Kuhara T, Ohse M, Inoue Y, Shinka T
Division of Human Genetics, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
J Mass Spectrom. 2009 Feb;44(2):214-21. doi: 10.1002/jms.1500.
The clinical presentation of inborn errors of pyrimidine degradation varies considerably from asymptomatic to severe neurological illness. We have reported a method to screen for and make a chemical diagnosis of beta-ureidopropionase deficiency, leading to the discovery of the first asymptomatic case of this disease. In this method, the recovery of beta-ureidopropionate and beta-ureidoisobutyrate, the key biomarkers, was very high,and the adoption of GC/MS and targeted analysis enabled us to simultaneously obtain information related and unrelated to pyrimidine metabolism. The present study reports the results of a large-scale screening of 24,000 newborns using dried urine on filter paper. Identification of a total of four asymptomatic patients among newborns suggests the high incidence (1/6000) of this disease in Japan. While these newborns were asymptomatic, two additional cases detected at the age of 5 years as well as 3 months with this method for high-risk screening had autism and West syndrome, respectively.The key biomarkers and alpha-ureidobutyrate used as an internal standard were found to give not only their di-trimethylsilyl derivatives but also tri-trimethylsilyl derivatives, upon derivatization. The mass spectra and retention times of their tri-trimethylsilyl derivatives and data handling for quantification of the markers are presented.Identification of individuals with defects in pyrimidine metabolism would realize personalized medication in cancer chemotherapy with pyrimidine analogs such as 5-fluorouracil.
嘧啶降解先天性缺陷的临床表现差异很大，从无症状到严重的神经系统疾病都有。我们报道了一种筛查和对β-脲基丙酸酶缺乏症进行化学诊断的方法，从而发现了该疾病的首例无症状病例。在该方法中，关键生物标志物β-脲基丙酸酯和β-脲基异丁酸酯的回收率非常高，采用气相色谱/质谱联用仪（GC/MS）和靶向分析使我们能够同时获取与嘧啶代谢相关和不相关的信息。本研究报告了使用滤纸上的干尿样对24000名新生儿进行大规模筛查的结果。在新生儿中总共鉴定出4例无症状患者，这表明该疾病在日本的发病率很高（1/6000）。虽然这些新生儿无症状，但通过这种高危筛查方法在5岁和3个月时分别检测出的另外两例病例分别患有自闭症和韦斯特综合征。发现用作内标的关键生物标志物和α-脲基丁酸酯在衍生化后不仅会生成其二-三甲基硅烷基衍生物，还会生成三-三甲基硅烷基衍生物。给出了它们的三-三甲基硅烷基衍生物的质谱图、保留时间以及用于标志物定量的数据处理。鉴定嘧啶代谢缺陷的个体将实现使用5-氟尿嘧啶等嘧啶类似物进行癌症化疗时的个性化用药。
