Phenylalanine Hydroxylase Deficiency: Response to BH4

描述（由申请人提供）：苯丙酮尿症（PKU），由于 苯丙氨酸羟化酶（PAH）缺乏症，通过饮食限制治疗 苯丙氨酸（Phe）。 苯丙氨酸限制饮食治疗苯丙酮尿症已被 很难并且经常不可能达到血液Phe的期望水平， 很多病人。 报告显示，学校表现不佳，智商下降， 当饮食放松时，大脑中的白色物质恶化。 此外，委员会认为， 没有商定的后续标准和血液Phe水平需要 在年龄较大的儿童和成人中进行。 另一个复杂的因素是 妊娠PKU，这是在风险与神经功能缺损的后代 和先天性心脏病 最近，一些PAH缺乏症患者 已经发现对高剂量的四氢生物蝶呤（BH 4）有反应。 四氢生物蝶呤是PAH活性所需的辅因子。 的报告 PAH缺陷对BH4的反应提示PAH的Km突变，而 BH4代谢正常。 这些患者的PAH分析显示， 突变，这表明可能存在广泛的PAH突变， 应该对BH4有反应 这项试点研究旨在调查，在一个 为期两年，PKU患者及其对BH4负荷的反应。 的 将研究BH4的代谢，将确定PAH的突变， 将通过监测血液中苯丙氨酸水平，原位研究对BH4的反应 定向诱变、酶表达和酶动力学 不同水平的BH4。 PKU体外表达的早期研究 突变的目的不是为了识别对BH4有反应的突变，因此， 大约400种PAH突变的数据不可用。 成功 这些研究将为许多患者的治疗带来新的研究。 与PKU，并为PAH的突变，以系统的新的研究， 确定哪些突变对BH4有反应。 用BH4治疗应该会导致 PKU患者和母亲PKU的结局更好。

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.