Annals of Clinical and Translational Neurology (May 2020)
Genetic modifiers of respiratory function in Duchenne muscular dystrophy
- Luca Bello,
- Grazia D’Angelo,
- Matteo Villa,
- Aurora Fusto,
- Sara Vianello,
- Beatrice Merlo,
- Daniele Sabbatini,
- Andrea Barp,
- Sandra Gandossini,
- Francesca Magri,
- Giacomo P. Comi,
- Marina Pedemonte,
- Paola Tacchetti,
- Valentina Lanzillotta,
- Federica Trucco,
- Adele D’Amico,
- Enrico Bertini,
- Guja Astrea,
- Luisa Politano,
- Riccardo Masson,
- Giovanni Baranello,
- Emilio Albamonte,
- Elisa De Mattia,
- Fabrizio Rao,
- Valeria A. Sansone,
- Stefano Previtali,
- Sonia Messina,
- Gian Luca Vita,
- Angela Berardinelli,
- Tiziana Mongini,
- Antonella Pini,
- Marika Pane,
- Eugenio Mercuri,
- Andrea Vianello,
- Claudio Bruno,
- Eric P. Hoffman,
- Lauren Morgenroth,
- Heather Gordish‐Dressman,
- Craig M. McDonald,
- CINRG‐DNHS Investigators,
- Elena Pegoraro
Affiliations
- Luca Bello
- Department of Neurosciences DNS University of Padova Padova Italy
- Grazia D’Angelo
- NeuroMuscular Unit Scientific Institute IRCCS E. Medea Bosisio Parini (Lecco) Italy
- Matteo Villa
- Department of Neurosciences DNS University of Padova Padova Italy
- Aurora Fusto
- Department of Neurosciences DNS University of Padova Padova Italy
- Sara Vianello
- Department of Neurosciences DNS University of Padova Padova Italy
- Beatrice Merlo
- Department of Neurosciences DNS University of Padova Padova Italy
- Daniele Sabbatini
- Department of Neurosciences DNS University of Padova Padova Italy
- Andrea Barp
- Department of Neurosciences DNS University of Padova Padova Italy
- Sandra Gandossini
- NeuroMuscular Unit Scientific Institute IRCCS E. Medea Bosisio Parini (Lecco) Italy
- Francesca Magri
- IRCSS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
- Giacomo P. Comi
- IRCSS Foundation Ca’ Granda Ospedale Maggiore Policlinico Milan Italy
- Marina Pedemonte
- Center of Translational and Experimental Myology IRCCS Istituto Giannina Gaslini Genova Italy
- Paola Tacchetti
- Center of Translational and Experimental Myology IRCCS Istituto Giannina Gaslini Genova Italy
- Valentina Lanzillotta
- Center of Translational and Experimental Myology IRCCS Istituto Giannina Gaslini Genova Italy
- Federica Trucco
- Center of Translational and Experimental Myology IRCCS Istituto Giannina Gaslini Genova Italy
- Adele D’Amico
- Unit of Neuromuscular and Neurodegenerative Disorders Bambino Gesù Children's Hospital IRCCS Rome Italy
- Enrico Bertini
- Unit of Neuromuscular and Neurodegenerative Disorders Bambino Gesù Children's Hospital IRCCS Rome Italy
- Guja Astrea
- Department of Developmental Neuroscience IRCCS Stella Maris Calambrone, Pisa Italy
- Luisa Politano
- Cardiomyology and Medical Genetics Department of Experimental Medicine “Vanvitelli” University of Campania Naples Italy
- Riccardo Masson
- Developmental Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
- Giovanni Baranello
- Developmental Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
- Emilio Albamonte
- Neurorehabilitation Unit Centro Clinico NeMO University of Milan Milan Italy
- Elisa De Mattia
- Neurorehabilitation Unit Centro Clinico NeMO University of Milan Milan Italy
- Fabrizio Rao
- Neurorehabilitation Unit Centro Clinico NeMO University of Milan Milan Italy
- Valeria A. Sansone
- Neurorehabilitation Unit Centro Clinico NeMO University of Milan Milan Italy
- Stefano Previtali
- Neuromuscular Repair Unit, Inspe and Division of Neuroscience IRCSS San Raffaele Scientific Institute Milan Italy
- Sonia Messina
- Department of Neurosciences and Nemo Sud Clinical Center University of Messina Messina Italy
- Gian Luca Vita
- Department of Neurosciences and Nemo Sud Clinical Center University of Messina Messina Italy
- Angela Berardinelli
- “C. Mondino” Foundation Pavia Italy
- Tiziana Mongini
- Neuromuscular Center AOU Città della Salute e della Scienza University of Torino Turin Italy
- Antonella Pini
- Child Neurology and Psychiatry Unit IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy
- Marika Pane
- Pediatric Neurology Department of Woman and Child Health and Public Health Child Health Area Università Cattolica del Sacro Cuore Rome Italy
- Eugenio Mercuri
- Pediatric Neurology Department of Woman and Child Health and Public Health Child Health Area Università Cattolica del Sacro Cuore Rome Italy
- Andrea Vianello
- Department of Cardio‐Thoracic Sciences, Respiratory Pathophysiology Division University‐City Hospital of Padova Padova Italy
- Claudio Bruno
- Center of Translational and Experimental Myology IRCCS Istituto Giannina Gaslini Genova Italy
- Eric P. Hoffman
- Binghamton University ‐ SUNY Binghamton New York
- Lauren Morgenroth
- Center for Genetic Medicine Children’s Research Institute Children’s National Health System Washington District of Columbia
- Heather Gordish‐Dressman
- Center for Genetic Medicine Children’s Research Institute Children’s National Health System Washington District of Columbia
- Craig M. McDonald
- University of California Davis Medical Center Sacramento California
- CINRG‐DNHS Investigators
- Elena Pegoraro
- Department of Neurosciences DNS University of Padova Padova Italy
- DOI
- https://doi.org/10.1002/acn3.51046
- Journal volume & issue
-
Vol. 7,
no. 5
pp. 786 – 798
Abstract
Abstract 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.