Malignant Hyperthermia: Get Facts on This Drug Reaction

Malignant hyperthermia facts*

*Malignant hyperthermia facts medical author: Melissa Conrad Stöppler, MD

• Malignant hyperthermia is a severe reaction to particular drugs that are often used during general anesthesia for surgery.
• Malignant hyperthermia occurs in 1 in 5,000 to 50,000 instances in which people are given anesthetic gases.
• 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 are some of the effects of this potentially life-threatening condition.
• Researchers have described at least six forms of malignant hyperthermia susceptibility, which are caused by mutations in different genes. For example, variations of the CACNA1S and RYR1 genes increase the risk of developing malignant hyperthermia.
• Malignant hyperthermia susceptibility is inherited in an autosomal dominant manner (which means that one copy of the altered gene in each cell is sufficient to increase the risk of the condition).

What is malignant hyperthermia?

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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.

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,
management, or treatment of malignant hyperthermia?

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

• Gene Review: Malignant Hyperthermia Susceptibility.
• Gene Tests:
  CACNA1S-Related Malignant
  Hyperthermia Susceptibility.
• Gene Tests:
  MHS2-Related Malignant Hyperthermia Susceptibility.
• Gene Tests:
  MHS3-Related
  Malignant Hyperthermia Susceptibility.
• Gene Tests:
  MHS4-Related Malignant Hyperthermia Susceptibility.
• Gene
  Tests:
  RYR1-Related Malignant Hyperthermia Susceptibility.

To locate a healthcare provider, see
How can I find a genetics professional
in my area? in the Handbook. Where can I find additional information about
malignant hyperthermia?

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What other names do people use for malignant hyperthermia?

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