四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床与基因研究  

Clinical and genetic analysis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

作　　者：杨凌[1] 宋昉[2] 沈明[1] 周忠蜀[1] 赵世萍[3] 李晓雯[4] 贺春[3] 张知新[1] 

机构地区：[1]中日友好医院儿科,北京100029 [2]首都儿科研究所遗传室,北京100020 [3]中日友好医院临床研究所,北京100029 [4]中日友好医院营养部,北京100029

出　　处：《临床儿科杂志》2007年第4期288-291,299,共5页Journal of Clinical Pediatrics

基　　金：国家自然科学基金资助(No.30672252)

摘　　要：目的探讨四氢生物蝶呤(tetrahydrobiopterin,BH_4)反应性苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)缺乏症临床表型和基因型的关系。方法38例高苯丙氨酸血症(hyperphenylalaninemia,HPA)患儿均进行口服BH_4负荷试验(20mg/kg)或Phe-BH_4联合负荷试验,同时进行尿蝶呤谱分析、红细胞二氢蝶啶还原酶(dihydropteri-dine reductase,DHPR)测定。对7例BH4反应性PAH缺乏症患儿采用聚合酶链反应(PCR)和单链构象多态性(sin-gle strand conformation polymorphism,SSCP)分析对PAH外显子进行突变筛检,并结合DNA直接测序方法进行突变分析。结果确诊10例BH_4反应性PAH缺乏症患儿,男6例,女4例;平均年龄7.8个月;生化代谢表型均为轻度或中度HPA。7例BH_4反应性PAH缺乏症患儿PAH基因型分别为S70del/-、R241C/R243Q、S70del/A389G、Y166X/-、R111X/-、EX6-96A>G/R241C和IVS4-1G>A/R241C。A389G是新发现的突变基因型。结论BH_4反应性PAH缺乏症多表现为轻、中度HPA生化代谢表型,R241C是BH_4反应性相关突变基因型中较常见的一种类型。推测S70del可能是一种BH_4反应性相关突变类型。Objectives To determine the genotype of children with tetrabydrobiopterin （BH4） - responsive phenylalanine hydroxylase （PAH） deficiency through the differential diagnosis of hyperphenylalaninemia （HPA） and to explore the association between phenotype and genotype of BH4-responsive PAH deficiency. Methods All the 38 HPA children, including 23 male and 15 female, were treated with BH4 （20 mg/kg per oral） alone or in combination with phenylalanine （100 mg/kg） . The urine pterin profile and the dihydropteridine reductase （DHPR） activity determined in dried blood spot on filter paper were analysed. PCR-single strand conformation polymorphism （SSCP） and DNA sequencing were used to determine the mutations of PAH gene. Results Ten children （6 male and 4 female, at an average age of 7.8 months） were diagnosed with BH4-responsive PAH deficiency. Their metabolism phenotype was mild or moderate HPA. The genotypes of 7 children with BH4- responsive PAH deficiency included S70del/- , R241C/R243Q, S70del/A389G, Y166X/-, R11 IX/-, EX6-96A 〉 G/R241C and IVS4-1G〉 A/R241C. One novel mutation of A589G was identified in this study. Conclusions The metabolism phenotype of BH4-responsive PAH deficiency is mostly expressed as mild or moderate HPA. R241C is a prevalent mutation associated with BI44-response and the mutation of S70del might also be involved.

关 键 词：四氢生物蝶呤反应性 基因突变 表型 高苯丙氨酸血症 

分 类 号：R726.8[医药卫生—儿科]