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.