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Anesthesiology:
Correspondence

The Practicality and Need for Genetic Testing for Malignant Hyperthermia

Collard, Charles D. M.D.‡; Shernan, Stanton K. M.D.; Fox, Amanda A. M.D.; Giesecke, Martin N. M.D.; Body, Simon C. M.B., Ch.B., M.P.H.

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In Reply:—

We thank the authors of both letters for their thoughtful and insightful comments. Drs. Stamer and Stuber correctly point out that we erred when we stated that “… abdominal surgical patients with one or more CYP2D6*1 alleles were found to be twice as likely to require additional postoperative analgesics if they did not express at least 1 wild-type CYP2D6 allele because of increased tramadol metabolism.”1 In fact, for the reasons that Drs. Stamer and Stuber so elegantly outline in their letter, we should have stated that abdominal surgical patients without one or more CYP2D6*1 alleles are twice as likely to require additional postoperative analgesics because of decreased tramadol metabolism.1
In response to Drs. Brandom and Muldoon, we agree that the incidence of malignant hyperthermia syndrome (MHS) is not the same as the number of MHS-susceptible individuals. Therefore, we should have more accurately stated that the incidence of MHS is approximately 1 in 15,000 anesthetic administrations in children and 1 in 50,000 in adults, with an estimated susceptibility of 1 in 8,500 individuals.2–4 Although susceptibility may be as high as 1 in 2,000 in France,5 Dr. Muldoon has also previously demonstrated that the frequencies of many common MHS mutations differ significantly between regions. Notably, the frequency and distribution of RYR1 mutations observed in the North American MHS population are markedly different from that of Europe.6
Indeed, it is because of such wide ethnic variations in the frequency of MHS-related polymorphisms, as well as the fact that many MHS-susceptible individuals have no known RYR1 polymorphisms, that we stand by our statement that widespread, commercial genetic testing of the population for this disorder currently remains impractical. We did not refer to genetic screening in selected individuals, but rather the wider population. Nor are we alone in questioning the current feasibility of widespread commercial genetic testing for MHS. For example, Hopkins4 stated that
the complexity of the molecular genetics of MHS precludes DNA-based diagnosis at present, especially when one considers the possibility of one gene defect being associated with susceptibility in only a proportion of individuals and another, as yet unidentified, defect being causative of the condition. This is complicated further by the well-established presence of genetic heterogeneity. The first step in a DNA-based diagnosis, therefore, will rely on initial identification of the abnormality, or abnormalities, causing MHS in individual pedigrees. It is likely that the first reliable DNA-based diagnoses will be carried out in individuals from families that have been extensively investigated by both in-vitro contracture test (IVCT) phenotyping and linkage analysis followed by mutation screening.
More recently, Girard et al.7 stated that
molecular genetic analysis should be used in selected families when possible and appropriate, and it is becoming an important supplement of IVCT. As a prerequisite for genetic testing, mutation frequencies in the geographic region served by the investigation center must be known. Such frequency investigations have already been published for Germany, Italy, North America, Switzerland, and the United Kingdom, but data for other countries are still missing. Screening for MH mutations without this knowledge is costly and is not recommended. The integration of molecular genetic results with pedigree information as well as IVCT data avoids open muscle biopsies and IVCT in a person whose family is known to have an MH mutation.
In addition, Dr. Muldoon herself has acknowledged problems with genetic testing for MHS:
Although genetic linkage analysis shows that 50–80% of European MHS families are linked to the RYR1 gene, mutations are reported in only 25–40% of MHS families so far. The majority of RYR1 gene mutations are clustered in the N-terminal region with amino acid residues from 35 to 614 and in the central region from 2163 to 2458. Most genetic screening studies target these two regions, which account for only approximately one fourth of the entire coding region of the RYR1 gene. Thus, the absence of RYR1 mutations in the rest of the screened population might be explained either by a mutation located outside the two regions analyzed in the current study or by the involvement of another gene.6
Finally, we agree with Drs. Brandom and Muldoon that it is important that clinicians become more sophisticated with respect to the recommended use and interpretation of genetic testing. As such, we point out that the Malignant Hyperthermia Association of the United States currently advises that only the following individuals be considered for genetic testing:*
1. Individuals who have a positive IVCT result.
2. Relatives of individuals who have a positive by IVCT result.
3. Individuals who have been found to have a mutation causative for MHS under a research protocol.
4. Relatives of individuals with a known mutation for MHS.
5. Individuals with a very high likelihood of having experienced an MHS episode.
In addition, despite the high cost of IVCT, the Malignant Hyperthermia Association of the United States does not currently recommend that genetic testing replace IVCT. Finally, genetic testing for MHS susceptibility is currently offered at only three places in the world, one of which is in the United States. Nonetheless, we are certain that with further advances in the field by experts such as Drs. Muldoon and Brandom, inexpensive genetic testing with reliable positive and negative predictive values will soon become available for population screening. However, that day is not here yet.
Charles D. Collard, M.D.‡
Stanton K. Shernan, M.D.
Amanda A. Fox, M.D.
Martin N. Giesecke, M.D.
Simon C. Body, M.B., Ch.B., M.P.H.
‡Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas. ccollard@houston.rr.com
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References

1. Uhl GR, Sora I, Wang Z: The mu opiate receptor as a candidate gene for pain: Polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci U S A 1999; 96:7752–5

2. Girard T, Urwyler A, Censier K, Mueller CR, Zorzato F, Treves S: Genotype-phenotype comparison of the Swiss malignant hyperthermia population. Hum Mutat 2001; 18:357–8

3. 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

4. Hopkins PM: Malignant hyperthermia: Advances in clinical management and diagnosis. Br J Anaesth 2000; 85:118–28

5. Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J: Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 2002; 97:1067–74

6. Sambuughin N, Sei Y, Gallagher KL, Wyre HW, Madsen D, Nelson TE, Fletcher JE, Rosenberg H, Muldoon SM: North American malignant hyperthermia population: Screening of the ryanodine receptor gene and identification of novel mutations. Anesthesiology 2001; 95:594–9

7. Girard T, Treves S, Voronkov E, Siegemund M, Urwyler A: Molecular genetic testing for malignant hyperthermia susceptibility. Anesthesiology 2004; 100:1076–80

* Available at: http://www.mhaus.org/index.cfm/fuseaction/Content.Display/PagePK/MolecularGeneticsFAQ.cfm. Accessed June 20, 2005. Cited Here...
† Available at: http://www.geneclinics.org/servlet/access?prg=j&db=genetests&site=gt&id=8888891&fcn=c&qry=19725&res=nous&res=nointl&key=jVyz4R2Z2hvNX&show_flag=c. Accessed June 20, 2005. Cited Here...

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