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Malignant hyperthermia, susceptibility to, 5(MHS5)

MedGen UID:
356151
Concept ID:
C1866077
Finding
Synonyms: CACNA1S-Related Malignant Hyperthermia Susceptibility; Malignant hyperpyrexia susceptibility type 5; Malignant hyperthermia susceptibility type 5; MHS5
 
Gene (location): CACNA1S (1q32.1)
 
Monarch Initiative: MONDO:0011163
OMIM®: 601887

Disease characteristics

Excerpted from the GeneReview: Malignant Hyperthermia Susceptibility
Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by certain volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure. In nearly all cases, the first manifestations of MH (tachycardia and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality is extremely high. [from GeneReviews]
Authors:
Henry Rosenberg  |  Nyamkhishig Sambuughin  |  Sheila Riazi, et. al.   view full author information

Additional descriptions

From OMIM
Malignant hyperthermia-5 (MHS5) is a muscle disorder in which an episode is triggered by exposure to volatile anesthetic agents or depolarizing muscle relaxants. A fulminant malignant hyperthermia crisis is characterized by hyperthermia, skeletal muscle rigidity, tachycardia or arrhythmia, respiratory and metabolic acidosis, and rhabdomyolysis (summary by Monnier et al., 1997). For a general phenotypic description and a discussion of genetic heterogeneity of malignant hyperthermia, see MHS1 (145600).  http://www.omim.org/entry/601887
From MedlinePlus Genetics
Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. Specifically, this reaction occurs in response to some anesthetic gases, which are used to block the sensation of pain, either given alone or in combination with a muscle relaxant that is used to temporarily paralyze a person during a surgical procedure. If given these drugs, people at risk of malignant hyperthermia may experience a rapid increase in heart rate and body temperature (hyperthermia), abnormally fast breathing, muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Without prompt treatment and cessation of the drugs, the body's reaction can cause multiple organs to be unable to function, including the heart (cardiac arrest) and kidneys (renal failure), and it can cause a blood clotting abnormality called disseminated intravascular coagulation. These complications may be life-threatening. (In medicine, the term malignant refers to conditions that are dangerous to one's health.)

People at increased risk of this disorder are said to have malignant hyperthermia susceptibility. Affected individuals may never know they have the condition unless they have a severe reaction to anesthesia during a surgical procedure or they undergo testing (for instance, if susceptibility is suspected because a family member had a severe reaction). Malignant hyperthermia may not occur every time anesthesia is used. Many individuals who develop a severe reaction have previously been exposed to a triggering drug and not had a reaction.

While malignant hyperthermia often occurs in people without other serious medical problems, certain inherited muscle diseases (including central core disease, multiminicore disease, and STAC3 disorder) are associated with malignant hyperthermia susceptibility.

Affected individuals may be at increased risk for "awake" malignant hyperthermia, in which the severe reaction occurs in response to physical activity, often while sick, rather than in reaction to exposure to a triggering drug.  https://medlineplus.gov/genetics/condition/malignant-hyperthermia

Clinical features

From HPO
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Hypercapnia
MedGen UID:
9359
Concept ID:
C0020440
Sign or Symptom
Abnormally elevated blood carbon dioxide (CO2) level.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Malignant hyperthermia
MedGen UID:
1830388
Concept ID:
C5779784
Pathologic Function
Malignant hyperthermia is characterized by a rapid increase in temperature to 39-42 degrees C. Malignant hyperthermia may occur in response to either inhalational anesthetics such as halothane, to muscle relaxants such as succinylcholine, or to exercise.

Professional guidelines

PubMed

Carlson KJ, Sun SA, Swan C, Koenig M, Derkay CS
Int J Pediatr Otorhinolaryngol 2022 Aug;159:111187. Epub 2022 May 30 doi: 10.1016/j.ijporl.2022.111187. PMID: 35660936
Haverfield EV, Esplin ED, Aguilar SJ, Hatchell KE, Ormond KE, Hanson-Kahn A, Atwal PS, Macklin-Mantia S, Hines S, Sak CW, Tucker S, Bleyl SB, Hulick PJ, Gordon OK, Velsher L, Gu JYJ, Weissman SM, Kruisselbrink T, Abel C, Kettles M, Slavotinek A, Mendelsohn BA, Green RC, Aradhya S, Nussbaum RL
BMC Med 2021 Aug 18;19(1):199. doi: 10.1186/s12916-021-01999-2. PMID: 34404389Free PMC Article
Hopkins PM, Girard T, Dalay S, Jenkins B, Thacker A, Patteril M, McGrady E
Anaesthesia 2021 May;76(5):655-664. Epub 2021 Jan 5 doi: 10.1111/anae.15317. PMID: 33399225

Curated

American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, RYR1 and CACNA1S Pathogenic Variants (Malignant Hyperthermia), 2019

Orphanet Emergency Guidelines: Malignant hyperthermia

Recent clinical studies

Etiology

Hopkins PM, Girard T, Dalay S, Jenkins B, Thacker A, Patteril M, McGrady E
Anaesthesia 2021 May;76(5):655-664. Epub 2021 Jan 5 doi: 10.1111/anae.15317. PMID: 33399225
Santos JM, Andrade PV, Galleni L, Vainzof M, Sobreira CFR, Schmidt B, Oliveira ASB, Amaral JLG, Silva HCA
Can J Anaesth 2017 Dec;64(12):1202-1210. Epub 2017 Sep 26 doi: 10.1007/s12630-017-0978-x. PMID: 28952030
Beam TA, Loudermilk EF, Kisor DF
Physiol Genomics 2017 Feb 1;49(2):81-87. Epub 2016 Dec 23 doi: 10.1152/physiolgenomics.00126.2016. PMID: 28011884
Jungbluth H, Voermans NC
Curr Opin Neurol 2016 Oct;29(5):642-50. doi: 10.1097/WCO.0000000000000372. PMID: 27538056
Rosenberg H, Davis M, James D, Pollock N, Stowell K
Orphanet J Rare Dis 2007 Apr 24;2:21. doi: 10.1186/1750-1172-2-21. PMID: 17456235Free PMC Article

