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

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.

Figure 1. Study flow chart

Participant selection from the parent (i.e., not including a currently recruiting extension) Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS), identifying subgroups analyzed in this article.

Figure 2. Kaplan-Meier plots of loss of ambulation by mutation group

Plots for participants with (A) deletions amenable to skipping of exon 44, (B) deletions amenable to skipping of exon 45, (C) deletions amenable to skipping of exon 51, (D) deletions amenable to skipping of exon 53, (E) deletion of exons 3–7, (F) single- or multi-exon duplications, (G) nonsense mutations, and (H) small frameshift mutations are compared in each graph with the reference group of participants with single- or multi-exon deletions not amenable to skipping of exons 44, 45, 51, or 53 (other deletions; thin black line). Thin colored lines refer to all the participants in each mutation group, while thick lines refer to glucocorticoid-treated participants only.