A NEW ERA IN DEALING WITH THE MALIGNANT HYPERTHERMIA SYNDROME
Henry Rosenberg, MD
President of MHAUS
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.
It has been my pleasure and privilege to be a part of the Malignant Hyperthermia Association of the United States since its founding in 1971 as Board member since then and as President since 1998.
During this time, I have witnessed, studied and commented on enormous changes related to the presentation, incidence, epidemiology and treatment of this rather unusual inherited disorder. It has been my privilege to work with many physicians, scientists, geneticists, and lay people to help spread the word about MH, and how to recognize and treat the syndrome effectively with training and dantrolene. In 1979 the primary treatment drug for MH, dantrolene, was approved by the FDA. It was introduced by a small pharmaceutical company in upstate New York called Norwich Eaton Pharmaceuticals. This company was later bought by Procter and Gamble and eventually was acquired by Par Pharmaceuticals in upstate New Jersey. The efforts by members of the staff, hotline, professional advisory committee and the Board of MHAUS led to widespread recognition of MH and led to a reduction of mortality from about 80% of cases in the US to now about 4-10% of cases. This, to those of us associated with MHAUS, is still too high. However, new information and findings has introduced the possibility of reducing the incidence of MH and importantly, the mortality and bad outcomes from the syndrome to almost zero. MHAUS has for the past 38 years published articles and posted information on Facebook, Twitter, Instagram and our regular newsletters, The Communicator, and the e-Newsletter, Hot Topics in MH in order to keep clinicians, nurses, scientists, pharmacists, administrators and patients aware of the dangers and the possibilities of improving the outcome from MH. A few years ago, we were especially grateful to the American Medical Association and other accrediting organizations for hospitals and outpatient centers for requiring that all clinical providers facilities caring for patients are educated and prepared to recognize and treat MH.
I am not writing at this time to simply review the history of the syndrome and of MHAUS or the important contributions of the past, but to discuss some major advances in understanding and interpreting the genetic changes found in those at risk for MH. MH was found to be a dominant syndrome, unrelated to gender in humans. This means that 50% of children of an MH susceptible patient are at risk for MH! Considering there are about 50 million anesthetics administered in the US, that is a pretty respectable number, particularly as you will read, the prevalence of one of the genetic changes that predispose to MH is one in one thousand people! A naturally occurring animal model for MH was identified in the 1970s in certain breeds of swine. By studying MH first in these animals, it was determined that MH was and inherited condition. This work was done by Dr. David MacLennan, Beverly Britt and Werner Kalow at the University of Toronto in Canada in the early 1970s. Another group at the University of Minnesota including Charles Louis, James Mickelson and Esther Gallant was also researching the topic and identified the genetic change in pigs a little after it was demonstrated by the group in Canada. They too deserve a great deal of credit.
Meanwhile researchers at Norwich Eaton Pharmaceuticals, Drs. Mary Elizabeth Kolb and Keith Ellis were investigating a drug manufactured by that company, dantrolene, which was found to cause muscle relaxation in humans and animals and was useful in patients suffering from muscle rigidity associated with tetanus toxicity. Their studies, together with a South African scientist/anesthesiologist, Dr. Gaisford Harrison, proved that dantrolene was an effective drug for treatment of MH in humans and animals. The announcement of the findings in the mid-1970s was dramatic and exciting and led to the decline in mortality from MH.
However, we all were still faced with how to determine who was at risk for MH prior to surgery and anesthesia and to positively identify those who had developed MH. A series of studies in Canada, the US, Australia, New Zealand and Europe with the anesthetic halothane and the drug caffeine on isolated muscle fibers showed that those at risk for MH developed strong contractures in a test apparatus when exposed to such agents. But the muscle had to be removed from the patient and treated very carefully. Nevertheless, the test, called the Caffeine Halothane Contracture Test in North America and the In Vitro Halothane/Caffeine Test in Europe and elsewhere, was very helpful in clarifying the inheritance of MH, identifying those at risk for MH, and diagnosing those who experienced an episode. Because of the inheritance of MH in an autosomal dominant pattern, many relatives were able to avoid an MH episode based on the test. However, the test, as accurate as it was, was inconvenient and expensive and required special laboratory facilities and was poorly reimbursed by insurance companies. Many testing centers in the US and Canada closed because of the cost of testing so that there is only one testing center in Canada and four in the US. Clearly, if one were able to identify the genetic change in those who were at risk for MH, the inconveniences and challenges of the muscle biopsy contracture test could be avoided and many more people identified as to their susceptibility. Over the years following the studies in the 1990s, three genes were identified as being related to rendering patients at risk for MH. The genes all elaborate proteins related to calcium movement in muscle cells. They are the Ryanodine Receptor, type one (Ryr-1), the CACNA1S gene and most recently a gene called STAC-3 which was found to be related to a rare muscle disorders in addition to MH in Lumbee Indians and some other people.
