Dystrophin isoform deficiency and upper-limb and respiratory function in Duchenne muscular dystrophy

Mary Chesshyre; Deborah Ridout; Georgia Stimpson; Valeria Ricotti; Silvana De Lucia; Erik H Niks; Volker Straub; Laurent Servais; Jean-Yves Hogrel; Giovanni Baranello; Adnan Manzur; UK NorthStar Clinical Network; Francesco Muntoni; iMDEX Network

doi:10.1111/dmcn.16282

Dystrophin isoform deficiency and upper-limb and respiratory function in Duchenne muscular dystrophy

Dev Med Child Neurol. 2025 Mar 14. doi: 10.1111/dmcn.16282. Online ahead of print.

Authors

Mary Chesshyre¹, Deborah Ridout², Georgia Stimpson¹, Valeria Ricotti^{1

3

4}, Silvana De Lucia⁵, Erik H Niks⁶, Volker Straub^{7

8}, Laurent Servais^{9

10

11}, Jean-Yves Hogrel¹², Giovanni Baranello¹, Adnan Manzur¹; UK NorthStar Clinical Network; Francesco Muntoni^{1

3

4}; iMDEX Network

Collaborators

Joana Domingos, Victoria Selby, Amy Wolfe, Lianne Abbott, Efthymia Panagiotopoulou, Mario Iodice, Maria Ash, Imelda de Groot, Merel Jansen, Maaike Pelsma, Marian Bobbert, Menno Van Der Holst, Yvonne D Krom, Marjolein J van Heur-Neuman, Thomas Voit, Valérie Decostre, Stéphanie Gilabert, Michela Guglieri, Alexander Murphy, Anna Mayhew, Mariacristina Scoto, Anna Sarkozy, Pinki Munot, Stephanie Robb, Elaine Chan, V Robinson, W Girshab, V Crook, E Milev, L Abbott, A Wolfe, E O'Reilly, J Watts-When, N Burnett, R Thomas, R Terespolsky, O Martinaeu, J Longatto, C Bettolo, M Guglieri, J Diaz-Manera, G Tasca, M Elseed, R Muni-Lofra, M James, D Moat, J Sodhi, K Wong, E Robinson, E Groves, R Rabb, H McMurchie, H Chase, Tracey Willis, C Rylance, N Birchall, E Wright, A Childs, K Pysden, C Martos, D Roberts, L Pallant, S Walker, A Henderson, R Madhu, R Karuvattil, Y Balla, S Gregson, S Clark, E Wraige, H Jungbluth, V Gowda, M Vanegas, J Sheehan, A Schofield, C Smith, I Hughes, E Whitehouse, S Warner, E Reading, N Emery, J Moustoukas, K Strachan, M Ong, M Atherton, N Mills, S Sanchez Marco, A Saxena, K Skone, J TeWaterNaude, H Davis, C Wood, A Majumdar, A Murugan, I Guarino, R Tomlinson, H Jarvis, L Wills, C Frimpong, J Watson, G Cobb, G Robertson, P Brink, J Burslem, C Adams, J Wong, S Joseph, I Horrocks, J Dunne, M DiMarco, S Brown, S McKenzie, K Torne, R Mohamed, V Velmurugan, M Prasad, S Sedehizadeh, A Schugal, R Keetley, S Williamson, K Payne, E Dowling, P Fenty, C de Goede, A Parkes, K Baxter, M Illingworth, N Bhangu, S Geary, J Palmer, K Shill, S Tirupathi, A Shah, D O'Donogue, J McVeigh, J McFetridge, G Nicfhirleinn, H Beattie, T Leyland, K Stevenson, N Hussain, D Baskaran, Z Lambat, R Sullivan, L Locke, G Ambegaonkar, D Krishnakumar, J Taylor, J Moores, E Stephen, J Tewnion, S Ramdas, M Sa, A Skippen, M Khries, C Lilien, H Ramjattan, F Taylor, H English, K Stewart, F Flint, E Bartram, R Noble

Affiliations

¹ Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.
² Population, Policy and Practice Research and Teaching Department, UCL GOS Institute of Child Health, London, UK.
³ NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, UCL, London, UK.
⁴ Great Ormond Street Hospital NHS Foundation Trust, London, UK.
⁵ AP-HP, Sorbonne University, Institute of Myology, AFM-Telethon, I-Motion Pediatric Clinical Trials Platform, Armand Trousseau Hospital, Paris, France.
⁶ Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.
⁷ The John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁸ NIHR Newcastle Biomedical Research Centre, University of Newcastle, Newcastle upon Tyne, UK.
⁹ Centre de Référence Des Maladies Neuromusculaires, CHU de Liège, University of Liège, Liège, Belgium.
¹⁰ Department of Paediatrics, MDUK Oxford Neuromuscular Centre, Oxford, UK.
¹¹ NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
¹² Institute of Myology, Paris, France.

PMID: 40084496
DOI: 10.1111/dmcn.16282

Abstract

Aim: To investigate the associations between mutations expected to differentially affect Dp140 expression and long-term trajectories of respiratory and upper-limb motor outcomes in Duchenne muscular dystrophy (DMD).

Method: In a retrospective analysis of population-based longitudinal data from three real-world and natural history data sources, individuals with DMD aged 5 years to 18 years were subdivided according to the predicted effects of the participants' DMD mutation on dystrophin isoform expression (group 1, Dp427 absent, Dp140/Dp71 present; group 2, Dp427/Dp140 absent, Dp71 present).

Results: A total of 459 participants were studied, with upper-limb outcomes assessed in 71 (27 in group 1 and 44 in group 2) and forced vital capacity percentage predicted (%pred) assessed in 434 (224 in group 1 and 210 in group 2). Mean grip strength %pred was on average 7.1 percentage points lower in group 2 than in group 1 (p = 0.03). Mean pinch strength %pred was on average 9.2 percentage points lower in group 2 than in group 1 (p = 0.04). Mean forced vital capacity %pred was on average 4.3 percentage points lower in group 2 than in group 1 (p = 0.01).

Interpretation: In individuals with DMD, DMD mutations predicted to affect Dp140 expression were associated with more severe trajectories of respiratory and upper-limb motor outcomes.

Abstract

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