中性脂肪沉积症伴肌病与核黄素反应性脂质沉积性肌病的临床及发病机制探究

发布时间：2018-04-15 23:22

本文选题：多种酰基辅酶A脱氢酶缺乏症 + 核黄素反应性脂质沉积性肌病　；参考：《南昌大学》2017年硕士论文

【摘要】：背景与目的:中性脂肪沉积症伴肌病(neutral lipid storage disease with myopathy,NLSDM)是一种少见的常染色体隐性遗传的脂肪代谢障碍性疾病,是由于patatin样磷酸脂酶结构域蛋白(PNPLA2)基因突变导致甘油三酯分解障碍所致。核黄素反应性脂质沉积性肌病(riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency,RR-MADD)是一种常染色体隐性遗传性脂代谢通路障碍性病,主要是由电子转移黄素蛋白脱氢酶基因(ETFDH)突变所致。肌肉活检病理检查发现这两类脂肪沉积性肌病患者的肌纤维内都有大量脂滴沉积,不同的是在大多数NLSDM患者的肌纤维中可以发现许多大小不等的脂质沉积空泡,部分患者伴随出现镶边空泡;而大多数RR-MADD患者中肌纤维内也出现大量细小脂质空泡,常常伴随肌纤维坏死变性。上述不同的病理改变提示这两类疾病的发病机制有所不同。因而有必要在总结上述两种脂质代谢障碍性疾病的临床和病理的基础上,对他们可能的病理发生机制进一步进行研究。为此我们报道江西地区8例RR-MADD和4例NLSDM患者的临床表现、病理表现,以及探讨可能的发病机制。材料与方法:选取2011年4月至2016年4月就诊于南昌大学第一附属医院神经内科的患者,行肌肉活检+冰冻酶组织化学染色及基因检查证实为脂质沉积性肌病的12例患者,其中8例为核黄素反应性脂质沉积性肌病、4例为中性脂肪沉积症伴肌病患者的临床、病理资料进行分析,行免疫荧光检测自噬及凋亡相关蛋白的表达。结果:1、8例RR-MADD患者,其中7例为散发,1例有家族史,临床表现主要为四肢近端肌无力、不能耐受疲劳、肌酸胀为特征,2例患者有进食后呕吐发生,2例患者有肢体麻木、感觉性共济失调,给予核黄素治疗肌无力临床症状有明显的改善。4例NLSDM患者,均为散发,临床表现主要为不对称性四肢近端肌无力,伴心脏受累,目前还未有特效的治疗药物。2、8例RR-MADD患者,肌肉活检均显示肌纤维内大量脂滴沉积,以Ⅰ肌纤维为主,2例患者肌纤维出现较多坏死改变。4例NLSDM患者,肌纤维内有大量脂滴沉积,均出现数量不等的镶边空泡,同时肌纤维出现肥大萎缩和结缔组织增生。3、8例RR-MADD患者,免疫荧光显示肌纤维内出现Bax、Caspase-3凋亡诱导蛋白在病变肌纤维内聚集表达,而抗凋亡蛋白(Bcl-2)无明显表达变化。4例NLSDM患者,免疫荧光显示肌纤维内出现LC3和P62自噬蛋白聚集高表达,肌纤维内出现Bax、Caspase-3凋亡蛋白无明显聚集表达。结论:1、RR-MADD和NLSDM这两类脂质沉积性肌病的临床存在较大的差异性,RR-MADD主要表现为对称性的肢体近端无力,多表现为肌无力症状的波动和疲劳现象,伴随胃肠道或周围神经症状;NLSDM主要表现为不对称性肢体和躯干无力,无症状的波动性,伴随心肌或糖尿病。2、RR-MADD和NLSDM的病理改变在疾病的中后期存在一定的差异性,RR-MADD主要为肌纤维的坏死和变性,NLSDM主要为肌纤维的萎缩肥大,以及镶边空泡改变。3、RR-MADD的病变肌纤维通过凋亡通路走向肌纤维变性;NLSDM的病变肌纤维通过自噬通路走向肌纤维变性。
[Abstract]:Background and objective: neutral fat deposition disease associated with myopathy (neutral lipid storage disease with myopathy, NLSDM) is the fat metabolic disorder is a rare autosomal recessive, is due to patatin like phospholipase domain protein (PNPLA2) gene mutation caused by the disorder caused by decomposition of triglyceride. Riboflavin responsive lipid storage myopathy (riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency, RR-MADD) is an autosomal recessive disorder of lipid metabolism pathway of sexually transmitted diseases, mainly Huang Sudan butter hydrogenase by electron transfer gene (ETFDH) mutation. Muscle biopsy pathology showed that these two kinds of fat storage myopathy patients in skeletal muscle fibers have a large number of lipid droplets. Is different in most NLSDM muscle fibers can be many different size lipid vacuoles were found, some patients with The muscle fibers showing rimmed vacuoles; in most patients with RR-MADD also appeared in a large number of small lipid vacuoles, often accompanied by necrosis of muscle fiber degeneration. The different pathological changes of the pathogenesis of these two diseases that are different. So it is necessary to summarize the clinical and pathological basis of the above two kinds of lipid metabolism disorders on the mechanism they may occur on the pathology of further study. We report the clinical manifestations, 8 cases of RR-MADD in Jiangxi area and 4 cases of NLSDM