Clinical, Pathological And Genetic Analysis In Central Core Disease

ObjectiveTo determine the frequency and the distribution of ryanodine receptor 1 (RyR1 ) gene mutations in central core disease and establish a genotype-phenotype correlation. IntroductionRyRl mutations are associated with central core disease (CCD) and multiminicore disease (MmD), in addition to malignant hyperthermia, and have been reported to be responsible for 47-67% patients with CCD and rare cases with MmD. However, up to date, the true frequency as well as the distribution of the mutations is still not yet determined since mutation screening is limited to the three "hot spots" and C-terminal region. Material and methodsTwenty-eight unrelated Japanese CCD patients were included in this study after informed consent. Clinical histories and muscle biopsies were carefully reviewed. Genomic DNA were extracted from either muscle tissue or blood lymphocytes. All the RyRl coding regions and flanking intron-exon boundaries were amplified and directly sequenced. ResultsWe identified 20 novel and four reported RyRl missense mutations in 26 of the 28 CCD patients (93%). Among them, 6 were located outside the known three mutational "hot spots". Sixteen of 28 (57%) CCD patients had mutations in the C-terminal "hot spot". Compound heterozygous mutations were found in 3 CCD patients. Patients with the C-terminal mutations had more severe clinical phenotype resulting to obvious muscle weakness and rather consistent muscle pathology characterized by interstitial fibrosis and predominance of uniform type 1 fibers. ConclusionsMost CCD patients (93%) are associated with RyRl mutations. Patients...