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

Luca Bello,Andrea Barp,Luca Caumo,Paola Campadello,Corrado Angelini,Chiara Calore,Elena Pegoraro,Gianni Sorarù,Marina Fanin,Claudio Semplicini

doi:10.1038/srep32439

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.

Highlights

Becker muscular dystrophy (BMD) is an X-linked disorder caused by non-truncating Duchenne muscular dystrophy (DMD) mutations, consisting approximately of 70% large deletions, 15% duplications, and 15% small mutations, leading to altered, but detectable dystrophin expression in muscle fibers[1,2]
Different BMD deletions affect the properties of the resulting dystrophin protein: the loss of functionally critical N- or C-terminal domains may result in DMD-like phenotypes[4,5,6], while the consequences of deletions in the dystrophin rod domain depend on structural “phase” between spectrin repeats and hinge regions[7]
Interest has been rekindled in this field since splice-modulating antisense oligonucleotides (AONs) have been introduced, aiming to convert the DMD phenotype into BMD with the exon skipping approach[16,17]

Summary

Introduction

Becker muscular dystrophy (BMD) is an X-linked disorder caused by non-truncating DMD mutations, consisting approximately of 70% large deletions, 15% duplications, and 15% small mutations, leading to altered, but detectable dystrophin expression in muscle fibers[1,2]. According to a classic definition, BMD patients lose ambulation after the age of 16 years, while in the severe allelic disorder Duchenne muscular dystrophy (DMD), caused by truncating mutation and absent dystrophin, ambulation is lost by 132. Unlike DMD18–22, there is scarce data in BMD about standardized functional measures such as the Six Minute Walk Test (6MWT)[23], the North Star Ambulatory Assessment (NSAA)[24,25,26], and Timed Function Tests (TFTs: run/walk 10 m, rise from the floor, climb four standard steps). We aimed to explore if these measures are feasible and clinically meaningful in BMD as they are in DMD, and to refine the description of the natural history of relevant BMD mutational subgroups

Objectives

Methods

Results

Conclusion