Malignant Hyperthermia Susceptibility

Actionability Pediatric Summary Report

Genes: CACNA1S (HGNC:1397) RYR1 (HGNC:10483)
Mode(s) of Inheritance:
Literature Search: 06/15/2015
Curation Status: In Preparation (0.0.0)
Release History
Related Reports
Adult Summary Report: (1.1.2)

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
CACNA1S N/A (0018493) 601887 Assertion Pending
RYR1 N/A (0018493) 145600 Assertion Pending

Actionability Assertion Rationale

  • This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
No scores were found.

Prevalence of the Genetic Condition

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.
View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146, Rosenberg H, et al. (2011) PMID: 21248738

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.
View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146, Gurunluoglu R, et al. (2009) PMID: 20827241, Malignant hyperthermia. Orphanet encyclopedia, ORPHA: 423.

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.
View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146, Malignant hyperthermia. Orphanet encyclopedia, ORPHA: 423.

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.

Mode of Inheritance

Prevalence of Genetic Variants

1-2 in 5000
Mutations in RYR1 are identified in up to 70-80% of MHS cases, while CACNA1S mutations account for 1% of cases.
Tier 3 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

Causative mutations have been estimated to have a prevalence of 1/2000-1/3000 in the French and Japanese populations.
Tier 3 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown
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 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown
Information on relative risk was not available.

Expressivity

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 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

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.

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: https://www.acmg.net/PDFLibrary/Malignant-Hyperthermia.pdf
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 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status.
Tier 2 View Citations

(2009) URL: www.mhaus.org.

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 View Citations

Gurunluoglu R, et al. (2009) PMID: 20827241

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 View Citations

(2009) URL: www.mhaus.org.

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 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

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 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

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.

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.
Context: Adult

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.
Context: Adult
Tier 4 View Citations

H Rosenberg, et al. (2003) NCBI: NBK1146

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.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
CACNA1S 601887 0018493 0011163
RYR1 145600 0018493 0007783

References List

Gurunluoglu R, Swanson JA, Haeck PC. (2009) Evidence-based patient safety advisory: malignant hyperthermia. Plastic and reconstructive surgery. 124(4 Suppl):68S-81S.

H Rosenberg, N Sambuughin, S Riazi, R Dirksen. Malignant Hyperthermia Susceptibility. (2003) [Updated Jan 31 2013]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1146/

Malignant hyperthermia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=423

MHAUS Recommendation Adverse effects of heat and exercise on MH susceptibility. Other (2009) URL: http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/adverse-effects-of-heat-and-exercise-in-relation-to-mh-susceptibility

Rosenberg H, Rueffert H. (2011) Clinical utility gene card for: malignant hyperthermia. European journal of human genetics : EJHG. 19(6).

Early Rule-Out Summary

This topic did not pass the early rule out stage due to insufficient evidence for actionability. Thus, this topic did not move forward for a full evidence curation and summary report. This topic may be reconsidered if additional evidence becomes available.

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?