Stanley C A, Hale D E, Coates P M, Hall C L, Corkey B E, Yang W, Kelley R I, Gonzales E L, Williamson J R, Baker L
Pediatr Res. 1983 Nov;17(11):877-84. doi: 10.1203/00006450-198311000-00008.
Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.
两个家庭中的三个孩子在幼儿期出现了与禁食相关的疾病发作，症状类似于瑞氏综合征：昏迷、低血糖、高氨血症和脂肪肝。其中一个孩子在一次发作期间死于脑水肿。临床研究表明，尽管游离脂肪酸水平升高（2.6 - 4.2毫摩尔/升），但禁食时无酮血症（血浆β-羟基丁酸酯低于0.4毫摩尔/升），这表明肝脏脂肪酸氧化受损。患病期间或禁食时尿二羧酸水平升高。血浆（18 - 25微摩尔/升）、肝脏（200 - 500纳摩尔/克）和肌肉（500 - 800纳摩尔/克）中的总肉碱水平较低；然而，用L-肉碱治疗未能纠正酮生成缺陷。体外对肝脏组织中脂肪酸底物酮生成的研究表明，短链脂肪酸的酮生成率正常，但所有中链和长链脂肪酸底物的酮生成率非常低。这些结果表明缺陷存在于线粒体内β-氧化途径的中间部分，在中链酰基辅酶A脱氢酶步骤。一种用于电子传递黄素蛋白连接的酰基辅酶A脱氢酶的新检测方法被用于检验这一假设。该检测方法通过电子传递黄素蛋白荧光的降低来跟踪其被酰基辅酶A-酰基辅酶A脱氢酶复合物还原的过程。以辛酰辅酶A为底物的结果表明，患者中链酰基辅酶A脱氢酶的活性低于正常活性的2.5%。短链和异戊酰辅酶A脱氢酶的活性正常；长链酰基辅酶A脱氢酶的活性为正常的三分之一。这些结果定义了一种先前未被认识的由于中链酰基辅酶A脱氢酶缺乏导致的脂肪酸氧化遗传性代谢紊乱。
