Evaluating Genetic Modifiers of Duchenne Muscular Dystrophy Disease Progression Using Modeling and MRI
| Autor: | Alison M Barnard, David W Hammers, William T Triplett, Sarah Kim, Sean C Forbes, Rebecca J Willcocks, Michael J Daniels, Claudia R Senesac, Donovan J Lott, Ishu Arpan, William D Rooney, Richard T Wang, Stanley F Nelson, H Lee Sweeney, Krista Vandenborne, Glenn A Walter |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Neurology |
| ISSN: | 1526-632X 0028-3878 |
| DOI: | 10.1212/wnl.0000000000201163 |
| Popis: | Background and Objectives:Duchenne 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 the study was to evaluate the effects of dystrophin mutations and genetic modifiers of DMD on rate and age of muscle replacement by fat.Methods:175 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. MRS was performed annually in the majority of instances; however, some individuals had additional visits at 3 or 6 month intervals. Fat fraction 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 fat fraction (mu) and the time required for fat fraction change (sigma). Computed mu and sigma values were evaluated for dystrophin mutations that have demonstrated the ability to lead to a mild phenotype as well as compared between different genetic polymorphism groups.Results:Participants with dystrophin gene deletions amenable to exon 8 skipping (n=4) had minimal increases in SOL fat fraction and had an increase in VL mu value by 4.4 years compared to a reference cohort (p=0.039). Participants with nonsense mutations within exons that may produce milder phenotypes (n=11) also had minimal increases in SOL and VL fat fractions. No differences in estimated fat fraction trajectories were seen for individuals amenable to exon 44 skipping (n=10). Modeling of the SPP1, LTBP4, and THBS1 genetic modifiers did not result in significant differences in muscle fat fraction 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.Discussion:The results of this study link the historically mild phenotypes seen in individuals amenable to exon 8 skipping and with certain nonsense mutations with alterations in trajectories of lower extremity muscle replacement by fat. |
| Databáze: | OpenAIRE |
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