Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases.
Ethylmalonic-adipic aciduria. In vivo and in vitro studies indicating deficiency of activities of multiple acyl-CoA dehydrogenases.
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乙基丙二酸尿。
DOI：
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发表时间：
1979
影响因子：
15.9
通讯作者：
K. Tanaka
中科院分区：
文献类型：
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作者：
S. Mantagos;M. Genel;K. Tanaka
本文报告一例5岁女童发生乙基丙二酸-己二酸尿症的机制。先证者和无症状的家庭成员培养的皮肤成纤维细胞的放射性底物的氧化也进行了测定，并与正常成纤维细胞和谷氨酸尿症II型患者的细胞进行了比较。喂食中链甘油三酯迅速诱导呕吐和嗜睡，伴随着尿乙基丙二酸盐的显著增加。血清异戊酸和尿异戊酰甘氨酸显着增加后，观察亮氨酸喂养，但尿戊二酸仅略有增加后，赖氨酸喂养。因此，临床研究的结果对于我们患者中脂肪酸氧化以外的途径是否被阻断仍然不明确。先证者培养的皮肤成纤维细胞对[1-（14）C]丁酸的氧化作用降低至对照组的14%。[2-（14）C]赖氨酸和[2-（14）C]亮氨酸的体外氧化也分别降低至对照的28%和23%。在谷氨酸尿症II型细胞中观察到这三种底物的氧化（分别为3%、9%和9%）严重得多。这些结果表明，在先证者中，脂肪酸、赖氨酸和亮氨酸的降解途径分别在丁酰辅酶A、戊二酰辅酶A和异戊酰辅酶A脱氢酶的步骤中被阻断，如II型谷氨酸尿症的情况。由于多种酰基辅酶A脱氢酶的活性降低，作为这些脱氢酶的氢受体的电子转移黄素蛋白的缺乏被假定为这两种疾病的潜在机制，但是这两种类型的细胞中残留活性的显著差异表明了遗传异质性。对该家族无症状成员细胞的研究也提出了常染色体隐性基因有一个以上突变等位基因的假设。
The mechanisms underlying ethylmalonic-adipic aciduria were studied in a 5-yr-old girl. Oxidation of radioactive substrates by cultured skin fibroblasts from the proband and asymptomatic family members was also determined and compared to that by normal fibroblasts and that by cells from a patient with glutaric aciduria type II. Feeding medium-chain triglycerides promptly induced vomiting and lethargy accompanied by a pronounced increase of urinary ethylmalonate. Significant increases of serum isovalerate and urinary isovalerylglycine were observed after leucine feeding, but urinary glutarate increased only slightly after lysine feeding. Thus, the results from clinical investigation remained equivocal as to whether pathways other than fatty acid oxidation were blocked in our patient. Oxidation of [1-(14)C]butyrate by cultured skin fibroblasts from the proband was reduced to 14% of control. In vitro oxidation of [2-(14)C]lysine and [2-(14)C]leucine was also reduced to 28 and 23% of control, respectively. Much more severe reduction in oxidation of these three substrates (3, 9, and 9%, respectively) was observed in glutaric aciduria type II cells. These results indicated that in the proband, degradative pathways of fatty acids, lysine, and leucine are blocked at the steps of butyryl-CoA, glutaryl-CoA, and isovaleryl-CoA dehydrogenases, respectively, as in the case of glutaric aciduria type II. Because activities of multiple acyl-CoA dehydrogenases are reduced, a deficiency of electron-transferring flavoprotein, which serves as a hydrogen-acceptor for these dehydrogenases, is postulated as the underlying mechanisms of these two diseases, but a genetic heterogeneity was indicated by significant differences in the residual activities in these two types of cells. The hypothesis of more than one mutant allele of an autosomal recessive gene was also suggested by the study on cells from asymptomatic members of the family.