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Targeted sequencing for Malignant Hyperthermia and related disorders
Malignant Hyperthermia (MH) is a skeletal muscle disorder characterized by a severe adverse reaction to certain commonly used volatile (gas) anesthetics and the muscle relaxant, succinylcholine. Patients susceptible to MH may experience hypermetabolism during anesthetic exposure characterized, in part, by muscle rigidity, life-threatening elevations in body temperature, dangerous elevations of serum potassium, acidosis, muscle breakdown (“rhabdomyolysis”) with elevated creatine kinase (CK) in blood, and possibly coca-cola colored urine (“myoglobinuria”) reflecting muscle damage. If untreated, the fatality rate from MH is about 70%. Alternative anesthetics are available for individuals known to be susceptible to MH. MH susceptible individuals may not always develop an MH crisis despite exposure to trigger anesthetics due to incomplete penetrance of the genetic abnormality. An MH crisis occurs in about 1 in 50,000-100,000 general anesthetics in adults and about one in 30,000 anesthetics in children who receive the trigger anesthetics even though the prevalence of the genetic changes that predispose to MH is about one in 1,000 individuals. The “gold standard” diagnostic test for MH is the 40 year old caffeine –halothane contracture test (CHCT or IVCT) involving open biopsy of thigh muscle with measurement, in vitro, of the contracture response to incremental concentrations of halothane and caffeine in dissected muscle bundles. This test has a sensitivity of 100% and a specificity of 80-90%.
Causative pathogenic variants for MH have been reported in the ryanodine receptor gene (RYR1) in up to 70% of MH patients and in the CACNA1S gene in 1% of cases; both genes are components of the calcium release channel in skeletal muscle cells. (An even smaller percentage of patients in certain ethnic isolates manifest variants in the STAC- 3 gene). Because the disorder is dominantly inherited, only one copy of a pathogenic variant is required for susceptibility to MH although a few individuals have been found to have more than one variant. However, the absence of a known causative mutation does not rule out MH susceptibility since not all variants causal for MH have been determined. The availability of molecular testing obviates the need for muscle biopsy in families in which a known pathogenic variant has been found in an MH susceptible family member.
Other triggers have been found that lead to muscle symptoms in the “awake state” in individuals with certain pathogenic variants in the RYR1 and CACNA1S genes and these include strenuous exertion in hot environments, exposure to other drugs such as cholesterol-lowering drugs (statins) or combinations of these triggers.
The new test includes targeted sequencing of regions of the DNA in both the RYR1 and CACNA1S genes that will detect all 37 functionally characterized causative pathogenic variants in these two genes that are listed at www.emhg.org. The test will also detect an additional 99 variants that are characterized as definitely (Class 5) or probably (Class 4) pathogenic as determined by established bioinformatic algorithm filtration. Indications for testing of individuals include the following: determination of MH susceptibility by the IVCT test or by a likely anesthesia-triggered episode or identification of a known causal mutation in another family member, and patients with exertional rhabdomyolysis, heat stroke, statin-induced myopathy or idiopathic hyperCKemia.
See the Full Test List or Test Profiles & Gene Sequence Analysis for details regarding ordering the test. The DNA Testing Consent Form (“Online Forms”) is also required for this testing.
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