NEW AMINO ACID DISORDERS IN CEREBRAL DISEASE

脑部疾病中的新氨基酸紊乱

• 批准号: 2260157
• 负责人: VIVIAN E SHIH
• 金额: $ 46.25万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-09-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2260157
• 关键词: betaine compound; central nervous system disorders; child (0-11); cystathionine beta synthase; cysteine; diet therapy; family genetics; gene mutation; glutarates; homocysteine; homocystinuria; human pregnant subject; human subject; human therapy evaluation; hydro lyase; inborn aminoacid metabolism disorder; inborn urea cycle disorder; laboratory rat; maple syrup urine disease; medical complication; metabolism disorder chemotherapy; molecular pathology; nutrition related tag; ornithine carbamoyl phosphate deficiency; phenylketonurias; pregnancy; racial /ethnic difference; structural genes; tissue /cell culture

This proposal includes investigation of the molecular pathology of three inborn errors, characterization of "new" and rare metabolic disorders, evaluation of clinical effects of early treatment and therapeutic regimens in several relatively frequent metabolic disorders, monitoring the health of women with inborn errors during pregnancy and evaluation of the outcome of their offspring. 1) In fumarase deficiency, a disorder of the citric acid cycle associated with severe neurologic impairment, the structural gene for human fumarase will be characterized and the mutations in deficient patients analyzed. In homocystinuria (HCS) due to cystathionine beta-synthase deficiency, DNA mutations and genetic heterogeneity will be investigated in patients with both the B6 responsive and nonresponsive forms and in those from varied ethnic backgrounds. In ornithine transcarbamylase deficiency, molecular analysis will focus on patients with very atypical clinical presentations. 2) Two unknown sulfur-containing amino acids detected in the urine of two unrelated neurologically impaired patients are probably derivatives of methionine, homocyst(e)ine or cyst(e)ine. These metabolites will be identified using analytical and chromatographic techniques. 3) Large excretion of D-2-hydroxy-glutarate was detected in an infant who developed encephalopathy at age 3 months. The metabolism of this unusual organic acid in humans is virtually unknown. Extrapolation from experimental animal data suggests that a dehydrogenase for the family of D-2-hydroxy acids or specific for D-2-hydroxyglutarate exists in humans and may be defective in this patient. Our proposed studies will establish the activity of these enzymes in human tissue for the first time and characterize any defect in this disease. 4) The effectiveness of long-term betaine treatment in HCS patients will be evaluated particularly in the prevention of vascular disease, osteoporosis, and ocular lens dislocation. 5) Long-term outcome of early treatment in patients with urea cycle disorders and maple syrup urine disease will continue. Evaluation of offspring outcome in maternal PKU and other inborn errors in relation to severity of maternal disease and effects of treatment will be performed. In women with disorders characterized by episodic metabolic crisis, the stress of pregnancy on metabolic homeostasis will be monitored. The goals of this work are to understand the relationship between the biochemical, molecular, pathophysiologic and clinical aspects in these disorders so that effective therapies can be developed.

该提案包括对三种疾病的分子病理学的研究 先天性错误，“新的”和罕见的代谢紊乱的特征， 早期治疗和治疗的临床效果评估 几种相对常见的代谢紊乱的治疗方案，监测 先天性缺陷妇女孕期健康状况及评估 他们的后代的结果。 1) 延胡索酶缺乏症，一种疾病 与严重神经系统损伤相关的柠檬酸循环， 人类富马酸酶的结构基因将被表征，并且 分析了缺陷患者的突变。 由于同型半胱氨酸尿症 (HCS) 胱硫醚β-合酶缺乏、DNA 突变和遗传 将在同时患有 B6 的患者中研究异质性 反应性和非反应性形式以及来自不同种族的人 背景。 在鸟氨酸转氨甲酰酶缺乏症中，分子 分析将重点关注临床非常不典型的患者 演示文稿。 2) 中检测到两种未知的含硫氨基酸 两个不相关的神经系统受损患者的尿液可能是 甲硫氨酸、高半胱氨酸或半胱氨酸的衍生物。 这些 将使用分析和色谱法鉴定代谢物 技术。 3) 检测到D-2-羟基戊二酸的大量排泄 一名 3 个月大时患脑病的婴儿。 新陈代谢 这种不寻常的有机酸在人体中的含量几乎是未知的。 从实验动物数据推断表明，脱氢酶 适用于 D-2-羟基酸家族或特定于 D-2-羟基戊二酸 存在于人类中，并且该患者可能存在缺陷。 我们提出的 研究将确定这些酶在人体组织中的活性 第一次并描述该疾病的任何缺陷。 4) 的 长期甜菜碱治疗 HCS 患者的有效性 特别是在预防血管疾病方面进行了评估， 骨质疏松症和晶状体脱位。 5) 早期的长期结果 尿素循环障碍和枫糖浆尿患者的治疗 疾病将会继续。 母亲 PKU 后代结局评估 以及与孕产妇疾病严重程度相关的其他先天性缺陷和 将进行治疗的效果。 对于患有疾病的女性 以偶发性代谢危机为特征，怀孕的压力 将监测代谢稳态。 这项工作的目标是 了解生化、分子、 这些疾病的病理生理学和临床方面，以便 可以开发出有效的疗法。