6-丙酮酰四氢蝶呤合成酶缺乏致四氢生物蝶呤缺乏症的诊断及1种新突变的发现

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摘要目的探讨6-丙酮酰四氢蝶呤合成酶(PTPS)缺乏所致四氢生物蝶呤缺乏症(BH₄D)的诊断及其基因突变特点,为开展BH₄D的基因诊断提供依据。方法 (1)归纳、总结临床症状、体征,复检血苯丙氨酸(Phe)浓度;(2)进行Phe(100 mg/kg)+四氢生物蝶呤(BH₄)(20 mg/kg)负荷试验、尿蝶呤谱分析、红细胞二氢蝶呤还原酶(DHPR)活性测定;(3)采用PCR-限制性片段长度多态性(PCR-RFLP)及常规基因测序法进行PTPS基因突变检测,分析基因型与临床表型的关系。结果 (1)患儿男,出生72 h后经新生儿疾病筛查检出其Phe浓度为176.1 μmoL/L,生后20 d复查仅出现肌张力稍低下、皮肤稍白,复检其Phe浓度升高至222.6 μmoL/L;(2)负荷试验前血Phe浓度271.2 μmol/L,Phe负荷3 h上升至756.0 μmol/L,BH4负荷6 h血Phe浓度迅速降至283.2 μmol/L;(3)尿新蝶呤为2.95 mmol/molCr,生物蝶呤为0.08 mmol/molCr,生物蝶呤百分比为2.64%;(4)DHPR活性1.71 nmol/(min·5 mm disc),为正常对照的45%,排除DHPR缺乏症;(5)患儿PTPS基因突变类型为c.259C>T (P87S)及IVS1-129A>G,IVS1-129A>G突变是首次报道的新突变,筛查50例正常儿童未检测到该突变。结论 (1)BH₄负荷6 h后血Phe浓度下降迅速,尿生物蝶呤明显降低,B%持续<10%,DHPR活性正常是6-丙酮酰四氢蝶呤合成酶缺乏症(PTPSD)的确诊依据;(2)P87S为中国人PTPS的热点突变,采用PCR-RFLP方法对热点突变进行快速筛查可提高基因诊断效率;(3)IVS1-129A>G可能是PTPS基因新的致病突变。

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关键词 ： 6-丙酮酰四氢蝶呤合成酶(PTPS), 四氢生物蝶呤缺乏症((BH₄D), 高苯丙氨酸血症(HPA), 突变分析

Abstract：Objective To characterize clinical presentation of a patient with mutations of 6-pyruvoyl tetrahydropterin synthase (PTPS) gene and to report the diagnosis of tetrahydrobiopterin deficiency (BH₄D) in children with hyperphenylalaninemia (HPA).Methods Symptoms and signs of a male patient were summarized and phenylalanine (Phe) levels were determined. The patient was subjected to combined Phe (100mg/kg) and BH₄(20 mg/kg) loading test to evaluate the degree of Phe level response to BH₄. Urinary neopterin and biopterin analysis as well as the determination of dihydropteridine reductase (DHPR) activity in dried blood spot were performed. PTPS gene was analyzed by PCR-restriction fragment length polymorphism and direct DNA sequencing.Results Phe level was 176.1 μmol/L within 72 h after birth. The patient presented with poor hand control and pale skin at 20th day after birth. His second Phe level was 222.6 μmol/L and he was diagnosed as HPA. Phe level increased to 756.0 μmol/L from baseline of 271.2 μmol/L at 3 h after taking Phe, and then decreased to 283.2 μmol/L at 6 h after taking BH4. Baseline urinary levels of neopterin and biopterin were 2.95 mmol/mol Cr and 0.08 mmol/mol Cr, respectively, and biopterin percentage was 2.52%. The patient had lower biopterin level. DHPR activity was 1.71 nmol/(min·5 mm disc), which was 45% of the normal control; so he was excluded diagnosis as DHPR deficiency. Genotyping showed that the patient carried a missense mutation c.259C>T (P87S) from his mother and splice site mutation IVS1-129A>G from his father. The IVS1-129A>G has not been reported in the literature.Conclusion The patient with 6-pyruvoyl tetrahydropterin synthase deficiency was characterized by quick decreasing Phe levels at 6 h after BH₄ loading test, low urinary biopterin levels, low biopterin percentage (<10%), and normal DHPR activity. The IVS1-129A>G may be a new mutation of PTPS gene.

Key words： 6-Pyruvoyl tetrahydropterin synthase (PTPS) Tetrahydrobiopterin deficiency (BH₄D) Hyperphenylalaninemia (HPA) Mutation

收稿日期: 2013-12-23

通讯作者: 余伍忠 (yuwz2013@126.com)

引用本文:

何江, 杨曦, 邹红云, 张琼, 余伍忠. 6-丙酮酰四氢蝶呤合成酶缺乏致四氢生物蝶呤缺乏症的诊断及1种新突变的发现[J]. 中国生育健康杂志, 2014, 25(6): 521-527.
HE Jiang, YANG Xi, ZOU Hongyun, ZHANG Qiong, YU Wuzhong. Tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency: Diagnosis and a novel mutation identification. Chinese Journal of Reproductive Health, 2014, 25(6): 521-527.

链接本文:

http://cjrh.bjmu.edu.cn/CN/ 或 http://cjrh.bjmu.edu.cn/CN/Y2014/V25/I6/521

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