Research for accuracy in disease detection and medical intervention in newborn screening system using tandem mass spectrometry

为了在日本建立实用的新生儿串联质谱筛查系统，对新生儿串联质谱筛查试点研究的对象进行了调查。采用本项目目标疾病如多重酰基辅酶a脱氢缺陷（GA-II）、中链酰基辅酶a脱氢酶缺乏症（MCAD）、极长链酰基辅酶a脱氢酶缺乏症、多重羧化酶缺乏症患者的干血斑点进行初步临界值检测。丙基肉碱与乙酰肉碱的比值是筛选丙酸型和经典型甲基丙二酸尿的较好指标。通过与广岛大学和京都大学的研究人员合作进行的酶活性测定和DNA突变分析，对筛查中发现的患者的疾病严重程度进行了估计。对病人的治疗是根据这些类别的结果进行的，除了病情最严重的病人外，几乎所有病人的情况都很好。采用不生锈的N2干燥剂和更便宜的试剂对方法进行了改进，以提高样品质量和成本负担。我们分析了大约20万个干血点，发现了25个患者，这使我们能够估计日本目标疾病的频率。在日本，有机酸血症，如丙酸血症和戊二酸I型，相对常见，脂肪酸氧化障碍，如MCAD缺乏症和GA-II，并不像以前认为的那么罕见。建议日本的筛查制度，包括对患者的医疗保健，应该针对这些目标疾病进行修改。

The subjects in newborn screening pilot study using tandem mass spectrometry were investigated in order to establish the practical screening system in Japan.The tentative cutoff values were tested using the dried blood spots of the patients with target disorders in this project, such as multiple acyl-CoA dehydrogenation defect (GA-II), medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, very-long-chain aryl-CoA dehydrogenase deficiency, and multiple carboxylase deficiency. The ratios of propionylcarnitine to acetylcarnitine were shown to be better marker for the screening of propionic academia and calssical methylmalonic aciduria.The severity of the diseases in patients found in this screening were estimated by the measurement of enzyme activities and the analysis of DNA mutation, which were done in cooperation with the researchers in Hiroshima University and Kyoto University. Therapies for the patients were conducted based on the results in this categories, and almost all patients, except for those with the severest form of the disease, are in good condition.The methods were modified using rust-free N2 drier and less expensive reagent to improve the sample quality and cost burden.We have analyzed about 200,000 dried blood spots and found 25 patients, which enable us to estimate the frequency of target diseases in Japan. In Japan, organic acidemias, such as propionic acidemia and glutaric aciduia type I, are relatively common, and fatty acid oxidation disorders, such as MCAD defiency and GA-II, are not so rare as believed before. It is suggested that screening system in Japan, including medical care for the patients, should be modified for such target diseases.