Clinical 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 volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into 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 cardiac arrest, and myoglobinuria with a risk for kidney failure. In nearly all individuals, the first manifestations of MH (hypercapnia, tachycardia, and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality can be over 80%.

Diagnosis/testing.

The diagnosis of MHS is established with in vitro muscle contracture testing by measuring the contracture responses of biopsied muscle samples to halothane and graded concentrations of caffeine. The diagnosis of MHS can also be established by identification of a pathogenic variant in RYR1 (in 60%-70% of individuals with MHS), CACNA1S (~1%), or STAC3 (<1%) by molecular genetic testing.

Management.

Targeted therapy: Administration of intravenous dantrolene sodium (initial dose of 2.5 mg/kg) as early as possible during an MH episode.

Treatment of manifestations: Early diagnosis of an MH episode is essential. Successful treatment of an acute episode of MH, in addition to administration of intravenous dantrolene sodium, includes: discontinuation of potent inhalation agents and succinylcholine; increase in minute ventilation to lower end-tidal CO₂; communication with Malignant Hyperthermia Association of the US (MHAUS) helpline; cooling measures if body temperature is >38.5 °C; treatment of cardiac arrhythmias if needed (do not use calcium channel blockers); monitoring blood gases, serum concentrations of electrolytes and CK, blood and urine for myoglobin, and coagulation profile; treatment of metabolic abnormalities.

Prevention of primary manifestations: Individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Individuals with MHS should carry proper identification (e.g., MedicAlert^® bracelet) as to their susceptibility.

Agents/circumstances to avoid: Avoid potent inhalation anesthetics and succinylcholine. Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result. Serotonin antagonist (5-HT3 antagonist) antiemetics should be used cautiously. Individuals with MHS should avoid extremes of heat but not restrict athletic activity unless there is a history of overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution. In individuals with MHS undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH.

Evaluation of relatives at risk: It is appropriate to clarify the status of at-risk relatives of an individual diagnosed with MHS to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include: multigene panel testing (if the MHS-related causative variant in the family is known) and muscle biopsy and contracture testing (if the MHS-causative pathogenic variant in the family is not known or if an at-risk relative is found to be negative for the familial pathogenic variant on targeted testing but has not undergone multigene panel testing).

Pregnancy management: If a pregnant woman with MHS requires a non-emergent surgery, 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 individual with MHS.

Genetic counseling.

MHS is inherited in an autosomal dominant manner. Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH. Each child of an individual with MHS has a 50% chance of being MH susceptible. If an MHS-causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MHS should be suspected in individuals presenting with clinical findings 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 MHS as determined by malignant hyperthermia (MH) experts using a Delphi method. Points are assigned according to weight and are then summed to produce a raw score, which translates to a likelihood of MH score, ranging from a raw score of 0 (MH rank 1: almost never / very unlikely) to a raw score ≥50 (MH rank 6: almost certain) [Larach et al 1994]. The more criteria an individual fulfills, the more likely that an MH episode has occurred. For example, with only temperature elevation during anesthesia, an individual is not likely to be susceptible to MH. A limitation of the scoring system is that not every clinical finding may be measured (e.g., arterial blood gas); MH must also be recognized very quickly and treated before all the signs appear.

Establishing the Diagnosis

The diagnosis of MHS is established in a proband with:

• A positive diagnostic contracture test OR
• A heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 3 identified by molecular genetic testing.

Note: (1) Molecular genetic testing is not 100% sensitive; MHS cannot be excluded based on failure to identify a pathogenic or likely pathogenic variant in one of the genes listed in Table 3. In such instances, contracture testing should be performed at an MH muscle biopsy center. (2) The pathogenicity of a variant is established through variant classification that includes numerous attributes, including functional analysis (see Molecular Genetics). (3) It is critical to distinguish variant pathogenicity for isolated or nonsyndromic MHS from MHS that is associated with symptomatic myopathy. The latter is a pleiotropic, phenotypically heterogeneous disorder with a broad differential diagnosis and a high degree of genetic heterogeneity (see Tables 4 and 5a). A pathogenic variant that causes myopathy may not cause MHS.

Clinical Description

The manifestations of malignant hyperthermia (MH) result from exposure to 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. MH is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism [Rosenberg et al 2015] with variable clinical presentations (depending on the triggering agents and environmental factors, such as metabolic state and body temperature) at the beginning of anesthesia.

The triggering substances initiate uncontrolled release of calcium from the sarcoplasmic reticulum via the skeletal muscle calcium release channel and may promote entry of extracellular calcium into the myoplasm leading to the sustained pathologic increase in cytosolic calcium in skeletal muscle cells [Yang et al 2007, Duke et al 2010, Riazi et al 2018a]. Increased myoplasmic calcium causes contracture of skeletal muscles and activates glycogenolysis and cell metabolism, resulting in excessive production of heat and excess lactate. Activation of the oxidative cycle leads to high oxygen consumption and high carbon dioxide production.

