From the Department of Physical Therapy (A.M.B., W.T.T., S.C.F., R.J.W., C.R.S., D.J.L., K.V.) Pharmacology and Therapeutics (D.W.H., H.L.S.), University of Florida, Gainesville; Center for Pharmacometrics and Systems Pharmacology (S.K.), Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando; Department of Statistics (M.J.D.), University of Florida, Gainesville; Department of Neurology (I.A.), Oregon Health & Science University, Portland; Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; Department of Human Genetics (R.T.W., S.F.N.), University of California Los Angeles, CA; and Department of Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville.
Neurology. 2022 Nov 22;99(21):e2406-e2416. doi: 10.1212/WNL.0000000000201163. Epub 2022 Sep 2.
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 this study was to evaluate the effects of dystrophin variations and genetic modifiers of DMD on rate and age of muscle replacement by fat.
One 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.
Participants 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 ( = 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 , , and thrombospondin-1 () genetic modifiers did not result in significant differences in muscle FF trajectories between genotype groups ( > 0.05); however, trends were noted for the polymorphisms associated with long-range regulation of and that deserve further follow-up.
The 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.
杜氏肌营养不良症（DMD）是一种进行性肌肉退行性疾病，具有明确的疾病表型，但个体间存在相当大的异质性，目前尚不清楚其原因。本研究旨在评估抗肌萎缩蛋白变异和 DMD 的遗传修饰因子对脂肪替代肌肉的速度和年龄的影响。
175 名接受皮质类固醇治疗的参与者来自影像学 DMD 自然史研究，对股外侧肌（VL）和比目鱼肌（SOL）进行了多次磁共振波谱（MRS）检查，以确定肌肉脂肪分数（FF）。大多数情况下，MRS 每年进行一次；然而，一些人每隔 3 或 6 个月进行额外的检查。使用非线性混合效应模型来模拟随时间变化的 FF 变化，以根据 VL 或 SOL 达到 FF 变化最大值的年龄（mu）和 FF 变化所需的时间（sigma）来估计疾病轨迹。对已证明具有导致轻度表型能力的抗肌萎缩蛋白变异以及不同遗传多态性组之间进行了计算的 mu 和 sigma 值的评估。
可进行外显子 8 跳跃的抗肌萎缩蛋白基因突变缺失（n = 4）的参与者 SOL FF 增加最小，与参考队列相比 VL mu 值增加了 4.4 年（ = 0.039）。在可能产生较轻表型的外显子内具有无意义变异的参与者（n = 11），SOL 和 VL 的 FF 也增加最小。可进行外显子 44 跳跃的参与者（n = 10）的估计 FF 轨迹无差异。对 、 和血小板反应蛋白-1（）遗传修饰因子进行建模，在不同基因型组之间的肌肉 FF 轨迹没有导致显著差异（>0.05）；然而，与 和 的长距离调控相关的多态性显示出趋势，值得进一步随访。
本研究结果将在可进行外显子 8 跳跃和某些无意义变异的个体中观察到的历史上较轻的表型与下肢肌肉被脂肪替代的轨迹改变联系起来。
