title: A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation.
abstract: Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University of Leipzig, Germany. ruef@medizin.uni-leipzig.de
authors.forename: Henrik
authors.initials: H
authors.lastname: Rueffert
authors.forename: Derk
authors.initials: D
authors.lastname: Olthoff
authors.forename: Christine
authors.initials: C
authors.lastname: Deutrich
authors.forename: Ralf
authors.initials: R
authors.lastname: Schober
authors.forename: Ursula G
authors.initials: UG
authors.lastname: Froster
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002110:Caffeine / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004413:Dysostoses / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005838:Genotype; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000150:complications / Q000473:pathology*; D009119:Muscle Contraction / Q000187:drug effects; D009139:Musculoskeletal Abnormalities / Q000150:complications / Q000235:genetics; D009154:Mutation; D020512:Myopathy, Central Core / Q000150:complications / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D004247:DNA; D006221:Halothane