Phenylalanine Hydroxylase Deficiency: Response to BH4

苯丙氨酸羟化酶缺乏症：对 BH4 的反应

• 批准号: 6362083
• 负责人: REUBEN MATALON
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362083
• 关键词: blood tests; enzyme deficiency; gene expression; gene mutation; genetic screening; genotype; human subject; human therapy evaluation; inborn aminoacid metabolism disorder; medical outreach /case finding; metabolism; metabolism disorder chemotherapy; patient oriented research; phenotype; phenylalanine 4 monooxygenase; phenylketonurias; pteridines; site directed mutagenesis; tetrahydrobiopterin; urinalysis

DESCRIPTION (provided by applicant): Phenylketonuria (PKU), due to phenylalanine hydroxylase (PAH) deficiency, is treated by dietary restriction of phenylalanine (Phe). Treatment of PKU with Phe-restricted diet has been difficult and often not possible to achieve the desired level of blood Phe for many patients. Reports indicate poor school performance, loss of IQ, and white matter deterioration in the brain when diet is relaxed. Furthermore, there is no agreed upon criteria for follow up and what blood Phe levels need to be pursued in older children and adults. Another complicating factor is pregnancy with PKU, which is at risk for offspring with neurological deficits and congenital heart defects. Recently, some patients with PAH deficiency have been found to respond to high doses of tetrahydrobiopterin (BH4). Tetrahydrobiopterin is a cofactor required for PAH activity. The reports of PAH deficiency responding to BH4 suggest Km mutations of PAH while the metabolism of BH4 is normal. Analysis of PAH in these patients showed various mutations, suggesting that there may be a wide range of PAH mutations that should respond to BH4. This pilot study is intended to investigate, over a period of two years, patients with PKU and their response to BH4 loading. The metabolism of BH4 will be studied, mutations of PAH will be determined, and the response to BH4 will be studied by monitoring blood Phe levels, in situ directed mutagenesis, enzyme expression, and enzyme kinetics in the presence of varying levels of BH4. Earlier studies of in vitro expression of PKU mutations were not aimed to identify mutations that respond to BH4, so such data are not available on approximately 400 mutations of PAH. Success of these studies will lead to new research on the treatment for many patients with PKU, and for a systematic new study of the mutations of PAH in order to identify which mutations respond to BH4. Treatment with BH4 should lead to a better outcome for PKU patients and for maternal PKU.

描述（由申请人提供）：由于 苯丙氨酸羟化酶（PAH）缺乏，受饮食限制治疗 苯丙氨酸（PHE）。 用PHE限制饮食对PKU进行治疗 困难，通常无法达到所需的血液PHE水平 许多患者。 报告表明学校表现不佳，智商丧失和 饮食放松时，大脑中的白质恶化。 此外， 没有同意跟进的标准，以及需要哪些血液级别的水平 要在大儿童和成人中追求。 另一个复杂因素是 PKU怀孕，有神经功能缺陷的后代风险 和先天性心脏缺陷。 最近，一些PAH缺乏症患者 已经发现对高剂量的四氢无生蛋白（BH4）有反应。 四氢无生蛋白是PAH活性所需的辅助因子。 报告 对BH4响应的PAH缺乏表明PAH的KM突变 BH4的代谢是正常的。 这些患者中PAH的分析显示了不同的 突变，表明可能存在广泛的PAH突变 应该回应BH4。 这项试验研究旨在调查 两年的时间为两年，患有PKU的患者及其对BH4加载的反应。 这 将研究BH4的代谢，确定PAH的突变，并 对BH4的反应将通过监测血液水平进行研究，原位 在存在下定向诱变，酶表达和酶动力学 不同水平的BH4。 早期研究PKU的体外表达 突变不是旨在识别响应BH4的突变，因此 大约400个PAH突变不可用数据。 成功 这些研究将为许多患者提供有关治疗的新研究 使用PKU，以及对PAH突变的系统新研究，以便为了 确定哪些突变对BH4响应。 用BH4治疗应导致 PKU患者和母体PKU的结果更好。