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Malignant Hyperthermia Susceptibility

Synonym: Malignant Hyperpyrexia. Includes: CACNA1S-Related Malignant Hyperthermia Susceptibility, MHS2-Related Malignant Hyperthermia Susceptibility, MHS3-Related Malignant Hyperthermia Susceptibility, MHS4-Related Malignant Hyperthermia Susceptibility, MHS6-Related Malignant Hyperthermia Susceptibility, RYR1-Related Malignant Hyperthermia Susceptibility

, MD, , PhD, , MD, and , PhD.

Author Information
, MD
Director, Department of Medical Education and Clinical Research
Saint Barnabas Medical Center
Livingston, New Jersey
President, Malignant Hyperthermia Association of the United States
Sherburne, New York
, PhD
Assistant Professor, Department of Anesthesiology
Uniformed Services University
Bethesda, Maryland
, MD
Assistant Professor, Department of Anesthesia
University of Toronto
Toronto, Ontario
, PhD
Professor, Department of Pharmacology and Physiology
University of Rochester Medical Center
Rochester, New York

Initial Posting: ; Last Update: January 31, 2013.


Disease characteristics. Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances release calcium stores from the sarcoplasmic reticulum and may promote entry of calcium from the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience: acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some affected individuals will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high.

Diagnosis/testing. A clinical grading scale helps determine if a malignant hyperthermia (MH) episode has occurred. Contracture testing, the standard diagnostic test for MH since the mid-1970s, relies on the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine, the anesthetic halothane, and other calcium-releasing agents. To date, two genes predisposing to MHS have been identified; four additional loci have been mapped, but the genes have not been identified. MHS1 is associated with mutations in RYR1, encoding ryanodine receptor type 1; MHS5 is associated with mutations in CACNA1S, encoding a skeletal muscle calcium channel. Up to 70% of MHS is caused by mutations in RYR1 and about 1% results from mutations in CACNA1S.

Management. Treatment of manifestations: Early diagnosis of MHS is essential. Successful treatment of an acute episode of MH includes:

  • Discontinuation of potent inhalation agents and succinylcholine;
  • Administration of dantrolene sodium intravenously;
  • Surface, intravenous and body cavity cooling with cold solutions for hyperthermic individuals; and
  • Treatment of metabolic abnormalities.

Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation; therefore, a coagulation profile should be obtained on all individuals experiencing fulminant MH. The presence of myoglobinuria mandates referral to a neurologist for further investigation.

Prevention of primary manifestations: Avoidance of potent volatile anesthetic agents and succinylcholine. Individuals undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe.

Agents/circumstances to avoid: Avoid extremes of heat, but do not restrict athletic activity unless there is a history of overt rhabdomyolysis and/or heat stroke. Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result. In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH. Serotonin antagonist antiemetics should be used cautiously.

Evaluation of relatives at risk: If the disease-causing mutation has been identified in the family, molecular genetic testing of at-risk relatives is warranted to identify those who have the mutation and will benefit from avoiding anesthetic agents that increase the risk for a malignant hyperthermia episode. Absence of a mutation does not imply that an at-risk individual is not MH susceptible.

Pregnancy management: If a pregnant woman with MHS requires non-emergent surgery during the pregnancy, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia or a total intravenous general anesthetic) should be administered. Continuous epidural analgesia is highly recommended for labor and delivery. If a Cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an MH-susceptible individual.

Genetic counseling. Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant manner. Most individuals diagnosed with MHS have a parent with MHS; however, the parent may not have experienced an episode of MH. The proportion of individuals with MHS caused by de novo mutations is unknown. Each child of an individual with MHS has a 50% chance of inheriting the disease-causing mutation. Although prenatal diagnosis for pregnancies at increased risk for MHS is possible, prenatal testing for pharmacogenetic conditions (like MHS) that have effective treatment and prevention is generally not offered or available.


Clinical Diagnosis

Consensus guidelines for the diagnosis and management of malignant hyperthermia have been published [Robinson & Hopkins 2001, Urwyler et al 2001, Sei et al 2004, Litman & Rosenberg 2005, Carpenter et al 2009, Glahn et al 2010]. Clinical diagnostic criteria for malignant hyperthermia susceptibility (MHS) are summarized in Table 1. The findings relate to signs occurring during or shortly after general anesthesia.

Each clinical finding is weighted as to significance in being associated with malignant hyperthermia as determined through a Delphic study of experts. Points are assigned according to weight and are then summed to produce a raw score, which translates to a likelihood score, range from 1 (score 0: “almost never/very unlikely”) to 6 (score ≥50: “almost certain”). The more criteria an individual fulfills, the more likely that a malignant hyperthermia (MH) episode has occurred. Thus, with only temperature elevation during anesthesia, an individual is not likely to be susceptible to malignant hyperthermia. Of course, a limitation of the scoring system is that not every clinical finding may be measured, e.g. arterial blood gas, or the syndrome is recognized very quickly and treated before all signs appear [Larach et al 1994].

Table 1. Criteria Used in the Clinical Grading Scale for Malignant Hyperthermia

Clinical Finding (Maximum Score) 1Manifestation 2
Respiratory acidosis (15)End-tidal CO2 >55 mmHg, PaCO2 >60 mmHg
Cardiac involvement (3)Unexplained sinus tachycardia, ventricular tachycardia, or ventricular fibrillation
Metabolic acidosis (10)Base deficit >8 mEq/L, pH <7.25
Muscle rigidity (15)Generalized rigidity, severe masseter muscle rigidity
Muscle breakdown (15)Serum creatine kinase concentration >20,000/L units, cola-colored urine, excess myoglobin in urine or serum, plasma [K+] >6 mEq/L
Temperature increase (15)Rapidly increasing temperature, T >38.8° C
OtherRapid reversal of MH signs with dantrolene (score=5), elevated resting serum creatine kinase concentration (score=10)
Family history (15)Consistent with autosomal dominant inheritance

From Larach et al [1994], Rosenberg et al [2002]

1. Clinical findings (except family history) are in order of relative importance.

2. Signs occurring during or shortly after general anesthesia in the untreated individual


Contracture test. Since the mid-1970s, the standard diagnostic test for MH has been the in vitro measurement of contracture response of biopsied muscle to graded concentrations of caffeine and the anesthetic halothane. The test is referred to as the caffeine/halothane contracture test (CHCT) in North America and the in vitro contracture test (IVCT) in Europe:

Note: The calcium-induced calcium release (CICR) test is used only in Japan, and no international standards exist.

  • The test must be performed on a biopsy of approximately 2.0 g of muscle from the vastus lateralis or medialis (some centers have used biopsies from other muscle groups, but the test has only been standardized for the vastus muscle group) within five hours of harvesting. Usually, the individual must be at a MH diagnostic center (see Testing Strategy, *Note) in order to undergo testing.
  • The individual is anesthetized with general anesthesia or with a femoral nerve block or one of its variants:
    • Direct muscle infiltration with local anesthetic is contraindicated because it could affect tissue viability.
    • In all cases, the anesthetic drugs used must be safe for MH-susceptible individuals.
  • The surgeon must not use electrocautery or stretch the muscle.

