Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.1
• GENE/GENE PANEL: RYR1, CACNA1S
• Condition: Malignant Hyperthermia Susceptibility
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• RYR1 ⇔ 145600 (malignant hyperthermia, susceptibility to, 1; mhs1): Assertion Pending
• CACNA1S ⇔ 601887 (malignant hyperthermia, susceptibility to, 5): Assertion Pending

Actionability 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.

Final Consensus Scores

Gene Condition Pairs: RYR1 ⇔ (OMIM:145600) CACNA1S ⇔ (OMIM:601887)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity from malignant hyperthermia event / Avoidance of triggering anesthetics	2	2D	3B	3	10DB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

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. [1, 2]

Clinical Features

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. [1, 3, 4]

Natural History

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. [1, 4]

2. How effective are interventions for preventing harm?

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) [1]

MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. (Tier 2) [5]

Surveillance

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) [3]

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) [5]

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) [1]

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) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Mutations in RYR1 are identified in up to 70-80% of MHS cases, while CACNA1S mutations account for 1% of cases. (Tier 3) [1]

Causative mutations have been estimated to have a prevalence of 1/2000-1/3000 in the French and Japanese populations. (Tier 3) [1]

Penetrance

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) [1]

Relative Risk

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) [1]

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 setting 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) [1]

Date of Search: 06.15.2015

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; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1146

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

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