I was privileged to attend the 30th Annual European MH Group (EMHG) meeting in the town of Nijmegen, Holland from June 8-10 this year. The EMHG was developed in the early 1980s by a group of clinical anesthesiologists and researchers interested in advancing the understanding of MH and providing optimum care to MH susceptibles and their families. The EMHG has focused on testing for MH susceptibility, muscle biopsy contracture tests as well as genetic tests and their relation to biochemical and physiologic changes that underlie the MH syndrome.
This year as in past years there were invited lectures by experts in disciplines related to MH other than anesthesiology as well as presentations by investigators and clinicians who have been studying MH and related syndromes.
The meeting was hosted by Dr. Marc Snoeck, director of the MH testing unit in Nijmegen and took place at a lovely conference center in a nearby suburb. About 50 MH experts and those interested in the syndrome ranging from medical students to Professors attended. They represented many countries including Switzerland, Austria, Denmark, Sweden, Germany, France, Italy, Great Britain, Israel, Australia, New Zealand, South Korea, the Netherlands and the USA. Drs. Sheila Muldoon director of the MH investigative unit at Uniformed Services University in Bethesda, MD, Dr. Jerry Kim from the University of Washington, Seattle and I attended from the USA.
It would take me many pages to summarize the information that was presented, but I would like to highlight several themes of the meeting.
Exercise/Heat and MH
One major issue is whether/how strenuous exercise and heat effects muscle function as well as the relationship between MH susceptibility and heat related illness. Dr. Maria Hopman, Professor of Physiology, Radboud University, Nijmegen, described studies that her group conducts in athletes. They utilize a swallowed capsule that transmits body temperature data to monitoring devices during an approximately 8 mile race. They observe that some patients develop a body temperature of over 104 degrees F during the race usually without harmful effects. Many routinely display a temperature of over 102 degrees. A few develop increased acid content in the blood and a few muscle breakdowns. Those patients who have a large body mass, restricted fluid intake prior to the race are more likely to have such problems. A few patients with exercise induced muscle breakdown (rhabdomyolysis) and elevated body temperature have been shown to have mutations in the ryanodine receptor gene (the principle gene that is associated with MH susceptibility). Unfortunately, there is not enough information to determine which, if any MH susceptibles will develop such problems ahead of time and, if indeed some patients who display ryanodine mutations are also at risk for anesthesia induced MH. Much more research is needed. Unfortunately very few exercise physiologists, athletic directors and sports organizations are aware of MH and the possible relation to heat stroke/muscle breakdown. For example, few, if any, patients who succumb to heat stroke or develop severe muscle breakdown with exercise are tested for MH susceptibility.
As articles in the medical literature appear concerning “awake” MH, I believe this will spur greater collaboration between MH investigators and those interested in adverse effects of heat and severe exercise.
Muscle Disorders and MH
A second major theme of the meeting is the relation between several, rather uncommon muscle disorders and MH. Studies have shown that many patients with Central Core myopathy, King Denborough syndrome and Multiminicore myopathy harbor mutations in the ryanodine receptor gene. These are inherited disorders of muscle function often associated with muscle weakness and MH susceptibility. Dr. Heinz Jungbluth a senior lecturer and consultant in Pediatric Neurology at King’s College, London, provided an in depth discussion of these and other muscle disorders related to MH. I found his statement that “Ryanodine receptor gene mutations are the most common cause of congenital myopathies” eye opening. There are a wide variety of such muscle disorders, fortunately none very common (see Table at end of this blog). Neurologists interested in muscle disorders are beginning to take notice of the implications of MH for a variety of muscle disorders.
Dr. Muldoon and I described several cases of apparent MH in young children who triggered without anesthetic agents. The cases I described were derived from Dr. Blanca Gener from Baracaldo, Spain, and her associates from Spain and the US, Jarret Burns, Edward Boyer, Miguel Vasquez, and Federico García-Bragado. I presented the cases because I felt that the MH community should hear of the investigations of deaths of two brothers without anesthesia who have mutations in the ryanodine receptor gene as well as an unusual muscle disorder, Multiminicore Disease. Perhaps in some cases the episode of presumed MH was precipitated by a febrile illness, but in others, this did not seem to be the case. At least four children had similar mutations in the ryanodine receptor gene. Others who also developed “awake” MH have been found to have other mutations in this gene, but at different locations. It should be emphasized that these are rare events. However, there is much more to learn.
Molecular Genetic Testing for MH
Another major theme of the meeting is the clarification of the number of mutations and genetic changes in the principle gene related to MH, the ryanodine receptor gene, and whether other genes might also predispose to the syndrome. In this way it is hoped that the accuracy of genetic testing will be significantly enhanced. The MH testing unit at Leeds, UK has the world’s largest experience with muscle biopsy testing for MH. They have tested over 6100 patients over the past 30 years. They have also associated many mutations with MH susceptibility. However, there are still many other DNA changes that require clarification. Newer, more powerful molecular genetic approaches called whole gene screening or exome screening that allow investigators to screen hundreds to thousand of genes the their DNA for the presence of mutations and unusual variants are being applied to the study of many disorders. Dr. Jerry Kim from University of Washington in conjunction with the testing center at Leeds and Dr. Katherine Stowell of the Institute of Molecular Biosciences, Massey University, New Zealand in conjunction with the testing center in Palmerston North, New Zealand described how they have begun to apply such techniques to the study of MH. They hope to identify other mutations and possibly other genes that standard techniques have not found. In particular, they are focusing on the 30% of patients with MH susceptibility and their families who do not seem to display mutations in the ryanodine receptor gene. Dr. Kim’s work is pointing to a few new mutations that bear investigation as to their role in leading to MH susceptibility. In time, whole gene screening will provide much needed information about the genetics of MH. However, these are complex techniques and require that the harmless DNA changes be sorted out from those that are causal for MH. Because of the large number of genes screened and the large number of DNA variants that are found, sophisticated mathematical and statistical tools are needed to understand the results. However, in the end, new information about the genetics of MH will be found.
A primary mission and goal of MHAUS is to provide clinicians and patient with the latest information concerning MH and MH like syndromes in a comprehensive and comprehensible manner. These are exciting times for those of us who have an intense interest in the syndrome since, thanks to ever more sophisticated laboratory and clinical measurement techniques, research scientists and clinicians are beginning to learn more about the various manifestations of the MH syndrome. Through more effective tools to understand the genetic predisposition to MH and predict those at risk, we hope lives will be saved.
Table: Muscle disorders showing mutations in the ryanodine receptor gene that predispose to MH
Central Core Disease
King Denborough syndrome
Nemaline Rod Myopathy
Late onset axial myopathy
Congenital fiber type disproportion