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Clinical and genetic analysis on neurodegenerative disorders

神经退行性疾病的临床和遗传学分析

基本信息

批准号：
21591066
负责人：
YABE Ichiro
金额：
$ 2.83万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

The aim of this study was to determine if muscle energy metabolism, as measured by 31P-magnetic resonance spectroscopy (MRS), is a metabolic marker for the efficacy of treatment of Machado-Joseph disease (MJD). The data showed that there was a significant difference between the groups in terms of the PCr/(Pi + PCr) ratio at rest (p=0.03) and the maximum rate of mitochondrial ATP production (Vmax) (p < 0.01). In addition, Vmax was inversely correlated with the scale for the assessment and rating of ataxia (SARA) score (r=-0.34, p=0.04). The MJD group also showed a reduction in Vmax over the course of two years (p<0.05). These data suggest that non-invasive measurement of muscle energy metabolism may represent a surrogate marker for MJD.In addition, in order to define the molecular basis of progressive external ophthalmoplegia and parkinsonism, we screened for mutations in PEO1, ANT1, POLG genes and the whole mitochondrial genome in two families. In results, we identified a compound heterozygous POLG substitutions in one of the families. In the other family, no mutations were detected in any of the three genes and the whole mitochondrial genome in the blood sample, although mitochondrial DNA deletions were observed in the muscle biopsy sample. Progressive external ophthalmoplegia and parkinsonism are genetically heterogenous disorders, and part of this syndrome may be caused by mutations in other, unknown genes.

本研究的目的是确定用31P-磁共振波谱(MRS)测量的肌肉能量代谢是否可以作为马查多-约瑟夫病(MJD)治疗效果的代谢标志。结果显示，静息状态下，线粒体DNA的最大生成速率(Vmax)与静息状态下的PCR值/(PI+PCR值)比值有显著差异(P=0.03)。此外，Vmax与共济失调评定量表(SARA)评分呈负相关(r=-0.34，p=0.04)。在两年的时间里，MJD组的Vmax也有所下降(p&lt；0.05)。这些数据表明，肌肉能量代谢的非侵入性测量可能是MJD的替代标记。此外，为了确定进行性外眼肌麻痹和帕金森病的分子基础，我们对两个家系的PEO1、ANT1、Polg基因和整个线粒体基因组进行了突变筛查。在结果中，我们在其中一个家族中发现了一种复合杂合Polg替代。在另一个家族中，尽管在肌肉活检样本中观察到线粒体DNA缺失，但在血液样本中三个基因和整个线粒体基因组中的任何一个都没有检测到突变。进行性眼外肌麻痹和帕金森综合症是遗传上的异质性疾病，这种综合征的一部分可能是由其他未知基因的突变引起的。