Recent advances in the pharmacogenetics of anesthetics are relevant to the practice of anesthesia. Therefore, we must address the misstatements and errors in the review article on this subject.1We restrict our comments to the section titled Inhalation Anesthetics, in which susceptibility to malignant hyperthermia (MH) is discussed.

In the first paragraph, there is an error. The incidence of MH episodes is not the same as the number of MH-susceptible individuals. We agree that in 1970, the estimated incidence of MH episodes was 1 in 15,000 anesthetics in anesthetized children and 1 in 50,000 anesthetics in anesthetized adults.2But the number of individuals who are likely to be susceptible to MH is much, much greater than the number of reports of anesthetic incidents. Monnier et al.  3estimated that the frequency of mutations producing MH susceptibility in the French population could be as great as 1 in 2,000 people.

We do not agree that genetic testing for MH is impractical. The utility of a genetic examination of the RYR1  has been demonstrated in the Swiss population.4Clearly, a genetic test of MH susceptibility can be useful to the anesthesiologist caring for members of a family in which a known MH-causative mutation was identified. A meeting of geneticists and MH researchers concluded that even with a sensitivity of 23% in the small population of North American patients studied, examination of a limited number of RYR1  exons is practical.5Examination of the entire coding region of the RYR1  will identify a greater number of mutations.6In 2005, more than one diagnostic Clinical Laboratory Improvement Act–approved genetic laboratory is preparing to offer a test of RYR1  to the public.

In 2005, the Web site of the European MH Group listed 23 causative mutations, but examination of the recent literature from North America and Europe records more than 100 mutations in RYR1 . Some of these have been found in only one family but clearly are associated with lethal MH episodes and positive contracture test results. The number of sequence variants is not as much a problem to the interpretation of the examination of RYR1  as are the classic requirements that the variant be observed in more than one family and be shown to decrease the threshold for release of calcium from the sarcoplasmic reticulum in an experimental model before it can be acknowledged as causative of MH. Therefore, many of the observable sequence variants will be interpreted as possibly associated with MH susceptibility based on the clinical history of the patient and the potential effect of that sequence variant on the function of the ryanodine receptor channel.

It is important to recognize the pharmacology of the phenotype from which the genetics of MH is described. The in vitro  contracture test that is used in North America is known as the caffeine–halothane contracture test (CHCT).7This test requires a surgical procedure and dissection of a large muscle strip for contractile studies, not extraction of muscle cells. The muscle specimen is separated into bundles of fibers, placed in temperature-controlled chambers, aerated with controlled tensions of oxygen and carbon dioxide, stimulated electrically, and then exposed to halothane, caffeine, or other drugs that affect ryanodine receptor function. It is the reproducible shift in the dose-sensitivity of muscle contraction to these compounds that has led to the use of CHCT as the diagnostic indicator of MH in North America. The in vitro  contracture test that is used in Europe is known as the IVCT. The test performed in North America is not identical to the IVCT. Therefore, it is appropriate to state that an in vitro  contracture test was used to determine the presence or absence of MH. There is more than one such test.

We agree that MH is a complex genetic disease. Nevertheless, the genetic test offered in 2005 can be useful to families and anesthesia providers who wish to secure a diagnosis of MH susceptibility. When there is no RYR1  sequence variant identified in an individual with a strong clinical history, CHCT should be performed.

Because of these considerations, we disagree with the economic discussion of genetic testing of MH susceptibility. The authors do not seem to know that the cost of the CHCT is $6,000–10,000, without the necessary added expense of travel to a diagnostic MH center. Because MH susceptibility is relatively rare, it is difficult to develop a screening test for this disorder. The most appropriate testing strategy should be based on the prior probability of the disorder being present before the test is performed.8If a mutation causative of MH is identified in an MH-susceptible proband, that RYR1  mutation can be looked for in first-degree relatives for a cost much less than 10% of the cost of the CHCT.

We hope that clinicians will become sophisticated in the interpretation of genetic test results. But the interpretation of genetic tests must include detailed understanding of the disease that the test was developed to identify. This will not happen in the case of MH susceptibility if the clinical phenomena of this disease, its diagnostic bioassay, and genetic studies to date are misrepresented.

*University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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Britt BA, Kalow W: Malignant hyperthermia: A statistical review. Can Anaesth J 1970; 17:293–315
Monnier N, Krivosic-Horber R, Payen J-F, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J: Presence of two different genetic traits in malignant hyperthermia families. Anesthesiology 2002; 97:1067–74
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Sambuughin N, Holley H, Muldoon S, Brandom BW, de Bantel AM, Tobin JR, Nelson TE, Goldfarb LG: Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the North American population. Anesthesiology 2005; 102:515–21
Larach MG: Standardization of the caffeine halothane muscle contracture test. North American Malignant Hyperthermia Group. Anesth Analg 1989; 69:511–5
Loke J, MacLennan DH: Bayesian modeling of muscle biopsy contracture testing for malignant hyperthermia susceptibility. Anesthesiology 1998; 88:589–600