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 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 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 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 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 is extremely high.

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 CACNA1S, RYR1, or STAC3 on molecular genetic testing.

Management.

Treatment of manifestations: Early diagnosis of an MH episode is essential. Successful treatment of an acute episode of MH includes: discontinuation of potent inhalation agents and succinylcholine; increase in minute ventilation to lower end-tidal CO₂; use of MHAUS helpline; administration of dantrolene sodium intravenously; 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 with MHS should not be exposed to potent volatile agents and succinylcholine. Individuals undergoing general anesthetics that exceed 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Individuals with MHS should carry proper identification 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 of a potential cardiac depressant effect. Serotonin antagonist (5HT3-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 MH 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: If the MHS-causative pathogenic variant in the family is known, molecular genetic testing can be used to established increased risk of MH in a heterozygous individual; molecular genetic testing alone cannot be used to identify family members who are not at increased risk for MH because of other possible genetic risk factors. If the pathogenic variant in the family is not known or if an at-risk relative is found to be negative for a familial pathogenic variant, muscle contracture testing can be used to assess susceptibility to MH.

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 MH-susceptible individual.

Genetic counseling.

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder. Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH. The proportion of individuals with MHS caused by a de novo pathogenic variant is unknown. Each child of an individual with MHS has a 50% chance of inheriting a causative pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if there is a known MH pathogenic variant in the family.

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 totaled 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 may also 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 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 variant in one of the genes listed in Table 3. In such cases contracture testing should be performed at an MH muscle biopsy center. (2) A variant is established as pathogenic through variant assessment that includes functional analysis (see Molecular Genetics).

Clinical Description

The manifestations of malignant hyperthermia (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. 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 (RyR1), and also 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 2018]. 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. HyperCKemia and rhabdomyolysis are more common when succinylcholine has been used but may be mild or not appear at all in some individuals, for reasons that are not clear. In some instances 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.

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

MH may appear at any point during anesthetization 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 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 instances, the first manifestations of MH occur in the operating room. In classic MH, the initial signs are tachycardia, rapidly rising end-tidal C0_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, on occasion sweating, and in rare cases cyanosis. Blood gas analysis usually reveals hypercarbia (P_CO2>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, lactacidemia, and myoglobinuria are characteristic but not always present. 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. 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 MH. Treatment with dantrolene results in much lower morbidity and mortality than first reported when MH was recognized in the 1960s [Larach et al 2008]; however, 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 (including absence of dantrolene), insufficient and unprepared personnel, and 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).

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.

Of note, an MH episode may not occur with every exposure to "trigger" agents; clinical manifestations depend on genetic predisposition, dose of trigger agents, and duration of trigger exposure.

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

Genotype-Phenotype Correlations

Genotype-phenotype correlations in MHS are difficult to study. No correlation between genotype and clinical phenotype is apparent because caffeine/halothane contracture test / in vitro contracture 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 limited number of studies have addressed genotype-phenotype correlations in individuals with RYR1-related MHS [Robinson et al 2002, Robinson et al 2003, Carpenter et al 2009]. Stronger contractures and shorter response times in the response to caffeine have been reported in individuals with an RYR1 pathogenic variant [Carpenter et al 2009].

No genotype-phenotype correlations for STAC3 have been identified.

No genotype-phenotype correlations for CACNA1S have been identified.

Penetrance

In a multicenter case-control study, the overall penetrance for RYR1-related MHS was 40.6%. The probability of developing MH on exposure to triggers was 0.25 among all individuals with an RYR1 pathogenic variant and 0.76 in survivors of MH reactions (95% CI of the difference 0.41 to 0.59) [Ibarra Moreno et al 2019].