However, identifying a gene was not the answer to the problem. These genes are found in all patients and most of the time they are responsible for the development of proteins that control muscle contracture in a normal manner. Through a good deal of diligent work in the US, UK, Germany, Italy, France , Canada, Japan, Australia and New Zealand, it has been found that about 50 specific DNA variants in these genes predispose to MH. The American College of Medical Genetics, an organization that has a strong interest in genetic disorders, includes these genes in their listing of “actionable genes”. This means that if one of these DNA changes is found by accident or on purpose, the physician and his /her care providers must counsel the patient and family on the risk of developing MH.
Fortunately, testing for genetic changes causing many disorders and cancers has also developed in a sophisticated manner. Furthermore, DNA testing requires only a blood or sputum sample but also requires a sophisticated, accredited laboratory setting that has received certification through CLIA, The Clinical Laboratory Improvement Amendments. Here the good news is that advances in technology have led to the ability to identify many genetic changes that predispose to medical conditions for an ever-declining price! Now it costs about $300 for sequencing the active portion of a person’s genome. Furthermore, studies from several laboratories have found that 70% of patients who develop MH demonstrate the presence of one of the 50 DNA changes that predispose to MH. To me this is simply amazing!
Already many individuals and their relatives have been diagnosed as being MH susceptible and avoided an MH episode by avoiding exposure to the triggering anesthetics that lead to MH. Many more will be identified in this manner. MHAUS will be discussing such testing over the next few months and investigating the cost of genetic testing for MH and the return on investment. We have been especially fortunate that Dr. Leslie G. Biesecker, Director of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health has devoted himself and others in his lab to exploring the details of the genetic diagnosis of MH. In addition, geneticists and anesthesiologists associated with the European MH Group (emhg.org) have also been studying the genetics of MH as well as the implications of changes in the genes in association with other very uncommon muscle disorders. Furthermore, the genetics group at Geisinger Medical Center in Pennsylvania has been genetically testing admissions to their facilities in order to diagnose those at risk for many inherited disorders, including MH.
Encouraging as this news has been, there are still further studies that are required to explore the genetics and biochemical changes in the muscle that lead to the presentation of MH. It is important to recall that even though about one in 1,000 people have a genetic change that predisposes to MH, the actual clinical incidence of the syndrome is much lower than that, perhaps one in 25,000-30,000 people who receive one of the trigger anesthetics as part of their care.
Furthermore, we do not understand why 25-30% of patients who develop MH do not demonstrate one of the known genetic changes found in MH-Susceptibles. In addition, what do we tell people who are found coincidentally to have one of the causative DNA changes indicative of risk for MH when we advise them about their participation in an exertional sporting activity? Just because they have the DNA changes found in MH and because 30% of those who suffered an episode of exertional heat stroke manifest one of the DNA changes found in MH, does that mean that all such individuals are at risk for developing a syndrome that might also be fatal, i.e., exertional heat stroke? Interestingly, even though I read about deaths from exertional heat stroke in young athletes, I rarely hear of genetic testing in those individuals.
The bottom line of my essay is that we are now in a position to prevent or significantly reduce episodes of MH as well as the adverse consequences of the syndrome in a manner that has been more effective than ever before. How best to use this knowledge in order to prevent death and disability from MH in all cases is perhaps the final step in this quest to eradicate this deadly disorder.
For all those associated with MHAUS and with similar organizations, thank you very much. We hope we can depend on your support as we go further.