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

• Duchenne muscular dystrophy
• Becker muscular dystrophy
• neuroleptic malignant syndrome
• myotonic syndromes

Symptoms of malignant hyperthermia usually occur only after administration of certain anesthetic drugs that trigger an adverse reaction. The symptoms usually develop quickly after the triggering agents are administered, but can also occur during the maintenance of anesthesia or when emerging from anesthesia. The characteristics of a malignant hyperthermia episode are variable and include muscle rigidity, high blood pressure (hypertension) increased levels of carbon monoxide in blood or exhaled gas, rapid irregular heart rate, rapid deep breathing, blue skin, acidity of the blood and muscle damage. Body temperature can rise rapidly (hyperthermia), but sometimes only occurs late in an episode. Rigidity of the jaw muscles (masseter muscle rigidity) after succinylcholine administration occurs in approximately 30% of individuals with MH. When an episode is not recognized and treated, internal bleeding, brain damage, skeletal muscle degeneration (rhabdomyolysis), and kidney and heart failure can result.. MH may occur in individuals who were previously unaffected by exposure to a triggering anesthesia.

Malignant hyperthermia is an autosomal dominant genetic condition caused by an abnormality in one of several genes that regulate the release of calcium from muscle. The abnormal gene results in a rise in cellular calcium in skeletal muscles following exposure to a triggering anesthetic. Increased calcium precipitates the symptoms of the disorder.

Malignant hyperthermia susceptibility type 1 (MHS1) is associated with abnormalities (mutations) in the RYR1 gene that is responsible for production of skeletal muscle ryanodine receptor type 1. Mutations in this gene account for about 50-70% of malignant hyperthermia cases. Malignant hyperthermia susceptibility type 5 (MHS5) is associated with mutations in the CACNA1S gene that is responsible for production of skeletal muscle calcium channel. Mutations in this gene account for about 1% of MHS cases. Four additional genes have been found to be associated with MHS but have not yet been identified. These genes are termed MHS2, MHS3, MHS4 and MHS6.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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 regardless of the sex of the resulting child.

The incidence of malignant hyperthermia is not known because many people who have it are not aware of the diagnosis until they have an adverse reaction to anesthesia. The incidence has been estimated to be between 1 in 5,000 administrations of anesthetic to 1 in 50,000 administrations of anesthetic. In Quebec, Canada the incidence has been estimated to be 1 in 200 people. In the USA, a high incidence of MHS has been reported in Wisconsin, Nebraska, West Virginia and Michigan.

Symptoms of the following disorders can be similar to malignant hyperthermia. Comparisons may be useful for a differential diagnosis:

Duchenne muscular dystrophy is an X-linked genetic disorder of skeletal (voluntary) muscles and is considered the most prevalent form of childhood muscular dystrophy. The disorder typically is recognized from approximately age three to six years and has a relatively rapid, progressive disease course. Duchenne muscular dystrophy is initially characterized by muscle weakness and wasting (atrophy) within the pelvic area that may be followed by involvement of the shoulder muscles. With disease progression, muscle weakness and atrophy affect the trunk and forearms and gradually progress to involve most major muscles of the body. Affected individuals are at risk for life-threatening adverse reactions following administration of succinylcholine or volatile anesthetics. (For more information on this disorder, choose "muscular dystrophy, Duchenne" as your search term in the Rare Disease Database.)

Becker muscle dystrophy is an X-linked genetic muscle disorder that usually begins in the teens or early twenties and symptoms vary greatly between affected individuals. Muscle deterioration progresses slowly but usually results in the need for a wheel chair. Muscles of the heart deteriorate (cardiomyopathy) in some affected individuals, and this process can become life threatening. Learning disabilities involving visual abilities may be present. Affected individuals are at risk for life-threatening adverse reactions following administration of succinylcholine or volatile anesthetics. (For more information on this disorder, choose "muscular dystrophy, Becker" as your search term in the Rare Disease Database).

Neuroleptic malignant syndrome is a rare but potentially life-threatening reaction to the use of almost any of a group of antipsychotic drugs or major tranquilizers (neuroleptics). These drugs are commonly prescribed for the treatment of schizophrenia and other neurological, mental, or emotional disorders. Several of the more commonly prescribed neuroleptics include thioridazine, haloperidol, chlorpromazine, fluphenazine and perphenazine. The syndrome is characterized by high fever, stiffness of the muscles, altered mental status (paranoid behavior), and autonomic dysfunction. Autonomic dysfunction alludes to defective operations of the components of the involuntary (autonomic) nervous system, leading to wide swings of blood pressure, excessive sweating and excessive secretion of saliva. (For more information on this disorder, choose "neuroleptic malignant syndrome" as your search term in the Rare Disease Database).

Myotonic syndromes such myotonic dystrophy and myotonia congenita have been associated with muscle rigidity following administration of succinylcholine. (For more information on these disorders, choose "dystrophy, myotonic or myotonia congenita" as your search term in the Rare Disease Database).

Diagnosis
Malignant hyperthermia is diagnosed by the caffeine/halothane contracture test (CHCT) that is also known as the in vitro contracture test (IVCT). This test is performed at a special center because the testing must be performed immediately after the muscle sample is obtained. A muscle biopsy is performed and the strength of the muscle contracture to caffeine and separately to anesthetic halothane are measured. This test identifies 100% of those affected with malignant hyperthermia. Approximately 3-20% of individuals who are diagnosed with malignant hyperthermia as a result of this test do not have the condition.

If the contracture test is positive, molecular genetic testing is used to confirm the diagnosis and to attempt to identify the specific gene mutation that is present. When a specific mutation is identified, molecular genetic testing can be offered to other family members. Molecular genetic testing for common mutations in the RYR1 gene is available but detects only about 25-30% of affected individuals. Genetic testing for any mutation in the RYR1 gene can detect up to 70% of affected individuals but is available on a research basis only.

Treatment
An acute episode of malignant hyperthermia is best treated by early diagnosis and administration of dantrolene sodium that can stop the progress of symptoms. The Malignant Hyperthermia Hotline of the Malignant Hyperthermia Association of the US is available 24 hours a day to provide additional assistance at 800-MH-HYPER (800-644-9737).

Prevention of malignant hyperthermia episodes can be achieved by identifying individuals at risk prior to surgery. Those with an established diagnosis who are planning surgery should request confirmation that dantrolene is available at the surgery facility and a treatment protocol has been established. Affected individuals should wear identification that indicates the diagnosis of malignant hyperthermia.

Individuals who have a close family member with malignant hyperthermia should consider testing and always report this family history prior to any planned surgery. It is possible to have malignant hyperthermia even if previous administrations of a triggering anesthetic occurred without complications.

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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

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

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