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Malignant hyperthermia, susceptibility to, 4

MedGen UID:
324944
Concept ID:
C1838102
Finding
Synonyms: Malignant hyperpyrexia susceptibility type 4; Malignant hyperthermia susceptibility type 4; MHS4-Related Malignant Hyperthermia Susceptibility
 
Monarch Initiative: MONDO:0010893
OMIM®: 600467

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 (MH) is a potentially lethal pharmacogenetic disease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants (summary by Sudbrak et al., 1995). For a phenotypic description and a discussion of genetic heterogeneity of susceptibility to malignant hyperthermia, see MHS1 (145600).  http://www.omim.org/entry/600467
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
Rhabdomyolysis
MedGen UID:
19775
Concept ID:
C0035410
Pathologic Function
Breakdown of muscle fibers that leads to the release of muscle fiber contents (myoglobin) into the bloodstream.
Acidosis
MedGen UID:
1296
Concept ID:
C0001122
Pathologic Function
Abnormal acid accumulation or depletion of base.
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
Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KP, Ellis FR, Müller CR, Urwyler A; European Malignant Hyperthermia Group
Br J Anaesth 2015 Oct;115(4):531-9. Epub 2015 Jul 18 doi: 10.1093/bja/aev225. PMID: 26188342
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Curated

Orphanet Emergency Guidelines: Malignant hyperthermia

Recent clinical studies

Etiology

Kruijt N, van den Bersselaar LR, Kamsteeg EJ, Verbeeck W, Snoeck MMJ, Everaerd DS, Abdo WF, Jansen DRM, Erasmus CE, Jungbluth H, Voermans NC
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O'Donnell PH, Danahey K, Ratain MJ
Clin Pharmacol Ther 2016 Apr;99(4):401-4. Epub 2016 Feb 15 doi: 10.1002/cpt.333. PMID: 26756170Free PMC Article
Ording H, Bendixen D
Eur J Anaesthesiol 1992 Sep;9(5):367-76. PMID: 1396623

Diagnosis

Li ZX, Wang HX, Yang Y, Qi RQ, Li YL, Yu AJ, Gao XH
Eur J Dermatol 2018 Oct 1;28(5):606-612. doi: 10.1684/ejd.2018.3417. PMID: 30530432
Miller DM, Daly C, Aboelsaod EM, Gardner L, Hobson SJ, Riasat K, Shepherd S, Robinson RL, Bilmen JG, Gupta PK, Shaw MA, Hopkins PM
Br J Anaesth 2018 Oct;121(4):944-952. Epub 2018 Aug 17 doi: 10.1016/j.bja.2018.06.028. PMID: 30236257Free PMC Article
O'Donnell PH, Danahey K, Ratain MJ
Clin Pharmacol Ther 2016 Apr;99(4):401-4. Epub 2016 Feb 15 doi: 10.1002/cpt.333. PMID: 26756170Free PMC Article
Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K
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Therapy

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J Craniofac Surg 2003 Sep;14(5):800-2. doi: 10.1097/00001665-200309000-00039. PMID: 14501352
Ording H, Bendixen D
Eur J Anaesthesiol 1992 Sep;9(5):367-76. PMID: 1396623
Mastaglia FL
Drugs 1982 Oct;24(4):304-21. doi: 10.2165/00003495-198224040-00003. PMID: 6128217

Prognosis

Arslan Ateş E, Türkyilmaz A, Yıldırım Ö, Alavanda C, Polat H, Demir Ş, Çebi AH, Geçkinli BB, Güney Aİ, Ata P, Arman A
J Hum Genet 2021 Nov;66(11):1113-1119. Epub 2021 May 28 doi: 10.1038/s10038-021-00936-8. PMID: 34050257
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Davis PJ, Brandom BW
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Clinical prediction guides

Arslan Ateş E, Türkyilmaz A, Yıldırım Ö, Alavanda C, Polat H, Demir Ş, Çebi AH, Geçkinli BB, Güney Aİ, Ata P, Arman A
J Hum Genet 2021 Nov;66(11):1113-1119. Epub 2021 May 28 doi: 10.1038/s10038-021-00936-8. PMID: 34050257
Knuiman GJ, Küsters B, Eshuis L, Snoeck M, Lammens M, Heytens L, De Ridder W, Baets J, Scalco RS, Quinlivan R, Holton J, Bodi I, Wraige E, Radunovic A, von Landenberg C, Reimann J, Kamsteeg EJ, Sewry C, Jungbluth H, Voermans NC
J Neurol 2019 Apr;266(4):876-887. Epub 2019 Feb 20 doi: 10.1007/s00415-019-09209-z. PMID: 30788618Free PMC Article
Li ZX, Wang HX, Yang Y, Qi RQ, Li YL, Yu AJ, Gao XH
Eur J Dermatol 2018 Oct 1;28(5):606-612. doi: 10.1684/ejd.2018.3417. PMID: 30530432
O'Donnell PH, Danahey K, Ratain MJ
Clin Pharmacol Ther 2016 Apr;99(4):401-4. Epub 2016 Feb 15 doi: 10.1002/cpt.333. PMID: 26756170Free PMC Article
Ording H, Bendixen D
Eur J Anaesthesiol 1992 Sep;9(5):367-76. PMID: 1396623

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

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