Dataset Information

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

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.

SUBMITTER: Bello L

PROVIDER: S-EPMC7261745 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

Bello Luca L D'Angelo Grazia G Villa Matteo M Fusto Aurora A Vianello Sara S Merlo Beatrice B Sabbatini Daniele D Barp Andrea A Gandossini Sandra S Magri Francesca F Comi Giacomo P GP Pedemonte Marina M Tacchetti Paola P Lanzillotta Valentina V Trucco Federica F D'Amico Adele A Bertini Enrico E Astrea Guja G Politano Luisa L Masson Riccardo R Baranello Giovanni G Albamonte Emilio E De Mattia Elisa E Rao Fabrizio F Sansone Valeria A VA Previtali Stefano S Messina Sonia S Vita Gian Luca GL Berardinelli Angela A Mongini Tiziana T Pini Antonella A Pane Marika M Mercuri Eugenio E Vianello Andrea A Bruno Claudio C Hoffman Eric P EP Morgenroth Lauren L Gordish-Dressman Heather H McDonald Craig M CM Pegoraro Elena E

Annals of clinical and translational neurology 20200428 5

<h4>Objective</h4>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 vari ...[more]

PMID: 32343055

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Project description:Background and objectivesDuchenne muscular dystrophy (DMD) is a progressive muscle degenerative disorder with a well-characterized disease phenotype but considerable interindividual heterogeneity that is not well understood. The aim of this study was to evaluate the effects of dystrophin variations and genetic modifiers of DMD on rate and age of muscle replacement by fat.MethodsOne hundred seventy-five corticosteroid treated participants from the ImagingDMD natural history study underwent repeated magnetic resonance spectroscopy (MRS) of the vastus lateralis (VL) and soleus (SOL) to determine muscle fat fraction (FF). MRS was performed annually in most instances; however, some individuals had additional visits at 3 or 6 monthss intervals. FF changes over time were modeled using nonlinear mixed effects to estimate disease trajectories based on the age that the VL or SOL reached half-maximum change in FF (mu) and the time required for FF change (sigma). Computed mu and sigma values were evaluated for dystrophin variations that have demonstrated the ability to lead to a mild phenotype as well as compared between different genetic polymorphism groups.ResultsParticipants with dystrophin gene deletions amenable to exon 8 skipping (n = 4) had minimal increases in SOL FF and had an increase in VL mu value by 4.4 years compared with a reference cohort (p = 0.039). Participants with nonsense variations within exons that may produce milder phenotypes (n = 11) also had minimal increases in SOL and VL FFs. No differences in estimated FF trajectories were seen for individuals amenable to exon 44 skipping (n = 10). Modeling of the SPP1, LTBP4, and thrombospondin-1 (THBS1) genetic modifiers did not result in significant differences in muscle FF trajectories between genotype groups (p > 0.05); however, trends were noted for the polymorphisms associated with long-range regulation of LTBP4 and THBS1 that deserve further follow-up.DiscussionThe results of this study link the historically mild phenotypes seen in individuals amenable to exon 8 skipping and with certain nonsense variations with alterations in trajectories of lower extremity muscle replacement by fat.

Dataset Information

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

Publications

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

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