Tetrahydrobiopterin responsiveness in patients with phenylketonuria

Objectives: To investigate the BH4 response in a group of patients with phenylketonuria (PKU) in order to offer this alternative treatment to the responsive patients. Design and methods: The 24-h-long Phe/BH4 loading test was performed on 64 PKU patients requiring dietary treatment. Results: All patients with mild-PKU and 75% of patients with moderate-PKU were BH4 responsive, while only 11% of classic-PKU patients showed good/partial response (P< 0.0001). The percentages of Phe decrease after the BH4 loading test were significantly different in the three PKU phenotypes (mild PKU: 67.9 ± 18.7; moderate PKU: 37.4 ± 16.8; and classical PKU: 21.9 ± 13.7; ANOVA with Bonferroni correction: P< 0.0001). We report four mutations (P147S, D222G, P275S, and P362T) not previously associated with BH4 responsiveness, all of them combined with mutations with zero predicted residual activity. Conclusion: Both the percentage of Phe decrease and the Phe value achieved 24 h after BH4 loading are valuable data in predicting a response. We report four mutations not previously associated with BH4 responsiveness.