Clinical and molecular study on Japanese patients with mitochondrial β-oxidation disorders

日本线粒体β-氧化障碍患者的临床和分子研究

基本信息

批准号：
13470165
负责人：
YAMAGUCHI Seiji
金额：
$ 1.54万
依托单位：
Shimane University, Faculty of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470165/
关键词：
inborn errors of metabolism mitochondrial β-oxidation disorder mass spectrometry gene analysis VLCAD deficiency glutaric acidemia type 2 newborn mass screening 有機酸代謝異常症ミトコンドリアβ酸化異常症病因解析乳児突然死症候群ライ症候群

项目摘要

Patients with mitochondrial fatty acid β-oxidation disorders (FAODs) have often acute encephalopathy-or sudden infant death-like illness, although such patients in the stable condition do not any clinical symptoms. Recently, newborn mass screening for FAODs as well as organic and amino acid disorders using ESI/MS/MS has attracted attention worldwide. Hence, we studied on the incidence and natural clinical course of Japanese patients with FAODs, and enzymatic and molecular diagnosis. The results were as follows :1) Survey of Japanese patients with FAODs : We investigated Japanese 71 patients with FAODs during the period between 1985 and 2001. CPT2 deficiency was most common, followed by VLCAD deficiency and glutaric academia type 2 (GA2). Age at onset, and prognosis of FAODs were investigated, being compared with that of organic acidemias (OAs). The age at onset of FAODs tended to be later than OAs, and the incidence of neurological impairments was smaller than that of OAs, in particula … More r in later onset cases.2) Molecular studies of VLCAD deficiency : We have found 21 Japanese VLCAD deficiency patients. Of the 21 patients, 18 cases were the myopathic form, in contrast with that in the western countries VLCAD deficient patients with the severer forms were more common. There were several common mutations in the VLCAD gene from Japanese patients.3) Molecular studies of GA2 : We first found two patients with GA2 due to α-subunit of ETF protein, and characterized the pathophisiology at the molecular levels. We also newly identified 3 patients with GA2 due to defeciency of β-subunit of ETF.4) Development of biochemical diagnostic methods using GC/MS : We developed the diagnostic method by serum free fatty acid analysis using GC/MS, This method could be a useful tool to compliment the data from newborn mass screening for FAODs using ESI/MS/MS. Furthermore, we developed a single method by urinary organic acid analysis by GC/MS to precisely detect patients with peroxisomal β-oxidation disorders. Less

线粒体脂肪酸β-氧化障碍（FAOD）患者经常出现急性脑病或婴儿猝死样疾病，尽管此类患者在病情稳定时没有任何临床症状。最近，新生儿大规模筛查FAOD以及器质性和猝死。使用ESI/MS/MS 的氨基酸紊乱引起了全世界的关注，因此，我们对日本FAOD 患者的发病率和自然临床病程以及酶学和分子诊断进行了研究，结果如下：1）对日本FAOD 患者的调查。 1985年至2001年间，我们对日本71名FAOD患者进行了调查。CPT2缺乏症最为常见，其次是VLCAD缺乏症和戊二酸学术界2型（GA2）。我们对FAODs的发病年龄和预后进行了调查，并与这些患者进行了比较。有机酸血症 (OA) 的发病年龄往往晚于 OA，且神经系统疾病的发病年龄也较晚。 2) VLCAD 缺陷的分子研究：我们发现 21 名日本 VLCAD 缺陷患者中，18 例为肌病型，与 OA 相比，其损伤更小。在西方国家，严重形式的 VLCAD 缺陷患者更为常见。日本患者的 VLCAD 基因存在几种常见突变。3) GA2 的分子研究：我们首先。发现了两名由于 ETF 蛋白的 α 亚基导致的 GA2 患者，并在分子水平上表征了 GA2 患者。我们还新鉴定了 3 名由于 ETF 的 β 亚基缺陷而导致的 GA2 患者。4) 使用 GC 的生化诊断方法的开发。 /MS：我们开发了使用 GC/MS 进行血清游离脂肪酸分析的诊断方法，该方法可能是补充使用 ESI/MS/MS 进行新生儿FAOD 筛查的数据的有用工具。通过 GC/MS 分析尿液有机酸的单一方法可精确检测患有过氧化物酶体 β-氧化障碍的患者。