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

Luca Bello, Lauren P. Morgenroth, Heather Gordish-Dressman, Eric P. Hoffman, Craig M McDonald, Sebahattin Cirak

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26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)401-409
Number of pages9
JournalNeurology
Volume87
Issue number4
DOIs
StatePublished - Jul 26 2016

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ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Bello, L., Morgenroth, L. P., Gordish-Dressman, H., Hoffman, E. P., McDonald, C. M., & Cirak, S. (2016). DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study. Neurology, 87(4), 401-409. https://doi.org/10.1212/WNL.0000000000002891