Version July 2025
INTRODUCTION —
This monograph discusses the interpretation and possible interventions following genetic testing for three genes (RYR1, CACNA1S, and STAC3) that can cause susceptibility to malignant hyperthermia (MHS).
It is not intended to replace clinical judgment in the decision to test or in the care of the individual who was tested. These details are discussed separately in UpToDate [1]. (See 'Resources' below.)
HOW TO READ THE REPORT
Review which genes were tested — Determine which genes were tested and whether testing involved gene sequencing or evaluating a panel of variants.
Gene sequencing should include all coding exons of these three genes (RYR1, CACNA1S, and STAC3). Interrogating only specific variants or subsets of coding exons is considered suboptimal, unless a familial pathogenic or likely pathogenic variant is known and testing is being done specifically for that variant.
Clinical correlation — Malignant hyperthermia (MH) is a hypermetabolic reaction with skeletal muscle rigidity and elevated body temperature due to sustained muscle contraction [2]. It generally requires a triggering exposure (volatile inhalation anesthetic agent or succinylcholine). Not all exposures to a triggering agent in an individual with MHS will necessarily cause MH, and prior reactions (or lack of reactions) do not predict future reactions.
The exact mechanism(s) by which implicated anesthetics interact with the variant receptors is not well understood. The pathophysiology of MH is discussed separately. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Pathophysiology'.)
Often the first sign of MH in an anesthetized patient is hypercapnia (increase in end-tidal carbon dioxide [CO2]). This is thought to occur due to excessive muscle contraction leading to acidosis. The rapid increase in body temperature and rhabdomyolysis can be fatal if not treated urgently. (See "Malignant hyperthermia susceptibility: Evaluation and management".)
In some individuals, a hypermetabolic state may be induced by increased body temperature or intensive exercise. (See "Malignant hyperthermia susceptibility: Evaluation and management", section on 'Non-anesthesia-related MH-like episodes'.)
Some individuals have a myopathy that may be identified later in life. (See 'Myopathy' below.)
Determine why testing was done — Determine whether testing was performed to evaluate a positive personal or family history of MH/MHS or as a cascade test for a relative who carries a known MHS causative gene variant.
Ascertain whether the individual and/or any close relative has had symptoms that could be attributed to MHS and whether they may have received a volatile inhalational anesthetic agent or succinylcholine. Often this information is only available in the anesthesia record, and the individuals may not know which agent(s) they have received. They may also not have had a procedure requiring anesthesia.
If testing is performed for a positive family history of MHS, it is prudent to confirm that the variant identified in the tested individual is the same causative variant present in the relative with MHS, whenever possible. If such an individual was only tested for variants in one of the three MHS genes or only underwent partial testing of RYR1 (so-called "hot-spot" sequencing) and testing was negative, further testing is needed.
Consultation with an MHS or genetics expert is prudent for individuals with a personal or family history suggestive of MHS. (See 'Resources' below.)
Guidance on evaluating myopathy is discussed briefly below and in more detail separately. (See 'Myopathy' below and "Congenital myopathies", section on 'Central core disease'.)
Variant of uncertain significance (VUS) — Pathogenicity of many variants in MHS genes remains uncertain. Typically, this is because there is insufficient information to determine whether the variant is associated with MHS or is merely a benign change from the reference sequence. When such a variant is encountered in clinical testing, it is most often classified as a VUS.
It can be challenging to make a proper clinical-molecular diagnosis in such individuals; their likelihood of having MHS depends on their pretest probability of disease.
●Individuals with a history of an MH reaction who carry a VUS in one of these genes (and no pathogenic variant in any of the others) should be treated as if they have MHS. They can continue to check periodically for information on the variant using a database (such as EMHG or ClinVar) or consulting with a genetics or MHS specialist, or they can undergo contracture testing. (See 'Resources' below and 'Contracture testing' below.)
●In individuals who do not have a personal or family history of MHS, a VUS in one of these genes is likely insufficient to conclude that they have MHS.
MHS GENETICS
Inheritance
●RYR1 and CACNA1S – RYR1- and CACNA1S-related malignant hyperthermia susceptibility (MHS) are inherited in an autosomal dominant pattern. Inheritance of a pathogenic variant in an MHS gene from one parent is sufficient to cause MHS. However, the family history may fail to show a typical autosomal dominant pattern (figure 1), since some relatives may not have been exposed to a volatile inhalation anesthetic, the exposure history may be uncertain, and not all exposures cause a malignant hyperthermia (MH) event.