MH clinical manifestations are variable; with prompt and rapid clinical response, some signs may not appear. Hypercapnia is common, as is tachycardia. Hyperthermia may be one of the early signs of MH. However, failure to monitor core temperature may lead to a delay in detecting hyperthermia. Skin temperature measurement is often misleading during MH crises [Larach et al 2010]. Acidosis may be mild if the syndrome is recognized and treated promptly. Elevated plasma creatine kinase (CK) levels (hyperCKemia) and rhabdomyolysis are more common when succinylcholine has been used but may be mild or not appear at all in some individuals. In some instances, rhabdomyolysis does not appear for several hours. Hyperkalemia, leading to cardiac arrhythmia and even cardiac arrest, is uncommon if MH 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 (see Figure 1) [Jurkat-Rott et al 2000].

Figure 1.

Clinical features of malignant hyperthermia susceptibility Note: Early diagnosis and rapid therapy are both lifesaving and lead to a reduction of clinical symptoms.

MH may appear at any point during anesthesia or within an hour or so after 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 (CO₂) levels, hypertension, marked temperature elevation, and arrhythmias are often 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 most instances, the first manifestations of MH occur in the operating room. In classic MH, the initial signs are tachycardia, rapidly rising end-tidal CO_2, 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, sweating on occasion, and cyanosis in rare instances. Blood gas analyses usually show hypercarbia (PCO₂ >60 mm Hg) and respiratory and metabolic acidosis without oxygen desaturation. Elevation of end-tidal CO₂ greater than 55 mm Hg 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, lactic acidemia, and myoglobinuria are also characteristic but not always present. The 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 kidney failure, disseminated intravascular coagulation (DIC), compartment syndrome, and recrudescence of the syndrome within the first 24-36 hours following the episode. 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 heart, kidney, or liver dysfunction; coma or change in consciousness level; pulmonary edema; and DIC [Larach et al 2010].

Early diagnosis and rapid therapy are lifesaving and lead to a reduction of clinical symptoms. Modern anesthetic care and monitoring often allow early detection of MH. Treatment with dantrolene results in much lower morbidity and mortality than when MH was first recognized in the 1960s; however, mortality may be as high as 11% [Rosero et al 2009]. The likelihood of any complication increases 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 these 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 (including absence of dantrolene), insufficient and unprepared personnel, and problems in stabilizing an affected individual before 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).

MH 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.

Note: An MH episode may not occur with every exposure to "trigger" agents; clinical manifestations depend on genetic predisposition, dose of trigger agents, duration of trigger exposure, and other preoperative factors including intense exercise and pyrexia [Riazi et al 2022]. Susceptible individuals may have one or even several uneventful anesthetic exposures to a triggering agent and then have a fulminant MH reaction to the same or a distinct triggering agent. The absence of a prior MH reaction is not a guarantee that a future reaction will not occur.

Signs similar to MH have also been reported without exposure to anesthetic agents. In some instances, similar signs follow overdose of MDMA agonists, or with heat and exercise.

Phenotype Correlations by Gene

Stronger contractures and shorter response times in response to caffeine exposure have been reported in individuals with an RYR1 pathogenic variant [Carpenter et al 2009] compared to those with either CACNA1S- or STAC3-related MHS-causing pathogenic variants.

Genotype-Phenotype Correlations

Genotype-phenotype correlations in individuals with MHS are limited. A few studies specifically addressed genotype-phenotype correlations in individuals with RYR1-related MHS [Manning et al 1998, Robinson et al 2002, Robinson et al 2003, Monnier et al 2005, Carpenter et al 2009].

No clinically relevant genotype-phenotype correlations for STAC3 have been identified.

Penetrance

In a multicenter case-control study, the overall penetrance for RYR1-related MHS was 40.6% [Ibarra Moreno et al 2019]. This contrasts with population genomic data that show a prevalence of pathogenic and likely pathogenic variants at one to two orders of magnitude greater than the rate of MH reactions [Mungunsukh et al 2019, Yu et al 2024]. These data suggest that the penetrance of RYR1-related MHS is less than 5%.

Prevalence

The incidence of MH is best described by the reported incidence per anesthesia procedure. The estimates of the incidence range from one in 3,000 anesthesia procedures to one in 50,000 anesthesia procedures, with most estimating an incidence in children of about one in 10,000 anesthesia procedures and in adults of one in 50,000 anesthesia procedures. The prevalence of MH in individuals undergoing surgery in New York State hospitals was estimated at one in 100,000 for adults [Brady et al 2009] and three in 100,000 for children [Li et al 2011]. Because many individuals who experience marked hyperthermia while undergoing surgery may be coded as being MH susceptible, the exact incidence and prevalence has been difficult to clarify. It appears certain that there are more than 1,000 cases of MH in the United States each year [Brandom & Muldoon 2004]. The incidence varies depending on the routine use of trigger anesthetics.

