四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床和基因检测

Clinical and gene detection of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

目的探讨四氢生物蝶呤反应性苯丙氨酸羟化酶(PAH)缺乏症这一新的临床变异型在高苯丙氨酸血症(HPA)中的发生率,并进一步了解其PAH基因突变类型。方法2001年1月至2004年12月,上海第二医科大学附属新华医院收治的106例中位年龄2个月(0.5～59个月)的HPA患儿纳入研究。所有患儿做辅酶的羟生物蝶呤(BH4,20mg/kg)或联合血苯丙氨酸(Phe,100mg/kg)负荷试验、尿蝶呤谱分析及红细胞二氢蝶啶还原酶活性(DHPR)测定。以口服BH4后24h内血Phe浓度下降30%以上且排除BH4缺乏症为诊断标准。对13例BH4反应性PAH缺乏症患儿进行PAH基因突变检测。结果106例HPA者中41例(38.7%)为BH4反应性的PAH缺乏症。血Phe浓度在服用BH4前为(816±431)μmol/L,服BH4后24h内降至(267±198)μmol/L,反应下降率(67±19)%。41例尿蝶呤及DHPR活性均正常。106例中轻度HPA(18例)其BH4反应性PAH缺乏症发生率为61.1%(11/18)。13例做PAH基因突变检测,R241C为最多见突变类型(43.8%)。结论61.1%轻度HPA(11/18)及42.4%(28/66)轻度PKU对BH4有较大反应性。BH4负荷试验是该病有效而简便的鉴别诊断方法。

Objective To get the incidence of tetrahydrobiopterin（ BH4 ） -responsive phenylalanine hydroxylase deficiency among HPAs,and to find the mutations of PAH in these patients. Methods From Jan. 2001 to Dec. 2004 a total of 106 patients with HPA （ aged 0. 5m - 4. 9y） were refered to this study. They were performed BH4 （20mg/kg） or combined with Phe（100mg/kg） loading test, urinary pterin analysis as well as dihydropteridine reductase （DHPR） activity determination in dried blood spot. Results Forty-one out of 106（ 38. 7% ） HPAs were considered as having BH4-responsive phenylalanine hydroxylase deficiency. Their Phe levels decreased from （ 816 - 431 ） μmol/L before taking BH4 to （267 - 198 ） μmol/L within 24h after BH41oading respectively, with a decrease rate of blood Phe levels of 67 - 19%. Urinary biopterin percentage and DHPR activity were all normal in 41 patients,so they were ruled out BH4 deficiency. The incidence of BH4-responsive PAH deficiency was 61.1% （ 11/18 ） in patients with mild HPA. Conclusion About 40% - 60% of patients with mild HPA and mild PKU have a response to BH4 in our group. The BH4 loading test is an effective and simple method of diagnosis for this kind of disease. The patients can be treated with single BH4 or combined with lowPhe diet.