title: Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies.
abstract: Malignant hyperthermia (MH) is a pharmacogenetic, autosomal dominantly inherited disorder of skeletal muscle triggered by volatile anesthetics and infrequently by extreme exertion and heat exposure. MH has variable penetrance with an incidence ranging from 1 in 5000 to 1 in 50,000-100,000 anesthesias. Mutations in the ryanodine receptor gene, RYR1, are found in 50-70% of cases. We hypothesized that a portion of patients with drug-induced muscle diseases, unrelated to anesthesia, such as severe statin myopathy, have underlying genetic liability that may include RYR1 gene mutations. DNA samples were collected from 885 patients in 4 groups: severe statin myopathy (n=197), mild statin myopathy (n=163), statin-tolerant controls (n=133), and non-drug-induced myopathies of unknown etiology characterized by exercise-induced muscle pain and weakness (n=392). Samples were screened for 105 mutations and variants in 26 genes associated with 7 categories of muscle disease including 34 mutations and variants in the RYR1 gene. Disease-causing mutations or variants in RYR1 were present in 3 severe statin myopathy cases, 1 mild statin myopathy case, 8 patients with non-drug-induced myopathy, and none in controls. These results suggest that disease-causing mutations and certain variants in the RYR1 gene may contribute to underlying genetic risk for non-anesthesia-induced myopathies and should be included in genetic susceptibility screening in patients with severe statin myopathy and in patients with non-statin-induced myopathies of unknown etiology.
authors.affiliation: Department of Pediatrics, School of Medicine & Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA. gdv@buffalo.edu
authors.forename: Georgirene D
authors.initials: GD
authors.lastname: Vladutiu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Isackson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kaufman
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Beth
authors.initials: B
authors.lastname: Cobb
authors.forename: Lisa
authors.initials: L
authors.lastname: Christopher-Stine
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wortmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000758:Anesthesia; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects; D008297:Male; D008305:Malignant Hyperthermia / Q000150:complications* / Q000235:genetics*; D008875:Middle Aged; D009135:Muscular Diseases / Q000150:complications* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel