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

2016; Lippincott Williams & Wilkins; Volume: 87; Issue: 4 Linguagem: Inglês

10.1212/wnl.0000000000002891

1526-632X

Luca Bello, Lauren P. Morgenroth, Heather Gordish‐Dressman, Eric P. Hoffman, Craig M. McDonald, Sebahattin Çirak, Avital Cnaan, Mathula Thangarajh, Richard T. Abresch, Erik Henricson, Venkatarman Viswanathan, Laura McAdam, Jean K. Mah, M. Tulinius, Monique M. Ryan, Yoram Nevo, Alberto Dubrovsky, Paula R. Clemens, Anne M. Connolly, Jean Teasley, T. E. Bertoríni, Richard Webster, Hanna Kolski, K. Gorni, Timothy Lotze, Peter Karachunski, John B. Bodensteiner, James J. Carlo,

Genetic Neurodegenerative Diseases

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.