Influencing Factors on the Use of Tetrahydrobiopterin in Patients with Phenylketonuria

OBJECTIVE: To explore and analyze the influencing factors of tetrahydrobiopterin therapy in patients with phenylketonuria. METHODS: 86 children with phenylketonuria (PKU) diagnosed and treated in our hospital from February 2019 to September 2021 were randomly enrolled. All the children underwent coenzyme hydroxybiopterin and urinary pterin spectrum analysis, and the children with deficiency received gene mutation testing. RESULTS: The results of urine pterin analysis showed that 82 patients had higher urinary N and B contents than the normal reference values, with the N/B slightly higher than the normal B% within the normal range. 4 patients had extremely high urinary N/B and B% <5% and were diagnosed as BH4 deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, and a combined stress test was performed. The blood Phe level was (720–1200) μmol/L 3 h after Phe loading, and the blood Phe concentration decreased to (120–240) μmol/L 4–6 h after oral administration of 7.5 mg/kg BH4 tablet. After one week of treatment, the blood Phe concentration decreased significantly to 239 ± 173 μmol/L, with a decrease rate of 52.14 ± 25.28%. It shows that the application of tetrahydrobiopterin intervention therapy is effective in patients with PKU. The results of the full-length cDNA analysis of the PTPS gene showed that a total of 4 gene mutations were found. A C ⟶ T substitution occurred at the 259th base, and the 87th proline (Pro) in the coding region was converted to serine (Ser) (P87S). G ⟶ A substitution at base 286 converts aspartic acid (Asp) at position 96 of the coding region to asparagine (Asn) (D96N). A ⟶ G substitution occurs at the 155th base to convert asparagine (Asn) at position 52 of the coding region to serine (Ser) (N52S). G ⟶ C substitution occurs at the 430th base to convert glycine at position 144 (Gly) to arginine (Arg) (G144R). G144R is a new mutation type. The gene mutation types of the 4 patients were P87S/D96N, N52S/G144R, D96N/P87S, and P87S/P87S, all of which were from their parents, which conformed to the law of autosomal recessive inheritance. CONCLUSION: PKU is caused by the defect of phenylalanine hydroxylase activity in children, which causes phenylalanine metabolism disorder, and tetrahydrobiopterin intervention therapy can affect the activity of phenylalanine hydroxylase, increase the decline rate of blood Phe, significantly reduce the level of phenylalanine in children, and promote intellectual recovery. The dose of tetrahydrobiopterin should be tailored, with small doses for mild phenotypes and long-term treatment using even smaller doses.