云南苯丙酮尿症综合干预技术体系的建立和临床应用  

Neonatal screening,diagnosis,treatment and prenatal genetic diagnosis of phenylketonuria in Yunnan province

作　　者：陈红[1,2] 唐新华[1,2] 章印红[1,2] 李利[3] 米弘英[3] 徐庆华[1,2] 朱姝[1,2] 苏洁[1,2] 朱宝生[1,2] 

机构地区：[1]昆明医科大学附属昆华医院 [2]云南省第一人民医院遗传诊断中心云南省出生缺陷与遗传病研究重点实验室,云南昆明650032 [3]云南省第一人民医院儿科

出　　处：《中国妇幼保健》2014年第5期657-660,共4页Maternal and Child Health Care of China

基　　金：昆明医科大学-云南省科技厅联合基金资助课题〔2010CD198〕

摘　　要：目的：在云南建立一个针对苯丙酮尿症（PKU）的筛查、鉴别诊断、饮食和药物控制及基因诊断、产前诊断的综合干预技术体系。方法：新生儿滤纸片干血斑荧光免疫技术检测血苯丙氨酸（Phe）浓度筛查高苯丙氨酸血症（HPA）患者；采用BH4负荷试验和尿蝶呤谱分析鉴别诊断四氢生物蝶呤缺乏症（BH4D）；通过无苯丙氨酸奶粉、低苯丙氨酸饮食控制诊断的PKU患儿发病，BH4D患儿补充BH4等药物预防患儿致愚。采用PAH基因13个外显子测序和PAH—STR连锁技术，完成基因诊断和产前诊断，预防患儿出生。结果：①2006年1月-2013年9月筛查了254218例新生儿，确诊了16例经典型PKU，4例中度PKU，9例轻度HPA，1例BH4D。云南新生儿中PKU的发生率为1／11555（22／254218）。②对18例经典型和中度PKU患儿使用无苯丙氨酸奶粉和饮食控制，并监测血Phe浓度均在正常范围内，婴幼儿智力发育正常。筛查出的2例中度PKU患儿家属拒绝治疗。③通过对云南20例经典型PKU患者PAH基因测序发现云南地区最常见的异常为11243R（30．0％），其次为Y356X（10．0％）。R111X（7．5％），IvS4＋2T〉A（7．5％），V399V（7．5％），主要涉及第7、11、3外显子和第4内含子。④完成3例胎儿PKU产前诊断，2例胎儿检出仅为基因突变携带者，分娩后随访正常；另1例胎儿仅能证明至少为突变携带，但因未检出先证者另外1个突变，加之连锁分析多态性不足，不能得出准确诊断结论，后孕妇遗传咨询后选择终止妊娠。结论：新生儿足跟血筛查PKU患儿，通过鉴别诊断确诊后，进行药物和饮食干预，同时采用PAH基因测序和PAH—STR技术，完成基因诊断和产前诊断，在产前预防患儿出生，形成一个相互支持的立体干预体系，可有效提高PKU预防和干预效率。Objective： To establish an effective control system toward phenylketonuria （PKU） in Yunnan province of China, mainly via technologies of neonatal screening, diagnosis, treatment management and prenatal genetic diagnosis. Methods： Neonatal PKU screening was performed in newborns in Yunnan from 2006 ~ 2013. The blood phenylalanine （Phe） concentration was tested by fluorometric method. The tetrahydrobiopterin deficiency （BH4D） was confirmed by the urinary protein analysis and BH4 loading test. PKU patients were treated with the free Phenylalanine formula and dietary restriction. The patients with BH4D were treated with BH4. Gene diagnosis was per- formed by sequencing of all 13 exons of PAH gene in the patients with PKU. Three different families with PKU history were performed PKU prenatal genetic diagnosis by combined use of PAH gene sequencing and PAH - STR linkage analysis. Results： @A total of 254 218 newbo- rns were screened from January 2006 to September 2013, with 16 cases confirmed with typical PKU, 4 cases with moderate PKU, 9 cases with HPA, and 1 with BH4D. @18 cases confirmed with typical and moderate PKU were treated with low or free phenylalanine milk and di- etary restriction, with normal controlled blood Phe concentrations and mental development. One treated child was already 7, with a normal performance in the primary school. But 2 families whose newborns were confirmed with moderate PKU refused the treatment. （~）PAH gene se- quencing on 20 cases with typical PKU revealed that the most frequently mutation in Yunnan was R243R （30. 0% ）, followed by Y356X （ 10. 0% ）, RlllX （7.5%）, IVS4 ＋2T 〉 A （7.5%）, V399V （7.5%）, and that exon 7, 11, 3 and intron 4 were most frequently in- volved. @Two fetuses performed prenatal genetic diagnosis were proven just mutation carriers by both PAH gene sequencing and linkage anal- ysis, follow - up after delivery showed two babies were normal. The third fetus was proven to be at least a carrier of c. 690 - 691 insG muta- tion

关 键 词：苯丙酮尿症 新生儿筛查 基因诊断 

分 类 号：R714.54[医药卫生—妇产科学]