脂肪营养不良综合征的临床表型和分子遗传学研究

发布时间：2018-05-21 14:19

本文选题：脂肪营养不良综合征 + 脂肪因子　；参考：《北京协和医学院》2017年博士论文

【摘要】：目的脂肪营养不良综合征是一种以特征性脂肪丢失伴严重代谢紊乱为特点的罕见疾病。不同类型脂肪营养不良综合征的患者在脂肪组织缺失程度和部位上具有很大差异,目前已报道的案例中对脂肪分布特征的描述多数笼统地概括为躯干或四肢,未进一步细化,因此从临床特点上对脂肪营养不良综合征分型缺乏较好的文献指导。此外,先天性脂肪营养不良综合征致病基因具有多态性,目前对疾病的诊疗中往往根据临床工作者的经验选择某几个可能性较大的基因进行测序,导致基因检测阳性率低;且部分先天性脂肪营养不良综合征致病基因仍不明确。另外研究表明瘦素和脂联素在脂肪营养不良综合征的发生发展过程中起重要作用;目前已发表的文献对脂肪营养不良综合征患者瘦素和脂联素关注不足,缺乏相关数据;这些脂肪因子在疾病的发生发展中的具体作用\不十分明确,不利于临床治疗的个体化。脂肪营养不良综合征的发病率低,临床资料极为缺乏。对疾病认识的不足,使多数患者无法得到及时有效的诊疗,极大地影响患者的生活质量。通过对在北京协和医院就诊的5名脂肪营养不良综合征患者,从临床表型、分子生物学和遗传学学层面进一步研究脂肪营养不良综合征,能帮助我们更好地了解疾病的发生发展,以期找到更有效的诊疗方法。方法收集并分析2015年1月至2017年2月北京协和医院内分泌科收治的5例脂肪营养不良综合征患者的临床资料;检测糖脂代谢指标、瘦素和脂联素水平;结合全身弥散加权显像和定量计算机断层扫描分析疾病脂肪组织的分布特点;进行全外显子测序,针对检测到的突变位点,通过数据分析和文献复习筛选可能的致病基因并分析其作用机制。结果临床资料和影像学结果均表明5名患者临床表型存在差异,包括脂肪分布特点;均出现不同程度和部位的脂肪萎缩,其中4名出现选择性脂肪堆积。所有患者在病程中均出现顽固性胰岛素抵抗和高脂血症,瘦素和脂联素水平显著降低。全外显子测序和数据分析结果表明患者L2和L5带有强致病性突变LMNA(分别为p.R482W和p.R349W),同时均带有弱致病性突变PLIN1(p.P194A)。患者L4临床表型符合家族性部分性脂肪营养不良综合征1型。噻唑烷二酮在改善多数患者糖代谢紊乱方面较其他多数口服降糖药有优势。结论先天性脂肪营养不良综合征的临床表型和致病基因极具多样性,目前仍存在未知的致病基因;它有可能是多致病基因共同作用的结果。建立临床表型库,完善临床资料有利于疾病的早诊疗。基于疾病机制进行个体化治疗有助于疾病的控制。
[Abstract]:Objective adipose dystrophy syndrome is a rare disease characterized by characteristic fat loss and severe metabolic disorder. There are significant differences in the degree and location of adipose tissue loss in patients with different types of adipose dystrophy syndrome. The description of fat distribution characteristics in reported cases is generally summarized as trunk or extremities without further refinement. Therefore, there is a lack of good literature guidance on the classification of adipose dystrophy syndrome from the clinical characteristics. In addition, the gene of congenital adipose dystrophy syndrome is polymorphic. At present, in the diagnosis and treatment of the disease, we often select some more likely genes for sequencing according to the experience of clinical workers, which leads to the low positive rate of gene detection. And some genes of congenital adipose dystrophy syndrome are still unclear. In addition, leptin and adiponectin play an important role in the development of adipose dystrophy syndrome. The specific role of these factors in the occurrence and development of the disease is not very clear, which is not conducive to the individualization of clinical treatment. The incidence of adipose dystrophy syndrome is low and the clinical data is extremely lacking. The lack of understanding of the disease makes most patients unable to get timely and effective diagnosis and treatment, which greatly affects the quality of life of patients. Five patients with adipose dystrophy syndrome who were treated at Peking Union Hospital were further studied in terms of clinical phenotype, molecular biology and genetics. It can help us to better understand the occurrence and development of the disease, and to find more effective methods of diagnosis and treatment. Methods the clinical data of 5 patients with adipose dystrophy were collected and analyzed from January 2015 to February 2017 in the Endocrinology Department of Peking Union Hospital, and the indexes of glucose and lipid metabolism, leptin and adiponectin levels were detected. Combined with DWI and quantitative computed tomography (QCT), the distribution of adipose tissue was analyzed, and the total exon sequencing was performed to detect mutation sites. The possible pathogenic genes were screened by data analysis and literature review. Results the clinical data and imaging results showed that there were differences in the clinical phenotypes of 5 patients, including the characteristics of fat distribution, fat atrophy in different degree and location, and selective fat accumulation in 4 of them. Obstinate insulin resistance and hyperlipidemia were found in all patients, and leptin and adiponectin levels were significantly decreased. The results of total exon sequencing and data analysis showed that L2 and L5 had strong pathogenicity mutation LMNA (p.R482W and p. R349WN, respectively), and both had weak pathogenicity mutation (PLIN1 / P194AN). The clinical phenotype of patient L 4 was consistent with type 1 of familial partial adipose dystrophy syndrome. Thiazolidinedione has an advantage over other oral hypoglycemic drugs in improving glucose metabolism disorders in most patients. Conclusion the clinical phenotypes and pathogenetic genes of congenital adipose dystrophy syndrome are very diverse and there are still unknown pathogenetic genes which may be the result of the interaction of multiple pathogenetic genes. The establishment of clinical phenotypic library and the improvement of clinical data are beneficial to the early diagnosis and treatment of diseases. Individualized treatment based on disease mechanism is helpful for disease control.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R589.2

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