Diagnosis

Hopkins PM, Girard T, Dalay S, Jenkins B, Thacker A, Patteril M, McGrady E
Anaesthesia 2021 May;76(5):655-664. Epub 2021 Jan 5 doi: 10.1111/anae.15317. PMID: 33399225
Ellinas H, Albrecht MA
Anesthesiol Clin 2020 Mar;38(1):165-181. doi: 10.1016/j.anclin.2019.10.010. PMID: 32008650
Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K
Orphanet J Rare Dis 2015 Aug 4;10:93. doi: 10.1186/s13023-015-0310-1. PMID: 26238698Free PMC Article
Rosenberg H, Davis M, James D, Pollock N, Stowell K
Orphanet J Rare Dis 2007 Apr 24;2:21. doi: 10.1186/1750-1172-2-21. PMID: 17456235Free PMC Article
Ali SZ, Taguchi A, Rosenberg H
Best Pract Res Clin Anaesthesiol 2003 Dec;17(4):519-33. doi: 10.1016/j.bpa.2003.09.012. PMID: 14661655

Therapy

Hopkins PM, Girard T, Dalay S, Jenkins B, Thacker A, Patteril M, McGrady E
Anaesthesia 2021 May;76(5):655-664. Epub 2021 Jan 5 doi: 10.1111/anae.15317. PMID: 33399225
Rosenberg H, Davis M, James D, Pollock N, Stowell K
Orphanet J Rare Dis 2007 Apr 24;2:21. doi: 10.1186/1750-1172-2-21. PMID: 17456235Free PMC Article
Ali SZ, Taguchi A, Rosenberg H
Best Pract Res Clin Anaesthesiol 2003 Dec;17(4):519-33. doi: 10.1016/j.bpa.2003.09.012. PMID: 14661655
Halliday NJ
J Craniofac Surg 2003 Sep;14(5):800-2. doi: 10.1097/00001665-200309000-00039. PMID: 14501352
Moore JL, Rice EL
Am Fam Physician 1992 May;45(5):2245-51. PMID: 1575119

Prognosis

Mohtisham FS, Sallam A, Shawli A
BMJ Case Rep 2019 May 8;12(5) doi: 10.1136/bcr-2018-229045. PMID: 31068350Free PMC Article
Beam TA, Loudermilk EF, Kisor DF
Physiol Genomics 2017 Feb 1;49(2):81-87. Epub 2016 Dec 23 doi: 10.1152/physiolgenomics.00126.2016. PMID: 28011884
Riazi S, Larach MG, Hu C, Wijeysundera D, Massey C, Kraeva N
Anesth Analg 2014 Feb;118(2):381-387. doi: 10.1213/ANE.0b013e3182937d8b. PMID: 23842196
Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program
Anesthesiology 2013 Nov;119(5):1043-53. doi: 10.1097/ALN.0b013e3182a8a8e7. PMID: 24195946Free PMC Article
Gronert GA
Anesthesiology 1980 Nov;53(5):395-423. doi: 10.1097/00000542-198011000-00007. PMID: 6999950

Clinical prediction guides

Riazi S, Bersselaar LRVD, Islander G, Heytens L, Snoeck MMJ, Bjorksten A, Gillies R, Dranitsaris G, Hellblom A, Treves S, Kunst G, Voermans NC, Jungbluth H
Neuromuscul Disord 2022 Aug;32(8):628-634. Epub 2022 Jun 11 doi: 10.1016/j.nmd.2022.06.003. PMID: 35738978
Santos JM, Andrade PV, Galleni L, Vainzof M, Sobreira CFR, Schmidt B, Oliveira ASB, Amaral JLG, Silva HCA
Can J Anaesth 2017 Dec;64(12):1202-1210. Epub 2017 Sep 26 doi: 10.1007/s12630-017-0978-x. PMID: 28952030
Beam TA, Loudermilk EF, Kisor DF
Physiol Genomics 2017 Feb 1;49(2):81-87. Epub 2016 Dec 23 doi: 10.1152/physiolgenomics.00126.2016. PMID: 28011884
Ording H
Ann Fr Anesth Reanim 1989;8(5):411-6. doi: 10.1016/S0750-7658(89)80007-3. PMID: 2697155
Gronert GA
Anesthesiology 1980 Nov;53(5):395-423. doi: 10.1097/00000542-198011000-00007. PMID: 6999950

Recent systematic reviews

Kruijt N, van den Bersselaar LR, Wijma J, Verbeeck W, Coenen MJH, Neville J, Snoeck M, Kamsteeg EJ, Jungbluth H, Kramers C, Voermans NC
Neuromuscul Disord 2020 Dec;30(12):949-958. Epub 2020 Oct 31 doi: 10.1016/j.nmd.2020.10.010. PMID: 33250373

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2019
      American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, RYR1 and CACNA1S Pathogenic Variants (Malignant Hyperthermia), 2019
    • Orphanet, 2013
      Orphanet Emergency Guidelines: Malignant hyperthermia

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