Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2
Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2
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DOI：
10.1016/j.ymgme.2008.01.002
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发表时间：
2008-05-01
影响因子：
3.8
通讯作者：
Yamaguchi, Seiji
中科院分区：
文献类型：
--
作者：
Yotsumoto, Yuka;Hasegawa, Yuki;Yamaguchi, Seiji
戊二酸血症2型(GA2)是一种常染色体隐性遗传病，由电子转移黄素蛋白(ETF)或ETF脱氢酶(ETFDH)缺乏引起，表现为从最严重的新生儿到晚发型。然而，导致这种疾病和临床严重程度的基因缺陷并没有得到很好的描述。为了了解表型与遗传缺陷之间的关系，我们调查了15例日本患者的临床和分子特征，其中包括4例先前报道的病例。3例为新生儿型，8例为晚发型，其中1例表现为极其轻微的表型。免疫印迹分析显示，所有患者的ETFα、ETFβ或ETFDH显著减少或消失。然而，没有特定的酶缺乏症占主导地位，并且与临床严重程度无关。遗传分析发现ETFA、ETFB和ETFDH基因有15个突变，包括无义突变、错义突变、剪接位点突变和小缺失。虽然几乎所有的突变都是日本患者独有的，也没有发现常见的突变，但其中一些似乎与特定的表型有关。我们的结果表明，日本GA2患者的临床和突变谱是不同的，基因诊断可能有助于预测预后，并为患有GA2的患者和家庭提供更准确的诊断信息。(C)2008 Elsevier Inc.保留所有权利。
Glutaric acidemia type 2 (GA2) is an autosomal recessive disorder resulting from a deficiency of electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) that manifests from most severe neonatal to late-onset forms. However, the genetic defect responsible for the disease and clinical severity is not well-characterized. In order to understand the relationship between the phenotype and genetic defect, we investigated the clinical and molecular features of 15 Japanese patients, including 4 previously reported cases. Three patients had the neonatal form and 8 patients had the late-onset form, I of whom presented an extremely mild phenotype. Immunoblot analysis showed that either ETF alpha, ETF beta, or ETFDH was significantly reduced or absent in all patients. However, no specific enzyme deficiency predominated, and there were no associations with the clinical severity. Genetic analyses identified 15 mutations including non-sense, missense, splice site mutations, and small deletions, in ETFA, ETFB and ETFDH genes. Although almost all mutations were unique to Japanese patients and no common mutations were found, some of them appeared to be associated with a specific phenotype. Our results suggest that clinical and mutational spectrums of Japanese GA2 patients are heterogeneous and that genetic diagnoses may help to predict a prognosis and provide more accurate diagnostic information for patients and families with GA2. (c) 2008 Elsevier Inc. All rights reserved.