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Genetics Home Reference: your guide to understanding genetic conditions
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Malignant hyperthermia

Reviewed October 2007

What is malignant hyperthermia?

Malignant hyperthermia is a severe reaction to particular drugs that are often used during surgery and other invasive procedures. Specifically, this reaction occurs in response to some anesthetic gases, which are used to block the sensation of pain, and with a muscle relaxant that is used to temporarily paralyze a person during a surgical procedure. If given these drugs, people at risk for malignant hyperthermia may experience muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), a high fever, increased acid levels in the blood and other tissues (acidosis), and a rapid heart rate. Without prompt treatment, the complications of malignant hyperthermia can be life-threatening.

People at increased risk for this disorder are said to have malignant hyperthermia susceptibility. Affected individuals may never know they have the condition unless they undergo testing or have a severe reaction to anesthesia during a surgical procedure. While this condition often occurs in people without other serious medical problems, certain inherited muscle diseases (including central core disease and multiminicore disease) are associated with malignant hyperthermia susceptibility.

How common is malignant hyperthermia?

Malignant hyperthermia occurs in 1 in 5,000 to 50,000 instances in which people are given anesthetic gases. Susceptibility to malignant hyperthermia is probably more frequent, because many people with an increased risk of this condition are never exposed to drugs that trigger a reaction.

What genes are related to malignant hyperthermia?

Variations of the CACNA1S and RYR1 genes increase the risk of developing malignant hyperthermia.

Researchers have described at least six forms of malignant hyperthermia susceptibility, which are caused by mutations in different genes. Mutations in the RYR1 gene are responsible for a form of the condition known as MHS1. These mutations account for most cases of malignant hyperthermia susceptibility. Another form of the condition, MHS5, results from mutations in the CACNA1S gene. These mutations are less common, causing less than 1 percent of all cases of malignant hyperthermia susceptibility.

The RYR1 and CACNA1S genes provide instructions for making proteins that play essential roles in muscles used for movement (skeletal muscles). For the body to move normally, these muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of certain charged atoms (ions) into muscle cells. The proteins produced from the RYR1 and CACNA1S genes are involved in the movement of calcium ions within muscle cells. In response to certain signals, the CACNA1S protein helps activate the RYR1 channel, which releases stored calcium ions within muscle cells. The resulting increase in calcium ion concentration inside muscle cells stimulates muscle fibers to contract.

Mutations in the RYR1 or CACNA1S gene cause the RYR1 channel to open more easily and close more slowly in response to certain drugs. As a result, large amounts of calcium ions are released from storage within muscle cells. An overabundance of available calcium ions causes skeletal muscles to contract abnormally, which leads to muscle rigidity in people with malignant hyperthermia. An increase in calcium ion concentration within muscle cells also activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis).

The genetic causes of several other types of malignant hyperthermia (MHS2, MHS4, and MHS6) are still under study. A form of the condition known as MHS3 has been linked to the CACNA2D1 gene. This gene provides instructions for making a protein that plays an essential role in activating the RYR1 channel to release calcium ions into muscle cells. Although this gene is thought to be related to malignant hyperthermia in a few families, no causative mutations have been identified.

Related Gene(s)

Changes in these genes are associated with malignant hyperthermia.

  • CACNA1S
  • CACNA2D1
  • RYR1

How do people inherit malignant hyperthermia?

Malignant hyperthermia susceptibility is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of a severe reaction to certain drugs used during surgery. In most cases, an affected person inherits the altered gene from a parent who is also at risk for the condition.

Where can I find information about diagnosis or management of malignant hyperthermia?

These resources address the diagnosis or management of malignant hyperthermia and may include treatment providers.

  • Gene Review: Malignant Hyperthermia Susceptibility (http://www.ncbi.nlm.nih.gov/books/NBK1146)
  • Genetic Testing Registry: Malignant hyperthermia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0024591)
  • Genetic Testing Registry: Malignant hyperthermia susceptibility type 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN031422)
  • Genetic Testing Registry: Malignant hyperthermia susceptibility type 3 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2930982)
  • Genetic Testing Registry: Malignant hyperthermia susceptibility type 4 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1838102)
  • Genetic Testing Registry: Malignant hyperthermia susceptibility type 5 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2930984)
  • Genetic Testing Registry: Malignant hyperthermia susceptibility type 6 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1866076)
  • MedlinePlus Encyclopedia: Malignant Hyperthermia (http://www.nlm.nih.gov/medlineplus/ency/article/001315.htm)

You might also find information on the diagnosis or management of malignant hyperthermia in Educational resources (http://www.ghr.nlm.nih.gov/condition/malignant-hyperthermia/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/malignant-hyperthermia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about malignant hyperthermia?

You may find the following resources about malignant hyperthermia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for malignant hyperthermia?

  • anesthesia related hyperthermia
  • Hyperpyrexia, Malignant
  • Hyperthermia, Malignant
  • Malignant Hyperpyrexia
  • MHS - Malignant hyperthermia

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about malignant hyperthermia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding malignant hyperthermia?

acidosis ; autosomal ; autosomal dominant ; breakdown ; calcium ; cell ; channel ; fever ; gene ; hyperthermia ; increased body temperature ; inherited ; ions ; muscle cells ; muscle relaxant ; pharmacogenetics ; pharmacogenomics ; protein ; rhabdomyolysis ; surgery ; surgical ; susceptibility

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Brandom BW. Genetics of malignant hyperthermia. ScientificWorldJournal. 2006 Dec 28;6:1722-30. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17195870?dopt=Abstract)
  • Gene Review: Malignant Hyperthermia Susceptibility (http://www.ncbi.nlm.nih.gov/books/NBK1146)
  • Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005 Jun 15;293(23):2918-24. (http://www.ncbi.nlm.nih.gov/pubmed/15956637?dopt=Abstract)
  • Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, Loke J, Sharma P, Tegazzin V, Figarella-Branger D, Roméro N, Mezin P, Bendahan D, Payen JF, Depret T, Maclennan DH, Lunardi J. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat. 2005 Nov;26(5):413-25. (http://www.ncbi.nlm.nih.gov/pubmed/16163667?dopt=Abstract)
  • Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat. 2006 Oct;27(10):977-89. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16917943?dopt=Abstract)
  • Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis. 2007 Apr 24;2:21. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17456235?dopt=Abstract)
  • Treves S, Anderson AA, Ducreux S, Divet A, Bleunven C, Grasso C, Paesante S, Zorzato F. Ryanodine receptor 1 mutations, dysregulation of calcium homeostasis and neuromuscular disorders. Neuromuscul Disord. 2005 Oct;15(9-10):577-87. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16084090?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: October 2007
Published: September 15, 2014