Anaplerotic therapy in Propionic Acidemia

丙酸血症的回补疗法

• 批准号: 7315111
• 负责人: NICOLA LONGO
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315111
• 关键词: Affect; Amino Acids; Ammonia; Birth; Cardiomyopathies; Caring; Carnitine; Child; Cholesterol; Chronic; Citrate; Citrates; Citric Acid; Citric Acid Cycle; Clinical; Clinical Trials; Defect; Development; Dietary Supplementation; Disease; Enzymes; Fatty Acids; Functional disorder; Generations; Glutamates; Glutamine; Grant; Hyperammonemia; Isoleucine; Lactic acid; Lead; Life; Medical; Metabolic; Metabolic Diseases; Metabolism; Methionine; Minor; Mitochondrial Diseases; Morbidity - disease rate; Muscle Tonus; Neonatal Screening; Non-Essential Amino Acid; Numbers; Organ; Ornithine; Outcome; Pancreatitis; Pathway interactions; Patients; Pilot Projects; Plasma; Production; Propionic Acids; Propionic acid; Pyruvate Carboxylase; Rare Diseases; Research; Research Personnel; Source; Testing; Threonine; Urine; Valine; acylcarnitine; base; concept; design; dietary supplements; fatty acid oxidation; improved; innovation; ketotic hyperglycinemia; medical complication; methylmalonic aciduria; methylmalonyl-CoA decarboxylase; mortality; organic acid; prevent; programs; succinyl-coenzyme A; tandem mass spectrometry

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.

描述（由申请方提供）：本项目的目的是确定能够补充柠檬酸循环的营养补充剂（贫血治疗）是否可以改善丙酸血症患者的高氨血症、谷氨酰胺水平和结局。 丙酸血症是一种罕见的隐性遗传疾病所造成的缺乏丙酰辅酶A羧化酶。 丙酰辅酶A羧化酶活性不足会损害琥珀酰辅酶A对柠檬酸循环的供应。 受影响的患者在出生时发生高氨血症，在代谢失代偿期间复发。 研究人员发现，丙酸血症患者血浆谷氨酰胺/谷氨酸水平降低，高氨血症患者血浆谷氨酰胺/谷氨酸水平降低而不是升高。 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，因此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，α-酮戊二酸产生缺陷所致。 三羧酸循环中间体的基本缺乏可减少ATP的产生，并解释丙酸血症患者的低肌张力、进行性器官功能障碍和不良结局。 为了验证这一假设，研究人员将确定饮食中补充α-酮戊二酸前体（以鸟氨酸α-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浆氨和总体结局。 目前丙酸血症的治疗是基于限制丙酸的前体（甲硫氨酸、缬氨酸、异亮氨酸、苏氨酸、奇数链脂肪酸、胆固醇）和给予肉毒碱以帮助去除有毒有机酸。 这种疗法不能有效预防疾病的长期并发症，即使是在出生时通过新生儿筛查确定的儿童中。 因此，这项研究将测试一种全新的方法来治疗患有严重和致残性代谢紊乱的患者，使用替代参与能量生成（ATP）的下游产品。 这种方法如果有效，可以扩展到许多其他疾病，包括其他有机酸中毒和线粒体疾病。