Continued progress in understanding the molecular genetics of malignant hyperthermia

A little over 50 years ago, Denborough and Lovell described the syndrome known today as malignant hyperthermia (MH). Little was known about this disorder at the time other than it carried a high fatality rate and was characterized by explosive hyperthermia in an otherwise apparently healthy individual undergoing general anesthesia. The unravelling of the principal features of the syndrome involved a combination of astute clinical observations, a fortuitous association with a similar syndrome in pigs, and assiduous laboratory investigations involving contributions from many countries. Seminal contributions to the understanding of MH were made by individuals associated with the University of Toronto, particularly Drs. Beverly Britt, Werner Kalow, Roderick Gordon, David MacLennan, and their many coworkers. In this issue of the Journal, Dr. MacLennan et al. continue to expand on earlier work in MH, particularly the molecular genetics of MH and the allied myopathy, Central Core Disease. Although the inheritance pattern of MH in humans was known by the 1980s, a turning point in the MH story occurred in 1990 when Dr. MacLennan’s team identified the mutation in the ryanodine receptor gene causal for MH in the swine model of MH. However, the molecular genetics of MH in humans has proven to be far more complex and obscure. This is due, in part, to the inherent complexity of the MH syndrome; to a variety of presentations that may be mimicked by several clinical situations; to a lack of typical phenotypic signs in the absence of anesthesia; to an association with several genes; and potentially, to scores of DNA variants that may lead to the pathophysiologic abnormality in MH, namely, calcium dysregulation in the skeletal muscle cell. Since MH may become manifest without warning and may progress rapidly to life-threatening hypercarbia, muscle breakdown, acidosis, and hyperthermia, much effort has been expended in attempting to identify those at risk for the syndrome. The mainstay diagnostic test for MH is the muscle biopsy contracture test first described by Drs. Britt and Kalow in the early 1970s. The test entails exposure of biopsied skeletal muscle to calcium-releasing agents, such as halothane, caffeine, ryanodine, and /or chloro-m-cresol. Since that time, the contracture test has served to clarify the inheritance of MH, the association with Central Core Disease, and multiple phenotypic presentations of the syndrome. Clearly, it is not applicable either to screening or to rapid identification of susceptibility. Furthermore, as with most laboratory tests, sensitivity and specificity are not 100%. Nevertheless, the test has served as the standard against which other tests are judged. One of the main current goals of research related to MH is the development of a minimally invasive, highly accurate diagnostic test for MH. Molecular genetics holds the promise of meeting that goal. In fact, clinical genetic testing for MH susceptibility is already available in many countries at the present time, but it requires careful patient selection because of the limited sensitivity of genetic testing. The road to the goal line of a sensitive and specific genetic test has proven to be replete with obstacles, just as it has been for many other inherited disorders. For instance, although the ryanodine receptor gene (RYR-1) and the ryanodine receptor or calcium release channel in the sarcoplasmic reticulum are most often associated with the syndrome, other calcium regulatory proteins, such as the dihydropyridine receptor and, more recently, calsequestrin, lead to intracellular calcium dysregulation and clinical MH H. Rosenberg, MD (&) Department of Medical Education and Clinical Research, Saint Barnabas Medical Center, Livingston, NJ, USA e-mail: hrosenberg@sbhcs.com