Malignant Hyperthermia (MH) is an autosomal dominant disorder of skeletal musclethat causes a life threatening reaction following administration of commonly usedinhalational anesthetics such as halothane, or the depolarizing muscle relaxantsuccinylcholine. Administration of the anesthetics during surgery causes an alteredrelease of calcium from the sarcoplasmic reticulum (SR) through the ryanodine receptor(RYR1), which in turn induces a cascade of biochemical events that culminates in anypermetabolic state (fulminant episode) with hyperthermia. If not treated, promptly bywithdrawing the anesthetic and administering dantrolene (a drug that inhibits release ofCa++ from the SR) mortality can be as great as 70%. Because most MH individualsappear normal and susceptibility becomes apparent only after exposure to anesthetics,identifying MH susceptible individuals prior to surgery is difficult requiring muscle biopsyand measurements of the contractile sensitivity to RYR1 agonists caffeine and halothane.The caffeine-halothane contracture test (CHCT) phenotypes patients as MHS(susceptible) or MHN (normal). The CHCT has a sensitivity of 93% and specificity of 78%.USUHS has performed over 400 CHCT tests on patients. Approximately 50% of patientsare diagnosed CHCT positive. Core C will review MH susceptible individuals, probandsand family members for clinical histories of adverse responses to anesthetic drugs,phenotype skeletal muscle samples with performance of a CHCT, and genotype CHCTpositive patients for causative mutations in RyR1 and the a1s-DHPR genes. They willcollect blood samples from these patients a) for mRNA for use in profiling studies, b) tomake permanent B-lymphocyte cell lines for physiologic and transcriptional profilingstudies, and c) for the isolation of dendritic cells. In addition, they will collect musclesamples to make myoblast cultures to be purified by Core B, and flash freeze discardedmuscle samples for transcriptional profiling studies.
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