Muscle bundles weighing 100-150 mg are mounted in a chamber containing buffer solution and, after a period of stabilization, are caused to contract with supramaximal electrical stimuli. The isometric contracture that develops following exposure to various pharmacologic agents that cause sarcoplasmic reticulum (SR) calcium release (e.g., halothane, caffeine, and ryanodine) is measured.

The two versions of the testing protocol with international standards of test performance and interpretation are the North American [Litman & Rosenberg 2005] and the European versions [Urwyler et al 2001]. The essential differences are: (1) the North American protocol utilizes exposure to 3% halothane, while the European version utilizes incremental exposure to halothane; and (2) the North American version requires testing of three muscle bundles for each drug, whereas the European version requires testing of two muscle bundles for each drug (see Table 2). Of note, in recent years, ryanodine (1.0 µmol/L) and 4-chloro-m-cresol have been used to elicit contractures as well.

Table 2. Testing Protocols for Malignant Hyperthermia

Designation 1North American ProtocolEuropean Protocol
MHSContracture of >0.7 g to 3% halothane
Contracture of >0.3 g to 2.0 mmol/L caffeine
Contracture of ≥0.2 g to ≤2% halothane
Contracture of ≥0.2 g to ≤2.0 mmol/L caffeine
MHE 2Contracture of 0.5-0.7 g to 3% halothaneContracture to halothane only or caffeine only
MHNNo contracture
Contracture of <0.5 g to halothane
Contracture of <0.3 g to 2.0 mmol/L caffeine
No significant contractures to either agent

Note: (1) Studies to determine the sensitivity and specificity of the contracture test show that both protocols have a sensitivity of about 100%. Specificity is generally between 80% and 97%, according to several studies with these protocols [Allen et al 1998]. (2) Some laboratories employ 1.0 or 2.0 μmol/L ryanodine or 4-chloro-m-chlorocresol in addition to halothane and caffeine to clarify equivocal results; however, these agents have not been incorporated into the standardized test.

1. MHS = malignant hyperthermia susceptible; MHE = malignant hyperthermia equivocal; MHN = malignant hyperthermia negative

2. In the North American protocol, the MHE designation is “optional”; and most centers report results as either MHN or MHS using a threshold of 0.5 g.

Sevoflurane has been investigated as a potential replacement for halothane in the MH testing protocol. Preliminary results suggest the rapid application of sevoflurane (8%), and not its incremental increase, induces significant contracture in MHS, and may differentiate MHS from MHN [Metterlein et al 2011a].

Molecular Genetic Testing

Genes. To date, only two genes in which mutation causes MHS have been identified:

Evidence for further locus heterogeneity. Four additional loci have been mapped; the genes have not been identified:

  • MHS2 (linked to chromosomal locus 17q11.2-q24)
  • MHS4 (3q13)
  • MHS6 (5p)
  • MHS3 (7q21-q22)

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in Malignant Hyperthermia Susceptibility

Gene Symbol / Locus NameProportion of MHS Attributed to Mutations in This GeneTest MethodMutations Detected
RYR1 / MHS170%-80%Targeted mutation analysisMutation panel 1
Sequence analysis / mutation scanning of all exons and flanking intronic regions 2, 3Sequence variants 4
Sequence analysis / mutation scanning of select exons & flanking intronic regions 2, 3 Sequence variants 4
UnknownDeletion / duplication analysisUnknown; none reported
UnknownLinkage analysis 5NA
CACNA1S / MHS51% 6Targeted mutation analysisp.Arg1086His
Sequence analysis / mutation scanning 2Sequence variants 4
Sequence analysis of select exonsSequence variants 4, 7
UnknownLinkage analysis 5NA
Unknown / MHS2UnknownLinkage analysis 5NA
Unknown / MHS3UnknownLinkage analysis 5NA
Unknown / MHS4UnknownLinkage analysis 5NA

1. A panel of the most common mutations (Table 4) detects approximately 25%-30% of individuals with malignant hyperthermia susceptibility (MHS) [Robinson et al 2002]. In some populations, (i.e., in Switzerland) a more limited panel is acceptable because of homogeneity of the population [Girard et al 2001]. Mutation panel is p.Cys35Arg, p.Arg163Cys, p.Arg163Leu, p.Gly248Arg, p.Gly341Arg p.Ile403Met, p.Tyr522Ser, p.Arg552Trp, p.Arg614Cys, p.Arg614Leu, p.Arg2163His, p.Arg2163Cys, p.Val2168Met, p.Thr2206Met, p.Ala2350Thr, p.Ala2428Thr, p.Gly2434Arg, p.Arg2435His, p.Arg2454Cys, p.Arg2454His, p.Arg2458His, p.Arg2458Cys, p.Gly341Arg, and p.Tyr522Ser (see Table 4). Mutation panels may vary by laboratory.

2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

3. Although many RYR1 mutations are clustered in three mutational hot spots, ranging from amino acid residues 35 to 614 (N-terminal region), 2117 to 2458 (central region), and 3916 to 4973 (C-terminal region) [Jurkat-Rott et al 2000, McCarthy et al 2000, Robinson et al 2006], mutations are found throughout the RYR1 coding region [Kraeva et al 2011]. When individuals who have either a positive contracture test or strongly suggestive clinical and family histories are selected, complete sequence analysis of the entire RYR1 coding region increases the detection rate to 70%-80% [Sambuughin et al 2005, Galli et al 2006].

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.

5. Linkage analysis for all MHS loci may be considered for genetic counseling in families in which at least ten family members in more than two generations have the unequivocal diagnosis of MHS by IVCT. Linkage studies are always based on accurate clinical diagnosis of MHS in the affected family members and accurate understanding of the genetic relationships in the family. In addition, linkage analysis depends on the availability and willingness of family members to be tested and on the presence of informative polymorphic markers.

6. Exact frequency is unknown because of the small number of individuals with MHS attributed to mutations in this gene.

7. Exons sequenced may vary by laboratory.

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • Failure to detect a mutation on molecular genetic testing does not rule out MH susceptibility.
  • Discordance between the contracture test and molecular genetic test results is observed in up to 10% of individuals.

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at [Rosenberg & Rueffert 2011 (full text)].

