TY - JOUR
T1 - Genetic modifiers of respiratory function in Duchenne muscular dystrophy
AU - Bello, Luca
AU - D’Angelo, Grazia
AU - Villa, Matteo
AU - Fusto, Aurora
AU - Vianello, Sara
AU - Vianello, Serena
AU - Merlo, Beatrice
AU - Sabbatini, Daniele
AU - Barp, Andrea
AU - Gandossini, Sandra
AU - Magri, Francesca
AU - Comi, Giacomo P.
AU - Pedemonte, Marina
AU - Tacchetti, Paola
AU - Lanzillotta, Valentina
AU - Trucco, Federica
AU - D’Amico, Adele
AU - Bertini, Enrico Silvio
AU - Astrea, Guja
AU - Politano, Luisa
AU - Masson, Riccardo
AU - Baranello, Giovanni
AU - Albamonte, Emilio
AU - De Mattia, Elisa
AU - De Mattia, Egidio
AU - Rao, Fabrizio
AU - Sansone, Valeria A.
AU - Previtali, Stefano
AU - Messina, Sonia
AU - Vita, Gian Luca
AU - Berardinelli, Angela
AU - Mongini, Tiziana
AU - Pini, Antonella
AU - Pane, Marika
AU - Mercuri, Eugenio Maria
AU - Vianello, Andrea
AU - Bruno, Claudio
AU - Hoffman, Eric P.
AU - Morgenroth, Lauren
AU - Gordish-Dressman, Heather
AU - Mcdonald, Craig M.
AU - Pegoraro, Elena
PY - 2020
Y1 - 2020
N2 - Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by −4.2%, forced expiratory volume in 1 sec by −5.0%, and peak expiratory flow (PEF) by −2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3’ of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately −6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
AB - Objective: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Methods and Results: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by −4.2%, forced expiratory volume in 1 sec by −5.0%, and peak expiratory flow (PEF) by −2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3’ of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately −6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. Interpretation: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
KW - Duchenne muscular dystrophy
KW - Duchenne muscular dystrophy
UR - http://hdl.handle.net/10807/260272
U2 - 10.1002/acn3.51046
DO - 10.1002/acn3.51046
M3 - Article
SN - 2328-9503
VL - 7
SP - 786
EP - 798
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
ER -