BACKGROUND: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare form of congenital myopathy, which is pathologically diagnosed by the presence of more than 99% of type 1 fiber, with no specific structural changes. Its pathogenic mechanism is still unknown. We recently reported that almost all patients with central core disease (CCD) with ryanodine receptor 1 gene (RYR1) mutations in the C-terminal domain had type 1 fibers, nearly exclusively, in addition to typical central cores. OBJECTIVE: To investigate whether CNMDU1 is associated with RYR1 mutation. METHODS: We studied 10 unrelated Japanese patients who were diagnosed to have CNMDU1 based on clinical features and muscle pathology showing more than 99% type 1 muscle fibers. We extracted genomic DNA from frozen muscles and directly sequenced all 106 exons and their flanking intron-exon boundaries of RYR1. RESULTS: Four of 10 patients had a heterozygous mutation, three missense and one deletion, all in the C-terminal domain of RYR1. Two missense mutations were previously reported in CCD patients. Clinically, patients with mutations in RYR1 showed milder phenotype compared with those without mutations. CONCLUSION: Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) in 40% of patients is associated with mutations in the C-terminal domain of RYR1, suggesting that CNMDU1 is allelic to central core disease at least in some patients.
BACKGROUND:Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare form of congenital myopathy, which is pathologically diagnosed by the presence of more than 99% of type 1 fiber, with no specific structural changes. Its pathogenic mechanism is still unknown. We recently reported that almost all patients with central core disease (CCD) with ryanodine receptor 1 gene (RYR1) mutations in the C-terminal domain had type 1 fibers, nearly exclusively, in addition to typical central cores. OBJECTIVE: To investigate whether CNMDU1 is associated with RYR1 mutation. METHODS: We studied 10 unrelated Japanese patients who were diagnosed to have CNMDU1 based on clinical features and muscle pathology showing more than 99% type 1 muscle fibers. We extracted genomic DNA from frozen muscles and directly sequenced all 106 exons and their flanking intron-exon boundaries of RYR1. RESULTS: Four of 10 patients had a heterozygous mutation, three missense and one deletion, all in the C-terminal domain of RYR1. Two missense mutations were previously reported in CCDpatients. Clinically, patients with mutations in RYR1 showed milder phenotype compared with those without mutations. CONCLUSION:Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) in 40% of patients is associated with mutations in the C-terminal domain of RYR1, suggesting that CNMDU1 is allelic to central core disease at least in some patients.
Authors: Elena Zvaritch; Natasha Kraeva; Eric Bombardier; Robert A McCloy; Frederic Depreux; Douglas Holmyard; Alexander Kraev; Christine E Seidman; J G Seidman; A Russell Tupling; David H MacLennan Journal: Proc Natl Acad Sci U S A Date: 2009-12-03 Impact factor: 11.205
Authors: Natalia Kraeva; Elena Zvaritch; Ann E Rossi; Sanjeewa A Goonasekera; Hilal Zaid; Wanda Frodis; Alexander Kraev; Robert T Dirksen; David H Maclennan; Sheila Riazi Journal: Neuromuscul Disord Date: 2012-11-24 Impact factor: 4.296