Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Malignant Hyperthermia Susceptibility
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Malignant hyperthermia (MH) has an estimated prevalence of 1/60,000-1/100,000. However, as many individuals undergoing surgery who experience marked hyperthermia may be coded as being MH susceptible, the exact prevalence has been difficult to clarify. It seems certain that there are more than 1,000 cases of MH in the US each year. It is unclear whether all MH cases are due to a mutation in RYR1 or CACNA1S.
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Clinical Features
(Signs / symptoms)
MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics, either alone or with a depolarizing muscle relaxant, may trigger uncontrolled skeletal muscle hypermetabolism. In rare cases, similar episodes may also be triggered by heat and exercise. An MH episode may begin with hypercapnia and tachycardia followed by hyperthermia. Additional symptoms may include increased CO2 production, increased O2 consumption, acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, and hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure.
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Natural History
(Important subgroups & survival / recovery)
In nearly all cases, the first manifestations of MH occur during anesthetization in the operating room, though manifestations may also occur within an hour or so of anesthesia termination. MH presentation can vary depending on the triggering agents and environmental factors, such as metabolic state and body temperature, at the beginning of anesthesia. Without proper and prompt treatment, mortality is extremely high. Even with treatment and survival, the individual is at risk for life-threatening consequences and recurrence of the syndrome within the first 24-36 hours following an episode. A significant male preponderance has been reported.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following identification of RYR1 and/or CACNA1S pathogenic variant(s) as a secondary finding:
If a pregnant woman with MHS requires 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 spinalepidural) 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. (Tier 4)
MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. (Tier 2)
No surveillance recommendations have been provided for the Adult context.
Circumstances to Avoid
Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (Desflurane, Enflurane, Halothane, Isoflurane, Sevoflurane) and depolarizing muscle relaxants (Succinylcholine). (Tier 2)
MHS patients who have not experienced adverse effects of heat and exercise should not restrict their activity, and those who have experienced adverse effects of heat or exercise should restrict their activity based on their own experience. (Tier 2)
In individuals with MH undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it is associated with development of clinical signs of MH. (Tier 3)
Serotonin antagonist (5HT3-anatagonist) antiemetics should be used cautiously. Sudden death was reported in a child with multiminicore disease caused by a mutation in RYR1 after receiving a therapeutic dose of ondansetron (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Mutations
Mutations in RYR1 are identified in up to 70-80% of MHS cases, while CACNA1S mutations account for 1% of cases. (Tier 3)
Causative mutations have been estimated to have a prevalence of 1/2000-1/3000 in the French and Japanese populations. (Tier 3)
(Include any high risk racial or ethnic subgroups)
The penetrance of MHS is unknown. What is known is that up to 50% of individuals with MHS have undergone anesthesia uneventfully despite use of one of the agents known to trigger MH. (Tier 4)
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available.
An MH episode may not occur with every exposure to "trigger" agents. Clinical manifestation may depend on genetic predisposition, dose of trigger agents, or duration of exposure. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified include avoidance of certain anesthetic agents and potential avoidance of heat and heavy exercise. These interventions are mildly burdensome and pose minimal risk.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Under usual care, a patient may be exposed to a triggering anesthetic agent which could result in high morbidity or potential mortality. (Tier 4)

Scoring Groups Info
Scoring Group
Gene Disease Pair(s)

Final Consensus Scores
OutcomeScoring Group / InterventionScoring GroupPair
Nature of the
Morbidity from malignant hyperthermia event GroupA / Avoidance of triggering anesthetics GroupA
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. H Rosenberg, N Sambuughin, S Riazi, R Dirksen. Malignant Hyperthermia Susceptibility. 2003 Dec 19 [Updated 2013 Jan 31]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from:
2. Rosenberg H, Rueffert H. Clinical utility gene card for: malignant hyperthermia. Eur J Hum Genet. (2011) 19(6).
3. Gurunluoglu R, Swanson JA, Haeck PC. Evidence-based patient safety advisory: malignant hyperthermia. Plast Reconstr Surg. (2009) 124(4 Suppl):68S-81S.
4. Malignant hyperthermia. Orphanet encyclopedia,
5. MHAUS Recommendation Adverse effects of heat and exercise on MH susceptibility. Other. (2009) Website:
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