四氢生物蝶呤负荷试验诊断四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床研究

目的探讨四氢生物蝶呤(BH4)反应性苯丙氨酸羟化酶(PAH)缺乏症的临床诊断方法,进一步了解其临床特征,为该型患儿应用BH4药物治疗提供科学依据。方法73例高苯丙氨酸血症(HPA)患儿,男47例,女26例,平均年龄1.93个月。所有患儿都进行口服BH4负荷试验,同时进行尿蝶呤谱分析、红细胞二氢蝶啶还原酶测定。对其中血苯丙氨酸(Phe)浓度<600μmol/L者给予口服Phe BH4联合负荷试验,对部分BH4反应性PAH缺乏症患儿,在普食条件下给予BH4片剂(10～20mg/kg)替代治疗6～7天,观察其疗效。结果(1)在BH4负荷试验中,不同类型HPA患儿的血Phe浓度表现出特征性的曲线改变,22例诊断为经典型苯丙酮尿症(PKU),39例中度PKU,12例四氢生物蝶呤缺乏症;(2)在中度PKU患儿中发现22例(56.4%)对BH4有反应;(3)6例BH4反应性PAH缺乏症患儿以BH410mg/kg治疗6～7天,其中4例血Phe浓度能控制到正常或接近正常治疗水平,另2例BH4需增加到20mg/kg使Phe浓度显著下降。结论在BH4负荷试验中,部分因苯丙氨酸羟化酶缺乏引起的中轻度PKU患儿对BH4有反应性,给予这些患儿BH4治疗可部分或全部替代低苯丙氨酸饮食治疗,拓宽了PKU的治疗方法,有助于提高患儿的生活质量。

Screening and diagnosis of tetrahydrobiopterin responsive phenylalanine hydroxylase deficiency with tetrahydrobiopterin loading test

OBJECTIVE: Tetrahydrobiopterin (BH(4)) responsive phenylalanine hydroxylase (PAH) deficiency is one of the forms of phenylketonuria (PKU). The aim of this study was to screen and diagnose BH(4) responsive PAH deficiency, to further understand its clinical characteristics, and to provide evidence for applying BH(4) drug therapy. METHODS: BH(4) 20 mg/kg loading test was performed in 73 patients with hyperphenylalaninemia (HPA) (47 males and 26 females), the mean age was 1.93 months. Combined phenylalanine (100 mg/kg) and BH(4) loading test was performed if patients had a basic blood phenylalanine concentration less than 600 micromol/L. The urine pterin profile analysis and the dihydropteridine reductase (DHPR) activity in dry blood filter spot were analyzed simultaneously. The patients with BH(4) responsive PAH deficiency were treated with BH(4) tablets (10 - 20 mg/kg x d) under normal diet for 6 to 7 days. Their blood phenylalanine concentration was checked. RESULTS: (1) The characteristic curve of phenylalanine level was observed in 73 patients after BH(4) loading test. Twenty-two patients were diagnosed as classic phenylketonuria (PKU), 39 were moderate PKU and 12 were BH(4) deficiency. (2) Twenty-two (56.4%) of 39 moderate PKU patients were found to be responsive to BH(4) and the blood phenylalanine was decreased by at least 30%. (3) Six patients with BH(4) responsive PAH deficiency were treated with BH(4) for 6 to 7 days, 4 patients had a normal phenylalanine concentration after 10 mg/kg BH(4) supplement, while other 2 patients needed a treatment of BH(4) at 20 mg/kg. CONCLUSION: Some patients with moderate PKU caused by phenylalanine hydroxylase deficiency were responsive to BH(4). Their blood phenylalanine significantly decreased after oral BH(4) loading. The BH(4) loading test is an effective diagnostic method to detect BH(4) sensitivity in PKU patients. BH(4) responsive PAH deficiency patient could be treated with BH(4) to replace low-phenylalanine diet treatment totally or partially, which may provide an optional treatment for the disease and improve the quality of life of the patients.