Gonsalves et al [2013] identified a prevalence of 0.46% (4/870) for MHS-related RYR1 pathogenic variants. Using RYR1 and CACNA1S genomic databases, the estimated prevalence of an MHS-related pathogenic variant was one in 1,556 [Mungunsukh et al 2019]. A recent population-based exome screening study showed that the incidence of pathogenic or likely pathogenic RYR1 variants can be as high as one in 600 [Kelly et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MHS, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

For management guidelines, see Published Guidelines / Consensus Statements and Figure 2 [Hopkins et al 2015, Hopkins et al 2018, Riazi et al 2018b, Glahn et al 2025].

Prevention of Primary Manifestations

Preventive measures for individuals known to be susceptible to MH:

• 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 anesthesia that exceeds 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 MH events.
• Individuals with any form of myotonia (see Differential Diagnosis) should not receive succinylcholine.
• Individuals with central core disease (OMIM 117000), multiminicore disease (OMIM 255320), nemaline myopathy, congenital fiber-type disproportion, or a dystrophinopathy should not receive trigger anesthetics.
• Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the MedicAlert^® Foundation.

Agents/Circumstances to Avoid

Individuals with MHS 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 (5-HT3 antagonist) antiemetics should be used cautiously, as sudden death has been reported in a child with multiminicore disease caused by a pathogenic variant in RYR1 (c.11948G>A [p.Arg3983His]) after receiving a therapeutic dose of ondansetron [Gener et al 2010].

Individuals with MHS are generally advised to avoid extremes of heat but not to restrict athletic activity or lifestyle unless they have experienced overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution.

In individuals with MHS 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

It is appropriate to clarify the status of at-risk relatives of an individual diagnosed with MHS to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include the following:

• Molecular genetic testing. If the MHS-related causative pathogenic variant in the family is known, molecular genetic testing can be used to establish increased risk of MH in a heterozygous individual. It is critical that the testing of relatives is done using a multigene panel (as described in Molecular Genetic Testing: Recommended Tier 1 Testing). Targeted testing only for the familial pathogenic variant is inadequate and discouraged. If the relative is tested with a multigene panel that includes RYR1, CACNA1S, and STAC3 and does not have the familial causative variant, nor any other pathogenic or likely pathogenic variant in the relevant genes, they are likely at or below the general population risk for MHS.
• Muscle biopsy and contracture testing. If the MHS-causative pathogenic variant in the family is not known or if an at-risk relative is found to be negative for the familial pathogenic variant on targeted testing but has not undergone multigene panel testing, muscle contracture testing (performed at an MH muscle biopsy center) can be used to assess susceptibility to MH. In the absence of such testing (which can be difficult to access), close relatives of an individual with MHS should also be treated as MH susceptible.

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 individual with MHS.

In the case of a fetus whose father has MHS but whose mother is not known to have MHS, regional anesthesia or general anesthesia without trigger agents is recommended. This is because administration of a triggering agent (specifically volatile anesthetics that can cross the placenta) to the unaffected mother can trigger an MH reaction in an affected fetus, which could be severe or fatal to the fetus.

For further information regarding the management of pregnant women with MHS, see 2009 guidelines developed by MHAUS and Hopkins et al [2015].

Therapies Under Investigations

Various agents (i.e., salbutamol, pyridostigmine, and N-acetylcysteine) have been investigated as potential treatments for RYR1-related disorders, but none have been proven to be effective. Oral dantrolene has shown to be effective in relieving daily muscular symptoms (myalgia, cramps, and rhabdomyolysis) not triggered by anesthetics in individuals with MHS [Ibarra Moreno et al 2024].

Rycal^®, a benzothiazepine-derived compound that stabilizes ryanidine receptor 1 (encoded by RYR1) in the closed state in skeletal and cardiac muscle by restoring calstabin binding, was shown to decrease the excessive calcium leak ex vivo when applied to muscle from individuals with RYR1-related myopathy [Kushnir et al 2020]. A Phase I clinical trial found Rycal S48168^® (ARM210^®) reduced fatigue and improved muscle strength in individuals with RYR1-related disorders [Todd et al 2024].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Note: Genetic counseling for myopathic disorders that predispose to classic malignant hyperthermia (MH) is not addressed in this section (see Clinical Description).

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH.
• An individual diagnosed with MHS may have the disorder as the result of a de novo pathogenic variant. De novo pathogenic variants have been detected; however, the proportion of individuals with MHS caused by a de novo variant is unknown.
• If neither parent is known to have MHS, evaluation of the parents is recommended to inform recurrence risk counseling and assess their risk for MH. Evaluations include:
  • Molecular genetic testing using a multigene panel (as described in Tier 1 Testing) if the MHS-causative pathogenic variant has been identified in the proband); and
  • Muscle contracture testing (performed at an MH muscle biopsy center) (see Evaluation of Relatives at Risk).
• If a molecular diagnosis has been established in the proband, the MHS-causative pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with MHS may appear to be negative because of reduced penetrance of the MHS-causative pathogenic variant or absence of a triggering event in heterozygous family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband.

