Information on the following diseases can be found in the Related Disorders section of this report:

• None

Temperature elevation, for which the syndrome is named, is often a late sign. Increased metabolism, manifested as elevated end-tidal carbon dioxide, is the earliest and most sensitive sign in anesthetized patients. Manifestations include: increased oxygen consumption, decreased mixed venous oxygen, hypoxia, cyanosis, and skin mottling. Respiratory and metabolic acidosis can ensue rapidly. Skeletal muscle rigidity is the most unique sign of MH. 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 general anesthetics.

The MH phenotype is inherited as an autosomal-dominant trait with incomplete penetrance and variable expression. 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 200 different mutations have been identified in the RYR1 gene, and only a small percentage of these mutations have been functionally characterized.

The incidence of MH during general anesthesia is estimated at 1/4,200 (suspicision of MH) to 1/250,000 (fulminant MH). Published reports probably underestimate the true incidence because of the difficulty in defining mild MH events. Demographic data on age and sex distribution of patients referred for testing indicates that 68% are males and 32% are females. MH is distributed worldwide and affects all ethnic groups, with a mean age of 21-23 years.

MH has been associated with or observed in a number of other conditions. The clinical congenital myopathy Central Core Disease (CCD) shares the RYR1 genetic loci associated with MH. This disorder is characterized by hypotonia and proximal muscle weakness, which presents in infancy, and leads to a delay of motor milestones. CCD histology shows the presence of amorphous, mitochondria depleted central areas (cores) in type 1 muscle fibers and pathological sarcoplasmic reticulum changes. Patients with CCD are at high risk for MH and almost all cases of CCD are diagnosed as MH-susceptible through in-vitro muscle contracture testing. CCD exhibits great variability both clinically and histologically and can range from normal to severe within a single family.

EXERTIONAL HEAT-ILLNESS, RHABDOMYOLYSIS, & MH: A subset of MH-susceptible individuals develop symptoms associated with exercise, emotional stress, and/or environmental heat exposure. According to a case report, a 12 year old boy who MH-like symptoms and died during exercise. The boy had a previous clinical MH episode and was found to harbor one of the RYR1 mutations established as causative for MH. A recent European study in 12 subjects with previous episodes of exertional rhabdomyolysis (ER) identified 10/12 subjects as MH-susceptible through muscle contracture testing. Furthermore, 3/10 of these MH-susceptible subjects were later identified with RYR1 gene mutations. The association between exertional heat illness and MH is further supported by recent genetic RYR1 mouse ‘knock-in' studies.

Diagnosis
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 adverse metabolic responses to anesthesia. Definitive diagnosis is made by the caffeine-halothane contracture test (CHCT) on vastus lateralis muscle specimens. However, the test is invasive and performed only in specialized MH diagnostic centers. Currently, two CLIA (Clinical Laboratory Improvement Amendments) laboratories offer diagnostic genetic RYR1 screening (Prevention Genetics in Marshfield, WI www.preventiongentics.org and the Center for Medical Genetics in Pittsburgh, PA http://path.upmc.edu/divisions/mdx/diagnostics.html)

Treatment
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

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

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Muldoon S, Deuster P, Voelkel M, Capacchione J, and Bunger R. Exertional Heat Illness, Exertional Rhabdomyolysis, and Malignant Hypertehrmia: Is There a Link? Current Sports Med Reports. 2008 March/April 7(2):74-80.

Levano S, Vukcevic M, Singer M, Matter A, Treves S, Urwyler A, Girard T. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutation. 2009 Apr; 30(4):590-8.

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.

Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL. RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell. 2008 Apr 4; 133(1):53-65.