Testing Strategy

Indications for muscle biopsy and contracture testing to confirm the diagnosis in a proband (see *Note)

Definite indications

  • Proband with a clinical history of MH
  • First-degree relative of a proband with a clinical history of MH, if the proband cannot be tested (e.g., too young, too old, MH death, not willing to undergo the muscle biopsy, no test center available)
  • At-risk family members when the MH-causing mutation is not known
  • Severe masseter muscle rigidity along with generalized rigidity during anesthesia with MH-triggering agents
  • Limited masseter muscle rigidity along with rhabdomyolysis and/or elevated plasma CK level (hyperCKemia)
  • Military service. The military requires determination of MH susceptibility by contracture testing in persons with a suspicion of MHS because individuals with MHS are not eligible for military service.

Possible indications. Debate exists as to other indications for diagnostic MH muscle biopsy. Some experts believe that individuals who experience any one of the following should undergo biopsy, following careful discussion of the pros and cons of the test:

  • Isolated masseter muscle rigidity with succinylcholine
  • Postoperative rhabdomyolysis and marked elevation of serum CK concentration without other signs of classic MH
  • Exercise related rhabdomyolysis in the absence of a known myopathy
  • Signs suggestive of but not definitive for MH

Not recommended:

  • Weight less than about 20 kg or age younger than five years
  • Diagnosis of neuroleptic malignant syndrome or serotonin syndrome

*Note: (1) Because the test is available on a limited basis, some physicians consider all individuals with a history suspicious for MH as MH susceptible and avoid anesthetic agents known to trigger MH. Although this strategy is useful, it does not provide guidance and specific answers to family members and limits the anesthetic options for the individual and his/her family. (2) Details regarding MH muscle biopsy centers can be obtained from the Malignant Hyperthermia Association of the US Web site ( (accessed January 2013).

Indications for molecular genetic testing (see **Note)

  • Confirmed clinical episode of MH
  • Positive halothane/caffeine contracture test
  • High likelihood of having experienced a MH episode, as determined by biopsy center/hotline consultants, and/or likely MH based on the Clinical Grading Scale (see Table 1)
  • Relative with a positive contracture test or a known MH-causing mutation
  • Unexplained death with signs of MH during or immediately after anesthesia
  • Exercise related rhabdomyolysis in the absence of a known myopathy

**Note: Recommendations pertain to North America. The European MH group does not perform molecular genetic testing unless an individual or his/her relative has had a positive contracture test.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Malignant hyperthermia susceptibility. The manifestations of MH result from exposure to certain volatile anesthetic agents (i.e., halothane, isoflurane, sevoflurane, desflurane, and enflurane) that act as triggers either alone or in conjunction with succinylcholine, a depolarizing muscle relaxant. At first, MH was thought, in all cases, to consist of an extremely elevated body temperature, skeletal muscle rigidity, and acidosis associated with a high mortality rate. However, it is now recognized that MH is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism [Hopkins 2000] with varied presentations, depending on the triggering agents and environmental factors, such as metabolic state and body temperature, at the beginning of anesthesia.

The triggering substances release calcium stores from the sarcoplasmic reticulum via the muscle ryanodine receptor, the calcium release channel leading to an increase in the concentration of free myoplasmic calcium. There is also evidence that store operated calcium (calcium contained in the extracellular fluid) entry also plays a role in the pathophysiology of MH [Duke et al 2010]. Increased myoplasmic calcium causes contracture of skeletal muscles and activates glycogenolysis and cell metabolism, resulting in production of heat and excess lactate. Activation of the oxidative cycle leads to high oxygen consumption and high carbon dioxide.

The clinical manifestations are somewhat variable depending on the clinician's response. Hypercapnia is common, as is tachycardia. Hyperthermia follows and may be an early sign of MH. However, failure to monitor core temperature may lead to a delay in detecting hyperthermia. Skin temperature is often misleading in MH crises [Larach et al 2010]. Acidosis may be mild if the syndrome is recognized and treated promptly. HyperCKemia and rhabdomyolysis are more common when succinylcholine has been used but may be mild or not appear at all in some cases, for reasons that are not clear. In some cases rhabdomyolysis does not appear for several hours. Hyperkalemia, leading to cardiac arrhythmia and even arrest, is uncommon if the syndrome is detected and treated promptly but may develop with remarkable rapidity.

In survivors, normalization of edematous muscle and serum CK concentration occurs within ten to 15 days, but symptom resolution may take longer (Figure 1) [Jurkat-Rott et al 2000].

Figure 1


Figure 1. Clinical features of malignant hyperthermia susceptibility

Note: Early diagnosis and rapid therapy are both life-saving and lead to a reduction of the clinical symptoms.

Adapted from Jurkat-Rott et al [2000] (more...)

MH may appear at any point during anesthetization or within an hour or so of the termination of anesthesia. If succinylcholine is used during induction of anesthesia, an acceleration of the manifestations of MH may occur; tachycardia, elevation of end-tidal carbon dioxide levels, hypertension, marked temperature elevation, and arrhythmias are seen over the course of five to ten minutes. However, a completely normal response to succinylcholine may be present in some individuals susceptible to MH; in these individuals, a potent inhalation agent is apparently necessary to trigger the syndrome.

In almost all cases, the first manifestations of MH occur in the operating room. In classic malignant hyperthermia, the initial signs are tachycardia, rapidly rising end-tidal C02, and tachypnea. Tachypnea is usually not recognized because most individuals receiving general anesthesia are paralyzed. Shortly after the heart rate increases, the blood pressure may increase, often associated with ventricular arrhythmias induced by sympathetic nervous system stimulation from hypercarbia, hyperkalemia, and catecholamine release. Thereafter, muscle rigidity or increased muscle tone may become apparent; and body temperature increases at a rate of 1°-2° C every five minutes.

At the same time, the CO2 absorbent used in general anesthesia becomes activated and warm to the touch from the exothermic reaction with the CO2 exhaled by the affected individual. The individual may display peripheral mottling and, on occasion, sweating and rarely cyanosis. Blood gas analysis usually reveals hypercarbia (PCO2>60 mmHg) and respiratory and metabolic acidosis without oxygen desaturation. Elevation of end-tidal CO2 greater than 55 mmHg is one of the earliest signs of MH; however, vigorous mechanical hyperventilation may prevent hypercarbia and delay the diagnosis [Karan et al 1994]. A mixed venous blood sample shows even more evidence of CO2 retention and metabolic acidosis. Hyperkalemia, hypercalcemia, lactacidemia, and myoglobinuria are characteristic but are not present in every case. Increase in serum CK concentration often exceeds 20,000 units/L in the first 12-24 hours.

Death results unless the individual is promptly treated (see Management). Even with treatment and survival, the individual is at risk for life-threatening myoglobinuric renal failure, disseminated intravascular coagulation (DIC), compartment syndrome, and recrudescence of the syndrome within the first 24-36 hours following the episode [Fortunato et al 2000]. A study of MH using a North American MH registry containing information about affected individuals reported between 1987 and 2006 showed that nonfatal complications occurred in 35% of these individuals. Twelve of these complications included cardiac, renal, or hepatic dysfunction; coma or change in consciousness level; pulmonary edema; and DIC [Larach et al 2010].