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 and/or is known to have an MHS-causative pathogenic variant, the risk to the sibs of having MHS is 50%.
• If the proband has a known MHS-causative pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of inheriting the pathogenic variant is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with MHS has a 50% chance of having MHS.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has had an episode of MH and/or is known to have an MHS-causative pathogenic variant, members of the parent's family are at risk.

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.

Specific risk issues. Risk for MH is predominantly a problem under general anesthesia with trigger anesthetics. Some individuals with MHS appear to also be at risk for heat stroke or exercise-induced rhabdomyolysis. MH has been reported to occur in individuals without anesthetic exposure [Groom et al 2011, Zvaritch et al 2019].

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If an MHS-causative variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Changes in intracellular calcium levels in skeletal muscle are largely controlled through calcium storage, release, and reuptake via the sarcoplasmic reticulum (SR), the primary intracellular calcium storage and release organelle in muscle. Ryanodine receptor 1 (RYR1), encoded by RYR1, functions as a calcium-permeable channel in the SR. RYR1 calcium release channels are located in the terminal region of the SR, which lies adjacent to either side of a transverse tubule membrane, an invagination of the surface membrane. This three-membrane structure (two terminal SR membranes bisected by a single transverse tubule membrane) is referred to as the triad. During excitation-contraction (EC) coupling, an action potential initiated at the neuromuscular junction rapidly propagates across the surface membrane and down the transverse tubule membranes. The resulting depolarization of the transverse tubule membrane potential activates dihydropyridine receptors, encoded by CACNA1S, which trigger the opening of RYR1 calcium release channels in the adjacent terminal SR. The massive release of SR calcium elevates myoplasmic calcium to levels sufficient to drive muscle contraction and force generation. SH3 and cysteine-rich domain-containing protein 3 (STAC3), encoded by STAC3, is an adapter protein that binds to the dihydropyridine receptor and is required for depolarization-mediated activation and opening of RYR1 SR calcium release channels. Thus, the three genes linked to MH (RYR1, CACNA1S, and STAC3) are all intimately involved in controlling calcium release from the SR during EC coupling.

In MHS, pathogenic variants in RYR1, CACNA1S, and STAC3 result in an increased sensitivity of the RYR1 SR calcium release channel to activators of these channels. Therapeutic levels of volatile anesthetics and succinylcholine are not normally sufficient to activate/open RYR1 SR calcium release channels. However, pathogenic variants in these proteins linked to MHS result in increased sensitization of the SR calcium release mechanism to therapeutic levels of these clinical agents. When this happens, RYR1 channels are directly activated by therapeutic levels of these agents, leading to uncontrolled calcium release, sustained muscle contraction, increased heat production, muscle damage, and metabolic crisis. Sustained muscle contraction results in increased oxygen use, carbon dioxide production, lactic acid accumulation, and, thus, metabolic acidosis and hypercapnia. Cell membrane damage due to hypercontractures results in increased permeability and release of creatine kinase (CK) and potassium into the circulation, which can lead to kidney damage and fatal arrhythmias, respectively.

Dantrolene sodium inhibits RYR1 calcium release/leak from the SR and thus reverses the process.

Mechanism of disease causation. Gain of function

Gene-specific laboratory technical considerations. Note that because of the gain-of-function disease mechanism, genetic heterogeneity, and variable expressivity of this disorder, data from functional studies are critical in reaching a likely pathogenic or pathogenic classification using ACMG criteria.

The consequence of RYR1 variants on RYR1 function can be analyzed by one or more of the following test systems using recombinant in vitro expression on a defined genetic background:

• Measurement of calcium release in response to trigger agents in HEK293 cells [Tong et al 1997, Sambuughin et al 2001b, Ying et al 2025]
• Measurement of calcium release in response to trigger agents in myotubes derived from dyspedic (RYR1 knockout) mice transfected with a rabbit RYR1 cDNA construct-containing variant being tested [Yang et al 2003]

In addition, MHS diagnosis can be established by calcium measurements and ligand-binding studies of the following preparation derived from affected individuals:

• Myotubes [Brinkmeier et al 1999]
• Microsomal SR preparations from muscle biopsy [Richter et al 1997]
• Microsomal SR preparations from lymphoblasts [Tilgen et al 2001]

All assays should be performed on samples from at least two independent affected individuals with the same variant.

Individuals with MHS with a positive halothane contracture response but not a positive caffeine contracture response exhibit a high incidence of both musculoskeletal clinical symptoms (e.g., weakness/fatigue, pain/cramps, sensitivity to heat or exercise, hyperCKemia, and altered histopathology) and abnormal calcium events in muscle [Figueroa et al 2019, Figueroa et al 2023].

An in vitro caffeine-induced Ca²⁺ release sensitivity assay has been validated to assess the relative functional impact of RYR1 variants purported to be associated with MHS [Ying et al 2025]. This assay can be used to support Variant Curation Expert Panel criteria weighting of RYR1 variants. Beyond the in vitro contracture test (IVCT), caffeine/halothane contracture test (CHCT), and Ca²⁺ release sensitivity assays, additional clear correlations of genotype to clinical phenotype are lacking. This is in part due to variability in IVCT/CHCT test results from various diagnostic laboratories and clinical episodes of MHS fulfilling all criteria being rare because of successful intervention during anesthetic complications. Several studies have documented discordance of genetic test results and muscle contracture tests [Deufel et al 1995, Ibarra Moreno et al 2020].