patients with pathological findings, and to explore the possible pathogenesis. Materials and methods: from April 2011 to April 2016 in the First Affiliated Hospital of Nanchang University with muscle biopsy + frozen tissue enzyme chemical staining and gene examination confirmed 12 cases of lipid storage myopathy patients, including 8 cases of riboflavin responsive lipid storage myopathy, 4 cases The neutral fat deposition in patients with myopathy with clinical, pathological data were detected by immunofluorescence analysis, expression of autophagy and apoptosis related proteins. Results: 1,8 RR-MADD patients, including 7 cases of sporadic, 1 cases with family history, the major clinical manifestations of proximal limb weakness, can not tolerate fatigue, swelling characteristics of creatine, 2 patients had vomiting after eating, 2 patients with limb numbness, sensory ataxia, giving riboflavin treatment significantly improved clinical symptoms of myasthenia gravis.4 NLSDM patients were sporadic, the major clinical manifestations of the asymmetry of the proximal limb weakness, with heart involvement, there is no specific treatment for.2,8 RR-MADD patients, muscle biopsy showed muscle fibers in a large number of lipid droplets deposition in muscle fibers, 1, 2 patients have more muscle fiber necrosis.4 NLSDM patients, the muscle fibers within a large number of lipid droplets, which are The number of rimmed vacuoles, muscle fibers atrophy and hypertrophy and hyperplasia of connective tissue of.3,8 patients with RR-MADD, immunofluorescence showed Bax in skeletal muscle fibers, Caspase-3 apoptosis inducing protein aggregation expression in lesions in skeletal muscle fibers, and anti apoptotic protein (Bcl-2) had no obvious changes in the expression of.4 in patients with NLSDM, immunofluorescence showed muscle the fiber LC3 and autophagy protein P62 aggregation high expression of Bax in skeletal muscle fibers, no obvious aggregation of Caspase-3 apoptosis protein expression. Conclusion: 1. Clinical RR-MADD and NLSDM these two kinds of lipid storagemyopathy differences, RR-MADD showed symmetric proximal limb weakness, showed more fluctuation and the phenomenon of fatigue symptoms of myasthenia gravis, accompanied by gastrointestinal symptoms or peripheral nerve; NLSDM mainly for the asymmetry of the limbs and trunk weakness, the volatility of asymptomatic, or diabetes associated with myocardial.2, RR-MADD The pathological changes in NLSDM, there are some differences in the disease in late RR-MADD, mainly for muscle fiber necrosis and degeneration of NLSDM, mainly for hypertrophy of muscle fiber atrophy, and rimmed vacuoles change.3 lesions, muscle fiber RR-MADD through apoptosis pathway to muscle fiber degeneration; muscle fiber lesions by NLSDM of the autophagy pathway to muscle fiber degeneration.

【学位授予单位】：南昌大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R589.2

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