Early diagnosis and rapid therapy are life-saving and also lead to a reduction of clinical symptoms. It should be noted that modern anesthetic care and monitoring often allow early detection of malignant hyperthermia. Treatment with dantrolene results in much lower morbidity and mortality than first reported when MH was recognized in the 1960s [Larach et al 2008] but the mortality may be as high as 11% [Rosero et al 2009]. The likelihood of any complication increased 2.9 times per 2° C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene administration [Larach et al 2010]. The most frequent complications associated with dantrolene administration are muscle weakness (14.6%), phlebitis (9.2%), and gastrointestinal upset (4.3%). There is a 25% increase in the risk for any of the above complications when the total dose of dantrolene as required by clinical indications is twice the recommended initial treatment dose of 2.5 mg/kg [Brandom et al 2011].

The presentation of MH outside a hospital setting may pose special problems. Several deaths from MH have occurred when the episode began in an ambulatory surgery setting. Probable causes include inadequate preparation for treating MH, insufficient personnel, and/or problems in stabilizing an affected individual prior to transfer to a hospital. It is suggested that all facilities have a plan to deal with MH and hold practice drills at regular intervals (see Larach et al [2012] for transfer of care protocols).

Malignant hyperthermia may also occur in the early postoperative period, usually within the first hour of recovery from anesthesia. Characteristic tachycardia, tachypnea, hypertension, and arrhythmias presage an episode of MH. Isolated myoglobinuria without an obvious increase in metabolism in the postoperative period (≤24 hours) should alert the anesthesiologist to the possibility of MH.

Of note, an MH episode may not occur with every exposure to "trigger" agents. Clinical manifestation may depend on genetic predisposition, dose of trigger agents, or duration of exposure.

Signs of MH have also been reported without exposure to anesthetic agents (see Differential Diagnosis). In some cases signs follow overdose of MDMA agonists; in other cases MH may be associated with heat and exercise.

Malignant hyperthermia susceptibility (MHS) phenotypes. Several distinct clinical presentations predispose to classic MH:

  • Central core disease and multiminicore disease are myopathies caused by mutations in RYR1 (see Genetically Related Disorders).
  • King or King-Denborough syndrome is characterized by: distinctive facies, ptosis, downslanted palpebral fissures, widely spaced eyes, epicanthal folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, single palmar crease, pectus excavatum, winging of the scapulae, lumbar lordosis, and mild thoracic scoliosis. Individuals present with hypotonia at birth, slightly delayed motor development, diffuse joint hyperextensibility, and mild proximal muscle weakness. Muscle biopsy reveals minimal but identifiable changes represented by fiber size variability, type I fiber predominance and atrophy, perimysial fibrous infiltration, and some disarray of the intermyofibrillary network. Mutations in RYR1 have been found in some individuals with King-Denborough syndrome [D’Arcy et al 2008, Dowling et al 2011].
  • Masseter muscle rigidity (MMR), or rigidity of the jaw muscles after administration of succinylcholine, presages clinical MH in up to 30% of cases. Even in the absence of clinical MH, myoglobinuria in individuals with MMR is common postoperatively. MMR probably occurs in individuals of all ages regardless of MHS status; however, MMR is more common in children, particularly following gas anesthesia induction.

Genotype-Phenotype Correlations

A limited number of studies have addressed genotype-phenotype correlations. See Robinson et al [2002], Robinson et al [2003], Carpenter et al [2009b].

Genotype-phenotype correlations in MHS are difficult to study. No correlation between genotype and clinical phenotype is apparent because CHCT/IVCT test results are variable among diagnostic laboratories, and clinical episodes of MHS that fulfill all criteria are rare because of successful intervention during anesthetic complications.

A recent study demonstrated that the RYR1 mutations p.Arg163Cys, p.Arg2163His, p.Arg2435His, and p.Thr4826Ile were associated with higher CK concentrations than the p.Gly2434Arg mutation. Stronger contractures and shorter response times in the response to caffeine were also features of these mutations [Carpenter et al 2009b].

Correlations exist between genotype and halothane-caffeine induced contracture response:


The penetrance of MH susceptibility is unknown. What is known is that up to 50% of individuals with MH susceptibility have undergone anesthesia uneventfully despite use of one of the agents known to trigger MH.


Anticipation is not observed.


The incidence of MH is best described by the reported incidence per anesthetic. Currently, the estimates of the incidence range from one in 3,000 anesthetics to one in 50,000 anesthetics, with most estimating an incidence in children of about one in 10,000 anesthetics and in adults of one in 50,000 anesthetics. The prevalence of MH in individuals undergoing surgery in New York state hospitals was estimated as 1:100,000 for adults [Brady et al 2009] and 3:100,000 in children [Li et al 2011]. Because many individuals undergoing surgery who experience marked hyperthermia may be coded as being MH susceptible, the exact incidence and prevalence has been difficult to clarify. It seems certain that there are more than 1,000 cases of MH in the US each year [Brandom & Muldoon 2004].

The incidence varies depending on the routine use of trigger anesthetics, as well as the prevalence of susceptibility mutations in the population; Monnier et al [2002] estimate the prevalence of one of the causative mutations at 1:2,000 to 1:3,000 individuals in the French population. Ibarra et al [2006] report similar numbers for the Japanese population.

Differential Diagnosis

Malignant hyperthermia. The combination of hypercarbia, muscle rigidity, tachycardia, hyperthermia, metabolic acidosis, and rhabdomyolysis during or shortly after anesthesia is distinctive for MH. Some syndromes share some elements of MH:

  • Sepsis shares the constellation of hyperthermia, hypercarbia, and acidosis. However, rigidity is uncommon, as is marked elevation of serum CK concentration. Leukocytosis, which is typically present with sepsis, is uncommon in MH.
  • Overheating from aggressive heating measures utilized during anesthesia, (especially in the pediatric population) causes hyperthermia, tachycardia, and sometimes acidosis.
  • Pheochromocytoma crisis marked by hypertension, tachycardia, and sometimes fever has been mistaken for MH, particularly in the postoperative period. If beta blockade is used to treat the tachycardia, heart failure may result from unopposed alpha activity.
  • Ischemic encephalopathy is manifest by failure to awaken from anesthesia, muscle rigidity sometimes progressing to opisthotonus, hyperthermia, and tachycardia. Seizures are common in this condition but not in MH.
  • Ascending tonic-clonic syndrome follows intrathecal injection of a water-soluble, high ionic radiologic contrast agent. When the agent ascends into the cerebral ventricles, the individual displays ascending tonic-clonic activity leading to frank seizures, rigidity accompanied by fever, and acidosis if respiration is compromised.
  • Thyrotoxicosis is marked by hyperthermia, hypercarbia, and tachycardia but not muscle rigidity.
  • Neuroleptic malignant syndrome (NMS) has all the features of MH, including: muscle rigidity, rhabdomyolysis, acidosis, and fever, but is manifest after administration of neuroleptic agents such as atypical antipsychotics, haloperidol, and drugs used in the treatment of schizophrenia. Postmortem high-resolution melting followed by sequencing of selected exons of RYR1 in 11 individuals who died of NMS revealed two mutations, one of which has previously been reported in individuals with MH [Sato et al 2010]. Serotonin syndrome, which is a rare reaction from serotonin uptake inhibitor drugs, displays similar signs. These syndromes occur in the non-anesthetized individual.
  • Dystrophinopathy (Duchenne or Becker muscular dystrophy). Affected individuals are at increased risk for rhabdomyolysis and life-threatening hyperkalemia with cardiac arrest following administration of succinylcholine or potent volatile anesthetics. Although these adverse events were first believed to represent a form of MH, it now appears that the pathophysiology of the hyperkalemic episodes differs from that of MH in many respects, although elevation of intracellular calcium concentration is probably common to both syndromes [Hayes et al 2008, Betzenhauser & Marks 2010].
  • Myotonic syndromes (myotonic dystrophy type 1, myotonic dystrophy type 2, myotonia congenita) can be associated with muscle rigidity mimicking MH after succinylcholine administration.


