Phenylalanine Hydroxylase Deficiency: Response to BH4

描述(申请人提供)：苯丙酮尿症(PKU)，因 苯丙氨酸羟化酶(PAH)缺乏症可通过限制饮食来治疗 苯丙氨酸(Phe)。限制Phe饮食治疗PKU已获成功 很难，而且往往不可能达到理想的血液Phe水平 很多病人。报告显示，学校表现不佳，智商下降，以及 当饮食放松时，大脑中的白质恶化。此外， 没有达成一致的随访标准以及血液Phe水平需要什么 在年龄较大的儿童和成年人中进行追踪。另一个复杂的因素是 怀有PKU的孕妇，其后代有神经缺陷的风险 和先天性心脏缺陷。最近，一些PAH缺乏症患者 已发现对大剂量四氢生物蝶呤(BH4)有反应。 四氢生物蝶呤是多环芳烃活性所必需的辅因子。的报道 对BH4反应的PAH缺乏提示PAH的Km突变，而 BH4代谢正常。对这些患者的PAH分析显示不同的 突变，这表明可能存在广泛的PAH突变 应该对BH4做出回应。这项初步研究旨在调查一个多年来 疗程两年，观察PKU患者对BH4负荷的反应。这个 将研究BH4的代谢，确定PAH的突变，以及 将通过现场监测血液Phe水平来研究对BH4的反应 存在时的定向突变、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，所以这样 目前还没有关于PAH大约400个突变的数据。取得的成功 这些研究将为许多患者的治疗带来新的研究 并对PAH的突变进行了系统的新研究，以便 确定哪些突变对BH4有反应。用BH4治疗应该会导致 对PKU患者和母体PKU有更好的结局。

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.