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 betweenmutations in the PAH gene, BH4 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 N 0.05) between the two groups at any of the time points considered (0, 6 and
12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6–60.3] to
56.5 [39.8–68.3] mg kg-1 day-1) and natural protein intake (from 1.0 [0.8–1.7] to 1.5 [1.0–1.8] g kg-1 day-1),
and some patientsmanaged to adopt normal diets.Higher phenylalanine and natural protein intakeswere positively
correlated with better physical outcomes in the diet-only group (p b 0.05). No correlation was found between
patient genotype and physical outcomes, results being similar regardless of the nutritional approach used.We did not detect any side effects due to 6R-tetrahydrobiopterin administration.
Conclusions: Our study indicates that treating 0–4-year-old phenylketonuric patientswith 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 6Rtetrahydrobiopterin
responsive genotypes did not predispose patients to better physical outcomes.
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