  • Succinylcholine may cause rhabdomyolysis that is not obvious on cursory physical examination in individuals who have any of the myotonic syndromes or dystrophinopathy.
  • Rhabdomyolysis may occur in the perioperative period in some individuals taking inhibitors of cholesterol formation [Turan et al 2011].

Environmental/exertional heat stress (EHS). Recent clinical, genetic, and laboratory studies using animal models provide evidence for a relationship between environmental or exertional heat stress (EHS) and MH susceptibility [Chelu et al 2006, Yang et al 2006, Durham et al 2008, Lanner et al 2012]. Some individuals who have experienced exertional heat illness have been found to be MH-susceptible based on contracture testing [Capacchione & Muldoon 2009]. In one study, one third of young military recruits who experienced exercise-induced heat illness had an abnormal contracture response.

Evidence of a relation between EHS and MHS is presented by Tobin et al [2001] in the case report of a 12-year-old boy who died from an MH-like event following participation in a football game. The boy had recovered from a previous clinical MH episode during general anesthesia with sevoflurane; sequence analysis revealed that both the boy and his father had a common RYR1 mutation (p.Arg163Cys). A more recent study found that two unrelated children who experienced fatal non-anesthetic awake episodes triggered by either a viral prodrome or exposure to environmental heat stress possessed an identical RYR1 mutation (p.Arg3983Cys), while one of the children also had a second mutation (p.Asp4505His) [Groom et al 2011].

In a study of 12 young men with exercise-induced rhabdomyolysis (ER), ten were determined to be MH susceptible on contracture testing and three had known MHS RYR1 mutations [Wappler et al 2001]. In addition, the two RYR1 mutations p.Arg401Cys and p.Arg614Cys are associated with MHS, EHS, and exercise-induced rhabdomyolysis [Davis et al 2002].

RYR1 variants have also been found to underlie ER in African American men [Sambuughin et al 2009]. This study identified three novel RYR1 variants: p.Ala933Thr, p.Gly2160Ser, and p.Thr4294Met, and two previously MH-associated variants (p.Ala1352Gly and a 9-bp insertion in exon 91) in ER subjects.

RYR1 and other myopathies. Underlying genetic changes in RYR1 may predispose to other musculoskeletal disorders. A recent study identified a large number of novel RYR1 mutations causing congenital myopathies with dominant or recessive inheritance [Klein et al 2012]. Another study by Li et al [2011] demonstrated an association between MH and other myopathies, especially muscular dystrophies. Vladutiu et al [2011] revealed that variants and mutations in RYR1 may contribute to the underlying genetic risk for non-anesthesia-induced myopathies, such as statin-induced myopathy.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with malignant hyperthermia susceptibility (MHS), the following evaluations are recommended:

  • Arterial blood gas analysis; serum concentration of electrolytes, lactate, and CK; coagulation studies; presence of myoglobin in the urine and elevated myoglobin levels in serum.
  • Continuous core temperature monitoring until the syndrome has resolved
  • Measurement of serum CK concentrations until normalized
  • Family history of anesthetic complications
  • Once the syndrome has resolved, neurologic assessment for evidence of muscle damage
  • Medical genetics consultation

Treatment of Manifestations

For management guidelines, see Guidelines/Consensus Statements and Figure 2.

Figure 2


Figure 2. MHAUS treatment guide for malignant hyperthermia

Copyright, The Malignant Hyperthermia Association of the United States (MHAUS)

Early diagnosis of MH, together with the administration of dantrolene sodium, is essential in the successful treatment of an acute episode of MH:

  • Discontinue use of potent inhalation agents and succinylcholine.
  • Increase minute ventilation to lower end-tidal CO2.
  • Get help. One resource is the Malignant Hyperthermia Association of the US (MHAUS) hotline for acute cases: 800-MH-HYPER (800-644-9737). Similar hotlines exist in other countries, specifically the UK, Germany, and Brazil.
  • Prepare and administer dantrolene: 2.5 mg/kg initial dose. Tachycardia, hypercarbia, and muscle rigidity respond rapidly; multiple doses of dantrolene may be needed. The suggested upper limit is 10 mg/kg; however, more may be given as needed. Continue dantrolene at 1.0 mg/kg every four to eight hours for 24-48 hours, titrating to the desired effect (resolution of hyperthermia, acidosis, and myoglobinemia). Dantrolene sodium is a hydantoin molecule that binds to a specific region of the RYR-1 channel. It decreases the uncontrolled release of intracellular calcium [Paul-Pletzer et al 2002]. The toxicity profile of dantrolene, when administered acutely, is extremely benign. Calcium channel blocking agents should not be administered with dantrolene because life-threatening hyperkalemia may result. Dantrolene may aggravate previously existing muscle weakness.
  • Begin cooling measures. If patient is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Stop cooling measures at core body temperature of 38.5° C.
  • Treat cardiac arrhythmias as needed. Do not use calcium channel blockers.
  • Obtain blood gases, serum concentration of electrolytes and CK, blood and urine for myoglobin, and coagulation profile. Check values every six to 12 hours. The earliest sign of rhabdomyolysis is myoglobinuria/myoglobinemia. Serum CK levels may not rise for several hours. Serum CK concentration may remain elevated for days and should be monitored until it returns to normal.
  • Treat hyperkalemia with hyperventilation, glucose and insulin, and calcium as dictated by laboratory and cardiovascular changes.
  • Ensure urine output of 2.0 mL/kg/hr with mannitol, furosemide, and fluids as needed.
  • Evaluate need for invasive monitoring and continued mechanical ventilation.
  • Observe the individual in an ICU for at least 36 hours because of the 25% chance of recrudescence following initial treatment. Dantrolene should be continued for at least 36 hours following successful treatment in a dose of about 1.0 mg/kg every six hours or more depending on whether signs of MH are present.
  • Affected individuals who display extreme hyperthermia are at risk for disseminated intravascular coagulation. A coagulation profile should be obtained on all individuals experiencing fulminant MH.
  • Refer the affected individual to the Malignant Hyperthermia Association of the US (MHAUS) for information and counseling. Complete the Adverse Metabolic Reaction to Anesthesia (AMRA) form for enrollment in the North American MH Registry.
  • Refer the individual to a MH diagnostic center for muscle biopsy and contracture testing after discussion with MH consultants associated with MHAUS.

