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

线粒体脂肪酸β氧化紊乱(FAOD)患者通常有急性脑病或婴儿猝死样疾病，尽管这类患者病情稳定，没有任何临床症状。最近，利用ESI/MS/MS对新生儿FAOD以及有机和氨基酸疾病进行大规模筛查引起了全世界的关注。因此，我们对日本FAOD患者的发病率、自然病程、酶学和分子诊断进行了研究。结果如下：1)日本FAOD患者调查：我们调查了1985-2001年间日本的71例FAOD患者。CPT2缺乏症最常见，其次是VLCAD缺乏症和戊二醛缺乏症(GA2)。观察FAOD的发病年龄、预后，并与有机酸血症(OAS)进行比较。FAOD的发病年龄往往晚于OAS，神经功能损害的发生率低于OAS，尤其是…VLCAD缺乏症的分子研究：我们发现了21例日本VLCAD缺乏症患者。在21例患者中，18例为肌病型，与西方国家相比，VLCAD缺陷患者更常见的是严重的形式。3)GA_2的分子研究：我们首次发现了两例因ETF蛋白α亚基引起的GA_2患者，并从分子水平上描述了其发病机制。4)GC/MS生化诊断方法的建立：我们利用GC/MS建立了血清游离脂肪酸的GC/MS诊断方法，该方法可以补充利用电喷雾串联质谱仪进行新生儿FAOD大规模筛查的数据。此外，我们还建立了一种通过GC/MS分析尿有机酸来准确检测过氧化β氧化障碍的单一方法。较少

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