I was pleased when Myron asked me to submit a commentary in memory of my dear friend Dr. Ron Litman.
Ron was one of the most creative, thoughtful, friendly individuals I have known. Although we did not work together as clinicians, we did collaborate on issues related to Malignant Hyperthermia, in particular the MHAUS hotline as well as clinical issues related to the syndrome. He also was a fine educator and mentored many students and produced an excellent textbook on Pediatric Anesthesiology (see the recent review: Yaster, Myron: "Litman’s Basics of Pediatric Anesthesia, 3rd Edition". Anesthesiology, vol. Publish Ahead of Print, March 08, 2024, doi: 10.1097/ALN.0000000000004889). His passing was a true loss to the specialty.
The 2 articles I would like to comment on are:
Original article
Yu KD, Betts MN, Urban GM, Schwartz MLB, Robinson TO, Moyer RJ, Taddonio SW, Vasudevan A, Johns A, Sturm AC, Kelly MA, Williams MS, Poler SM, Buchanan AH. Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program. Anesthesiology. 2024 Jan 1;140(1):52-61. doi: 10.1097/ALN.0000000000004786. Erratum in: Anesthesiology. 2024 Feb 20;: PMID: 37787745.
Original article
Yu H, Tan L, Deng X. Improving Dantrolene Mobilization in Regions with Limited Availability. Anesthesiology. 2024 Feb 8. doi: 10.1097/ALN.0000000000004892. Epub ahead of print. PMID: 38329334.
The first1 concerns the practical aspects of genomics of MH, the second from China2 describes the deadly consequences of lack of preparation to deal with MH, especially lack of dantrolene Over 50% mortality!.
I am sure that you are all aware that MH is inherited in an autosomal dominant manner in humans, what medications trigger MH, how preparation and steps in treatment have reduced the mortality of MH from about 70% to about 10% (still too high). Identification of those at risk is however still a problem because the availability of the halothane caffeine contracture test in the US has all but disappeared because of the cost of maintaining the testing centers and the invasive nature of the procedure. There are now only three testing centers in the USA and one is primarily for the military.
However, over the past ten years, work on the genetics of MH has shown that three genes contain DNA variants that are causal for the disorder(RYR 1, CACNA1S and STAC 3). The European MH Group has developed guidelines for the use of genetic testing which are used in Europe, Canada, New Zealand, Australia and several other countries. Furthermore, the cost of genetic testing has dropped dramatically over recent years, to about $250 for panel testing, involving the three genes. There are several hundred variants in the genes that are pathogenic or likely pathogenic for MH, but to date, only about 50 have been so identified, other variants still remain to be classified. The lead laboratory working on this issue in our country is that of Dr. Les Biesecker at the National Human Genome Research Institute. The EMHG has also working on the problem and identified a similar number of variants. In the countries I have mentioned, and others, the first diagnostic step in assessing whether a patient has developed MH is a genetic test. The contracture test is used as a secondary test. Not so in our country. Most providers are unaware of the utility of genetic testing for MH. There are about 20 commercial genetic testing companies in the US. Just about all follow standard sequencing procedures. A thorough review of the testing centers in regard to MH is underway by MHAUS. Some are listed on the MHAUS web site.
Not only is it important to define susceptibility for the patient, but it is important for his/her relatives to be aware of susceptibility. When a genetic test reveals a specific variant, it is even less costly than when testing the whole exome, or whole genome. The first article I have listed is from a very well developed genetics (and EHR) initiative at Geisinger medical center in Pennsylvania.1 They showed in now two publications, that when 130,000 patients admitted to the medical center volunteer to have whole exome sequencing performed, one in 600 to 850 harbor one of the known pathogenic or likely pathogenic variants for MH! Fortunately, the penetrance for the syndrome is quite low but some demonstrate other myopathic symptoms. That equates to about 400,000 people in the US harbor one of the MH variants. The estimates of MH anesthetic cases is approximately 1000 per year. Furthermore, an ongoing study from the North American MH Registry of MHAUS at U of Florida in collaboration with the NHGRI demonstrates close to 80% of those with positive contracture test harbor one of the pathogenic variants. Not perfect, but what is perfect in medicine?
It is important to remember that MH is an inherited disorder like many others and advances in care depend on collaboration between clinicians and geneticists, genetic counselors and pharmacogeneticists. That expertise is needed to review the genetic findings, follow the patient for long periods of time potentially and provide consultation for family as well as other clinicians. We regularly hear that knowledge of MH is not widespread among many branches of clinical medicine. Furthermore, many patients who have whole exome or whole genome testing for reasons not related to MH turn up with a variant in one of the three genes related to MH. Information and action on such secondary findings are sometimes posed to the MH hotline experts.
There is a lot more to the story since a variety of myopathies and other disorders such as heat stroke are sometimes associated with MH pathogenic variants.
The bottom line in my view, is that a closer collaboration with the genetics community is important for the specialty. Let’s remember that other disorders and conditions that impact anesthesia care are also genetically based. Perhaps when the answer to the standard preop question “has anyone in your family died unexpectedly during anesthesia or in the recovery room?” is “YES”, the next step is genetic testing in order to guide anesthesia care but also to provide information for the patient’s family. I also advise those who manage an MH episode, to report the details to the North American MH Registry and seek consultation with a member of your genetics team.
Advances in genetics are guiding care in many areas of medicine and pharmacology. Anesthesiology has pioneered understanding and application of pharmacokinetics and pharmacodynamics. It’s time to add pharmacogenomics to the triad.
What are your thoughts? Send your comments to Myron who will post in a Friday reader response.
References
1. Yu KD, Betts MN, Urban GM, et al. Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program. Anesthesiology 2024;140(1):52-61. (In eng). DOI: 10.1097/aln.0000000000004786.
2. Yu H, Tan L, Deng X. Improving Dantrolene Mobilization in Regions with Limited Availability. Anesthesiology 2024 (In eng). DOI: 10.1097/aln.0000000000004892.