title: DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study.
abstract: To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments.
  
  
  
  We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n = 186), or small mutations identified by sequencing (n = 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers.
  
  
  
  Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p = 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain.
  
  
  
  As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.
authors.affiliation: From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Bello
authors.affiliation: From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Morgenroth
authors.affiliation: From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: From the Children's National Health System (L.B., L.P.M., H.G.-D., E.P.H., S.C.), Washington, DC; Department of Neuroscience (L.B.), University of Padova, Italy; University of California Davis Medical Center (C.M.M.), Sacramento; and Institute of Human Genetics (S.C.), University Children's Hospital, and Center of Molecular Medicine, University of Cologne, Germany.
authors.forename: Craig M
authors.initials: CM
authors.lastname: McDonald
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
mesh_terms: D000293:Adolescent; D003062:Codon / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D015331:Cohort Studies; D018450:Disease Progression; D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020233:Gait Disorders, Neurologic / Q000235:genetics* / Q000503:physiopathology*; D017353:Gene Deletion; D020440:Gene Duplication / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies
chemical_list: D003062:Codon; D018389:Codon, Nonsense; C484258:DMD protein, human; D016189:Dystrophin; D005938:Glucocorticoids