May 15-17, 2014
The European MH Group consisting of clinicians and scientists interested in and studying MH and related disorders met in the beautiful town of Wurzburg, Germany, in the northern part of Bavaria. Wurzburg was the home of Dr. Wilhelm Conrad Roentgen, who discovered x-rays and was the first recipient of the Nobel Prize in Physics. His laboratory is maintained in the University and is open for visitors. Wurzburg, located on the Main River, is known for its excellent white wine. The meeting was organized by the Wurzburg MH Unit and hosted by Drs. Frank Schuster, Norbert Roewer (Chair, Department of Anesthesia) and Dr. Clemens Muller-Reible. It included abstract presentations, posters and two guest lectures, one on “personalized medicine” and the other on “HyperCKemia- a neurologist’s point of view.” There were about 50 attendees from Europe, South America, Canada, New Zealand, Israel, Russia and the US. North American attendees included Dr. Sheila Muldoon, Dr. Sheila Riazi (Toronto) and me.
About 30 presentations covered clinical presentations of MH; testing for MH by muscle biopsy contracture test; genetics of MH; muscle pharmacology and physiology and a variety of other topics. Some of the highlights from my point of view:
Unavailability of Dantrolene
Not every country is prepared for MH; a report from Portugal (Dr. A. Marques) described a case of MH where treatment was significantly delayed because of the lack of immediate availability of dantrolene. The clinicians treated the 19-year-old patient symptomatically and with a calcium channel blocking agent and after a two-hour delay after diagnosis during surgery, dantrolene was administered. Fortunately, the patient survived, but had a prolonged hospital stay and suffered muscle damage in his legs. Further there is no testing center for MH in Portugal (or for that matter in Spain either).
Dr. A. Kazantseva from Saint Petersburg, Russia, described her efforts in forming an MH interest group and testing center for MH in Russia. There are currently no testing centers and dantrolene is not registered as an official drug in this large country. Similar issues exist in many other countries.
MH Case in ICU
I was startled to hear about a case of MH that developed in a patient in an Intensive Care Unit (Dr. S. Johannsen, Wurzburg). What was different about this case was that the clinicians were using a relatively new device called AnaConDa, which delivers a low concentration of gas anesthesia (e.g., sevoflurane) in order to achieve sedation during mechanical ventilation for respiratory failure in the ICU. After four days of use of the device, the patient developed signs of MH, which was subsequently verified by contracture testing. He was treated with dantrolene and survived. This device was developed by a company in Sweden (Sedana Medical, www.sedanamedical.com) and is used in many countries. It is not approved for use in the USA. I expect that there will be many more cases of MH resulting from the use of this device in the future. As an anesthesiologist, I am also concerned about the effects of long-term administration of general anesthesia, even at low concentrations, on organ system function as well as the effect of anesthetic pollution of the atmosphere in the ICU. According to the company, only one case of MH has been described associated with the use of the device (Schuster F, et al. Critical Care 2014;18:411). I urge anyone who has identified an MH episode associated with the device to contact MHAUS.
Dr. Rene Krivosic-Horber, testing center in Lille, France examined their database of patients who were tested from 1964-2013 and assessed whether the presence of any mutation in the RYR-1 gene was associated with a more severe clinical course of MH, and whether the vigor of the muscle contracture response in the muscle biopsy test was related to the presence of a mutation. There was no association with the clinical severity of the syndrome, but those with mutations displayed stronger contractures to both halothane and caffeine.
Dr. Sheila Riazi described the experience with the caffeine –halothane contracture testing in the Toronto diagnostic unit for patients who did not have an anesthetic related MH episode, but were tested for such reasons as chronically elevated muscle enzymes, post exercise muscle breakdown and post-viral chronic fatigue. 104 of 154 patients had an abnormal contracture test. One third had abnormal muscle histology, 3 carried causative mutations, 75% of those with chronically elevated muscle enzymes had a positive test, as did 60% with chronic fatigue defined as chronic muscle pain, weakness and cramps lasting more than three months after viral illness. Such chronic fatigue syndromes are not generally felt to be associated with MH susceptibility and therefore, further work will be needed to substantiate the findings.
As the field of molecular genetics for purposes of clinical diagnosis develops and advances, studies of the molecular genetics of MH also progresses. Advanced analytic techniques called “Next Generation Sequencing” identify all the base pairs of a gene in a highly accurate manner (not 100% ). More and more DNA variants are being discovered in the principal gene associated with MH, the Ryanodine Receptor gene and the secondary gene, the Dihidropyridine Receptor gene. F. Grutter from Basel searched the published literature from 2006 through 2012 and identified 316 variants in the RYR 1 gene, with a third not yet characterized as predisposing to MH and many not in the existing database maintained by the group. (Over 15,000 base pairs make up the RYR-1 gene). Based on a review of the characteristics of DNA variants, three mutations have been added to the “definitely causative” list of mutations by the group, bringing the total to 33.
Next generation sequencing was applied to 80 MHS patients where genetic testing with current methods did not find mutations (D. Fiszer and colleagues from Leeds, UK). However, with using Next Gen Sequencing new variants in the RYR 1 gene were identified and predicted to be of significance in predisposing to MH. Among the group of 80 were 38 who developed heat stroke. Similarly, K. Stowell from the New Zealand MH group used next generation sequencing to identify variants in a family with suspected MH that had not been noted previously. The Leeds MH group is now able to offer genetic testing for MH susceptibility, which has been recognized by the National Health Service of UK. This is an important step since such approval is required for payment for such testing. ( I recently learned that PreventionGenetics, based in Marshfield, Wisconsin offers genetic testing for MH and is also using Next Generation Sequencing techniques.)
Dr. Clemens Muller of the University Wurzburg summarized their experience with genetic testing for MH demonstrated the genetic heterogeneity of MH and implied that a quick and cheap test for identifying MH susceptibility prior to surgery is a long way off.
Nevertheless, slow but steady progress is being made in identifying the genetic changes that predispose to MH in many patients. As with many other inherited disorders, computer algorithms are now being applied to the many newly discovered DNA variants in order to identify those likely to lead to disease. The challenge is still to show that a particular genetic change leads to a change in the patient’s phenotype.
Because acceptance of a DNA variant as causal for MH has been based on rigid criteria and includes functional test requiring manipulation of the genetic makeup of a cell, progress in adding new mutations to the list of those considered to predispose to MH has been very slow. After analyzing their experience with genetic testing and muscle biopsy contracture testing, the EMHG has decided under certain circumstances the requirement for a functional test will be eliminated.
Despite this progress in genetic characterization of MH, it should be noted there are probably other, yet unidentified genes, which can lead to clinical MH in up to 20% of MH susceptible families.
At the same time European MH diagnostic centers are advancing in their studies of the molecular genetics of MH, they are also refining the muscle biopsy contracture test to increase the reproducibility of results.
The European MH Group meeting highlights the recent advances in understanding MH and related syndromes. In particular, the pace of discovery related to the molecular genetics of MH and related syndromes is increasing very rapidly. Those of us interested in MH are grateful to the concerted efforts of the diagnostic and research units related to MH in Europe. There are certainly more anesthesiologists, anesthesiology departments in European Hospital and Universities working on the problem of MH than in any other continent. It is a credit to the cooperation and leadership of the group that so many advances have been made in recent years.