•For an individual with a personal or family history of MH/MHS who has a pathogenic or likely pathogenic variant in RYR1 or CACNA1S, the diagnosis of MHS is confirmed.
•If an individual with a negative personal or family history of MH/MHS has an incidental finding of a pathogenic or likely pathogenic variant in RYR1 or CACNA1S, they should be considered to have MHS until proven otherwise.
●STAC3 – STAC3-related MHS is inherited in an autosomal recessive pattern. In most cases, an individual with MH/MHS will have inherited a pathogenic or likely pathogenic variant from both parents. Interpretation of a positive result from genetic testing requires further testing (such as testing parents). An MHS or genetics expert should be consulted. (See 'Resources' below.)
Specific genes — Approximately 80 percent of individuals with MHS will have a pathogenic or likely pathogenic variant in an MHS gene identified by genetic testing; this is considered first-line testing and is sufficient for a confirmed diagnosis [3].
RYR1 — Ryanodine receptors (RyRs) are large homotetrameric ion channels that release calcium from intracellular stores during excitation-contraction coupling [4]. There are three tissue-specific genes. The skeletal muscle gene is RYR1 [2].
Pathogenic variants in RYR1 are the most common cause of MHS [2]. Hundreds of variants in RYR1 have been classified, although only a minority are pathogenic or likely pathogenic. From a comprehensive report of 335 variants in RYR1, 86 were classified as pathogenic or likely pathogenic, 30 were benign or likely benign, and 219 were variants of uncertain significance (VUS) [5].
In addition to MHS, some pathogenic variants in RYR1 can cause exertional rhabdomyolysis, atypical periodic paralyses, and central core disease (CCD), a congenital myopathy associated with hypotonia and weakness [4]. An association with statin myopathy is unclear. (See "Statin muscle-related adverse events".)
While the above referenced RYR1 variants are associated with autosomal dominant inheritance of MHS, other pathogenic variants in RYR1 are associated with myopathy, which can be inherited in an autosomal recessive or autosomal dominant pattern. (See 'Myopathy' below and "Congenital myopathies", section on 'Central core disease'.)
CACNA1S — CACNA1S encodes the alpha-1 subunit of the dihydropyridine (DHP) receptor, a skeletal muscle voltage-activated calcium channel upstream of the RyR [6].
Pathogenic variants in CACNA1S can cause MHS, but these are less prevalent than RYR1 variants.
STAC3 — STAC3 encodes a protein that interacts with the alpha-1 subunit of the DHP receptor.
Pathogenic variants in STAC3 can cause MHS as well as STAC3-related congenital myopathy (also called Bailey-Bloch congenital myopathy or Native American myopathy [NAM]).
CLINICAL IMPLICATIONS
Counseling — Malignant hyperthermia (MH) is a life-threatening condition that can occur when an individual with MHS is exposed to certain volatile anesthetics or succinylcholine (also called suxamethonium) [7]. (See "Malignant hyperthermia susceptibility: Evaluation and management".)
Individuals with MHS should receive education and counseling of the following (algorithm 1):
●Inform all clinicians providing surgical or anesthetic care about the diagnosis of MHS and that they must avoid volatile anesthetic gasses and succinylcholine. (See 'Management of anesthesia' below.)
●Wear a medic-alert bracelet to make their MHS status visible to any clinicians caring for them. Information is available from MHS organizations. (See 'MHS organizations' below.)
●Share the diagnosis with all first-degree relatives so they can have the option for testing if desired. (See 'Implications for relatives' below.)
●Maintain hydration, especially with exercise; avoid hyperthermia; and be especially careful in hot, humid weather. (See 'Myopathy' below.)
●Referral to a neurologist to evaluate for possible myopathy syndromes.
Individuals with a variant of uncertain significance (VUS) in an MHS gene should inform all clinicians about their VUS and the possibility that they may have MHS. Other implications depend on the perceived likelihood of MHS.
