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. 2025 Sep;12(9):1732-1742.
doi: 10.1002/acn3.70097. Epub 2025 Jun 24.

Influence of Dystrophin Isoform Deficiency on Motor Development in Duchenne Muscular Dystrophy

Mary Chesshyre  1 , Deborah Ridout  2 , Georgia Stimpson  1 , Laurent Servais  3   4   5 , Giovanni Baranello  1   6 , Adnan Manzur  1 ; UK NorthStar Clinical Network; Francesco Muntoni  1   6
Collaborators, Affiliations

Influence of Dystrophin Isoform Deficiency on Motor Development in Duchenne Muscular Dystrophy

Mary Chesshyre et al. Ann Clin Transl Neurol. 2025 Sep.

Abstract

Objective: In Duchenne muscular dystrophy (DMD), lack of the shorter dystrophin isoforms Dp140 and Dp71 is associated with increased central nervous system (CNS) involvement. We aimed to investigate how CNS involvement affects motor development in young DMD boys.

Method: Three hundred and forty-two DMD boys aged 3-6 years were subdivided according to DMD mutation expected effects on isoform expression: Group 1 (Dp427 absent, Dp140/Dp71 present, n = 170); Group 2 (Dp427/Dp140 absent, Dp71 present, n = 154) and Group 3 (Dp427/Dp140/Dp71 absent, n = 18). Mixed effects logistic regression was used to investigate relationships between isoform group and the odds of achieving higher North Star Ambulatory Assessment (NSAA) subitem scores for 15 subitems, adjusting for age at visit and glucocorticoid exposure.

Results: The odds of achieving a full score of 2 were significantly lower for 11 NSAA subitems in Group 2 compared to Group 1, 5 NSAA subitems in Group 3 compared to Group 1, and 2 NSAA subitems in Group 3 compared to Group 2. The odds of achieving a score of 2 or 1 compared to 0 were significantly lower in Group 2 compared to Group 1 for the 2 NSAA subitems studied using this comparison.

Interpretation: We found strong and significant associations between the odds of achieving higher NSAA subitem scores and expected patterns of dystrophin isoform involvement, with a cumulative effect of loss of isoforms. This suggests an important relationship between dystrophin isoforms in the brain and the ability to carry out gross motor milestones.

Keywords: Duchenne muscular dystrophy; dystrophin isoform; motor development; north star ambulatory assessment.

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Conflict of interest statement

Mary Chesshyre, Deborah Ridout, Georgia Stimpson and Adnan Manzur report no financial disclosures or potential conflicts of interest. Laurent Servais reports consultancy/board member in DMD for Dyne, Pepgen, Santhera, Pfizer, Roche, Santhera and Italfarmaco. Laurent Servais has received personal fees from Dyne, Pepgen, Wave, Roche, Italfarmaco, Santhera and Pfizer. Francesco Muntoni reports grants for the submitted work from Muscular Dystrophy UK (Grant reference: 22GRO‐PG24‐0598) and Brain Involvement iN Dystrophinopathies (BIND) European Union Horizon 2020 award Grant agreement: 847826. The BIND project (grant agreement No: 847826 [40]) has received funding from the European Union's Horizon 2020 research and innovation programme. Outside of the submitted work, Francesco Muntoni has received a grant from Sarepta Therapeutics (D‐BRAIN grant to UCL) and personal fees from Dyne Therapeutics (SAB), Sarepta (SAB) and PTC Therapeutics (SAB). Giovanni Baranello reports grants and personal fees from Sarepta and Roche and personal fees from Pfizer from outside of the submitted work.

Figures

FIGURE 1
FIGURE 1
The estimated percentage achieving a full score of 2 at age 3, 4, 5 or 6 according to isoform group for those in the GC naïve group for 13 of the NSAA subitems. The 13 NSAA subitems are stand up from chair (panel A), stand on one leg ‐ right (panel B), stand on one leg ‐ left (panel C), climb box step ‐ right (panel D), descend box step ‐ right (panel E), climb box step ‐ left (panel F), descend box step ‐ left (panel G), lifts head (panel H), gets to sitting (panel I), rise from floor (panel J), stands on heels (panel K), jump (panel L) and walk run (10m) (panel M). %2 = estimated percentage achieving a full score of 2. lt, left; rt, right. Blue is isoform group 1; pink is isoform group 2 and green is isoform group 3.
See this image and copyright information in PMC

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