DeVivo D C, Haymond M W, Leckie M P, Bussman Y L, McDougal D B, Pagliara A S
J Clin Endocrinol Metab. 1977 Dec;45(6):1281-96. doi: 10.1210/jcem-45-6-1281.
A 10 month old female infant was evaluated for severe lactic acidosis. Clinically she was well nourished and had a substantial amount of adipose tissue despite recurrent episodes of acidosis. Her psychomotor development was retarded, her movements were dystonic and generalized seizures punctuated her course. Metabolic abnormalities included elevated blood concentrations of lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, alanine, proline and glycine, decreased blood concentrations of glutamine, aspartate, valine and citrate, and intermittent elevations of serum cholesterol. A trial on a high-fat diet worsened the clinical condition and intensified the ketoacidosis and hyperalaninemia. Analysis of hepatic tissue obtained by open biopsy revealed increased concentrations of lactate, alanine, acetyl-CoA and other short-chain acyl-CoA esters, and decreased concentrations of oxaloacetate, citrate, alpha-ketoglutarate, malate and aspartate. The blood and tissue metabolic perturbations reflected a deficiency of hepatic pyruvate carboxylase. The apparent Km of hepatic citrate synthase for oxaloacetate was 4.6 micrometer. Calculated tissue oxaloacetate concentrations were 0.50--0.84 micrometer suggesting that tricarboxylic acid cycle activity was severely limited by the decreased availability of this substrate. An iv glucose tolerance test resulted in the paradoxical synthesis of ketone bodies. This observation, coupled with the intermittent hypercholesterolemia and the increased tissue acetyl-CoA concentrations, suggests that pyruvate carboxylase is important in modulating the fractional distribution of intracellular acetyl-CoA between the tricarboxylic acid cycle, the beta-hydroxy-beta-methyl-glutaryl-CoA cycle (and the synthesis of cholesterol and ketone bodies), and fatty acid synthesis. Treatment in future cases might be directed toward increasing tissue concentrations of oxaloacetate.
一名10个月大的女婴因严重乳酸酸中毒接受评估。临床上，她营养良好，尽管反复出现酸中毒，但仍有大量脂肪组织。她的精神运动发育迟缓，动作呈张力障碍性，病程中伴有全身性癫痫发作。代谢异常包括血液中乳酸、丙酮酸、β-羟丁酸、乙酰乙酸、丙氨酸、脯氨酸和甘氨酸浓度升高，血液中谷氨酰胺、天冬氨酸、缬氨酸和柠檬酸浓度降低，以及血清胆固醇间歇性升高。高脂饮食试验使临床状况恶化，酮症酸中毒和高丙氨酸血症加剧。通过开放性活检获得的肝组织分析显示，乳酸、丙氨酸、乙酰辅酶A和其他短链酰基辅酶A酯浓度升高，草酰乙酸、柠檬酸、α-酮戊二酸、苹果酸和天冬氨酸浓度降低。血液和组织代谢紊乱反映了肝丙酮酸羧化酶的缺乏。肝柠檬酸合酶对草酰乙酸的表观Km为4.6微米。计算得出的组织草酰乙酸浓度为0.50--0.84微米，这表明三羧酸循环活性因该底物可用性降低而受到严重限制。静脉葡萄糖耐量试验导致酮体反常合成。这一观察结果，加上间歇性高胆固醇血症和组织乙酰辅酶A浓度升高，表明丙酮酸羧化酶在调节细胞内乙酰辅酶A在三羧酸循环、β-羟-β-甲基戊二酰辅酶A循环（以及胆固醇和酮体的合成）和脂肪酸合成之间的分数分布中起重要作用。未来病例的治疗可能旨在提高组织草酰乙酸浓度。
