新生儿筛查诊断的223例高苯丙氨酸血症的诊治及随访

Diagnosis,treatment and long-term following up of 223 patients with hyperphenylalaninemia detected by neonatal screening programs

目的了解我国各种病因所致的高苯丙氨酸血症(HPA)的发生率,探讨新生儿早期诊治患者血苯丙氨酸(Phe)控制与智能发育关系。方法对新生儿筛查发现的223例 HPA 患儿,采用四氢生物蝶呤(BH_4)负荷试验、尿蝶呤谱分析、二氢蝶啶还原酶活性测定进行病因诊断,对治疗者进行生长和智能发育评价,相关基因突变分析。结果 223例中苯丙氨酸羟化酶缺乏症(PAHD)129例(57.8%),BH_4反应性 PAHD 64例(28.7%),6-丙酮酰四氢蝶呤合成酶缺乏症(PTSD)30例(13.5%)。149例接受随访(年龄4个月至22岁),其中136例生后1.6个月(0.5～3.5个月)根据病因接受相应治疗,13例不需治疗随访。136例治疗者中108例(79.4%)智能发育正常,对58例患者进行智商(IQ)与血 Phe 浓度相关分析显示两者成负相关(r=-0.439,P<0.01)。9例 PTSD 者携带9种 PTS 基因突变,286G→A及259C→T占45%,13例 BH_4反应性 PAHD 者携带7种 PAH 基因突变,R241C 多见(43.8%)。结论新生儿筛查发现的 HPA 需快速进行病因鉴别诊断,早期治疗者近80%智能发育正常,血 Phe 浓度控制是智能发育的重要因素。

Objective To investigate the incidence of hyperphenylalaninemia（HPA） caused by different etiologic factors in China and the relationship between the phenylalanine and mental development of patients with HPAs who were diagnosed by neonatal screening and early treated. Methods Two hundred and twenty-three patients with HPA detected by neonatal screening programs were refered to us at the age of （41 ±27） days after birth. The differential diagnosis was performed by BH4 （20 mg/kg） loading test, urinary pterin analysis and dihydropteridine reductase （DHPR） activity determination respectively. The control of phenylalanine （Phe） metabolism, growth and mental development were evaluated in all treated patients. Related gene mutation analysis was performed in some patients Results One hundred and twentynine of 223 patients （57.8%） were diagnosed as phenylalanine hydroxylase deficiency（ PAHD ）, 64 patients （28.7%） as BH4 responsive PAHD, 30 patients （13.5%） as 6-pyruvoyl tetrahydropterin synthase deficiency （PTSD）. One hundred and forty-nine patients were followed at age of 4 m-22 y in our clinic. The 136 of 149 patients were treated according to different etiology at the age of 1.6 m（0. 5-3.5 m） after birth. Thirteen patients were followed up without the need for treatment. All patients had normal growth development. One hundred and eight （79.4%） of 136 treated patients had normal mental development. The negative correlation（r = -0.439, P 〈 0.01 ） between IQ and average Phe levels were observed in 58 patients. Twenty-eight patients were able to go to primary school or even university. Nine kinds of PTS gene mutations were found in 9 cases with PTSD, among which 286G→A and 259C→T were most commonly seen, accounting for 45%. Seven kinds of PAH gene mutations were found in 13 cases with BH4 responsive PAHD with the R241C （43.8%） mutation being the most frequent one. Concluion The differential diagnosis should be quickly made in all HPA patients detected by neonatal screening. Near 80% patients early treated had normal mental development. The good control of blood Phe level is a key factor for mental development.