Course:MEDG550/Student Activities/Malignant Hyperthermia Susceptibility

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Malignant hyperthermia susceptibility (MHS) is a pharmacogenomic condition, meaning it is a condition related to genetics and how your body reacts to certain medications. MHS affects how the mineral, calcium, is regulated in your muscles. Normal regulation of calcium is specifically important in the skeletal muscles that allow us to move our bodies. If calcium is not regulated correctly, an individual may have a higher chance of having a life-threatening episode of malignant hyperthermia (MH).[1] MH is a severe reaction to drugs that are used during medical procedures (anesthetics). The first symptoms of MH are typically stiff muscles, high fever (hyperthermia), rapid breathing and an elevated heart rate. Intense exercise and hot environments can also trigger MH.[2] Episodes of MH can also lead to too much of the mineral, potassium, and a protein called myoglobin in the blood. When our muscles work hard, like during intense exercise or if they get injured, they can break down and release a substance called myoglobin into the bloodstream. Myoglobin is a protein that's normally found in muscles, but if too much is released into the blood, it can be harmful. This muscle breakdown (rhabdomyolysis) can be deadly if not identified and treated quickly.[3][4]

Signs and Symptoms

In nearly all cases, the first sign of MH occurs in the operating room when the body responds quickly and intensely to a drug given before a procedure.[2] This reaction can happen at any point between being given the drug and up to an hour after stopping taking the drug. In 63.5% of episodes of MH, high body temperature is one of the first warning signs.[5] Other common early signs include an increased heart rate, muscle stiffness and high levels of carbon dioxide in the blood. If these episodes are not treated, they can lead to an increased risk of blood clotting problems, brain injury, and heart, liver or kidney failure.[4] The individual's urine may also be a dark brown "cola" colour, indicating that there is excess myoglobin in the blood urine.[6]

Causes

Figure 1. Proportion of changes in the genes RYR1, CACNA1S, and STAC3 that are known to lead to Malignant Hyperthermia Susceptibility. [7][8][9][10][11][12]

Malignant Hyperthermia Susceptibility is what scientists call multifactorial, as there is more than one reason why someone might be at an increased risk for having an episode of malignant hyperthermia. These reasons include age, temperature, type of drug being given, the types/amount of drugs that are given at the same time and a person's genetics.[4]

Genes provide instructions that tell our body how to work. By testing the genes of people who have experienced episodes of MH, health care workers and researchers have found a number of changes in three genes that contribute to malignant hyperthermia susceptibility: RYR1, CACNA1S and STAC3 (Figure 1). [7] These genes provide instructions for making the proteins that play an important role in muscle contraction for movement.[1][2][13] Differences in these genes can cause a person's skeletal muscles to contract abnormally when they are given certain drugs, leading to the signs and symptoms of the condition. [14][15]

Most individuals at an increased risk for this condition have no symptoms unless they are given a drug that triggers the reaction. Drugs that are given during surgery (anesthetic agents like halothane, sevoflurane, isoflurane, desflurane, and enflurane) and muscle relaxants (specifically, succinylcholine) can act as triggers. [4] In rare cases, environmental causes such as extreme heat or physical exercise can trigger MH, especially in children and young adults.[14]

Genetics

Figure 2. Autosomal dominant Inheritance pattern. Every individual with MHS has a 50% chance of passing it down to every child.

A person typically carries two copies of each gene, one inherited from each parent. Malignant hyperthermia susceptibility (MHS) is inherited in an autosomal dominant fashion (Figure 2).[2] This means that a change in only one of the two copies is enough to cause this condition. Most people diagnosed with MHS have a parent who is also a carrier of the gene change and therefore has MHS. It is possible that the parent may not have experienced any episodes of MH.[2][16][13]

This condition can also be caused by a new (de novo) change in the gene that was not inherited from either parent. An individual with MHS has a 50% chance of passing on this condition to each of their children. MHS affects both women and men and can be inherited from either parent.[4]

Associations with Other Conditions

Other conditions that affect the muscular system and are caused by a gene change in RYR1 are also known to increase the risk that an individual has an episode of MH. These conditions include:

How Common is an episode of Malignant Hyperthermia?

