Department of Biochemistry and Molecular Biology, Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Mol Genet Metab. 2011 Apr;102(4):407-12. doi: 10.1016/j.ymgme.2010.12.003. Epub 2010 Dec 13.
Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). Although newborn screening for PKU with early dietary treatment improved severe, irreversible brain damage, older patients suffer reversible losses in executive function when Phe concentrations are elevated. The maintenance of strict nutritional control in older children and adults remains difficult. An adjunct to dietary therapy, oral tetrahydrobiopterin (BH(4)) has recently been approved by the Food and Drug Administration as a stable, synthetic BH(4) called Kuvan™. Published studies of Kuvan response in PKU varies and involved primarily children. In this prospective study we evaluated dose-response, response frequency and factors predicting response in 21 patients with PKU (aged 8-30 years), who required life-long dietary treatment. Response to Kuvan was defined at 24h (acute) and over 4 weeks (chronic) as a ≥ 30% decline in the Phe or P/T ratio. A dose of 20mg/kg Kuvan was chosen with 29% responding in 24h and 33% of patients at 4 weeks. We then compared baseline Phe, Tyr, P/T, Phe intake, and frequency of "severe" versus "moderate" mutant PAH alleles among acute and chronic responders and non-responders to Kuvan. Predictors of response to Kuvan, both acute and chronic were baseline Phe and baseline P/T. Baseline Phe and P/T were higher among non-responders (P<0.05). By contrast baseline Tyr was similar (P=0.45). Phe intake tended to be higher (18 ± 20mg/kg/24h) among Kuvan responders than non-responders (15 ± 11 mg/kg/24h), P<0.07 NS. Similarly the frequency of "severe" mutant PAH alleles tended to be more frequent (67%) among non-responders than responders (40%) by Chi(2) test, P=0.08 NS. These results were reproducible in a "responder" to Kuvan. To assess directly the effect of elevated blood Phe, Phe was lowered in four, "non-responder" patients, but all failed to respond to Kuvan. We conclude that baseline blood Phe and P/T ratio can predict increased probability for response to Kuvan by patients with classic PKU, but the in vivo mechanisms of response to Kuvan remain enigmatic.
苯丙酮尿症（PKU）是由苯丙氨酸羟化酶基因（PAH）突变引起的，导致血液苯丙氨酸（Phe）升高，酪氨酸（Tyr）降低，Phe/Tyr 比值升高。尽管新生儿 PKU 的筛查和早期饮食治疗改善了严重的、不可逆的脑损伤，但当 Phe 浓度升高时，年龄较大的患者仍会出现执行功能的可逆性丧失。在年龄较大的儿童和成人中维持严格的营养控制仍然很困难。饮食治疗的辅助药物，口服四氢生物蝶呤（BH4）最近已被美国食品和药物管理局批准为一种稳定的合成 BH4，称为 Kuvan。已发表的 PKU 患者对 Kuvan 反应的研究结果各不相同，主要涉及儿童。在这项前瞻性研究中，我们评估了 21 例 PKU 患者（年龄 8-30 岁）的剂量反应、反应频率和预测反应的因素，这些患者需要终生饮食治疗。Kuvan 的反应定义为 24 小时（急性）和 4 周（慢性）时 Phe 或 P/T 比值下降≥30%。选择 20mg/kg Kuvan 剂量，24 小时内有 29%的患者有反应，4 周时有 33%的患者有反应。然后，我们比较了急性和慢性 Kuvan 反应者和无反应者之间的基线 Phe、Tyr、P/T、Phe 摄入量以及“严重”与“中度”突变 PAH 等位基因的频率。Kuvan 反应的预测因素，无论是急性还是慢性，都是基线 Phe 和基线 P/T。无反应者的基线 Phe 和 P/T 较高（P<0.05）。相比之下，基线 Tyr 相似（P=0.45）。Kuvan 反应者的 Phe 摄入量（18±20mg/kg/24h）高于无反应者（15±11mg/kg/24h），P<0.07 NS。同样，通过卡方检验，无反应者中“严重”突变 PAH 等位基因的频率（67%）也高于反应者（40%），P=0.08 NS。在一个 Kuvan 反应者中也得到了类似的结果。为了直接评估升高的血液 Phe 的影响，我们降低了 4 名“无反应者”患者的血液 Phe，但他们都未能对 Kuvan 产生反应。我们得出结论，经典 PKU 患者的基线血液 Phe 和 P/T 比值可以预测对 Kuvan 反应的可能性增加，但 Kuvan 反应的体内机制仍然很神秘。