Myoglobinuria. The presence of myoglobinuria mandates referral to a neurologist for further investigation.

Prevention of Primary Manifestations

Preventive measures for individuals known to be susceptible to MH or for any individual with an equivocal contracture test response (MHE) (treated clinically as MHS):

  • For any individual undergoing anesthesia, obtain a thorough anesthetic history to determine the possibility of the individual or a family member having experienced an MH episode. When suspicion of MHS exists, family members should not be given trigger anesthetic agents, i.e., potent volatile anesthetic agents such as halothane, sevoflurane, desflurane, enflurane, and isoflurane or the depolarizing agent succinylcholine.
  • In general, individuals undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Skin liquid crystal temperature sensors are not recommended as they have been found to be unreliable indicators of changing temperature during human malignant hyperthermia (MH) events.
  • Individuals with any form of myotonia (see Differential Diagnosis) should not receive succinylcholine.
  • Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the Medic Alert Foundation, Turlock, California (

Agents/Circumstances to Avoid

Individuals who are MH susceptible should avoid potent inhalation anesthetics and succinylcholine.

Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result.

Serotonin antagonist (5HT3-anatagonist) antiemetics should be used cautiously, as sudden death has been reported in a child with multiminicore disease caused by a mutation in RYR1 (p.Arg3983His) after receiving a therapeutic dose of ondansetron [Gener et al 2010].

Individuals with MH are generally advised to avoid extremes of heat but not to restrict athletic activity or lifestyle unless they have experienced overt rhabdomyolysis or heat stroke.

In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH [Metterlein et al 2011b].

Evaluation of Relatives at Risk

If a disease-causing mutation has been identified in the family, molecular genetic testing of at-risk relatives is warranted to identify those who also have the mutation and thus will benefit from avoiding anesthetic agents that increase the risk for a malignant hyperthermia episode.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

If a pregnant woman with MHS requires non-emergent surgery during the pregnancy, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Standard American Society of Anesthesiologists mandated monitoring should be used, along with core temperature monitoring. Fetal monitoring should follow standard guidelines. Dantrolene should not be administered in preparation for surgery or labor and delivery.

Continuous epidural analgesia is highly recommended for labor and delivery. If a Cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended, if not otherwise contraindicated. If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an MH-susceptible individual.

In the case of a fetus whose father is known to be MH susceptible but whose mother is not known to be MH susceptible, regional anesthesia or general anesthesia without trigger agents is recommended.

For further information regarding the management of pregnant women with MHS, see 2009 guidelines developed by the Malignant Hyperthermia Association of the United States.

Therapies Under Investigations

Preliminary investigation by Lanner et al [2012] has shown that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in a knock-out mouse model of MH. This finding is suggestive of possible effectiveness of AICAR in the prophylactic treatment of humans with enhanced susceptibility to exercise/ heat-induced sudden death associated with RYR1 mutations.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with MHS have a parent with MHS; the parent may not have experienced an episode of MH.
  • A proband with MHS may have the disorder as the result of a new gene mutation. De novo mutations have been detected; the proportion of individuals with MHS caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include contracture testing or molecular genetic testing, if available and if the mutation in the proband has been identified.

Note: Although most individuals diagnosed with MHS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or decreased penetrance of the MHS-causing allele.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has MHS, the risk to the sibs is 50%.
  • When the parents are clinically unaffected based on contracture testing and/or molecular genetic testing, the risk to the sibs of a proband appears to be low.
  • If an MHS-causing mutation cannot be detected in the genomic DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with MHS has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Specific risk issues. Risk for MH is predominantly a problem under general anesthesia with trigger anesthetics. A very small number of individuals with MH susceptibility appear to be at risk for heat stroke or exercise-induced rhabdomyolysis. MH has been reported to occur in individuals without anesthetic exposure [Tobin et al 2001, Groom et al 2011].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic heterogeneity. Even if the same mutation is not found in a family member of an individual with a causative mutation, the family member may still be at risk for MH: in a few families, a family member has been found to have a mutation different from that identified in the proband [Monnier et al 2003, Clarke et al 2010].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be considered.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for pharmacogenetic conditions which (like MH susceptibility) have effective treatment and prevention are not common. Prenatal testing is generally not offered. However, Girard et al [2006] reported a child diagnosed with MH based on molecular genetic testing on cord blood obtained at delivery.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • European Malignant Hyperthermia Group (EMHG)
    Dr. P. Jane Halsall, University Department of Anaesthesia, St James' University Trust Hospital
    Beckett Street
    Clinical Science Building
    Leeds LS9 7TF
    United Kingdom
    Phone: +44 113 206 52 74
    Fax: +44 113 283 69 72
  • Malignant Hyperthermia Association of the United States (MHAUS)
    11 East State Street
    PO Box 1069
    Sherburne NY 13460
    Phone: 800-644-9737 (Toll-free Emergency Hotline); 607-674-7901; 315-464-7079
    Fax: 607-674-7910
  • North American Malignant Hyperthermia Registry
    The NAMHR collects, analyzes, and disseminates information on the presentation, diagnosis, treatment, and response to treatment of MH in affected individuals.
    Phone: 888-274-7899 (toll-free)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Malignant Hyperthermia Susceptibility: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Malignant Hyperthermia Susceptibility (View All in OMIM)


Molecular Genetic Pathogenesis

A relationship between MH and environmental or exertional heat stroke has been corroborated using animal models of MH. It has long been known that pigs with MHS undergo lethal hypermetabolic episodes following prolonged elevations in ambient temperature. In addition, heat-induced MH reactions in the absence of triggering anaesthetics have been reported for heterozygous RYR1 knock-in mice harboring either the p.Tyr522Ser [Chelu et al 2006] or p.Arg163Cys [Yang et al 2006] MHS-causing mutation. The mechanism for enhanced temperature sensitivity of these mice was shown to result from S-nitrosylation of RYR1 increasing the temperature sensitivity of the release channel to activation, resulting in inappropriate channel openings and raised intracellular calcium levels [Durham et al 2008, Lanner et al 2012].

