Letter to the editor: In response to Landfeldt E et al.,predictors of loss of ambulation in Duchenne Muscular Dystrophy: A systematic review and meta-analysis

Dear Editor,

A recently published meta-analysis in the Journal of Neuromuscular Diseases ¹ analyzed predictors of loss of ambulation (LoA) in individuals with Duchenne Muscular Dystrophy (DMD). In the meta-analysis of 13 eligible studies, mutations amenable to skipping exon 53 were associated with prolonged ambulation, while distal mutations (intron 44 and downstream), deletion of exons 49–50, and mutations amenable to skipping exon 45 and exon 51 were associated with earlier LoA. The authors proposed that deletions amenable to exon 53 skipping were associated with later LoA compared to other deletions in DMD. However, previous clinical observations do not fully support the notion that mutations amenable to exon 53 skipping lead to prolonged ambulation.

Among deletions amenable to exon skipping, exon 44 skippable mutations have been linked to prolonged ambulation in individuals with DMD. ² For other skippable mutations, several studies found no significant difference in age at LoA between for most mutation subgroups.^2,3 In contrast to the recently published meta-analysis results, data from two French observational natural history studies reported that patients with mutations amenable to skipping exon 53 lost ambulation significantly earlier than those with other disease-causing variants. ⁴ A longitudinal study conducted across centers in Italy, Belgium and United Kingdom also revealed that mutations amenable to skip exon 53 had overall lower baseline six minutes walking test (6MWT) values and more negative long-term changes in 6MWT than the other subgroups, with nearly similar results in the subgroup amenable to skip exon 51. ³

Furthermore, a previous meta-analysis by Muntoni et al. ⁵ found that the pooled effect estimates for various skip-amenable mutation classes were modest, suggesting that different genotypes in DMD have a limited impact on motor outcomes. Patients with exon 44 skip-amenable mutations had higher median ages at key ambulatory progression milestones, while those with exon 51 skip-amenable mutations reached these milestones earlier. In adjusted analyses, patients with exon 53 skip-amenable mutations showed mean changes in the North Star Ambulatory Assessment (NSAA) total score of −1.0 (−1.9 to 0.1) and −0.1 (−0.8 to 0.6) units, compared to other skip-amenable mutations and the broader patient population, respectively.

Based on current literature, it seems difficult to conclude that mutations amenable to exon 53 skipping are associated with prolonged ambulation. DMD is a rare disease, and only 8–10% of patients are eligible for exon 53 skipping treatments. Given the limited role of genetic mutation subtypes and the influence of multiple factors on outcomes, this misinterpretation could lead to confusion among clinicians and patients regarding the efficacy of exon skipping therapies and potentially mislead clinical trial designs.