Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Abstract

Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD).

Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included "Duchenne muscular dystrophy" as a Medical Subject Heading or free text term, in combination with variations of the term "predictor". Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model.

Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. ≥350 metres and <330 vs. ≥330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n = 5 studies). Deletion of exons 3-7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49-50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n = 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n = 6 studies). In total, 33% of studies exhibited some risk of bias.

Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.

Keywords: 6MWT; Motor function; NOS; Neuromuscular Disease; guidelines; treatment.

Fig. 1

PRISMA diagram of the selection process of the included publications.

Fig. 2

Mean and median age at loss of ambulation, by glucocorticoid therapy. Note: Canada (CA). China (CN). Japan (JP). Serbia (RS). The Netherlands (NL). Turkey (TR). United States of America (US). * Multi-national (see article for details). †The Netherlands, Italy, France, and the United Kingdom. ‡Bulgaria, the Czech Republic, Denmark, Germany, Hungary, Poland, and the United Kingdom.

Fig. 3

Forest plot of treatment effect of glucocorticoids on loss of ambulation in patients with DMD. Note: Estimates from Bello et al. [16], Bello et al. [17], and Wang et al. [48] were excluded from the meta-analysis as their respective patient cohorts were represented in other included studies of larger sample size (in some cases within treatment strata). Confidence interval (CI). Deflazacort (DFZ). Prednisolone (PRED). Prednisone (PDN).

Fig. 4

DMD mutations spots associated with later loss of ambulation in DMD. Note: Deletion of exons 3–7 vs. other out-of-frame deletion [16, 48]. Exon 8 skipping amenable deletion vs. other exon skippable [23, 48]. Proximal (mutation upstream intron 44) vs. distal (mutation intron 44 and downstream) [30]. Exon 44 skipping amenable deletion vs. other out-of-frame deletion or other exon skippable [16, 23, 44, 48, 51]. Single exon 45 deletions vs. other mutations [48]. Exon 53 skipping amenable deletion vs. other deletion [40]. Nonsense mutations vs. other deletions were also associated with later loss of ambulation [51] (not shown in figure).

Fig. 5

DMD mutations spots associated with earlier loss of ambulation in DMD. Note: Distal (mutation intron 44 and downstream) vs. proximal (mutation upstream intron 44) [30]. Exon 45 skipping amenable deletion vs. exon 8 skipping amenable deletion [23]. Deletion of exons 49–50 vs. other mutations [48]. Exon 51 skipping amenable deletion vs. other deletion [48], and exon 51 skipping amenable deletion vs. exon 8 skipping amenable deletion [23].