Episodes of malignant hyperthermia occur in between 1 in 10,000 and 1 in 220,000 individuals who receive a drug during surgery. [17] The true number of people who have MHS is not known, as many people never have a surgery or require the drugs (anesthetics) that can cause this reaction.

Reactions are twice as common in males than in females. Approximately 52% of all MH reactions occur in children under 15 years old. [2][4] Currently, it is unclear whether people of certain ethnic backgrounds are more likely to be affected.[18]

Diagnosis

Malignant hyperthermia may not occur every time an anesthetic is used, and there can be variability in how quickly the body reacts. This variability and inconsistency can make MHS challenging to diagnose.[4] It is also possible that individuals with MHS from the same family show varying symptoms of the condition, or not show it at all.[2] MHS is suspected in individuals who experience an episode of malignant hyperthermia, and testing is required to confirm this diagnosis.

The diagnosis of MHS is established in an individual with:

  1. A positive diagnostic muscle contracture test; OR
  2. A gene change in one of the genes associated with MHS found by genetic testing.

Muscle Biopsy - Contracture test

This is the current ‘gold standard’ test for diagnosing MHS. This test requires looking at a small sample of the thigh muscle and measuring how good it is at contracting in response to known triggers of MH. This is an invasive surgical procedure that is only done in select clinics/hospitals.[2][4]

Genetic Testing

For this test, a sample of blood is collected and sent to the lab for genetic testing. An MHS diagnosis is made if a known disease-causing change is found in one of the three genes associated with MHS: CACNA1S, RYR1, or STAC3. We are still learning about different gene changes that can cause MHS. Current genetic testing techniques do not detect 100% of MHS-causing genetic changes. Therefore, susceptibility to MH cannot be excluded based on genetic testing results alone. In such cases, contracture testing can be performed to exclude a diagnosis.[1][2][4]

Prevention, Management and Treatment

All close biological family members of an individual in which MH has occurred should also be considered MH susceptible, until proven otherwise. It is important to note that previous use of an anesthetic drug during surgery without a problem does not rule out MHS. Death from malignant hyperthermia can occur in individuals with MHS who have previously undergone multiple surgeries safely. [16]

Figure 3. The Malignant Hyperthermia Association of the United States (MHAUS) treatment guide for malignant hyperthermia. A copy of this can be provided to your health care provider to include in your file.

Prevention

Individuals with MHS should avoid extreme heat and vigorous physical exercise, especially if alone. They should also carry documentation of their susceptibility or wear a medical alert bracelet. MH susceptible individuals should make this diagnosis known to their doctors and anesthesiologist before undergoing surgery and should ask for the use of MH non-triggering medications.[1][2] If undergoing general anesthesia for longer than 30 mins, the individual’s temperature should be monitored. If undergoing cardiac bypass surgery, aggressive rewarming after the procedure should also be avoided. [2][16]

Management

It is essential to recognize an episode of MH quickly, in order to stop the administration of the triggering agent (often an anesthetic and/or succinylcholine), and to administer a muscle relaxant called dantrolene. MH is also treated by increasing ventilation to lower carbon dioxide levels, cooling the body with ice packs or mists, and addressing other symptoms as they arise.[1] Individuals are usually monitored after an episode of MH and referred for genetic counselling or diagnostic testing to confirm MHS.

Pregnancy Management

If a pregnant woman with MHS requires a non-emergent surgery, a non-triggering anesthetic (e.g., an epidural, a local or spinal anesthetic, or a general anesthetic) should be administered. If a general anesthetic is required, it should be administered through the blood with an anesthesia machine prepared for an MH susceptible individual.[2]

Treatment

There are currently no treatments for MHS, instead the symptoms of a malignant hyperthermia episode are treated to avoid serious injury and death.

