Malignant hyperthermia is a severe reaction to particular anesthetic 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, either given alone or in combination with a muscle relaxant that is used to temporarily paralyze a person during a surgical procedure. If given these drugs, people at risk of malignant hyperthermia may experience a rapid increase in heart rate and body temperature (hyperthermia), abnormally fast breathing, muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Without prompt treatment and cessation of the drugs, the body's reaction can cause multiple organs to be unable to function, including the heart (cardiac arrest) and kidneys (renal failure), and it can cause a blood clotting abnormality called disseminated intravascular coagulation. These complications may be life-threatening. (In medicine, the term malignant refers to conditions that are dangerous to one's health.)

People at increased risk of this disorder are said to have malignant hyperthermia susceptibility. Affected individuals may never know they have the condition unless they have a severe reaction to anesthesia during a surgical procedure or they undergo testing (for instance, if susceptibility is suspected because a family member had a severe reaction). Malignant hyperthermia may not occur every time anesthesia is used. Many individuals who develop a severe reaction have previously been exposed to a triggering drug and not had a reaction.

Affected individuals may be at increased risk for "awake" malignant hyperthermia, in which the severe reaction occurs in response to physical activity, often while sick, rather than in reaction to exposure to a triggering drug.

While malignant hyperthermia often occurs in people without other serious medical problems, certain inherited muscle diseases (including central core disease, multiminicore disease, and STAC3 disorder) are associated with malignant hyperthermia susceptibility.

Certain variations of the RYR1 and CACNA1S genes increase the risk of developing malignant hyperthermia. Mutations in the RYR1 gene account for most cases of malignant hyperthermia susceptibility, while mutations in the CACNA1S gene cause 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) in 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 turn on (activate) the RYR1 channel. When the RYR1 channel is active, it releases calcium ions from storage into the fluid-filled space inside muscle cells. The resulting increase in calcium ion concentration inside the cells stimulates muscles 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, abnormally large amounts of calcium ions are released from storage within muscle cells. The abnormal increase in calcium ion concentration within muscle cells activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An overabundance of calcium ions also causes skeletal muscles to contract, which leads to muscle rigidity.

Up to half of people with malignant hyperthermia susceptibility do not have a mutation in one of the known genes. The causes of these cases are still under study.

Normal Function

The CACNA1S gene provides instructions for making the main piece (subunit) of a structure called a calcium channel. Channels containing the CACNA1S protein are found in muscles used for movement (skeletal muscles). These skeletal muscle calcium channels play a key role in a process called excitation-contraction coupling, by which electrical signals (excitation) trigger muscle tensing (contraction).

Calcium channels made with the CACNA1S subunit are located in the outer membrane of muscle cells, so they can transmit electrical signals from the cell surface to inside the cell. The channels interact with another type of calcium channel called ryanodine receptor 1 (RYR1) channels (produced from the RYR1 gene). RYR1 channels are located in the membrane of a structure inside the cell that stores calcium ions. Signals transmitted by CACNA1S-containing channels turn on (activate) RYR1 channels, which then release calcium ions inside the cells. The resulting increase in calcium ion concentration within muscle cells stimulates muscles to contract, allowing the body to move.

Health Conditions Related to Genetic Changes

Malignant hyperthermia

CACNA1S gene mutations account for a very small percentage of all cases of malignant hyperthermia. Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. The reaction involves a high fever (hyperthermia), a rapid heart rate, muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Complications can be life-threatening without prompt treatment. Researchers have identified several mutations in the CACNA1S gene that are associated with an increased risk of this condition. These mutations replace single amino acids in the CACNA1S protein.

Channels made with the altered CACNA1S proteins likely activate the RYR1 channel improperly in response to certain drugs (particularly some anesthetics and a type of muscle relaxant used during surgery). As a result, large amounts of calcium ions are released from storage within muscle cells. An overabundance of calcium ions activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An increase in calcium ion concentration also causes skeletal muscles to contract abnormally, which leads to muscle rigidity.

Hypokalemic periodic paralysis

At least 11 mutations in the CACNA1S gene have been identified in people with hypokalemic periodic paralysis, a condition that causes episodes of extreme muscle weakness, usually in the arms and legs. CACNA1S gene mutations cause up to 70 percent of all cases of this disorder.

Mutations in the CACNA1S gene change single protein building blocks (amino acids) used to make the CACNA1S protein, which alters the structure and function of calcium channels in skeletal muscle cells. The altered channels open more slowly than usual, reducing the flow of calcium ions into these cells. This disruption in calcium ion transport prevents muscles from contracting normally. It is unclear precisely how these changes lead to episodes of muscle weakness in people with hypokalemic periodic paralysis.

Other Names for This Gene

• CAC1S_HUMAN
• CACH1
• CACN1
• CACNL1A3
• calcium channel, voltage-dependent, L type, alpha 1S subunit
• Cav1.1
• CCHL1A3
• DHPR
• dihydropyridine receptor
• dihydropyridine-sensitive L-type calcium channel alpha-1 subunit
• HOKPP
• HypoKPP
• hypoPP
• MHS5
• Voltage-dependent L-type calcium channel subunit alpha-1S
• voltage-gated calcium channel subunit alpha Cav1.1

Genomic Location

Normal Function

The RYR1 gene provides instructions for making a protein called ryanodine receptor 1 (also called the RYR1 channel). This protein is part of a group of related proteins called ryanodine receptors, which form channels that, when turned on (activated), release positively charged calcium atoms (ions) from storage within cells. RYR1 channels play a critical role in muscles used for movement (skeletal muscles).

