With funding and in collaboration with a group from the National Institutes of Health (NIH), a team of UF researchers is working to refine the genetic markers of malignant hyperthermia (MH) using whole exome sequencing.
Ultimately, the project aims to make a genetic analysis a more reliable way to diagnose a person’s genetic susceptibility to malignant hyperthermia (MH), which is a potentially lethal response to exposure to potent inhaled anesthetics and succinylcholine, commonly used drugs during anesthesia care.
The project comes as work through the North American Malignant Hyperthermia Registry (NAMHR), hosted at UF, continues to advance. The team crossed the halfway point of legacy chart conversions into a more easily searchable electronic database in May. They also recently completed a research project evaluating the evolving use of a new dantrolene formulation, the primary injection treatment for malignant hyperthermia.
The genetic research is a collaboration with the laboratory of Leslie G. Biesecker, MD, a clinical and molecular geneticist and chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) of the NIH.
Principal Investigator Nikolaus Gravenstein, MD, the Jerome H. Modell, MD, Professor of Anesthesiology and Professor of Neurosurgery and Periodontology, and Amy Gunnett, RN, CCRC, Interim Manager of Clinical Research, are leading the research team. Other team members include Cameron R. Smith, MD, PhD, Assistant Professor of Anesthesiology; Patrick Tighe, MD, MS, Associate Professor of Anesthesiology; Cynthia Garvan, PhD, Professor of Anesthesiology; Bruce Spiess, MD, FAHA, Professor of Anesthesiology and Associate Chair of Research; Anna Woods, RN, Research Coordinator; Amanda Slater, Clinical Research Coordinator III, and Carla Zingariello, DO, Clinical Assistant Professor in the Department of Neurology.
Malignant hyperthermia susceptibility (MHS) is a potentially lethal but otherwise asymptomatic disease that manifests on exposure to a halogenated anesthetic and/or succinylcholine.
The NAMHR database contains clinical and patient/family data dating back over three decades. In a fraction of cases, the registrants also have muscle biopsy and genetic profiles. While the genetic characterization of MHS has evolved since the database was launched, it remains substantially incomplete.
Research has identified variants in three genes. These variants are present in 50% to 70% of people with MHS. The new project aims to estimate the prevalence of the three known genetic markers of MH and to determine any genetic variants present in the 30% to 50% of people with MHS who do not have one of the three known variants (RYR1, STAC3, CACNA1s).
The UF team is contacting and consenting NAMHR registrants with a high likelihood of having experienced a malignant hyperthermia crisis and connecting them with Dr. Biesecker. After collection of blood specimens facilitated by the UF team, his laboratory will perform exome sequencing to enable a more complete, sensitive, and specific characterization of the genetic markers of MHS.
If successful and more genetic markers are identified to improve the genetic screening sensitivity and specificity, then genetic analysis could replace the current complex, expensive and debilitating gold standard muscle biopsy test. By doing so, a susceptible person and any similarly MHS family members could be identified before a triggering agent exposure and malignant hyperthermia event, which still has a 4% to 10% mortality rate despite dantrolene therapy.