Genetic modifiers of upper limb function in Duchenne muscular dystrophy

Daniele Sabbatini, Aurora Fusto, Sara Vianello, Matteo Villa, Joanna Janik, Grazia D'Angelo, Eleonora Diella, Francesca Magri, Giacomo P Comi, Chiara Panicucci, Claudio Bruno, Adele D'Amico, Enrico Bertini, Guja Astrea, Roberta Battini, Luisa Politano, Riccardo Masson, Giovanni Baranello, Stefano C Previtali, Sonia MessinaGianluca Vita, Angela Berardinelli, Tiziana Mongini, Antonella Pini, Marika Pane, Eugenio Mercuri, Eric P Hoffman, Lauren Morgenroth, Heather Gordish-Dressman, Tina Duong, Craig M McDonald, Luca Bello, Elena Pegoraro

Research output: Contribution to journalArticlepeer-review


Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

Original languageEnglish
Pages (from-to)4884-4894
Number of pages11
JournalJ. Neurol.
Issue number9
Publication statusE-pub ahead of print - May 5 2022


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