Drs. M.A. Denborough and R.R. Lovell first formally described the syndrome we know today as malignant hyperthermia (MH) in a Letter to the Editor of Lancet titled “Anaesthetic Deaths in a Family” in 1960. 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, myonecrosis, 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 dantrolene in reversing the clinical signs of MH.
From the 1970s to the present, 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.
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’s group at the University of Toronto was the first to demonstrate a consistent mutation in the gene that elaborates the ryanodine receptor in skeletal muscle (RYR-1). However, in humans it was soon apparent that many other mutations (the count at present 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% 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% in families at risk to MH.
The adaptation of mutation detection to clinical diagnostic testing started a few years ago in Europe. Guidelines for testing have been published by the European MH group (www.emhg.org).
In the spring of 2005, Prevention Genetics, a company located in Marshfield, WI, began offering molecular genetic testing for MH in the US. The laboratory is CLIA and CAP certified.
There are several important issues to bear in mind when 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 and 40%. Second, the absence of a mutation does not rule out MH susceptibility. Third, a referral for testing should be made 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. And 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 should also be considered for genetic testing after discussion with a biopsy center director or a genetic counselor.
Patients with a positive caffeine halothane test will first have their DNA assessed for the presence of 17 known mutations at a cost of about $790. 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 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.
Patients and physicians are urged to provide the North American MH Registry with a detailed clinical history in order to advance the understanding of the relation between clinical events and the molecular genetics of MH. Appropriate forms are available for this purpose by contacting the Registry (www.mhreg.org). The Registry database and collection vehicle are approved by the IRB of the University of Pittsburgh Medical Center and are 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 website (www.mhaus.org) or by contacting MHAUS directly.
Dr. Rosenberg is President of the Malignant Hyperthermia Association of the United States (MHAUS) and Director of the Department of Medical Education and Clinical Research at the St. Barnabas Medical Center in Livingston, NJ. He is also a Professor of Anesthesiology at Mt. Sinai School of Medicine, NY.