Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.
A clinical grading scale helps determine if a malignant hyperthermia (MH) episode has occurred. Contracture testing, the standard diagnostic test for MH since the mid-1970s, relies on the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine, the anesthetic halothane, and other calcium-releasing agents. To date, two genes predisposing to MHS have been identified; four additional loci have been mapped, but the genes have not been identified. MHS1 is associated with mutations in RYR1, encoding ryanodine receptor type 1; MHS5 is associated with mutations in CACNA1S, encoding a skeletal muscle calcium channel. Up to 70% of MHS is caused by mutations in RYR1 and about 1% results from mutations in CACNA1S. Molecular genetic testing for RYR1 and CACNA1S is available on a clinical basis.
Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant manner. Most individuals diagnosed with MHS have a parent with MHS; however, the parent may not have experienced an episode of MH. The proportion of individuals with MHS caused by de novo mutations is unknown. Each child of an individual with MHS has a 50% chance of inheriting the disease-causing mutation. Although prenatal diagnosis for pregnancies at increased risk for MHS is possible, prenatal testing for pharmacogenetic conditions (like MHS) that have effective treatment and prevention is generally not offered or available.