Anaplerotic therapy in Propionic Acidemia

描述（由申请人提供）：该项目的目的是确定能够填补柠檬酸循环的营养补充剂是否可以改善丙酸血症患者的高氨血症、谷氨酰胺水平和预后。丙酸血症是一种罕见的由丙酰辅酶a羧化酶缺乏引起的隐性疾病。丙酰辅酶a羧化酶活性不足损害了琥珀酰辅酶a对柠檬酸循环的供应。受影响的患者在出生时出现高氨血症，在代谢失代偿发作期间复发。研究人员发现丙酸血症患者血浆中谷氨酰胺/谷氨酸水平降低，高氨血症患者血浆中谷氨酰胺/谷氨酸水平降低而不是升高。由于a-酮戊二酸盐是内源性谷氨酸/谷氨酰胺合成的主要来源，他们的假设是丙酸血症患者的慢性高氨血症是由于柠檬酸（Krebs）循环功能不足导致a-酮戊二酸盐产生缺陷。克雷布斯循环中间体的基本缺乏可以减少ATP的产生，并解释了丙酸血症患者的低肌张力、进行性器官功能障碍和不良预后。

DESCRIPTION (provided by applicant): The objective of this project is to define whether nutritional supplements capable of filling-up the citric acid cycle (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients with propionic acidemia. Propionic acidemia is a rare recessive disorder caused by deficiency of propionyl CoA carboxylase. Deficient activity of propionyl CoA carboxylase impairs the supply of succinyl CoA to the citric acid cycle. Affected patients develop hyperammonemia at birth that recurs during episodes of metabolic decompensation. The investigators have found that plasma levels of glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather than increase, with hyperammonemia. Since a-ketoglutarate is the main source of endogenous glutamate/glutamine synthesis, their hypothesis is that chronic hyperammonemia in patients with propionic acidemia is due to a functional insufficiency of the citric acid (Krebs) cycle with defective production of a-ketoglutarate. The basic deficiency of intermediates of the Krebs cycle could decrease production of ATP and explain the low muscle tone, progressive organ dysfunction, and poor outcome of patients with propionic acidemia. To test this hypothesis, the investigators will determine whether dietary supplementation with a-ketoglutarate precursors (in the form of ornithine a-ketoglutarate, glutamine, or citrate) can improve plasma ammonia and overall outcome in patients with propionic acidemia. The current therapy of propionic acidemia is based on restriction of precursors of propionic acid (methionine, valine, isoleucine, threonine, odd chain fatty acids, cholesterol) and administration of carnitine to help remove toxic organic acids. This therapy is not effective in preventing the long-term complications of the disease, even in children identified at birth by newborn screening. Thus this research will test a completely new way of treating patients with severe and disabling metabolic disorders using replacement of downstream products involved in the generation of energy (ATP). This approach, if effective, could be extended to a number of other diseases, including other organic acidemias and mitochondrial disorders.