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

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Today’s final Duchenne genetics TREAT-NMD Duchenne masterclass themed pick is from @journal_nd by Landfeldt et al on predictors of loss of ambulation in Duchenne. I’m back home meanwhile but sharing pictures of Klaus in Dubai doi 10.3233/JND-230220

Loss of ambulation is a major disease milestone in Duchenne and it is predictive of trajectory (early loss of ambulation is associated with e.g., earlier need for assisted ventilation and earlier occurrence of other milestones).

Here authors performed a meta-analysis on factors that influence loss of ambulation. 3500 papers were considered and 45 deemed relevant. The paper has a massive table summarizing all papers.

Here the highlights: steroids delay loss of ambulation, with daily steroids giving the largest delay. Earlier onset of symptoms is predictive of earlier loss of ambulation as are early loss of motor functions such as stair climbing and rising from floor.

The mutation type also influences loss of ambulation: later for exon 44 skippable deletions and exon 3-7 deletions and earlier for exon 45 and exon 51 skippable deletions. Nonsense mutations seem to not behave differently from other variants.

Genetic modifiers where a protective allele leads to later loss of ambulation are found for SPP1, CD40, LTBP4, and TCTEC1D1. Asian and Hispanic patients on average lose ambulation earlier than others. Patients with more fat infiltration as measured by MRI lose ambulation earlier.

Finally, compared to natural history control patients treated with eteplirsen or ataluren lose ambulation later. Authors discuss that a limitation of their study is the reliance on details in the publications which were sometimes limited.

While the paper reports nothing new, it does summarize all factors impacting loss of ambulation. These factors can be taken into account when predicting trajectories or designing trials. Also, they should be taken into account when comparing to natural history.

Finally, especially the finding that different races appear to have different trajectories is important and should be studied more as there are implications for management, life (planning for loss of ambulation etc.), and trial design.

Also, it would be important to study why there is variation in trajectory, this can be genetic (may lead to therapeutic interventions), but also related to lifestyle, access to healthcare etc. Many of these factors are actionable.