Tetrahydrobiopterin deficiency due to 6-pyruvoyl tetrahydropterin synthase deficiency: Diagnosis and a novel mutation identification

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Chinese Journal of Reproductive Health ›› 2014, Vol. 25 ›› Issue (6) : 521-527.

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

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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

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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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