NORD gratefully acknowledges Sheila M. Muldoon, MD, Maria Voelkel, and John Capacchione, MD, Uniformed Services University of the Health Sciences, Department of Anesthesiology, for assistance in the preparation of this report.
Malignant hyperthermia (MH) is a dominantly inherited disorder of skeletal muscle that predisposes susceptible individuals to a life threatening adverse reaction (fulminant MH event) upon exposure to potent volatile anesthetics (halothane, isoflurane, sevoflurane, desflurane, etc.) and the skeletal muscle relaxant succinylcholine.
The anesthetic drugs trigger an uncontrolled calcium (Ca2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RYR1) causing a rapid and sustained rise in myoplasmic Ca2+. The high intracellular Ca2+ activates Ca2+ pumps at the SR and the sarcolemma to reuptake calcium into SR or to transport it into the extracellular space respectively. The energetic cost to regain cellular Ca2+ control causes a need for ATP, which in turn produces heat. Muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis.1 If not treated promptly, by withdrawing the anesthetic and administering dantrolene, mortality can be greater than 70%.2 In some individuals, fulminant MH events can be induced by stress, exercise and high environmental temperatures in the absence of anesthetics.3 Pediatric patients may be at greater risk.4
A fulminant MH episode is characterized by hypermetabolism that produces heat (hypethermia), increased oxygen uptake, and carbon dioxide production, along with hyperkalemia, and acidosis with hyperlacactemia. Skeletal muscle rigidity may either be localized to the masseter muscle or generalized. Muscle damage is reflected by increases in serum creatine kinase, potassium, calcium, and phosphate. Rhabdomyolysis with myoglobinuria and myoglobinemia often occurs. The time of onset after induction of general anesthesia may vary from minutes to hours, and patients may have had previously uneventful exposure to anesthetics.
The MH phenotype is inherited as an autosomal-dominant trait with incomplete penetrance and variable expression. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Molecular genetic studies in humans have established the type 1 ryanodine receptor (RYR1) calcium release channel gene on chromosome 19 (19q13.1) as the primary locus for MH. A number of studies in different populations reported that mutations in the RYR1 gene account for approximately 50% of MH cases, while 1% of MH cases have been linked to the CACNA1S gene located on chromosome 1 (1q32) (encoding the a1 subunit of the voltage-gated dihydropyridine receptor (DHPR)). Currently, more than 400 different variants have been identified in the RYR1 gene (Leiden Open Variation Database).5 Only 31 of these have been functionally characterized and meet all the requirements for inclusion in the European MH Group (EMHG) panel of mutations causative for MH.
The incidence of MH during general anesthesia is estimated at 1/4,200 (suspicion of MH) to 1/250,000 (fulminant MH). Published reports probably underestimate the true incidence because of the difficulty in defining mild MH events. In the past decade, two independent studies have estimated the incidence of RYR1 variants in the general population as 1 in 2,000 to 1 in 3,000 persons. More recent exome studies suggest that the frequency of RYR1 variants may be higher than that.6
Demographic data on age and sex distribution of patients referred for testing indicates that 68% are males and 32% are females. Acute MH is distributed worldwide and affects all ethnic groups, with a mean age of 21-23 years.
Many individuals with MH are otherwise unaffected. Thus, identifying these individuals before they are given general anesthesia is difficult. Family history of the disorder is important, as is the history of any adverse metabolic responses to anesthesia. Definitive diagnosis of MH susceptibility is made by in vitro contracture test performed on biopsied leg muscle. These tests are based on the differential contractile response of normal and MH muscle to halothane and caffeine. In North America, the test is the caffeine halothane contracture test (CHCT), and in Europe the test is the in vitro contracture test (IVCT). Both tests are invasive, requiring a muscle biopsy, and can only be performed in specialized MH diagnostic centers.
Currently, three CLIA (Clinical Laboratory Improvement Amendments) laboratories offer diagnostic RYR1 genetic testing: Prevention Genetics (Marshfield, WI; http://www.preventiongenetics.org), the Center for Medical Genetics (Pittsburgh, PA; http://path.upmc.edu/divisions/mdx/diagnostics.html), and Medical Neurogenetics (Atlanta, GA; http://www.medicalneurogenetics.com). If one of the mutations causative for MH is identified, the patient can be safely labeled as MH susceptible; however, if no mutation in the RYR1 is identified, the MH diagnosis cannot be ruled out.2
Successful treatment of an MH episode involves the rapid cessation of the anesthetic triggering agent, cooling, and administration of Dantrolene intravenously. Dantrolene inhibits the calcium release channel in skeletal muscle without affecting neuromuscular transmission and is effective for both prophylaxis and treatment of fulminant MH. The recommended initial dose is 2.4 mg/kg intravenously, with further increments as needed for an acute episode. Further details about MH treatment are more information about MH for patients and physicians are available at the following URL: www.MHAUS.org
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1.Rosenberg H, Davis M, James D, Pollock N, Stowell. Malignant Hyperthermia. Orphanet Journal of Rare Diseases, 2007 April; 2:21. Epublication: http://www.ojrd.com/content/2/1/21.
2.Capacchione JF, Larach MG, Sambuughin N, Voelkel M, Muldoon S. Malignant Hyperthermia. In: Anesthesiology, 2nd ed. Longnecker DE, Brown DL, Newman MF, Zapol WM, eds. New York, McGraw-Hill Medical. 2012, Chapter 87, pp. 1491-1504.
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4.Brandom BW. Unexpected MH Deaths without Exposure to Inhalation Anesthetics in Pediatric Patients. Pediatric Anesthesia. Submitted; review in process.
5.Brandom B, Bina S, Wong C, Wallace T, Visoiu M, Isackson P, Vladutiiu G, Sambuughin N, Muldoon S. Ryanodine Receptor Type 1 Gene Variants in the MH Susceptible Population of the United States. Anesthesia and Analgesia, 2013 May; 116 (5): 1078-1086.
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7.Clarke NF, Waddell LB, Cooper ST, Perry M, Smith RL, Kornberg AJ, Muntoni F, Lillis S, Straub V, Bushby K, Guglieri M, King MD, Farrell MA, Marty I, Lunardi J, Monnier N, North KN. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat. 2010; 31:1544-50.
8.Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Müller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol. 2010; 68: 717-726.
9.Maggi L, Scoto M, Cirak S, Robb SA, Klein A, Lillis S, Cullip T, Feng L, Manzur AY, Sewry CA, Abb S, Jungbluth H, Muntoni F. Congenital myopathies-Clinical features and frequency of individual subtype diagnosed over a 5-year period in the United Kingdom. Neuromusc Disorder. 2013; 23: 195-205.
10.Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology. 2001 Jan; 94(1): 95-100.
11.Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet. 2009; 76: 1218-1224.
12.Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA. 2001 July 11; 286(2): 168-9.
13.Chelu MG, Gonnasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Chattachariee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J. 2006 Feb; 20(2): 329-30.
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