Anaplerotic therapy in Propionic Acidemia

描述(由申请人提供)：本项目的目标是确定能够填充柠檬酸循环的营养补充剂(回流疗法)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隐性遗传性疾病，由丙酰辅酶A羧基酶缺乏引起。丙酰辅酶A羧基酶活性不足会影响柠檬酸循环中琥珀酰辅酶A的供应。受影响的患者在出生时就会出现高氨血症，在代谢失代偿期间会复发。研究人员发现，丙酸血症患者的血浆谷氨酰胺/谷氨酸水平降低，而高氨血症患者的血浆谷氨酰胺/谷氨酸水平降低而不是增加。由于α-酮戊二酸是内源性谷氨酸/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)循环功能不全导致a-酮戊二酸产生缺陷。Krebs循环中间产物的基本缺乏可以减少ATP的产生，并解释了丙酸血症患者肌张力低下、进行性器官功能障碍和预后不良的原因。 为了验证这一假设，研究人员将确定饮食中补充a-酮戊二酸前体(以鸟氨酸a-酮戊二酸、谷氨酰胺或柠檬酸盐的形式)是否可以改善丙酸血症患者的血氨和总体预后。目前丙酸血症的治疗是基于限制丙酸前体(蛋氨酸、缬氨酸、异亮氨酸、苏氨酸、奇链脂肪酸、胆固醇)和给予肉碱以帮助清除有毒有机酸。这种疗法在预防疾病的长期并发症方面并不有效，即使是在出生时通过新生儿筛查确定的儿童也是如此。因此，这项研究将测试一种全新的方法来治疗严重和致残的代谢紊乱患者，使用与能量产生(ATP)有关的下游产品的替代。如果这种方法有效，可能会扩展到其他一些疾病，包括其他有机酸血症和线粒体疾病。

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.