he syndrome we know today as malignant hyperthermia was first formally described in a letter to the editor in the journal Lancet in 1960 by M. A. Denborough, M.D., and R. R. Lovell, M.D., titled “Anaesthetic Deaths in a Family.” They described a near fatality in a patient with a family history of deaths in apparently healthy individuals during or shortly after anesthesia. Once the syndrome was described, rapid progress was made in describing how, in certain individuals, anesthetic gases and succinylcholine could precipitate muscle rigidity, myonecroses, acidosis, hyperthermia and death. Families from all parts of the world were reported with this syndrome, which apparently followed an autosomal dominant inheritance pattern.

A major advance in the understanding of the pathomechanism of MH was the demonstration that various swine breeds develop a similar set of clinical signs, often in the absence of anesthesia, termed “porcine stress syndrome” or “pale, soft exudative pork syndrome.” The pig model is similar in many ways to human MH but different in others. Nevertheless it helped in the understanding of the clinical presentations of MH and in the demonstration of the efficacy of intravenous dantrolene in reversing the clinical signs of MH.

In the 1970s through today, investigators in the United States, Europe, Australia, New Zealand, Japan and South Africa enhanced our knowledge of the clinical description of MH, the characterization and standardization of the muscle biopsy contracture test, the demonstration of defective intracellular calcium flux in MH and the differentiation of MH from other syndromes.

Molecular Genetics Era Dawns
When the molecular genetic era dawned in the 1980s, several groups began the investigation of the molecular genetic defects responsible for MH. Using the pig model, David MacLennan, M.D., and his group at the University of Toronto and Tommy McCarthy, Ph.D., and his group in Ireland demonstrated a consistent mutation in the gene that elaborates the ryanodine receptor in skeletal muscle (RYR-1). In humans, however, it was soon apparent that many other mutations (the count at the present time is 23) in that gene and in others are causal for MH. In those patients with a positive halothane-caffeine contracture test for MH, approximately 30 percent of such patients were shown to harbor one of 15-20 known RYR-1 mutations. The good news is that the specificity of the mutation analysis is close to 100 percent in families at risk for M.H. The adaptation of mutation detection to clinical diagnostic testing began a few years ago in Europe. Guidelines for testing have been published by the European Malignant Hyperthermia Group <www.emhg.org>.

In spring 2005, PreventionGenetics, a company located in Marshfield, Wisconsin, began offering molecular genetic testing for MH in the United States. The laboratory is certified through the Clinical Laboratory Improvement Amendments and the College of American Pathologists.

Within a few weeks, the DNA diagnostic laboratory at the University of Pittsburgh Medical Center also will offer molecular genetic testing for MH.  Laboratory director Jeffrey A. Kant, M.D., Ph.D., is CLIA certified and can be reached at (412) 648-8519.

Patient Referral
There are several important issues to bear in mind in considering referral of a patient for MH testing by molecular techniques:

• First, the test is not a screening test. The sensitivity of the test in a population of patients with a positive contracture test is somewhere between 30 percent and 40 percent.

• Second, the absence of a mutation does not rule out MH susceptibility.

• Third, a referral should be made for testing only by a physician or genetic counselor.

• Fourth, a blood sample is all that is required for testing.

• Fifth, the test does not replace the contracture test. Because of the limited sensitivity of the genetic test, those without a mutation should be referred for contracture testing to determine MH susceptibility since the caffeine-halothane test is very sensitive.

• Sixth, if one of the known mutations for MH is found in a family member, other family members with that mutation are MH-susceptible for certain and may bypass the contracture test.

Who should be referred for testing?

a. Those patients with a positive caffeine-halothane test or a confirmed clinical episode of MH.

b. Those with an identified mutation as part of a research protocol.

c. Family members of these patients listed above also should be considered for genetic testing after discussion with a biopsy center director or a genetic counselor.

Cost of the Test
Patients with a positive caffeine-halothane test will first have their DNA assessed for the presence of 19 known mutations at a cost of about $800. If one of the mutations is found, that mutation may be sought in specimens from family members. The cost for the assay for a specific mutation is about $200. Reimbursement for such testing is dependent on the specific insurance company. Although not required, genetic counseling is advised for those undergoing genetic testing.

What are the advantages of the genetic test?
Genetic testing will help to avoid the use of the invasive muscle biopsy contracture test. As such it is less expensive than the contracture test and does not carry the morbidity of the muscle biopsy. Another advantage of such testing (in some cases) is the clarification of the likelihood that a perioperative morbidity or mortality is related to MH since the DNA analysis may be performed on preserved tissue samples.

It is clear that with time, the sensitivity of the test will improve significantly. In an individual, this may not require a repeat sample since the DNA analysis is based on sequencing the hot spots of the gene, and DNA variants of undetermined significance at this point may turn out to be causal for MH with further investigation.

In order to better understand the relation between clinical events and molecular genetics of MH, patients and physicians are urged to provide the North American MH Registry with a detailed clinical history. Appropriate forms will be provided for this purpose by contacting the Registry at (888) 274-7899; the Registry Web address is <www.mhreg.org>. The Registry database and collection vehicle is approved by the Institutional Review Board of the University of Pittsburgh Medical Center and is in full compliance with regulations for protection of confidential medical information.

The MHAUS Board and Professional Advisory Council and Hotline consultants are very pleased with the introduction of genetic testing for MH in North America. Nevertheless we realize that this is just the first step in devising a highly sensitive, specific, minimally invasive diagnostic test for MH. We also expect that other laboratories will offer clinical genetic testing for MH in the near future.

Further information on the test, including frequently asked questions, may be found on the MHAUS Web site <www.mhaus.org> or by contacting MHAUS directly at (607) 674-7901.

Henry Rosenberg, M.D., is Director, Department of Medical Education, Saint Barnabas Medical Center, Livingston, New Jersey.