Clinical Trials

There are currently no clinical trials in North America studying the effects of, or treatments for MHS or malignant hyperthermia. If you are interested you can find a list of all ongoing MH clinical trials at any time here.

Genetic Counselling

If a person has MHS, they have a 50% chance of passing on the changed copy of their gene to each of their children. This also means they likely inherited this from one of their parents who may also be at an elevated risk for MH.[1] You can learn more about this condition and your risk by talking to a genetic counsellor. Genetic counsellors are healthcare professionals that can provide information and assess an individual’s and family members' risks based on family history. They may also assist with facilitating genetic testing and family planning, when appropriate.

Risks to family members

Parents of a MH susceptible individual

  • Most individuals with MHS have a parent with MHS; the parent may not have experienced an episode of MH.[1][2]
  • Parents should be treated as MH susceptible and are eligible for genetic testing or a muscle contracture test to confirm diagnosis.[1][2]

Siblings of a MH susceptible individual

The risk to the siblings depends on their parents' genetics.[1][2]

  • If a parent is known to have a MHS gene change, the risk that any child inherited the variant is 50%.[1][2]
  • If the gene change was not detected in either parent, the risk of inheriting the variant is estimated to be 1%.[19]
  • If both parents are unaffected based on muscle contracture testing, then the risk for siblings is the same as that of the general population.[1][2]

Other family members

The risk to other family members also depends on whether the gene change in running in the family, or was new in the individual. All biological parents, siblings, and children of any individual diagnosed with MHS should be considered at risk for MH until tested.[2]

Preconception and Prenatal Testing

Preimplantation genetic testing is possible for families once the specific MHS gene change has been found in an affected family member. Prenatal testing would be offered to pregnancies that are at an increased risk.[1][2]

Psychosocial Considerations

A malignant hyperthermia (MH) episode can be extremely traumatic and may result in long-lasting side effects and injuries. Individuals who suffered the life-threatening MH event, as well as family members and caregivers who witnessed it may be fearful or anxious of future surgeries. This concern could ultimately impact an individual's likelihood to receive necessary surgical intervention.

Genetic or muscle contracture testing can help establish a diagnosis. A confirmed MHS diagnosis can be valuable by reassuring family members about any genetic risks and helping individuals make informed decisions, especially when planning surgeries. Knowing about MHS before surgery allows medical professionals to take precautions, lowering the chances of triggering an MH crisis. A diagnosis of MHS can also help explain previous unexplained malignant hyperthermia episodes.

Patient Resources

People with MHS may encounter additional challenges if they lack knowledge and understanding of their condition. Patient-friendly information materials, like guidance manuals, can increase understanding of and adherence to preventive measures and therapies. One group of researchers created a digital manual for individuals with MHS. They found that this manual increased their patients' understanding of MH without negatively impacting their quality of life.[20]

Geneticcounseling.jpg

For additional information and resources, please visit:


To find a genetic counsellor near you, please visit:

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93. Published 2015 Aug 4. doi:10.1186/s13023-015-0310-1
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 Rosenberg H, Sambuughin N, Riazi S, Dirksen R. Malignant Hyperthermia Susceptibility. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; December 19, 2003.
  3. ↑ Biesecker LG, Dirksen RT, Girard T, et al. Genomic Screening for Malignant Hyperthermia Susceptibility. Anesthesiology. 2020;133(6):1277-1282.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Rosenberg H, Davis M, James D, Pollock N, Stowell K (April 2007). "Malignant hyperthermia". Orphanet Journal of Rare Diseases. 2: 21. doi:10.1186/1750-1172-2-21. PMC 1867813. PMID 17456235.
  5. ↑ Larach MG, Allen GC, Brandom BW, Lehman EB. Temperature changes are not late signs of malignant hyperthermia: A NAMH Registry of MHAUS study. Anesthesiology. 2008;109:A374.
  6. ↑ Larach, M. G., Gronert, G. A., Allen, G. C., Brandom, B. W., & Lehman, E. B. (2010). Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesthesia & Analgesia, 110(2), 498-507.
  7. ↑ 7.0 7.1 Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997;60:1316–25. PubMed PMID: 9199552.
  8. ↑ Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identificationof the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet. 2001;59:178–84. PubMed PMID: 11260227.
  9. ↑ Kraeva N, Riazi S, Loke J, Frodis W, Crossan ML, Nolan K, Kraev A, Maclennan DH. Ryanodine receptor type 1 gene mutations found in the Canadian malignant hyperthermia population. Can J Anaesth. 2011;58:504–13. PubMed PMID: 21455645.
  10. ↑ Galli L, Orrico A, Lorenzini S, Censini S, Falciani M, Covacci A, Tegassin V, Sorrentino V. Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia. Hum Mutat. 2006;27:830. PubMed PMID: 16835904.
  11. ↑ Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, Saint-Amant L, Satish A, Cui WW, Zhou W, Sprague SM, Stamm DS, Powell CM, Speer MC, Franzini-Armstrong C, Hirata H, Kuwada JY. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun. 2013;4:1952. PubMed PMID: 23736855.
  12. ↑ Zaharieva IT, Sarkozy A, Munot P, Manzur A, O'Grady G, Rendu J, Malfatti E, Amthor H, Servais L, Urtizberea JA, Neto OA, Zanoteli E, Donkervoort S, Taylor J, Dixon J, Poke G, Foley AR, Holmes C, Williams G, Holder M, Yum S, Medne L, Quijano-Roy S, Romero NB, Fauré J, Feng L, Bastaki L, Davis MR, Phadke R, Sewry CA, Bönnemann CG, Jungbluth H, Bachmann C, Treves S, Muntoni F. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018;39:1980–94. PubMed PMID: 30168660.
  13. ↑ 13.0 13.1 Carpenter D, Robinson RL, Qunnel RJ, Ringrose C, Hogg M, Cason F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA, Hopkins PM. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009;103:538–48. PubMed PMID: 19648156.
  14. ↑ 14.0 14.1 Wang, Hui J.; Lee, Chang Seok; Yee, Rachel Sue Zhen; Groom, Linda; Friedman, Inbar; Babcock, Lyle; Georgiou, Dimitra K.; Hong, Jin; Hanna, Amy D.; Recio, Joseph; Choi, Jong Min (2020-10-09). "Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation". Nature Communications. 11 (1): 5099. doi:10.1038/s41467-020-18865-z. PMC 7547078.
  15. ↑ Carpenter D, Robinson RL, Quinnell RJ, et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009;103(4):538-548. doi:10.1093/bja/aep204
  16. ↑ 16.0 16.1 16.2 Glahn KP, Ellis FR, Halsall PJ, et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth. 2010;105(4):417-420. doi:10.1093/bja/aeq243
  17. ↑ In, J., Ahn, E. J., Lee, D. K., & Kang, H. (2017). Incidence of malignant hyperthermia in patients undergoing general anesthesia: Protocol for a systematic review and meta-analysis. Medicine, 96(49).
  18. ↑ Bin, X., Wang, B., & Tang, Z. (2022). Malignant hyperthermia: a killer if ignored. Journal of PeriAnesthesia Nursing, 37(4), 435-444.
  19. ↑ Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. PubMed PMID: 26656846.
  20. ↑ Rodrigues, G., de Andrade, P. V., Dos Santos, J. M., do Amaral, J. L. G., & da Silva, H. C. A. (2022). Impact of a digital manual for guidance on malignant hyperthermia: patient education. Orphanet Journal of Rare Diseases, 17(1), 1-9.
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