In addition to pathogenic CACNA1S variants exhibiting positive IVCT/CHCT results, other CACNA1S variants result in either CACNA1S-related myopathy or CACNA1S-related hypokalemic periodic paralysis. The relative MH susceptibility of these individuals is unclear.

Exon 91 of RYR1 is highly guanine-cytosine rich.

Author Notes

Sheila Riazi (ac.nhu@izair.aliehs) is actively involved in clinical research regarding individuals with malignant hyperthermia susceptibility and would be happy to communicate with persons who have any questions regarding diagnosis of malignant hyperthermia or other considerations.

Sheila Riazi and Leslie Biesecker (vog.hin.liam@bsel) are interested in hearing from clinicians treating families affected by RYR1-related disorders in whom no causative variant has been identified through molecular genetic testing.

Acknowledgments

The authors are supported by grants from the National Institutes of Health (R01AR082209 and R01AR078000 to RTD and HG200328-19 and HG200388-11 to LGB) and University of Toronto (Department of Anesthesiology and Pain Medicine Merit award to SR).

Author History

Leslie G Biesecker, MD (2025-present)
Robert T Dirksen, PhD (2006-present)
Sheila Riazi, MD (2013-present)
Henry Rosenberg, MD (2003-present)
Nyamkhishig Sambuughin, PhD; Henry M Jackson Foundation (2003-2006; 2010-2025)

Revision History

• 7 August 2025 (sw) Comprehensive update posted live
• 16 January 2020 (sw) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 19 January 2010 (me) Comprehensive update posted live
• 12 May 2006 (me) Comprehensive update posted live
• 19 December 2003 (me) Review posted live
• 19 June 2003 (hr) Original submission

