipes equinus deformity of bilateral lower limbs, a condition similar to compartment syndrome, following MH in a previously healthy pediatric patient. MRI revealed high intensity in the bilateral soleus muscles but not in the gastrocnemius muscles. We discuss the possible mechanisms of the deformity of the lower limbs after the MH crisis.
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PMID:Transient talipes equinus deformity of bilateral lower limbs following malignant hyperthermia: a case report and review of literature. 1622 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.
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PMID:Central core disease. 1750 18

Multi-minicore Disease (MmD) is a recessively inherited neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown. Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background. Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis; calcium-binding motifs within the selenoprotein N protein also suggest a possible role in calcium handling. The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms. In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.
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PMID:Multi-minicore Disease. 1763 Oct 35

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia (MH) susceptibility trait, Central Core Disease (CCD) and other congenital myopathies characterized by early onset and predominant proximal weakness. We report a patient presenting at 77 years with a predominant axial myopathy associated with prominent involvement of spine extensors, confirmed on MRI and muscle biopsy, compatible with a core myopathy. RYR1 mutational analysis revealed a novel heterozygous missense mutation (c.119G>T; p.Gly40Val) affecting the RYR1 N-terminus, previously predominantly associated with MH susceptibility. This case expands the spectrum of RYR1-related phenotypes and suggests that MH-related RYR1 mutations may give rise to overt neuromuscular symptoms later in life, with clinical features not typically found in CCD due to C-terminal hotspot mutations. Late-onset congenital myopathies may be under-recognised and diagnosis requires a high degree of clinical suspicion.
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PMID:Late-onset axial myopathy with cores due to a novel heterozygous dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. 1930 94

The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this.
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PMID:RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine. 2495 53

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic myopathy triggered by exposure to volatile anesthetics and/or depolarizing muscle relaxants. Susceptibility to MH is primarily associated with dominant mutations in the ryanodine receptor type 1 gene (RYR1). Recent genetic studies have shown that RYR1 variants are the most common cause of dominant and recessive congenital myopathies - central core and multi-minicore disease, congenital fiber type disproportion, and centronuclear myopathy. However, the MH status of many patients, especially with recessive RYR1-related myopathies, remains uncertain. We report the occurrence of a triplet of RYR1 variants, c.4711A>G (p.Ile1571Val), c.10097G>A (p.Arg3366His), c.11798A>G (p.Tyr3933Cys), found in cis in four unrelated families, one from Belgium, one from The Netherlands and two from Canada. Phenotype-genotype correlation analysis indicates that the presence of the triplet allele alone confers susceptibility to MH, and that the presence of this allele in a compound heterozygous state with the MH-associated RYR1 variant c.14545G>A (p.Val4849Ile) results in the MH susceptibility phenotype and a congenital myopathy with cores and rods. Our study underlines the notion that assigning pathogenicity to individual RYR1 variants or combination of variants, and counseling in RYR1-related myopathies may require integration of clinical, histopathological, in vitro contracture testing, MRI and genetic findings.
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PMID:Compound RYR1 heterozygosity resulting in a complex phenotype of malignant hyperthermia susceptibility and a core myopathy. 2595 40