Functional changes in Becker muscular dystrophy: implications for clinical trials in dystrophinopathies

Abstract

We performed a 1-year longitudinal study of Six Minute Walk Test (6MWT), North Star Ambulatory Assessment (NSAA), and timed function tests in Becker muscular dystrophy (BMD). Skeletal muscle dystrophin was quantified by immunoblot. We grouped deletions ending on exon 45 ("del 45-x", n = 28) or 51 ("del x-51", n = 10); isolated exon 48 deletion ("del 48", n = 10); and other mutations (n = 21). Only patients in the "del 45-x" or "other" groups became non-ambulatory (n = 5, log-rank p = n.s.) or unable to run (n = 22, p < 0.001). All measures correlated positively with dystrophin quantity and negatively with age, and were significantly more impaired in the "del 45-x" and "other" groups. After one year, NSAA score decreased significantly (-0.9 ± 1.6, p < 0.001); in the "del 45-x" group, both NSAA (-1.3 ± 1.7, p = 0.001) and 6MWT (-12 ± 31 m, p = 0.059) decreased. We conclude that patients with "del x-51" or "del 48" mutations have mild or asymptomatic BMD, while "del 45-x" mutations cause comparatively severe weakness, and functional deterioration in 1 year. Furthermore, exon 51 skipping could be more effective than exon 45 skipping in Duchenne muscular dystrophy.

Figure 1. Kaplan-Meier plots of loss of ability to walk and run.

Age at LoA is represented, grouped by (A) mutation group (“del 45-x”, “del 48”, “del x-51”, and “other”), and (B) dystrophin quantity (0–33%, 34–66%, 67–100%). The proportion of patients able to run at increasing ages are represented by (C) mutation group, and (D) dystrophin quantity. Censored patients (able to walk or run at last follow-up) are indicated by crosses.

Figure 2. Correlation matrix of dystrophin quantity, age, and functional measures.

Panels in the diagonal indicate measures represented on corresponding columns and rows. Upper panels show correlation parameters (Spearman’s ρ and corresponding p-value) between measures on corresponding the row and column, while lower panels show scatter plots, with data points color-coded for mutation group, and corresponding regression lines. Correlations between dystrophin quantity and age is not shown, because age represented here is age at study procedures, and not age at biopsy (which may be years or decades earlier).

Figure 3. Functional changes after 1 year in different BMD mutation groups.

Box plots showing baseline and 1-year values of (A) 6MWT distance, (B) NSAA score, (C) 10 m run/walk velocity, (D) rise from floor velocity, and (E) climb 4 standard steps velocity. Boxes are color-coded for mutation group, and trajectories of each individual patient are illustrated by dots connected by segments. Thick lines represent median values.

Figure 4. Functional changes after 1 year in different dystrophin quantity level groups.

Box plots showing baseline and 1-year values of (A) 6MWT distance, (B) NSAA score, (C) 10 m run/walk velocity, (D) rise from floor velocity, and (E) climb 4 standard steps velocity. Boxes are color-coded for dystrophin levels of 0–33%, 34–66%, and 67–100% relative to control, and trajectories of each individual patient are illustrated by dots connected by segments. Thick lines represent median values.

Figure 5. Power calculation for a hypothetical 1-year trial in typical BMD, using NSAA as an outcome measure.

This power calculation assumes selection of BMD patients with a typical BMD phenotype based on functional or genetic criteria, and exclusion of patients with mild/asymptomatic or DMD-like phenotypes; an accepted type I error rate of α = 0.05, and a required statistical power (1−β) = 0.8, and a blinded placebo-controlled design. The number of patients per study arm required for adequate power increases, as the hypothetical difference in 1-year NSAA change between treatment and placebo decreases.