南京地区新生儿高苯丙氨酸血症筛查27年回顾

Neonatal hyperphenylalaninemia screening from 1985 to 2012 in Nanjing： a retrospective analysis of 27 years

目的了解南京地区新生儿高苯丙氨酸血症的发生率、分型、治疗及预后。方法本研究为回顾性研究。选择1985年9月1日至2012年9月1日共27年在南京地区出生的新生儿，在新生儿出生72h已充分哺乳后采集足跟血，于新生儿出生后20d内由南京市新生儿疾病筛查中心采用荧光定量法测定血苯丙氨酸浓度。对确诊高苯丙氨酸血症的81例患儿进行四氢生物蝶呤负荷试验、尿蝶呤谱分析和红细胞二氢蝶啶还原酶活性测定以鉴别诊断。治疗随访期间定期监测血苯丙氨酸浓度与智能发育水平，并进行苯丙氨酸羟化酶基因突变分析。采用方差分析、LSD法和Pearson相关性分析等统计学方法研究血苯丙氨酸浓度与智能发育的关系。结果（1）南京地区新生儿高苯丙氨酸血症的发生率为1／8800（81／712818），确诊的81例高苯丙氨酸血症患儿中苯丙氨酸羟化酶缺乏症78例（96．3％），其中经典型苯丙酮尿症37例，轻度苯丙酮尿症23例，轻度高苯丙氨酸症18例；四氢生物蝶呤缺乏症3例（3．7％），均为6-丙酮酰四氢蝶呤合成酶缺乏症。（2）81例高苯丙氨酸血症患儿中8例放弃治疗，其中2例死亡，6例患儿均存在不同程度的智能发育落后，1例合并癫痫；6例治疗过程中失访；坚持治疗的67例高苯丙氨酸血症患儿末次随访年龄为3个月～26岁。55例接受智能发育评估的患儿中5例患儿智能发育异常（智商〈75分）。（3）智能发育水平与血苯丙氨酸控制浓度呈负相关（r=0．53，P〈0．05），与血苯丙氨酸初始浓度无相关性（r=0．39，P〉0．05）。（4）20例接受苯丙氨酸羟化酶基因突变分析患儿共携带18种PAH基因突变，其中突变频率最高的为EX6—96A〉G和R241C（34．28％）。结论南京地区新生儿高苯丙氨酸血症的发生率高于全国平均水平。早期诊断并规范治疗的患儿90％以上智能发育正常。南京地区PAH基因的突变热点为EX6—96A〉G和R241C，与其他地区有所不同。

Objective To explore the incidence, classification, treatment and prognosis of neonatal hyperphenylalaninemia（HPA） in Nanjing. Methods Infants born from September 1st, 1985 to September 1st, 2012 in Nanjing were investigated. Heel blood samples of neonates were collected at 72 hours after birth, and the concentration of blood phenylalanine was determined by fluorescent quantitative method in Nanjing Neonatal Screening Center within 20 days after birth. The deferential diagnosis was performed in all 81 cases diagnosed as HPA by tetrahydrobiopterin loading test, urinary pterin analysis and dihydropteridine reductase activity determination. The blood phenylalanine concentration and mental development were followed up regularly on infants with HPA. Mutations of phenylalanine hydroxylase （PAH） gene were analyzed by gene sequencing in 20 patients with PAH deficiency. The relationship between phenylalanine concentration and mental development was analyzed by variance analysis, LSD and Pearson correlation analysis. Results （1） The incidence of HPA in neonates in Nanjing was 1/8800（81/712 818）. Among 81 confirmed cases, 78 cases （96.3%） suffered from PAH deficiency, including 37 classical phenylketonurias （PKU）, 23 mild PKU and 18 mild HPA; the three patients （3.7~/00） with tetrahydrobiopterin deficiency were all 6-pyruvoyl tetrahydropterin synthase deficiency. （2） Among these 81 cases, eight refused to any treatment （two of them died）, six had mental retardation （one with epilepsy）, and six were lost in follow-up. For the rest 67 patients who received medical treatment, the ages at the last visit were three months to 28 years old.