Impact of three decades of improvement in standards of care for Duchenne muscular dystrophy

Jiménez, Claudia; Moreno,; Eagle, Michelle; Mayhew, A.; Mj, James; Straub,; Bushby, Kate

doi:10.1016/j.nmd.2015.06.066

Cited by 5 publications

(5 citation statements)

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“…Furthermore, LoA predicts other major disease milestones such as the need for ventilatory support and survival. 37,38 We observed an approximately 2-year delay of median LoA in 20 participants who had mutations amenable to exon 44 skipping. Similar results were observed in a retrospective genotype-phenotype association study carried out in the Netherlands.…”

Section: Resultsmentioning

confidence: 79%

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DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

et al. 2016

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

et al. 2016

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“…However, both scoliosis and survival have shown strong correlations with LoA. 38 Genotype-phenotype correlations for cardiac and respiratory endpoints in the CINRG-DNHS will be the object of separate studies. This study provides mutation-specific natural history data regarding LoA in DMD, carefully adjusting for the effect of other disease-modifying variables.…”

Section: Resultsmentioning

confidence: 99%

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Bello

Morgenroth

Gordish‐Dressman

et al. 2016

Neuromuscular Disorders

101

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“…3 Age at LoA is a clinically meaningful measure of disease severity in DMD and is correlated with respiratory failure, need for spinal surgery, and survival. 4 Understanding the bases of its variability could point at novel therapeutic targets, improve prognosis and personalization of treatments, and allow more accurate design and analysis of clinical trials.…”

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confidence: 99%

Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

Bello

Flanigan

Weiss

et al. 2016

The American Journal of Human Genetics

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The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

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Impact of three decades of improvement in standards of care for Duchenne muscular dystrophy

Cited by 5 publications

References 0 publications

DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

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