Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Malignant Hyperthermia [T88.3]

OMIM numbers: 1456500, 601887, 180901 (RYR1), 114208 (CACNA1S)

Dipl.-Biol. Birgit Busse

Scientific Background

Malignant hyperthermia (MH) is a pharmacogenetically caused Ca2+ regulatory disorder of the skeletal muscles. In genetically predisposed patients, volatile anesthetics (fluranes) as well as depolarizing muscle relaxants (e.g. suxamethasone) can lead to a potentially life-threatening hypermetabolic crisis. The signs and symptoms may vary strongly and can range from a moderate course with minor manifestations to a fulminant MH crisis. Classical signs of a fulminant MH crisis in its early stage are tachycardia, hypercapnia, hypoxemia and masseter spasm, in latter phases additional acidosis, hyperkalemia, rhabdomyolysis and hyperthermia. The use of the antidote dantrolene reduced the mortality rate of MH crises to < 5%. The prevalence of MH in the German population is estimated to be 1 in 10,000. The incidence for a fulminant MH crisis is approx. 1 in 60,000. Administration of trigger substances to predisposed patients has to be avoided. Without trigger substances, an inapparent myopathy is usually present.

The gold standard of MH diagnosis is the in vitro contracture test (IVCT). Furthermore, molecular genetic analysis is an important part of the diagnosis. Mutations in the ryanodine receptor 1 (RYR1) and the dihydropyridine receptor (L-type voltage-dependent calcium channel, CACNA1S) are associated with a predisposition for MH. Inheritance is autosomal dominant with incomplete penetrance. Approx. 75% of all families with MH exhibited mutations in one of these genes. Detection of a causal mutation allows the identification of other at risk relatives by targeted mutation analysis. Since in studies not all affected patients exhibited mutations in the RYR1 or CACNA1S gene, a negative molecular genetic result can not rule out the presence of a MH. Therefore, if MH is suspected but the genetic test results are negative IVCT should be conducted to confirm the diagnosis.