For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by an increase in the concentration of calcium ions inside muscle cells.

RYR1 channels are located in the membrane surrounding a structure in muscle cells called the sarcoplasmic reticulum. This structure stores calcium ions when muscles are at rest. In response to certain signals, the RYR1 channel releases calcium ions from the sarcoplasmic reticulum into the cell fluid. The resulting increase in calcium ion concentration in muscle cells stimulates muscles to contract, allowing the body to move. The process by which electrical signals trigger muscle contraction is called excitation-contraction (E-C) coupling.

Health Conditions Related to Genetic Changes

Central core disease

More than 100 mutations in the RYR1 gene have been identified in people with central core disease. This condition is characterized by muscle weakness, primarily affecting the muscles near the center of the body (proximal muscles), such as the muscles in the upper legs and hips. Affected individuals also have an increased risk of malignant hyperthermia (described below).

Most of the RYR1 gene mutations involved in central core disease affect single protein building blocks (amino acids) in critical regions of the ryanodine receptor 1 protein. These mutations change the structure of the RYR1 channel, which alters the normal flow of stored calcium ions within muscle cells. A disruption in calcium ion release prevents muscles from contracting normally, leading to the muscle weakness characteristic of central core disease.

Researchers have proposed two mechanisms to explain how RYR1 gene mutations underlie muscle weakness in people with central core disease. Some genetic changes cause the RYR1 channel to be "leaky," allowing calcium ions to flow slowly but continually out of the sarcoplasmic reticulum. The leaky channels greatly reduce the amount of stored calcium ions. As a result, not enough calcium ions are available in the sarcoplasmic reticulum to trigger muscle contractions. Muscle weakness results from the inability of skeletal muscles to contract appropriately.

Other RYR1 gene mutations change the structure of the RYR1 channel in a way that impedes the normal flow of calcium ions. Although the sarcoplasmic reticulum stores plenty of these ions, the receptor cannot release them in response to the usual signals. Without enough calcium ions flowing out of the sarcoplasmic reticulum at the appropriate time, muscles cannot contract normally and muscle weakness results. This mechanism is known as E-C uncoupling.

Congenital fiber-type disproportion

At least 11 mutations in the RYR1 gene have been found to cause congenital fiber-type disproportion, a disorder that causes general muscle weakness that typically does not worsen over time. Some mutations change single amino acids in the ryanodine receptor 1 protein. Other RYR1 gene mutations create a premature stop signal in the instructions for making the receptor, resulting in an abnormally short, nonfunctional protein. Researchers suspect that disruption of the RYR1 channel may play a role in the muscle weakness and other features of congenital fiber-type disproportion, although the role of RYR1 gene mutations in this condition is unclear.

It is not yet clear whether people with congenital fiber-type disproportion caused by RYR1 gene mutations have an increased risk of malignant hyperthermia (described below).

Malignant hyperthermia

RYR1 gene mutations are the most common genetic risk factor for malignant hyperthermia. Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. The reaction involves a high fever (hyperthermia), a rapid heart rate (tachycardia), muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Complications can be life-threatening without prompt treatment.

At least 48 mutations in the RYR1 gene are known to increase the risk of malignant hyperthermia in people without features of a muscle disorder (such as central core disease, described above, or multiminicore disease, described below). Most of these mutations change single amino acids in important regions of the ryanodine receptor 1 protein. These mutations alter the structure of the RYR1 channel, causing it to open more easily and close more slowly in response to certain drugs (particularly some anesthetic gases and a type of muscle relaxant used during surgery). As a result, large amounts of calcium ions are released from the sarcoplasmic reticulum inside muscle cells. An overabundance of calcium ions activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An increase in calcium ion concentration within muscle cells also causes skeletal muscles to contract abnormally, which leads to muscle rigidity.

Many other changes in the RYR1 gene have been described in people with an increased risk of malignant hyperthermia. It is unclear, however, whether these variations are directly related to malignant hyperthermia risk.

Multiminicore disease

More than 20 mutations in the RYR1 gene have been found to cause atypical forms of multiminicore disease. Multiminicore disease is characterized by muscle weakness, and the atypical forms can have additional features. The condition is also associated with an increased risk of malignant hyperthermia (described above).

RYR1 gene mutations involved in multiminicore disease change single amino acids in the ryanodine receptor 1 protein, which alters the structure and function of the protein. The effects of these changes are unclear. Some mutations may reduce the amount of ryanodine receptor 1 protein produced by the cell or lead to an unstable version of the protein. Other mutations may interfere with the normal regulation of the RYR1 channel. Researchers believe that some RYR1 gene mutations change the shape of the channel in such a way that calcium ions cannot flow through properly. A disruption in calcium ion transport prevents muscles from contracting normally, leading to the muscle weakness characteristic of multiminicore disease.

Centronuclear myopathy

MedlinePlus Genetics provides information about Centronuclear myopathy

Other Names for This Gene

• CCD
• MHS
• MHS1
• PPP1R137
• ryanodine receptor 1 (skeletal)
• ryanodine receptor type1
• RYDR
• RYR
• RYR-1
• RYR1_HUMAN
• sarcoplasmic reticulum calcium release channel
• skeletal muscle ryanodine receptor
• Skeletal muscle-type ryanodine receptor
• SKRR

Genomic Location

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 would trigger a reaction and bring them to medical attention.