Brandom, Barbara W.

AbstractWhole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca2+ ATPase type 1 (SERCA1), a calcium pump, expressed in fast‐twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise‐induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease‐associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH‐like symptoms in Brody patient.

Background The authors determined associated cardiac arrest and death rates in cases from Canada and the United States as reported to The North American Malignant Hyperthermia (MH) Registry and analyzed factors associated with a higher risk of poor outcomes. Methods The authors searched the database for AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports with inclusion criteria as follows: event date between January 1, 1987, and December 31, 2006; "very likely" or "almost certain" MH as ranked by MH Clinical Grading Scale; location in Canada or the United States; and one or more anesthetic agents given. The exclusion criterion was a pathologic condition other than MH independently judged by the authors. Severe MH outcomes were analyzed as regards clinical history and presentation, using Wilcoxon rank sum tests for continuous variables and Pearson exact chi-square tests for categorical variables. A Bonferroni correction adjusted for multiple comparisons. Results Of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death. The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr). Associated factors were muscular build (odds ratio, 18.7; P = 0.0016) and disseminated intravascular coagulation (odds ratio, 49.7; P < 0.0001). Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide (216 vs. 87 min; P = 0.003). Unrelated factors included patient or family history, anesthetic management, and the MH episode. Conclusions Modern US anesthetic practice did not prevent MH-associated cardiac arrest and death in predominantly young, healthy patients undergoing low- to intermediate-risk surgical procedures.