Published Guidelines / Consensus Statements

Literature Cited

• 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]
• Brady JE, Sun LS, Rosenberg H. LiG. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001–2005. Anesth Analg. 2009;109:1162–6. [PubMed: 19762744]
• Brandom BW, Larach MG, Chen MS, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg. 2011;112:1115–23. [PMC free article: PMC3498049] [PubMed: 21372281]
• Brandom BW, Muldoon SM. Estimation of the incidence of malignant hyperthermia using a capture-recapture method in the USA. Abstract A1267. Las Vegas, NV: American Society of Anesthesiologists Annual Meeting. 2004.
• Brinkmeier H, Kramer J, Kramer R, et al. Malignant hyperthermia causing Gly2435Arg mutation of the ryanodine receptor facilitates ryanodine-induced calcium release in myotubes. Br J Anaesth. 1999;83:855–61. [PubMed: 10700782]
• Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007;106:901-6. [PubMed: 17457120]
• Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg. 2009;109:1065–9. [PubMed: 19617585]
• Carpenter D, Robinson RL, Qunnel RJ, Ringrose C, Hogg M, Cason F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA, Hopkins PM. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009;103:538–48. [PubMed: 19648156]
• Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J. 2006;20:329–30. [PubMed: 16284304]
• Davis M, Brown R, Dickson A, Horton H, James D, Laing N, Marston R, Norgate M, Perlman D, Pollock N, Stowell K. Malignant hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. Br J Anaesth. 2002;88:508–15. [PubMed: 12066726]
• Deufel T, Sudbrak R, Feist Y, Rübsam B, Du Chesne I, Schäfer KL, Roewer N, Grimm T, Lehmann-Horn F, Hartung EJ, et al. Discordance, in a malignant hyperthermia pedigree, between in vitro contracture-test phenotypes and haplotypes for the MHS1 region on chromosome 19q12-13.2, comprising the C1840T transition in the RYR1 gene. Am J Hum Genet. 1995;56:1334-42. [PMC free article: PMC1801094] [PubMed: 7762556]
• Duke AM, Hopkins PM, Calaghan SC, Halsall JP, Steele DS. Store-operated Ca2+ entry in malignant hyperthermia-susceptible human skeletal muscle. J Biol Chem. 2010;285:25645–53. [PMC free article: PMC2919128] [PubMed: 20566647]
• Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Gilman CP, Galvan DL, Baker M, Shirokova N, Protasi P, Dirksen RT, Hamilton S. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock-in mice. Cell. 2008;133:53–65. [PMC free article: PMC2366094] [PubMed: 18394989]
• Figueroa L, Kraeva N, Manno C, Ibarra-Moreno CA, Tammineni ER, Riazi S, Rios E. Distinct pathophysiological characteristics in developing muscle from patients susceptible to malignant hyperthermia. Br J Anaesth. 2023;131:47-55. [PMC free article: PMC10308439] [PubMed: 36792386]
• Figueroa L, Kraeva N, Manno C, Toro S, Ríos E, Riazi S. Abnormal calcium signaling and the caffeine halothane contracture test. Br J Anaesth. 2019;122:32-41. [PMC free article: PMC6334558] [PubMed: 30579404]
• Flucher BE. Skeletal muscle Ca_V1.1 channelopathies. Pflugers Arch. 2020;472:739-54. [PMC free article: PMC7351834] [PubMed: 32222817]
• Gardner L, Miller DM, Daly C, Gupta PK, House C, Roiz de Sa D, Shaw MA, Hopkins PM. Investigating the genetic susceptibility to exertional heat illness. J Med Genet. 2020;57:531-41. [PubMed: 32054689]
• Gener B, Burns JM, Griffin S, Boyer EW. Administration of ondansetron is associated with lethal outcome. Pediatrics. 2010;125:e1514–7. [PubMed: 20439600]
• Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, Snoeck MM, Urwyler A; European Malignant Hyperthermia Group. Recognition and management of a malignant hyperthermia crisis: updated 2024 guideline from the European Malignant Hyperthermia Group. Br J Anaesth. 2025;134:221-23. [PubMed: 39482150]
• Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG, et al. Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013;119:1043–53. [PMC free article: PMC4077354] [PubMed: 24195946]
• Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee HS, Qiu X, Sambuughin N, Dirksen RT. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology. 2011;115:938–45. [PMC free article: PMC3203251] [PubMed: 21918424]
• Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018;157:645–61. [PubMed: 30459030]
• Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531–9. [PubMed: 26188342]
• Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W, Sprague SM, Stamm DS, Powell CM, Speer MC, Franzini-Armstrong C, Hirata H, Kuwada JY. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun. 2013;4:1952. [PMC free article: PMC4056023] [PubMed: 23736855]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Ibarra Moreno CA, Hu S, Kraeva N, Schuster F, Johannsen S, Rueffert H, Klingler W, Heytens L, Riazi S. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic RYR1 mutations. Anesthesiology. 2019;131:983–91. [PMC free article: PMC9912949] [PubMed: 31206373]
• Ibarra Moreno CA, Kraeva N, Zvaritch E, Figueroa L, Rios E, Biesecker L, Van Petegem F, Hopkins PM, Riazi S. A multi-dimensional analysis of genotype-phenotype discordance in malignant hyperthermia susceptibility. Br J Anaesth. 2020;125:995-1001. [PMC free article: PMC7729844] [PubMed: 32861507]
• Ibarra Moreno CA, Silva HCA, Voermans NC, Jungbluth H, van den Bersselaar LR, Rendu J, Cieniewicz A, Hopkins PM, Riazi S. Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review. Br J Anaesth. 2024;133:759-67. [PMC free article: PMC11443134] [PubMed: 39107166]