Prevalence

The incidence of MH is best described by the reported incidence per anesthetic. 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 at 1:100,000 for adults [Brady et al 2009] and 3:100,000 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 US 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. Based on genetic variation data of more than 60,000 individuals (gnomad.broadinstitute.org; accessed 6-1-22), the combined prevalence of MHS-related RYR1 pathogenic variants was estimated at 1:2750 [Riazi et al 2018]. Using RYR1 and CACNA1S genomic databases, the estimated prevalence of an MHS-related pathogenic variant was 1:1556 [Mungunsukh et al 2019].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with malignant hyperthermia susceptibility (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 Guidelines / Consensus Statements and Figure 2 [Litman & Rosenberg 2005, Glahn et al 2010, Hopkins et al 2015, Hopkins et al 2018, Riazi et al 2018].

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 ryanodine receptor 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 the individual is hyperthermic, administer iced solutions, ice packs to groin, axilla, and neck, nasogastric lavage with iced solution, or more aggressive measures as needed. Monitor body temperature every 30 minutes. 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 (INR, PTT, D-dimer) 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 (INR, PTT, D-dimer) 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 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:

• 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 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 Duchenne or Becker muscular dystrophy should not receive trigger anesthetics.
• Individuals with MHS should carry proper identification as to their susceptibility; identification bracelets are available through the Medic Alert Foundation.

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-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 (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

It is appropriate to clarify the status of at-risk relatives of an affected individual in order 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:

• If the MHS-causative pathogenic variant in the family is known, molecular genetic testing can be used to established increased risk of MH in a heterozygous individual; molecular genetic testing alone cannot be used to identify family members who are not at increased risk for MH because of other possible genetic risk factors [Hopkins et al 2015].
• If the pathogenic variant in the family is not known or if an at-risk relative is found to be negative for the familial pathogenic variant, muscle contracture testing can be used to assess susceptibility to MH.

Note: Molecular genetic testing can only be used to assess inherited risk of MH if the familial variant has been established as pathogenic through variant assessment that includes functional analysis, and assessment of co-segregation.

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.

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

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 knockout mouse model of MH. This finding is suggestive of possible effectiveness of AICAR in the prophylactic treatment of humans with enhanced susceptibility to exercise- or heat-induced sudden death associated with RYR1 pathogenic variants.

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 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; the parent may not have experienced an episode of MH.
• A proband 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, recommendations for evaluation of the parents include molecular genetic testing if the MHS-causative pathogenic variant has been identified in the proband and muscle contracture testing (see Evaluation of Relatives at Risk).
• 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 inheriting the pathogenic variant 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 theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If both parents are clinically unaffected based on contracture testing, the risk to the sibs of a proband is the same as in the general population.

Offspring of a proband. Each child of an individual with MHS has a 50% chance of inheriting the MHS-causative pathogenic variant.

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.

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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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).

Prenatal Testing and Preimplantation Genetic Testing

Once the MHS-causative pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

Intracellular calcium is controlled through a storage site within the muscle called the sarcoplasmic reticulum. A channel called the ryanodine receptor type 1 (RYR1), encoded by RYR1, controls the release of calcium from the sarcoplasmic reticulum, In MHS, pathogenic variants in RYR1 cause the RYR1 channel to become leaky, leading to an uncontrolled rise in calcium levels within the muscle cell. When this happens, muscle contraction is activated, metabolism increases in order to sustain the contraction, and heat results from the metabolic processes.

Uncontrolled muscle contraction also increases production of acid in the muscle as a result of depletion of energy stores. The cell membrane permeability decreases leading to potassium leakage, which may lead to fatal arrhythmias and creatine kinase leakage into the circulation.

Dantrolene sodium reverses the leak of calcium from the sarcoplasmic reticulum and stops 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.

Functional 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]
• Measurement of calcium release in response to trigger agents in myotubes of the dyspedic mouse (RYR1-knockout) transfected with a rabbit RYR1 cDNA construct-containing variant being tested [Yang et al 2003].

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

• Myotubes [Brinkmeier et al 1999];
• Microsomal sarcoplasmic reticulum preparations from muscle biopsy [Richter et al 1997];
• Microsomal sarcoplasmic reticulum 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.

Acknowledgments

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

• 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

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