Study of metabolic screening, diagnosis, evaluation of treatment, and molecular analysis for organic and fatty acid disorders

1)建立了遗传性有机和脂肪酸代谢紊乱筛查的诊断支持系统：a)建立了羊水中有机酸代谢紊乱的精确产前诊断方法，该方法简单、快速；b)建立了β-氧化的酶学评价方法。通过对几例FAOD患者培养细胞的分析，证实了该方法的实用性。2)快速-GUS法：采用极窄的色谱柱，建立了快速GC/MS方法。3)培养的脂肪酸氧化紊乱(FAOD)成纤维细胞的细胞功能：VLCAD缺乏症(VLCADD)、MCAD缺乏症(MCADD)、CPU缺乏症和戊二酸2型(GA2)等FAOD患者的细胞在高温条件下培养，中链脂肪酸的氧化加速，而较长链脂肪酸的氧化受到抑制。提示FAOD患者在发热状态下有发生急性脑病的潜在风险。另一方面，降脂药物苯扎贝特改善了FAOD细胞的代谢状况。4)日本FAOD的分子基础：对10多例日本VLCADD和GA2患者进行了分子水平的分析。5)串联质谱仪对疾病病原学及新生儿筛查效果的研究：提示日本与亚洲其他国家的疾病比例不同。新生儿筛查发现的患者之间的结果比起病阶段后检测到的要好得多。

Metabolic screening, diagnosis, evaluation of clinical course, and molecular analysis on organic and fatty acid disorders were studied, and the following achievements were obtained.1) Development of the diagnostic support systems for new screening for inherited metabolic disorders of organic and fatty acids: a) A precise method of prenatal diagnosis for organic acid disorders was developed by analysis of amniotic fluid supernatant using two methods, GUMS and Tandem MS, which is very simple and fast; b) The method of enzymatic evaluation of beta-oxidation was developed. The utility of the method was confirmed with analysis of cultured cells from several patients with FAODs.2) Fast-GUMS method: Fast-GC/MS method, using extremely narrow column was developed. The analytical time was cut down to 1/4 of the conventional GUMS using capillary column.3) Cell function of cultured fibroblasts from fatty acid oxidation disorders (FAOD): Cells from FAODs patients such as VLCAD deficiency (VLCADD), MCAD deficiency (MCADD), CPU deficiency and glutaric acidemia type 2 (GA2) were cultured in the condition of high temperature, and it was revealed that oxidation of medium chain fatty acids was accelerated, while that of longer chain fatty acids was inhibited. It suggested that FAOD patients potentially have a risk of acute encephalopathy in the febrile condition. On the other hand, metabolic condition of FAOD cells was improved by Bezafibrate, a hypolipidemic drug.4) Molecular basis of Japanese FAODs: Over 10 Japanese patients with VLCADD and GA2 were analyzed at the molecular levels. Genotypes of these diseases were heterogeneous in Japanese.5) Study of etiology of diseases and effect of newborn screening using tandem MS: It was suggested that he proportion of diseases between Japanese and the other Asian counties was different. Outcomes between patients detected by newborn screening was much better than those detected after onset stage.