• Johnston JJ, Dirksen RT, Girard T, Hopkins PM, Kraeva N, Ognoon M, Radenbaugh KB, Riazi S, Robinson RL, Saddic Iii LA, Sambuughin N, Saxena R, Shepherd S, Stowell K, Weber J, Yoo S, Rosenberg H, Biesecker LG. Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2022;31:4087-93. [PMC free article: PMC9703808] [PubMed: 35849058]
• Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve. 2000;23:4–17. [PubMed: 10590402]
• Karan SM, Crowl F, Muldoon SM. Malignant hyperthermia masked by capnographic monitoring. Anesth Analg. 1994;78:590–2. [PubMed: 8109781]
• Kelly MA, Leader JB, Wain KE, Bodian D, Oetjens MT, Ledbetter DH, Martin CL, Strande NT. Leveraging population-based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project. Am J Med Genet C Semin Med Genet. 2021;187:83-94. [PubMed: 33576083]
• Kraeva N, Sapa A, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: A retrospective cohort study and updated systematic review. Can J Anaesth. 2017;64:736–43. [PubMed: 28326467]
• Kushnir A, Todd JJ, Witherspoon JW, Yuan Q, Reiken S, Lin H, Munce RH, Wajsberg B, Melville Z, Clarke OB, Wedderburn-Pugh K, Wronska A, Razaqyar MS, Chrismer IC, Shelton MO, Mankodi A, Grunseich C, Tarnopolsky MA, Tanji K, Hirano M, Riazi S, Kraeva N, Voermans NC, Gruber A, Allen C, Meilleur KG, Marks AR.. Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. Acta Neuropathol 2020;139:1089e104 [PMC free article: PMC7788518] [PubMed: 32236737]
• Lanner JT, Georgiou DK, Dagnino-Acosta A, Ainbinder A, Cheng Q, Joshi AD, Chen Z, Yarotskyy V, Oakes JM, Lee CS, Monroe TO, Santillan A, Dong K, Goodyear L, Ismailov II, Rodney GG, Dirksen RT, Hamilton SL. AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nat Med. 2012;18:244-51. [PMC free article: PMC3274651] [PubMed: 22231556]
• Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, Rosenberg H, Valedon A, Watson CB, et al. Special article: Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114:94–100. [PubMed: 22052978]
• Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110:498–507. [PubMed: 20081135]
• Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE, Ording H, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80:771–9. [PubMed: 8024130]
• Li G, Brady JE, Rosenberg H, Sun LS. Excess comorbidities associated with malignant hyperthermia diagnosis in pediatric hospital discharge records. Paediatr Anaesth. 2011;21:958–63. [PubMed: 21722230]
• Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA. 2005;293:2918–24. [PubMed: 15956637]
• Manning BM, Quane KA, Ording H, Urwyler A, Tegazzin V, Lehane M, O'Halloran J, Hartung E, Giblin LM, Lynch PJ, Vaughan P, Censier K, Bendixen D, Comi G, Heytens L, Monsieurs K, Fagerlund T, Wolz W, Heffron JJ, Muller CR, McCarthy TV. Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation. Am J Hum Genet. 1998;62:599-609. [PMC free article: PMC1376943] [PubMed: 9497245]
• Metterlein T, Zink W, Kranke E, Haneya A, Graf B, Kranke P. Cardiopulmonary bypass in malignant hyperthermia susceptible patients: a systematic review of published cases. J Thorac Cardiovasc Surg. 2011b;141:1488–95. [PubMed: 21376345]
• Miller DM, Daly C, Aboelsaod EM, et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth 2018;121:944–52. [PMC free article: PMC6208294] [PubMed: 30236257]
• 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;26:413-25. [PubMed: 16163667]
• Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997;60:1316–25. [PMC free article: PMC1716149] [PubMed: 9199552]
• Mungunsukh O, Deuster P, Muldoon S, O'Connor F, Sambuughin N. Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. Br J Anaesth. 2019;123:e461–e463. [PubMed: 31301762]
• Ng Kwet Shing RH, Smith SL. A novel rapid formulation of intravenous dantrolene: Preclinical assessment. Eur J Anaesthesiol Intensive Care. 2024;3:e0059. [PMC free article: PMC11798400] [PubMed: 39917422]
• Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg. 2009;109:1054–64. [PubMed: 19762732]
• Paul-Pletzer K, Yamamoto T, Bhat MB, Ma J, Ikemoto N, Jimenez LS, Morimoto H, Williams PG, Parness J. Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor. J Biol Chem. 2002;277:34918–23. [PubMed: 12167662]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Riazi S, Bersselaar L, Islander G, Heytens L, Snoeck MMJ, Bjorksten A, Gillies R, Dranitsaris G, Hellblom A, Treves S, Kunst G, Voermans NC, Jungbluth H. Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH). Neuromuscul Disord. 2022;32:628-34. [PubMed: 35738978]
• Riazi S, Kraeva N, Hopkins PM. Malignant hyperthermia in the post-genomics era: new perspectives on an old concept. Anesthesiology. 2018a;128:168–80. [PMC free article: PMC5726912] [PubMed: 28902675]
• Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018b;65:709-21. [PubMed: 29600483]
• Richter M, Schleithoff L, Deufel T, Lehmann-Horn F, Hermann-Frank A. Functional characterisation of distinct ryanodine receptor mutation in human malignant hyperthermia susceptible muscle. J Biol Chem. 1997;272:5256–60. [PubMed: 9030597]
• Robinson RL, Anetseder MJ, Brancadoro V, Van Broekhoven C, Carsana A, Censier K, Fortunato G, Girard T, Heytens L, Hopkins PM, Jurkat-Rott K, Klinger W, Kozak-Ribbens G, Krivosic R, Monnier N, Nivoche Y, Olthoff D, Rueffert H, Sorrentino V, Tegazzin V, Mueller CR. Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing? Eur J Hum Genet. 2003;11:342–8. [PubMed: 12700608]
