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

线粒体脂肪酸β-氧化障碍（FAODs）患者常表现为急性脑病或婴儿猝死样疾病，但病情稳定时无任何临床症状。近年来，使用ESI/MS/MS对新生儿进行FAODs以及有机和氨基酸疾病的大规模筛查引起了全世界的关注。因此，我们研究了日本FAODs患者的发病率和自然临床过程，以及酶和分子诊断。结果如下：1）日本FAODs患者的调查：我们调查了1985年至2001年期间日本71例FAODs患者。CPT 2缺乏症最常见，其次是VLCAD缺乏症和谷氨酸2型（GA 2）。对FAODs的发病年龄、预后进行了调查，并与有机酸中毒（OAs）进行了比较。FAODs的发病年龄晚于OAs，神经功能损害的发生率低于OAs，特别是神经功能缺损的发生率高于OAs。 关于我们 2）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，而在西方国家VLCAD缺陷型患者中，以肌病型多见。日本人VLCAD基因存在几种常见的突变。3）GA 2的分子研究：首次发现2例由ETF蛋白α亚基引起的GA 2患者，并从分子水平对其病理生理学进行了表征。我们还新发现了3例由于ETF-A β亚基缺陷而导致的GA 2患者。4）使用GC/MS的生化诊断方法的开发：我们建立了一种用GC/MS分析血清游离脂肪酸的诊断方法，该方法可以作为一种有用的工具来补充用ESI/MS/MS进行新生儿FAODs筛查的数据。我们开发了一种通过GC/MS分析尿有机酸的单一方法，以精确检测过氧化物酶体β-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