Abnormal fatty acid metabolism is a core component of spinal muscular atrophy
Abnormal fatty acid metabolism is a core component of spinal muscular atrophy
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DOI：
10.1002/acn3.50855
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发表时间：
2019-07-26
影响因子：
5.3
通讯作者：
Kothary, Rashmi
中科院分区：
文献类型：
--
作者：
Deguise, Marc-Olivier;Baranello, Giovanni;Kothary, Rashmi
目的脊髓性肌萎缩症（spinal muscular atrophy，SMA）是一种遗传性神经肌肉疾病，可导致儿童瘫痪和死亡。最初被认为是一种运动神经元疾病，神经元外受累越来越多地被认识到。本研究的主要目的是研究SMA患者和该疾病的小鼠模型中脂质代谢的改变。方法：我们分析了从一个大型队列的I-III型SMA儿童患者收集的临床数据以及I型SMA肝脏尸检数据。同时，我们在SMA小鼠模型中进行了组织学、脂质分析和转录谱分析。结果：我们确定了72例SMA患者队列中发生血脂异常的易感性增加，病理样本中发生肝脂肪变性。同样，在研究的所有SMA小鼠模型中均存在脂肪酸代谢异常。具体而言，Smn（2B/-）小鼠显示肝甘油三酯和血脂异常升高，类似于非酒精性脂肪肝（NAFLD）。有趣的是，这种表型出现在去神经之前。这项工作强调代谢异常是SMA的一个重要特征，建议在患者中实施营养和筛查指南，因为这些缺陷可能会增加代谢窘迫和心血管风险。本研究强调需要一种系统性治疗方法，以确保所有SMA患者终生获益最大。
Objective Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn(2B/-) mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.