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

目的 探讨四氢生物蝶呤（tetrahydrobiopterin，BH4）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。负荷试验（20ms／kg）或Phe-BH。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（dihyaropteridine 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（single 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BH4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BH4反应性PAH缺乏症患儿PAH基因型分别为S70del／-、R241C／R243Q、S70del／A389G、Y166X／-、R11lX/-、EX6-96A〉G／R241C和IVS4-1G〉A／R241C。A389G是新发现的突变基因型。结论 BH4反应性PAH缺乏症多表现为轻、中度HPA生化代谢表型，R241C是BH4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BH4反应性相关突变类型.

Clinical and genetic analysis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Objectives To determine the genotype of children with tetrahydrobiopterin(BH4)-responsive pheny-lalanine 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/-,R111X/-,EX6-96A > G/R241C and IVS4-1G > A/R241C. One novel mutation of A389G 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 BH4-response and the mutation of S70del might also be involved.