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

患有线粒体脂肪酸β氧化障碍（FAODs）的患者通常患有急性脑病或婴儿猝死样疾病，尽管这些患者在病情稳定时没有任何临床症状。近年来，利用ESI/MS/MS筛查新生儿FAODs以及有机和氨基酸紊乱的研究受到了世界各国的关注。因此，我们研究了日本FAODs患者的发病率和自然临床病程，以及酶和分子诊断。结果如下：1)日本FAODs患者调查：我们调查了1985 ~ 2001年日本FAODs患者71例。CPT2缺乏症最为常见，其次是VLCAD缺乏症和2型戊二酸（GA2）。研究了FAODs的发病年龄和预后，并与有机酸血症（OAs）进行了比较。FAODs发病年龄倾向于晚于OAs，且神经功能损害发生率小于OAs，特别是发病较晚的病例。2) VLCAD缺乏症的分子研究：我们发现21例日本VLCAD缺乏症患者。21例患者中有18例为肌病型，与西方国家相比，VLCAD缺陷患者以较严重的形式更为常见。日本患者的VLCAD基因有几种常见的突变。3) GA2的分子研究：我们首次发现了2例由ETF蛋白α-亚基引起的GA2患者，并在分子水平上对其病理病理进行了表征。4)气相色谱/质谱（GC/MS）生化诊断方法的建立：建立了气相色谱/质谱（GC/MS）分析血清游离脂肪酸的诊断方法，该方法可作为补充ESI/MS/MS筛查新生儿FAODs的有效工具。此外，我们建立了一种单一的尿有机酸GC/MS分析方法，用于精确检测β-过氧化物酶体氧化障碍患者。少

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