The MHS3 locus was linked to chromosome 7q21-q22. At this locus, the candidate gene CACNA2D1, which encodes a subunit of the L-type voltage-dependent calcium channel that is intimately associated at the skeletal muscle triadic junctions with the ryanodine receptor, had no pathologic mutations in a family linked to MHS3 [Schleithoff et al 1999]. Linkage to MHS3 was not confirmed in studies of other families with MHS and no CACNA2D1 mutation has yet been found in association with MHS.


Normal allelic variants. RYR1 consists of 106 exons (two of which are alternatively spliced) encompassing a total of 160 kb and produces one of the largest known proteins with 5038 amino acids. RYR1 has at least 16 normal variants in the coding region [Gillard et al 1992, Brown et al 2000] (see Table 4).

Pathologic allelic variants. More than 300 mutations in RYR1 have been associated with MHS and/or CCD. Most of the RYR1 mutations are private (i.e., observed in only one or a few families); thus, mutation detection is a major challenge. Almost all MHS-causative mutations are missense; however, an in-frame deletion of a single amino acid (p.Glu2348del) in the central region of RYR1 [Sambuughin et al 2005] and a single-nucleotide deletion at the extreme C-terminal end of the protein [Rossi et al 2007] have also been reported. See Table 4 and Table 5 (pdf).

Table 4. RYR1 Allelic Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
ReferenceReference Sequences
Normalc.2537C>Tp.Ser846LeuRobinson et al [2006]NM_000540​.2
c.4767A>Cp.Gln1589ProRobinson et al [2006]
c.5360C>Tp.Pro1787LeuGillard et al [1992]
c.6178G>Tp.Gly2060CysGillard et al [1992]
c.7648C>Gp.Val2550LeuMonnier et al [2000]
c.10747G>Cp.Glu3583GlnRobinson et al [2006]
c.11266C>Gp.Gln3756GluBrown et al [2000]
Pathologicc.103T>Cp.Cys35ArgLynch et al [1997]
c.487C>Tp.Arg163CysQuane et al [1993]
c.488G>Tp.Arg163LeuMonnier et al [2005]
c.742G>Ap.Gly248ArgGillard et al [1992]
c.2797G>Ap.Ala933ThrSambuughin et al [2009]
c.1021G>C or c.1021G>Ap.Gly341ArgQuane et al [1994b]
c.1201C>Tp.Arg401CysDavis et al [2002]
c.1209C>Gp.Ile403MetQuane et al [1993]
c.1565A>Cp.Tyr522SerQuane et al [1994a]
c.1654C>Tp.Arg552TrpKeating et al [1997]
c.1840C>Tp.Arg614CysGillard et al [1991]
c.1841G>Tp.Arg614LeuQuane et al [1997]
c.4055C>Gp.Ala1352GlySambuughin et al [2009]
c.6478G>Ap.Gly2160SerSambuughin et al [2009]
c.6488G>Ap.Arg2163HisManning et al [1998b]
c.6487C>Tp.Arg2163CysManning et al [1998b]
c.6502G>Ap.Val2168MetManning et al [1998b]
c.6617C>Tp.Thr2206MetManning et al [1998b]
Sambuughin et al [2001a]
c.7048G>Ap.Ala2350ThrSambuughin et al [2001b]
c.7282G>Ap.Ala2428ThrRueffert et al [2002]
c.7300G>Ap.Gly2434ArgKeating et al [1994]
c.7304G>Ap.Arg2435HisZhang et al [1993]
c.7360C>Tp.Arg2454CysBrandt et al [1999]
c.7361G>Ap.Arg2454HisBarone et al [1999]
c.7373G>Ap.Arg2458HisManning et al [1998a]
c.7372C>Tp.Arg2458CysManning et al [1998a]
c.10579C>Tp.Pro3527SerFerreiro Fardeau [2002]
c.11947C_Tp.Arg3983CysGroom et al [2011]
c.12881C>Tp.Thr4294MetSambuughin et al [2009]
c.13513G_Cp.Asp4505HisGroom et al [2011]
c.14477C>Tp.Thr4826IleBrown et al [2000]
c.14510delAp.Arg4837fs*4839Rossi et al [2007]
c.14545G>Ap.Val4849IleJungbluth et al [2002]
c.14693T>Cp.Ile4898ThrLynch et al [1999]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. RYR1 encodes the skeletal muscle calcium release channel located in the sarcoplasmic reticulum (SR) (also known as ryanodine receptor type 1). The functional channel is a homotetramer of 560-kd subunits and releases calcium stored in the SR in response to membrane depolarization transduced by the dihydropyridine receptor (DHPR). The cytoplasmic domain, also called the foot structure, is formed by the first approximately 4000 amino acids and bridges the gap between the SR and the transverse tubular membrane. The last 1000 amino acids form the transmembrane domain and contain the permeation pathway and pore of the channel [Ramachandran et al 2009].

Abnormal gene product. MHS-causing mutations in RYR1 cause Ca2+ release channels in the sarcoplasmic reticulum to exhibit an increased sensitivity to activation by both endogenous (e.g., voltage sensor) and exogenous (e.g., caffeine, halothane) triggers. This global hypersensitivity of the SR Ca2+ mechanism predisposes skeletal muscle uncontrolled Ca2+ release during an MH event.


Normal allelic variants. The gene spans 90 kb and consists of 44 exons.

Pathologic allelic variants. A few dominant mutations have been identified in several families with MHS [Jurkat-Rott et al 2000, Carpenter et al 2009, Pirone et al 2010, Toppin et al 2010]. Three mutations (p.Arg1086His, p.Thr1354Ser, and p.Arg174Trp) have been functionally characterized [Weiss et al 2004, Pirone et al 2010, Eltit et al 2012]. See Table 6.

Table 6. CACNA1S Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

Normal gene product. CACNA1S encodes the α1 subunit of the pentameric (α1, α2-δ, β, and γ) dihydropyridine receptor (DHPR, also termed voltage sensor or L-type calcium channel) in skeletal muscle. The skeletal muscle DHPR is located in the transverse tubule membrane and acts simultaneously as both a voltage sensor for activation of the SR ryanodine receptor and as a voltage-dependent L-type Ca2+ channel [Dirksen & Avila 2002]. The α1 subunit contains all the pore and gating structures of the channel and comprises four homologous repeats connected by large cytoplasmic loops. The fourth transmembrane segment of each repeat (S4) possesses positively charged amino acids approximately every third residue and contributes to the "voltage-sensing" region of the channel. Sarcolemmal depolarization during an action potential induces voltage-driven conformational changes in the S4 segments of the DHPR that rapidly trigger the opening of nearby SR Ca2+ release channels (ryanodine receptors or RyR1s). Although the intracellular loop that links the second and third repeat (II-III loop) plays a critical role in mechanical activation of RyR1 by the DHPR following depolarization [Nakai et al 1998], other regions of the DHPR α1 [Leong & MacLennan 1998] and β subunits [Cheng et al 2005] of the DHPR have also been suggested to interact with RyR1 and influence RyR1-mediated SR Ca2+ release [Eltit et al 2012].

