Cellular Pathophysiology of “MHH”, A Large Group of Patients with Equivocal Diagnosis of Malignant Hyperthermia

Abstract

Is Malignant Hyperthermia a disease? Experts call it a “condition” and define it as a susceptibility (MHS), diagnosed by tests (CHCT or IVCT) that measure the response of a muscle biopsy to set concentrations of caffeine and halothane. Of 40 patients who tested positive recently at the Malignant Hyperthermia Investigation Unit, MHIU, of the Canadian University Health Network, 10 (25%, here called MHS) were positive to both agonists and 30 (75%, here denominated MHH) were positive to halothane but not caffeine. None of the MHH had mutations in known MH-linked locations (hot spots) of RyR1. These patients were compared with the normally reacting subjects (MHN, 25 patients) using a “clinical index”, built from the collection of clinical symptoms, including pain, weakness and creatine kinase levels, and a “calcium index”, cobbled from measures of Ca2+ signals, spontaneous and evoked, and steady [Ca2+] in cytosol, of myotubes derived from patient biopsies. The average clinical index was significantly greater in the MHH than the MHN; it was also greater in the MHH than in the MHS, but not significantly so. The difference between MHS and MHN was not significant. The calcium index was elevated approximately equally in MHH and MHS, in comparison with MHN. Additional cellular-level measurements, in progress, may reveal greater differences between groups with positive MH diagnosis. Conclusions from the initial sample: (1) most MHH are clinically sick, while MHS have only a susceptibility; (2) the cellular studies allow detection of defects in calcium management that apply to most of the susceptible individuals, whether they are abnormally reactive to one or both agonists in conventional MH tests. We are currently testing the hypotheses that MHH and MHS have mechanistically different pathogenesis and genetically different etiologies.