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

何江, 杨曦, 邹红云, 张琼, 余伍忠

中国生育健康杂志 ›› 2014, Vol. 25 ›› Issue (6) : 521-527.

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中国生育健康杂志 ›› 2014, Vol. 25 ›› Issue (6) : 521-527.
遗传与出生缺陷

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

  • 何江, 杨曦, 邹红云, 张琼, 余伍忠
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Tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency: Diagnosis and a novel mutation identification

  • HE Jiang, YANG Xi, ZOU Hongyun, ZHANG Qiong, YU Wuzhong
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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。

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.

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

Key words

6-Pyruvoyl tetrahydropterin synthase (PTPS) / Tetrahydrobiopterin deficiency (BH4D) / Hyperphenylalaninemia (HPA) / Mutation

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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[J]. Chinese Journal of Reproductive Health, 2014, 25(6): 521-527

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