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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。
Purpose Tetrahydrobiopterin (BH4) normalizes the blood phenylalanine level in patients with BH4 deficiency but is not effective in patients with phenylketonuria (PKU). Recently, mild PKU patients responding to BH4 were found in neonatal PKU screening. This study investigates the role of BH4 and phenylalanine hydroxylase (PAH) mutations in patients with mild PKU and mild hyperpigmentalemia (HPA) who respond to BH4. Methods Single dose (10 mg / kg), four times, one week [20 mg / (kg · d)] of BH4 oral load were applied to mild HPA patients with normal biopterin metabolism found in neonatal PKU screening Trial and long-term BH4 treatment to assess their reactivity to the BH4 oral loading test. Results In a single-dose BH4 oral load test, there was no reduction in plasma phenylalanine levels in a typical PKU patient. Patients who had a blood phenylalanine level decrease of more than 20% in a single-dose BH4 oral load test also fell more than 20% in the four BH4 oral load trials. The 1 week BH4 stress test confirmed that BH4 responds to patients who showed weak reactivity in a single dose and 4 BH4 stress tests. Many patients with mild PKU and mild HPA with the R241C gene locus respond to BH4 treatment. No mutations in the R241C, P407S and A373T genes were found in typical PKU patients without BH4 reactivity. Conclusion One-week BH4 stress test is the most effective for the diagnosis of BH4-reactive PAH deficiency. Alleles R241C, P407S and A373T are associated with H4 reactivity in patients with mild HPA and mild PKU. BH4 treatment is a novel and effective drug treatment for mild HPA and mild PKU and is expected to replace the one that limits the phenylalanine diet.