Contracture testing — The in vitro contracture test (IVCT) is considered a secondary test for individuals for whom genetic testing is inconclusive [3]. It is performed on a muscle biopsy (typical size, 1.5 to 2 inches) [8]. Testing is definitive if positive, but sensitivity is estimated at only about 85 percent. (See "Malignant hyperthermia susceptibility: Evaluation and management", section on 'Contracture test'.)
This test is only available in a few specialized centers. Because it involves an invasive procedure, it is generally reserved for individuals for whom there is a strong suspicion of MHS (clinical event or strongly positive family or personal history) and for whom a causative genetic variant cannot be identified. It may be performed more commonly in European countries than in the United States.
Management of anesthesia
●Prevention of MH – All individuals who have MHS based on clinical or genetic features (see 'MHS genetics' above) who require anesthesia should receive nontriggering anesthesia and should not be exposed to volatile inhalational anesthetic agents or succinylcholine (suxamethonium). (See "Malignant hyperthermia susceptibility: Evaluation and management", section on 'Management of anesthesia in malignant hyperthermia-susceptible patients'.)
Individuals with possible MHS (based on a history suggestive of MH or diagnosis of MHS in a relative) should follow the same principles until tested.
When receiving any anesthetic, these individuals should have close monitoring of core body temperature and minute ventilation in addition to other vital signs, end-tidal carbon dioxide (CO2), and other standard American Society of Anesthesiologists (ASA)-recommended monitoring [9].
●Treatment of MH – This subject is discussed separately. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)
Myopathy — Some individuals with pathogenic variants in MHS genes may have an exertional myopathy or exertional rhabdomyolysis in addition to MHS. Syndromes are summarized in the table (table 1). Myopathies may be apparent early in life (eg, severe scoliosis due to muscle weakness), or may be mild and unappreciated until adulthood. An association with statin-induced myopathy is unclear. (See "Rhabdomyolysis: Epidemiology and etiology" and "Rhabdomyolysis: Clinical manifestations and diagnosis".)
These individuals should avoid dehydration, especially during exercise, and should be careful in hot, humid weather due to the risk of nonexertional heat illness (heat stroke). (See "Exertional heat illness in adolescents and adults: Management and prevention".)
Early use of an antipyretic for fever is prudent. (See "Pathophysiology and treatment of fever in adults", section on 'Treatment of fever and hyperpyrexia'.)
IMPLICATIONS FOR RELATIVES —
All first-degree relatives of an individual with MHS should be offered testing (termed "cascade testing"). Other relatives may also be candidates for cascade testing (eg, grandchildren, if children are not available). Ideally, the causative variant is first identified in an affected individual, and relatives can be tested for that variant. (See "Malignant hyperthermia susceptibility: Evaluation and management", section on 'Testing for family members'.)
Genetic testing is generally preferred because it is noninvasive. Results are sufficient for diagnosis if positive or if negative for a known familial variant, with caveats mentioned above. (See 'How to read the report' above.)
Genetic testing can be performed at any age. Unlike hereditary cancer syndromes, where genetic testing carries major implications for prevention and surveillance, MHS is a risk factor for a complication that can occur at any age and is easy to avoid once the diagnosis is established. Some data suggest that the penetrance of MHS (likelihood of a reaction if exposed to a triggering agent) is higher in childhood than in adulthood. Thus, there is not a strong rationale to delay testing until adulthood.
RESOURCES
Guidelines and UpToDate topics
●Guidelines – (See "Society guideline links: Malignant hyperthermia".)
●Anesthesia – (See "Anesthesia for children with myopathy and for children who undergo muscle biopsy".)
●MH susceptibility – (See "Malignant hyperthermia susceptibility: Evaluation and management".)
●MH acute management (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)
Genetics experts
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
MHS organizations
●Malignant Hyperthermia Association of the United States (MHAUS) – mhaus.org/healthcare-professionals/
●24-hour emergency support from MHAUS – 1-800-MH-HYPER (1-800-644-9737)
●European Malignant Hyperthermia Group – emhg.org/
●Malignant Hyperthermia Group of Australia and New Zealand (MHANZ) – malignanthyperthermia.org.au/malignant-hyperthermia-group-of-australia-and-new-zealand/
●RYR1 Foundation – ryr1.org/
ACKNOWLEDGMENT —
Dr. Biesecker contributed to this article in his personal capacity. The views expressed are his own and do not necessarily represent the views of the National Institutes of Health or the United States Government.
