6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype

Abstract Background and Aims Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0–4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. Methods We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH 4 responsiveness and growth outcome. Results No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial=−0.57±1.54; final=−0.52±1.29; BMI Z-score: initial=0.17±1.05; final=0.18±1.00) or the diet-only group (height Z-score: initial=−0.92±0.96; final=−0.78±1.08; BMI Z-score: initial=0.17±0.97; final=−0.07±1.03) over the 1-year observation period. Furthermore, we found no significant differences ( p >0.05) between the two groups at any of the time points considered (0, 6 and 12months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6–60.3] to 56.5 [39.8–68.3] mgkg −1 day −1 ) and natural protein intake (from 1.0 [0.8–1.7] to 1.5 [1.0–1.8] gkg −1 day −1 ), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p Conclusions Our study indicates that treating 0–4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.