在人类和犬类杜氏肌营养不良症和贝克肌营养不良症中，血浆脂质异常的高发表明存在一种新型原发性遗传性血脂异常。
High prevalence of plasma lipid abnormalities in human and canine Duchenne and Becker muscular dystrophies depicts a new type of primary genetic dyslipidemia.
机构信息
Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (UBC), Vancouver, BC, Canada; Centre for Heart & Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO; National Center for Advancing Translational Sciences, NIH, Rockville, MD.
出版信息
J Clin Lipidol. 2020 Jul-Aug;14(4):459-469.e0. doi: 10.1016/j.jacl.2020.05.098. Epub 2020 May 29.
BACKGROUND
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive muscle diseases caused by mutations in the DMD gene, with DMD being the more severe form. We have recently shown that increased plasma low-density lipoprotein-associated cholesterol causes severe muscle wasting in the mdx mouse, a mild DMD model, which suggested that plasma lipids may play a critical role in DMD. We have also observed that loss of dystrophin in mice causes unexpected elevations in plasma lipoprotein levels.
OBJECTIVE
The objectives of the study were to determine whether patients with DMD and BMD also present with clinically relevant plasma lipoprotein abnormalities and to mitigate the presence of confounders (medications and lifestyle) by analyzing the plasma from patients with DMD/BMD and unmedicated dogs with DMD, the most relevant model of DMD.
METHODS
Levels of low-density lipoprotein-associated cholesterol, high-density lipoprotein cholesterol, and triglycerides were analyzed in patients with DMD and BMD and female carriers. Samples from unmedicated, ambulatory dogs with DMD, unaffected carriers, and normal controls were also analyzed.
RESULTS
We report that 97% and 64% of all pediatric patients with DMD (33 of 36) and BMD (6 of 11) are dyslipidemic, along with an unusually high incidence in adult patients with BMD. All dogs with DMD showed plasma lipid abnormalities that progressively worsened with age. Most strikingly, unaffected carrier dogs also showed plasma lipid abnormalities similar to affected dogs with DMD. Dyslipidemia is likely not secondary to liver damage as unaffected carriers showed no plasma aminotransferase elevation.
CONCLUSIONS
The high incidence of plasma lipid abnormalities in dystrophin-deficient plasma may depict a new type of genetic dyslipidemia. Abnormal lipid levels in dystrophinopathic samples in the absence of muscle damage suggest a primary state of dyslipidemia. Whether dyslipidemia plays a causal role in patients with DMD warrants further investigation, which could lead to new diagnostic and therapeutic options.
背景
杜氏肌营养不良症（DMD）和贝克肌营养不良症（BMD）是由 DMD 基因突变引起的等位 X 连锁隐性肌肉疾病，其中 DMD 更为严重。我们最近发现，增加血浆低密度脂蛋白相关胆固醇会导致 mdx 小鼠（一种轻度 DMD 模型）严重肌肉萎缩，这表明血浆脂质可能在 DMD 中起关键作用。我们还观察到，小鼠中肌营养不良蛋白的缺失会导致血浆脂蛋白水平意外升高。
目的
本研究的目的是确定 DMD 和 BMD 患者是否也存在临床相关的血浆脂蛋白异常，并通过分析 DMD/BMD 患者和未经治疗的 DMD 犬（最相关的 DMD 模型）的血浆来减轻混杂因素（药物和生活方式）的影响。
方法
分析了 DMD 和 BMD 患者以及未经治疗的、活动能力正常的 DMD 犬、未受影响的携带者和正常对照者的血浆中低密度脂蛋白相关胆固醇、高密度脂蛋白胆固醇和甘油三酯水平。
结果
我们报告称，36 名 DMD 患儿中有 97%（33 名）和 11 名 BMD 患儿中有 64%（6 名）患有血脂异常症，且 BMD 成年患者的发病率异常高。所有 DMD 犬均表现出随年龄增长逐渐恶化的血浆脂质异常。最引人注目的是，未受影响的携带者犬也表现出与受影响的 DMD 犬相似的血浆脂质异常。血脂异常症可能不是继发于肝损伤，因为未受影响的携带者的血浆氨基转移酶没有升高。
结论
缺乏肌营养不良蛋白的血浆中高发生率的血脂异常可能描绘了一种新型的遗传性血脂异常症。在没有肌肉损伤的情况下，肌营养不良症样本中的异常脂质水平提示原发性血脂异常症。血脂异常症在 DMD 患者中是否起因果作用还需要进一步研究，这可能会带来新的诊断和治疗选择。
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