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Key Points

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  • Disease sum mary:

    • Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered by potent halogenated volatile anesthetics and depolarizing muscle relaxants and in rare case by strenuous exercise and/or heat exposure, too.

    • Susceptible individuals have an inherited abnormality of muscle metabolism that is compensated under everyday life conditions (no clinical symptoms). However, patients with central core disease (CCD) who are at risk for MH may display muscle weakness.

    • Upon exposure to triggering agents muscle cell metabolism is massively accelerated with potentially fatal consequences. The resulting hypermetabolic syndrome is characterized by typical clinical signs such as tachycardia, hypercapnia, acidosis, muscle rigidity, and breakdown as well as hyperthermia.

    • The underlying abnormality relates to an uncontrolled release of calcium from the sarcoplasmic reticulum (SR) resulting in elevation of intracellular calcium. This in turn leads to activation of muscle contractile elements, and elevated anaerobic and aerobic metabolism.

    • The ryanodine receptor subtype 1 (RYR1; fast calcium-releasing channel) is considered to play a key role in the pathogenesis of MH. It controls the calcium release from the SR into the cytoplasm in normal skeletal muscle cells.

    • The response of the RYR1 to MH triggering substances is functionally affected in MH patients. This results in an uncontrolled calcium release via the SR membrane.

    • Early recognition of MH and its immediate treatment is essential for the patient’s survival. Besides symptomatic therapy dantrolene sodium is the only effective and specific treatment drug for MH (RYR1 antagonist).

    • MH susceptibility may reliably be detected by standardized in vitro contracture testing of biopsied skeletal muscle. Upon exposure to compounds such as halothane, caffeine, ryanodine, and other calcium release agents, marked contracture of the muscle is noted.

    • DNA analysis can be used in up to 30% of MH families, mainly for the screening of family members that carry a MH-associated mutation in the RYR1 gene.

    • A patient advocacy organization exists in the United States, Malignant Hyperthermia Association of the United States (MHAUS) (www.mhaus.org). A registry of patients with MH in North America is sponsored by MHAUS.

    • In Europe, the European MH Group (www.emhg.org) sponsors meetings and research into the syndrome.

  • Hereditary basis:

    • The disposition to MH is inherited in humans in an autosomal dominant fashion with variable penetrance and expressivity.

    • The majority of MH cases (>70%) is linked to the ryanodine receptor 1 gene (RYR1) located on chromosome 19q13.1 (MHS-1). Another gene locus is the DHPR gene. Other gene loci (MHS 2-6) are of minor importance.

    • There is a considerable allelic heterogeneity in the RYR1 gene with over 200 mutations which were detected in MH patients. About 30 RYR1 mutations were proven causal for MH.

  • Differential diagnosis:

    • Malignant neuroleptic syndrome, sepsis, serotonergic syndrome, heat stroke, thyroid crisis, drug intoxication (ecstasy, cocaine), hyperkalemic cardiac arrest during anesthesia in patients with occult myopathy

    • Iatrogenic: rapid uptake of carbon dioxide incident to laparoscopic surgery, overheating, hypoventilation, anesthesia machine malfunction

    • Neuromuscular disorders

      • CCD: causal relationship to MH (same ...

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