Michals-Matalon Kimberlee, Bhatia Gita, Guttler Flemming, Tyring Stephen K, Matalon Reuben
Department of Health and Human Performance, University of Houston, Houston, TX 77204, USA.
J Nutr. 2007 Jun;137(6 Suppl 1):1564S-1567S; discussion 1573S-1575S. doi: 10.1093/jn/137.6.1564S.
A favorable response, indicated by decline of blood phenylalanine (Phe) in patients with phenylketonuria (PKU), to orally administered 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) has been reported in many countries following the first publication in 1999. In this review, we describe the experience in the United States with PKU patients and their response to BH4. A significant response to BH4 is arbitrarily considered as a decrease of 30% or greater of blood Phe concentration 24 h after administration of BH4. In our studies, 18 of 37 patients with PKU (49%) responded to oral BH4 by >30% decrease in blood Phe concentration. Four PKU patients responded with a decrease of blood Phe concentration between 17.3 and 26.3%. It is suggested that patients with sufficient response to BH4 are candidates who will benefit from BH4 as it becomes available for PKU management. In a separate trial, 20 patients with PKU were screened with ascending doses of BH4: 10, 20, and 40 mg/kg. A favorable response was found in 10 subjects (50%) after 10 mg/kg BH4 and 14 subjects (70%) after 20 mg/kg BH4. There was no additional advantage to 40 mg/kg BH4. A 1-wk trial with 10 and 20 mg/kg BH4 in the same 20 patients showed blood Phe concentrations lowest after 7 d of BH4. The BH4-responsive patients were genotyped and most were compound heterozygotes with 1 mild mutation on 1 allele, responsible for the increase of the residual activity of Phe hydroxylase when BH4 was added. Individuals with the same genotype exhibit different responses upon administration of BH4, attributed to epigenetic factors, such as the metabolic makeup of the individual. Patients with PKU, regardless of their genotype or classification, need to be screened for response to BH4. The majority of patients are identified by 10 mg/kg BH4.
自1999年首次发表相关报告以来，许多国家都报道了苯丙酮尿症（PKU）患者口服6 - R - L - 赤藓糖型 - 5,6,7,8 - 四氢生物蝶呤（BH4）后，血苯丙氨酸（Phe）水平下降，表明出现了良好反应。在本综述中，我们描述了美国PKU患者的情况以及他们对BH4的反应。对BH4的显著反应被任意定义为在给予BH4后24小时血Phe浓度下降30%或更多。在我们的研究中，37例PKU患者中有18例（49%）对口服BH4有反应，血Phe浓度下降超过30%。4例PKU患者血Phe浓度下降了17.3%至26.3%。提示对BH4反应充分的患者是有可能从BH4用于PKU治疗中获益的候选者。在另一项试验中，对20例PKU患者给予递增剂量的BH4进行筛查：10、20和40 mg/kg。10 mg/kg BH4后，10名受试者（50%）出现良好反应；20 mg/kg BH4后，14名受试者（70%）出现良好反应。40 mg/kg BH4没有额外优势。对同一20例患者进行的为期1周的10和20 mg/kg BH4试验显示，给予BH4 7天后血Phe浓度最低。对BH4有反应的患者进行了基因分型，大多数是复合杂合子，一个等位基因上有1个轻度突变，这是添加BH4后苯丙氨酸羟化酶残余活性增加的原因。具有相同基因型的个体在给予BH4后表现出不同反应，这归因于表观遗传因素，如个体的代谢构成。PKU患者，无论其基因型或分类如何，都需要进行BH反应筛查。大多数患者通过10 mg/kg BH4进行鉴定。
