DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

Neurology. 2016 Jul 26;87(4):401-9. doi: 10.1212/WNL.0000000000002891. Epub 2016 Jun 24.


Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Codon / genetics
  • Codon, Nonsense / genetics
  • Cohort Studies
  • Disease Progression
  • Dystrophin / genetics*
  • Exons / genetics
  • Female
  • Gait Disorders, Neurologic / genetics*
  • Gait Disorders, Neurologic / physiopathology*
  • Gene Deletion
  • Gene Duplication / genetics
  • Glucocorticoids / therapeutic use
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Muscular Dystrophy, Duchenne / drug therapy
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / physiopathology*
  • Mutation / genetics
  • Prospective Studies


  • Codon
  • Codon, Nonsense
  • DMD protein, human
  • Dystrophin
  • Glucocorticoids