Abnormal gene product. Three of the five identified MHS-causing mutations in CACNA1S (p.Arg1086His, p.Arg1086Cys, and p.Arg1086Ser) result in mutation of a highly conserved arginine residue in the intracellular loop linking repeats III and IV of the DHPR α1 subunit. Similar to that observed for MH-causing mutations in RYR1, the p.Arg1086His mutation in CACNA1S increases the sensitivity of the SR Ca2+ release mechanism to activation by both caffeine and voltage [Weiss et al 2004]. A fourth CACNA1S mutation, p.Arg174Trp, was identified in a family with MH that does not harbor an RYR1 mutation [Carpenter et al 2009a]. The p.Arg174Trp mutation was recently proposed to sensitize RyR1 to MH triggers by enhancing basal RyR1 Ca2+ leak out of the SR [Eltit et al 2012]. Finally, a p.Thr1354Ser mutation located in the IVS5-S6 extracellular pore-loop was shown to accelerate L-type Ca2+ current activation in addition to increasing the caffeine sensitivity of RyR1-mediated SR Ca2+ release [Pirone et al 2010].

Thus, MHS is similarly caused by mutations in RYR1 (MHS1) and both the α1 (MHS5) and α2 δ subunits (MHS3) of the skeletal muscle DHPR, proteins that are each critically involved in coordinating the excitation-contraction process in skeletal muscle. This indicates that the pathogenesis of MH reflects a dysfunction in the muscle EC coupling process and that MHS resulting from mutations at other loci (e.g., MHS2, MHS4, and MHS6) is likely to involve functional alterations to other protein members of the release complex.

Calsequestrin type 1 (calsequestrin-1) is an acidic, moderate-affinity, high-capacity Ca2+-binding protein located in the terminal cisternae of the sarcoplasmic reticulum. The protein is encoded by CASQ1 and functions to concentrate exchangeable Ca2+ ions near sites of RYR1-mediated Ca2+ release. Calsequestrin-1 is physically tethered to RYR1 via triadin and junctin, forming a quaternary RYR1-triadin-junctin-calsequestrin-1 complex that modulates the luminal Ca2+ sensitivity of the RYR1 Ca2+ release channel [Beard et al 2004]. Interestingly, genetically engineered mice lacking calsequestrin-1 develop normally, but when anesthetized with MH trigger agents such as halothane develop malignant hyperthermia. This finding indicates that intracellular hypercalcemia originating from many different fundamentally distinct etiologies can result in an MH response [Dainese et al 2009].


Published Guidelines/Consensus Statements

North American Guidelines for Testing

  1. Litman RS, Rosenberg H. Malignant hyperthermia – update on susceptibility testing. Available online. 2005. Accessed 1-23-13.
  2. Sei Y, Sambuughin N, Muldoon S. Malignant hyperthermia genetic testing in North America Working Group Meeting. Bethesda, Maryland. September 4-5, 2002. Availabe online. 2004. Accessed 1-23-13.

European Guidelines for Testing

  1. Urwyler A, Deufel T, McCarthy T, West S; European Malignant Hyperthermia Group. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Available online. 2001. Accessed 1-23-13. [PubMed: 11573677]
  2. Robinson RL, Hopkins PM. A breakthrough in the genetic diagnosis of malignant hyperthermia. Available online (registration or institutional access required). 2001. Accessed 1-23-13.
  3. Carpenter D, Robinson RL, Quinnell RJ, Ringrose C, Hogg M, Casson F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA, Hopkins PM. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Available online. 2009. Accessed 1-23-13. [PubMed: 19648156]

Guidelines on Diagnosis, Management, and Transfer of Care from Ambulatory Surgery Centers

  1. Glahn KP, Ellis FR, Halsall PJ, Müller CR, Snoeck MM, Urwyler A, Wappler F; European Malignant Hyperthermia Group. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Available online. 2010. Accessed 1-23-13. [PubMed: 20837722]
  2. Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Available online. 2012. Accessed 1-23-13. [PubMed: 22052978]

North American Consensus Statements

  1. Mitochondrial myopathies and malignant hyperthermia susceptibility (pdf)
  2. MH susceptibility and operating room personnel (pdf)
  3. Temperature monitoring during surgical procedures (pdf)
  4. Preparation of anesthesia workstations to anesthetize mh-susceptible patients (pdf)
  5. Parturient with MHS partner (pdf)
  6. Adverse effects of heat and exercise in relation to MH susceptibility (pdf)

Literature Cited

  1. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS. Anesthesiology. 1998;88:579–88. [PubMed: 9523799]
  2. Barone V, Massa O, Intravaia E, Bracco A, Di Martino A, Tegazzin V, Cozzolino S, Sorrentino V. Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families. J Med Genet. 1999;36:115–8. [PMC free article: PMC1734304] [PubMed: 10051009]
  3. Beard NA, Laver DR, Dulhunty AF. Calsequestrin and the calcium release channel of skeletal and cardiac muscle. Prog Biophys Mol Biol. 2004;85:33–69. [PubMed: 15050380]
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Suggested Reading

  1. Britt BA, Kalow W. Malignant hyperthermia: aetiology unknown. Can Anaesth Soc J. 1970;17:316–30. [PubMed: 4317096]
  2. Hirshey Dirksen SJ, Larach MG, Rosenberg H, Brandom BW, Parness J, Lang RS, Gangadharan M, Pezalski T. Special article: Future directions in malignant hyperthermia research and patient care. Anesth Analg. 2011;113:1108–19. [PMC free article: PMC3184381] [PubMed: 21709147]
  3. Lerman J. Perioperative management of the paediatric patient with coexisting neuromuscular disease. Br J Anaesth. 2011;107 Suppl 1:i79–89. [PubMed: 22156273]
  4. MacLennan DH, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk RG, Frodis W, Britt BA, Worton RG. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature. 1990;343:559–61. [PubMed: 1967823]
  5. Torpy JM, Lynm C, Glass RM. JAMA patient page. Malignant hyperthermia. JAMA. 2005;293:2958. [PubMed: 15956641]

Chapter Notes


Supported by grants from the National Institutes of Health (AR044657, AR053349 and AR052354 to RTD).

Author History

Robert T Dirksen, PhD (2006-present)
Sheila Riazi, MD (2013-present)
Henry Rosenberg, MD (2003-present)
Nyamkhishig Sambuughin, PhD (2003-2006; 2010-present)

Revision History

  • 31 January 2013 (me) Comprehensive update posted live
  • 19 January 2010 (me) Comprehensive update posted live
  • 12 May 2006 (me) Comprehensive update posted to live Web site
  • 19 December 2003 (me) Review posted to live Web site
  • 19 June 2003 (hr) Original submission
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