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.

Muscle MRI and functional outcome measures in Becker muscular dystrophy

“…In a recent observational study of a BMD cohort followed at our Institution 12 , the correlations between specific DMD mutations and BMD sub-phenotypes were confirmed, using standardized functional measures such as the 6MWT 16 and the North Star Ambulatory Assessment (NSAA) 17 – 19 . Here we describe the results of a cross-sectional MRI study carried out at the same time as the baseline evaluations, in a large part of the participants to the aforementioned observational study, who were evaluated with measures of ambulatory function at the time of the MRI and after one year, aiming to test if muscle MRI can discriminate between BMD patients with stable disease, versus those who are prone to functional deterioration.…”

“…NSAA and 6MWT were performed by trained evaluators as described 12 , within 3 months of the MRI and after 12 ± 1 months. Functional status at baseline was described as four categories: (1) able to walk, climb stairs, and rise from the floor; (2) unable to rise from the floor; (3) unable to climb stairs; (4) unable to walk.…”

“…As shown in previous studies, BMD phenotype is partly predicted by specific DMD mutations: deletions including in-frame exons in the proximal rod domain 3 , or the hinge 3 domain encoded by exons 50–51 4 , 5 , have been associated to mild phenotypes, while deletions situated in the exon 45–53 mutational hotspot 6 , but not including exons 50–51, usually cause “typical” BMD 7 – 9 . Some of these BMD deletions are “natural models” of deletions obtained at the transcript level by exon-skipping treatment of out-of-frame DMD deletions with antisense oligonucleotides (AON) 10 , 11 , so that the clinical observation of some BMD genotype groups might shed light on the potential efficacy of these therapies 5 , 8 , 12 .…”

Allogeneic Mesenchymal Stem Cells as a Treatment for Aging Frailty

“…The 6-minute walk distance (6-MWD) test is a measure of functional exercise capacity [105], which can reflect a frail subject's ability to perform basic activities of daily living. The test has been specifically used to assess subjects with diseases of the musculoskeletal, pulmonary, and cardiovascular systems [106][107][108]; and as such, the subjects experienced a significant improvement in all treatment groups at 3 and 6 months postinfusion with the greatest improvement in the 100M cell-dose group in the phase I [55]. Pulmonary function was measured via FEV1, and improved in the 200M cell-dose group [55].…”

Late‐onset Becker‐type muscular dystrophy in a Border terrier dog

“…This difference might only suggest a different mutation site. In humans, the site of deletion affects the property of the dystrophin protein, resulting in different truncated proteins sizes and different phenotypes (Bello et al 2016).…”