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The conclusions expressed in this essay and the projections for the future are mine and have not yet gone through the rigorous review process of MHAUS.
I was first introduced to the problem of MH when I was a resident in Anesthesiology at the Hospital of the University of Pennsylvania in the 1970s. Several years before I started my training a student nurse died with what turned out to be signs of Malignant Hyperthermia. When this event happened, dantrolene was not yet available and the scientific understanding of the disorder was very shallow. It was reported that 80% of those who experienced an MH episode died. Rather than relate my experiences and devotion to preventing such deaths, I will skip ahead to the present and the future in order to make you aware of recent developments that may very well lead to the “End of MH”.
Since the very first cases of MH were described in Australia and Canada, it was determined that in humans Malignant Hyperthermia (MH) is inherited in a dominant fashion. This means that if a person inherits an abnormal genetic change s/he will be at risk for developing this deadly disorder. Change in several genes have been linked to the predisposition to MH.These are the Ryanodine Receptor type 1 (RYR 1), CACNAIS, and STAC 3 genes. All of the genes play a role in muscle cell calcium metabolic control. Patients who inherit or develop a specific mutation in the DNA of one of the genes are at risk for developing clinical MH. Each gene is made up of hundreds to thousands of base pairs that are required to produce the proteins that control cellular metabolism. Most commonly, mutations in the DNA of the very large RYR 1 gene that influences the release of calcium into the cell are the most common reason for a patient being at risk for MH.
Research into the mechanism of action of the calcium release and cellular control of calcium has been in progress for about two decades or more.
One major problem in detecting those at risk for MH is that the gene is very large (one of the largest in the body) and up to about 50 DNA changes have been found in MH susceptibles that are “pathogenic”, that is will lead to protein changes that alter cellular control of muscle metabolism. There are any number of chapters and articles that explain the detailed changes that take place at the cellular level. Investigators from many countries have participated in clarifying the underlying defects in muscle metabolism that leads to a case of MH.
Pharmacogenomics is the term given to the identification of the DNA changes that will predict disease. For example, risk for breast cancer is associated with modifications in the BRCA1 gene. Accordingly, if there is a family history of breast cancer, patients are often referred for genetic analysis to determine if the individual in question has inherited the mutation found in the relative who developed breast cancer. If so, appropriate steps can be taken to detect the earliest stages of the disease and institute treatment and prevention measures.
Applying the same logic to MH it is possible to determine a person’s risk for MH if s/he manifests a genetic change that is pathogenic for the disorder. This has already, in many cases, taken the place of the muscle biopsy contracture test, but the story is not yet complete. Since MH occurs sporadically often without a family history of the disorder it is difficult to carry out detection based on the same approach as in other disorders. However, if one were to examine the genetic makeup of all patients presenting for anesthesia and surgery, those who turn up with one of the known pathogenic mutations could avoid exposure to the trigger drugs and thereby avoid the chance of developing MH.
Although that is completely feasible, the companies that offer genetic tests would have to offer such a service and insurance companies would have to pay for such testing. That is an entirely more complex issue than I wish to address.
What has been accomplished recently is agreement among the world’s experts in MH that it is possible to identify one or more of the mutations that predispose to MH( called “pathogenic”). Thanks to the decades of basic research into MH and to the dramatic developments in the field of molecular genetics, the reduction in the cost of seeking mutations that predispose to MH, the possibility of performing preoperative genetic testing on all patients scheduled for anesthesia and surgery is feasible. Over the decades, the problem of MH has diminished due to the extensive education and training offered by MHAUS , Anesthesiology societies and similar organizations along with the discovery of dantrolene and training clinicians on how to be prepared to manage the MH susceptible patients. Hence the mortality and major morbidity related to MH has decreased from 80% of cases in the 1970's to about 10% of cases in recent years. However, our aim at MHAUS has always been to eliminate death from MH. We have gotten closer to that goal, but one major issue is that we are usually dealing with cases of MH after they occur. Pharmacogenomics offers the chance to change that risk dramatically. As such molecular pharmacogenomics is offering new opportunities in prevention of devastating disorders.
Over the past several years, a group of anesthesiologists, geneticists and other scientists have focused on identifying the mutations predictive for MH. This consortium has been led by Dr. Les Biesecker, head of the Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute of the National Institutes of Health of the US. These outstanding experts from America, Canada, Australia, New Zealand and Europe have contributed their expertise in evaluating the many variants that have been found in association with individuals who displayed an MH episode and also, in many cases, displayed typical MH changes in the muscle biopsy contracture test. Approximately 70% of known MH susceptibles show one of the pathogenic DNA variants. If all those presenting for surgery were genetically analyzed for the presence of one of the known mutations, then MH trigger agents could be avoided, thereby preventing an MH episode. In addition, family members could be tested to see who might also have the mutation. Because MH does not occur with every exposure in a susceptible, it is hard to be definitive about absolutely ending MH in this fashion, but it would be close. The implications of such a process are many including limitations on the use of the common gas anesthetic agents, but just about all anesthesia providers are familiar with the alternative techniques.
It has been exciting for me to be part of this esteemed group of scientists. Many names will be familiar to you such as Robert Dirksen, Sheila Riazi, Philip Hopkins, Thierry Girard. Jennifer Johnston who works with Dr. Biesecker has been of crucial importance in sorting through the many genetic variants in question.
I am presenting this information to you because the article titled” Genomics of Malignant Hyperthermia Susceptibility” has been accepted for publication in Anesthesiology, one of the premier journals in the field. While it has not been published officially a “preview” of the article is available on the Anesthesiology.org web site in the section called “Online First”. The article was carefully and thoroughly reviewed by the journal and its experts who posed challenging questions to the authors.
In my view this publication and work will introduce the topic of genomic medicine in the practice of Anesthesiology in a mostly theoretic, but eminently practical manner. Additional work on the topic will be conducted through the North American MH Registry located at the University of Florida, Gainesville as well as the research centers in Canada, UK, US, New Zealand, Australia, Switzerland and many other countries.. We at MHAUS will address more of the findings from the Registry in the near future as they work on the genomics and clinical presentations of MH as well as cataloging calls to the MHAUS hotline.
To me, this article marks the beginning of a new and exciting area in clinical medicine and represents a major milestone in Anesthesiology and pharmacology.
I have had an interest in MH since I was a resident in Anesthesiology and have followed and contributed to the clinical and laboratory progress in understanding this complex problem. I could say a lot more but urge you to find the article, read it, and send questions and comments to us at MHAUS. If at all possible, we will post the article on the MHAUS web site.
Thank you for your interest in MH and in your support of our small, but powerful organization.
What has been accomplished is remarkable but it is not an end, but a beginning of a new era with many challenges ahead. We will need your support to move forward.
View the article on Anesthesiology.org