四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

目的四氢生物蝶呤(BH4)可以使BH4缺乏症病人的血液苯丙氨酸水平正常化,但是对苯丙酮酸尿症(PKU)病人无效。最近在新生儿PKU筛查中发现了对BH4有反应的轻度PKU患者。本研究将探讨BH4和苯丙氨酸羟化酶(PAH)基因突变在对BH4有反应的轻度PKU和轻度高苯丙酸血症(HPA)患者中的作用。方法对经新生儿PKU筛查中发现的生物蝶呤代谢正常的轻度HPA患者,进行单次(10mg/kg)、4次、1周[20 mg/(kg·d)]的BH4口服负荷试验及长期BH4治疗,评估其对BH4口服负荷试验的反应性。结果在单剂量BH4口服负荷试验中,典型PKU患者的血苯丙氨酸水平没有降低。在单剂量BH4口服负荷试验中血苯丙氨酸水平下降超过20%的患者,在4次BH4口服负荷试验中下降亦超过20%。1周BH4负荷试验确认在单剂量和4次BH4负荷试验中表现出弱反应性的病人对BH4有反应。许多患轻度PKU和轻度HPA且有R241C基因位点的病人,都对BH4治疗有反应。在无BH4反应性的典型PKU病人中未发现R241C、P407S和A373T基因突变。结论1周BH4负荷试验用于诊断BH4反应性PAH缺乏症最为有效。等位基因R241C、P407S和A373T与轻度HPA和轻度PKU病人具有H4反应性有关。BH4治疗是针对轻度HPA和轻度PKU的一种新颖、有效的药物治疗,有望代替限制苯丙氨酸饮食的方法。

Objective Tetrahydrobiopterin （BH4） is known to normalize blood phenylalanine levels in BH4 deficiency, but not in phenylketonuria （PKU）. Recently the patients with mild PKU who were responsive to BH4 were found in neonatal screening for PKU. This study aimed to investigate the effect of BH4 and phenylalanine hydroxylase （PAH） gene mutations in patients with BH4 responsive mild PKU and mild hyperphenylalaninemia （HPA）. Methods The responsiveness of the BH4 loading test was evaluated in HPA patients detected by neonatal PKU screening. All patients were normal in biopterin metabolism and were diagnosed as HPA with PAH gene mutations. A single-（ 10 mg/kg） , and four-time-, one-week-BH4 [20 mg/（kg·day）] loading test and a long-term BH4 treatment were performed for them. Results In a single BH4 loading test, no classic PKU patients demonstrated decreases in serum phenylalanine levels. The patients with a decrease greater than 20% in serum phenylalanine levels in the single-BH4-loading test showed a similar decrease in the four-dose-BH4 loading test. The one-week-BH4 administration test clarified the BH4 effect not only in responsive patients, but also in patients who showed low responsiveness in single- or four-dose-BH4 loading test. The majority of patients with mild HPA and mild PKU who had the R241C allele responded to BH4 administration. R241C, P407S and A373T mutation were never found in classic PKU patients without BH4 responsiveness. Conclusions The one- week-BH4 administration test is the most effective for the diagnosis of the BH4 responsive PAH deficiency. R241C, P407S and A373T alleles represented the causes of mild HPA or mild PKU in patients with BH4 responsiveness. BH4 treatment is a new and effective pharmacotherapy which replaces the phenylalanine restricted diet for mild HPA and mild PKU patients.