Association of genetic mutations and loss of ambulation in childhood-onset dystrophinopathy

Abstract

Background: Quantifying associations between genetic mutations and loss of ambulation (LoA) among males diagnosed with childhood-onset dystrophinopathy is important for understanding variation in disease progression and may be useful in clinical trial design.

Methods: Genetic and clinical data from the Muscular Dystrophy Surveillance, Tracking, and Research Network for 358 males born and diagnosed from 1982 to 2011 were analyzed. LoA was defined as the age at which independent ambulation ceased. Genetic mutations were defined by overall type (deletion/duplication/point mutation) and among deletions, those amenable to exon-skipping therapy (exons 8, 20, 44-46, 51-53) and another group. Cox proportional hazards regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Mutation type did not predict time to LoA. Controlling for corticosteroids, Exons 8 (HR = 0.22; 95% CI = 0.08, 0.63) and 44 (HR = 0.30; 95% CI = 0.12, 0.78) were associated with delayed LoA compared to other exon deletions.

Conclusions: Delayed LoA in males with mutations amenable to exon-skipping therapy is consistent with previous studies. These findings suggest that clinical trials including exon 8 and 44 skippable males should consider mutation information prior to randomization.

Keywords: Duchenne muscular dystrophy; MD STARnet; exon skipping; loss of ambulation; natural history study.

Figure 1:

Kaplan-Meier curves for mutation type groups. Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) 1982–2012. Kaplan-Meier curves comparing probability of ambulation as a function of age in years for the three major mutation groups: deletion, duplication, and point mutation.

Figure 2:

Kaplan-Meier curves for exon skippable subgroups. Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) 1982–2012. Kaplan-Meier curves comparing age (in years) at loss of ambulation for (A) exon 8 skippable deletions, log-rank χ² (1) = 9.68, p < 0.01; (B) exon 20 skippable deletions, log-rank χ² (1) = 0.18, p > 0.05; (C) exon 44 skippable deletions, log-rank χ² (1) = 5.05, p < 0.05; (D) exon 45 skippable deletions, log-rank χ² (1) = 3.51, p > 0.05; (E) exon 46 skippable deletions, log-rank χ² (1) = 0.54, p > 0.05; (F) exon 51 skippable deletions, log-rank χ² (1) = 2.45, p > 0.05; (G) exon 52 skippable deletions, log-rank χ² (1) = 1.26, p > 0.05; and (H) exon 53 skippable deletions, log-rank χ² (1) =1.47, p > 0.05. In all subplots, the comparison group is comprised of all males classified as having a deletion genetic type not in the indicated exon skippable subgroup.

Figure 3:

Pairwise hazard ratios for exon skippable subgroups based on Model I. Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) 1982–2012. Pairwise hazard ratio (HR) estimates for each exon skippable subgroup when controlling for steroid use. A HR estimate greater than one indicates a younger age for loss of ambulation for the group on the left hand side relative to the group listed on the right hand side. Right facing arrows indicate an estimated HR larger than 10. Confidence intervals are corrected for multiple comparisons using the Tukey-Kramer method.