• Robinson RL, Brooks C, Brown SL, Ellis FR, Halsall PJ, Quinnell RJ, Shaw MA, Hopkins PM. RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat. 2002;20:88–97. [PubMed: 12124989]
• Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: A review. Orphanet J Rare Dis. 2015;10:93. [PMC free article: PMC4524368] [PubMed: 26238698]
• Rosero EB, Adesanya AL, Timarra CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States 2000-2005. Anesthesiology. 2009;110:89–94. [PubMed: 19104175]
• Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, Hopkins PM, Johannsen S, Snoeck MM, Urwyler A, Glahn KPE; European Malignant Hyperthermia Group. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126:120-30. [PubMed: 33131754]
• Ryanodex. A new dantrolene formulation for malignant hyperthermia. Med Lett Drugs Ther. 2015;57:100. [PubMed: 26147894]
• Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet. 2009;76:564–8. [PubMed: 19807743]
• Sambuughin N, Mungunsukh O, Klein MG, Ren M, Bedocs P, Kazman JB, Cofer K, Friel LP, McNally B, Kwon K, Haigney MC, Leggit JC, Pazgier M, Deuster PA, O'Connor FG. Genetics of exertional heat illness: revealing new associations and expanding heterogeneity. Int J Mol Sci. 2024;25:11269. [PMC free article: PMC11508780] [PubMed: 39457051]
• Sambuughin N, Nelson TE, Jankovic J, Xin C, Meissner G, Mullakandov M, Ji J, Rosenberg H, Sivakumar K, Goldfarb LG. Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families. Neuromuscul Disord. 2001b;11:530–7. [PubMed: 11525881]
• Sato T, Nishio H, Iwata M. Kentotsuboi, Tamura A, Miyazaki T, Suzuki K. Postmortem molecular screening for mutations in ryanodine receptor type 1 (RYR1) gene in psychiatric patients suspected of having died of neuroleptic malignant syndrome. Forensic Sci Int. 2010;194:77–9. [PubMed: 19931341]
• Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet. 2001;59:178–84. [PubMed: 11260227]
• Tilgen N, Zorzato F, Halliger-Keller B, et al. Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis. Hum Mol Genet. 2001;10:2879–87. [PubMed: 11741831]
• Todd JJ, Lawal TA, Chrismer IC, Kokkinis A, Grunseich C, Jain MS, Waite MR, Biancavilla V, Pocock S, Brooks K, Mendoza CJ, Norato G, Cheung K, Riekhof W, Varma P, Colina-Prisco C, Emile-Backer M, Meilleur KG, Marks AR, Webb Y, Marcantonio EE, Foley AR, Bönnemann CG, Mohassel P. Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial. eClinicalMedicine 2024;68:102433. [PMC free article: PMC10839573] [PubMed: 38318125]
• Tong J, Oyamada H, Demaurex N, Grinstein S, McCarthy TV, MacLennan DH. Caffeine and Halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and/or central core disease. J Biol Chem. 1997;272:26332–9. [PubMed: 9334205]
• Turan A, Mendoza ML, Gupta S, You J, Gottlieb A, Chu W, Saager L, Sessler DI. Consequences of succinylcholine administration to patients using statins. Anesthesiology. 2011;115:28–35. [PubMed: 21606827]
• van den Bersselaar LR, Heytens L, Silva HCA, Reimann J, Tasca G, Díaz-Cambronero Ó, Løkken N, Hellblom A, Hopkins PM, Rueffert H, Bastian B, Vilchez JJ, Gillies R, Johannsen S, Veyckemans F, Muenster T, Klein A, Litman R, Jungbluth H, Riazi S, Voermans NC, Snoeck MMJ. European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders. Eur J Neurol. 2022;29:3486-507. [PMC free article: PMC9826444] [PubMed: 35971866]
• Vladutiu GD, Isackson PJ, Kaufman K, Harley JB, Cobb B, Christopher-Stine L, Wortmann RL. Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Mol Genet Metab. 2011;104:167–73. [PMC free article: PMC3171598] [PubMed: 21795085]
• Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology. 2001;94:95–100. [PubMed: 11135728]
• Yang T, Allen PD, Pessah IN, Lopez JR. Enhanced excitation-coupled calcium entry in myotubes is associated with expression of RyR1 malignant hyperthermia mutations. J Biol Chem. 2007;282:37471–8. [PubMed: 17942409]
• Yang T, Riehl J, Esteve E, Matthaei KI, Goth S, Allen PD, Pessah IN, Lopez JR. Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology. 2006;105:1164–75. [PubMed: 17122579]
• Yang T, Ta TA, Pessah IN, Allen PD. Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. J Biol Chem. 2003;278:25722–30. [PubMed: 12732639]
• Ying EZ, Douglass A, Hawari MA, Groom L, Stowell K, Dirksen RT, Johnston JJ, Biesecker LG. Calibrating a functional assay for variant classification in RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2025;34:945-51. [PMC free article: PMC13031167] [PubMed: 40192509]
• Yu KD, Betts MN, Urban GM, Schwartz MLB, Robinson TO, Moyer RJ, Taddonio SW, Vasudevan A, Johns A, Sturm AC, Kelly MA, Williams MS, Poler SM, Buchanan AH. Evaluation of malignant hyperthermia features in patients with pathogenic or likely pathogenic RYR1 variants disclosed through a population genomic screening program. Anesthesiology. 2024;140:52-61. [PubMed: 37787745]
• Zaharieva IT, Sarkozy A, Munot P, Manzur A, O'Grady G, Rendu J, Malfatti E, Amthor H, Servais L, Urtizberea JA, Neto OA, Zanoteli E, Donkervoort S, Taylor J, Dixon J, Poke G, Foley AR, Holmes C, Williams G, Holder M, Yum S, Medne L, Quijano-Roy S, Romero NB, Fauré J, Feng L, Bastaki L, Davis MR, Phadke R, Sewry CA, Bönnemann CG, Jungbluth H, Bachmann C, Treves S, Muntoni F. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018;39:1980–94. [PubMed: 30168660]
• Zvaritch E, Gillies R, Kraeva N, Richer M, Jungbluth H, Riazi S. Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series. Can J Anaesth. 2019;66:540-5. [PubMed: 30805902]