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, 786 estimated that forced vital capacity (FVC) declined yearly by À4.2%, forced expiratory volume in 1 sec by À5.0%, and peak expiratory flow (PEF) by À2.9%. 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 À6%) 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.

Cardiac medication management in Duchenne muscular dystrophy

“…Glucocorticoid (GC) therapy is currently standard of care in DMD as multiple studies have shown this therapy helps slows the progressive decline in skeletal muscle and pulmonary function 15,19 20,21 …”

Cardiopulmonary phenotypic variability and discordance in Duchenne muscular dystrophy: Implications for new therapies

“…There are numerous candidates for modifiers of the dystrophin gene and the latest candidates have been described in various publications 29,31,32 . Most of the studies describe how modifiers affect skeletal muscle, with a few reports focusing on modifiers of pulmonary and cardiac function 32‐34 . While there is an association between pulmonary phenotype and age at loss of ambulation (e.g., patients with the most severe pulmonary phenotype experience loss of ambulation at the earliest age), 14 the relationship between skeletal muscle deterioration and cardiopulmonary phenotypes is not well‐studied.…”

Longitudinal motor function in proximal versus distal DMD pathogenic variants

“…An enduring challenge even in a monogenic disease such as DMD is disease heterogeneity, and variability in clinical outcomes is evident across multiple organs 4‐16 . Both DMD genotype and genetic modifiers affect motor, respiratory, and cognitive outcomes in DMD.…”

“…Recently, boys with distal DMD pathogenic variants were shown to have lower pulmonary function measures compared to those with proximal DMD pathogenic variants 5 . Similarly, cognitive burden in DMD vary depending between boys with proximal and distal DMD pathogenic variants 14‐18 .…”

“…An enduring challenge even in a monogenic disease such as DMD is disease heterogeneity, and variability in clinical outcomes is evident across multiple organs. [4][5][6][7][8][9][10][11][12][13][14][15][16] Both DMD genotype and genetic modifiers affect motor, respiratory, and cognitive outcomes in DMD. Bello et al using the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS) cohort showed that boys with a non-sense mutation in DMD lost ambulation at a median age of 11.1 y, compared with those boys with deletions amenable to DMD exon 44 skipping, who lost ambulation at a median age of 14.8 y.…”