Abstract
Background: Evidence on the long-term impact of sapropterin in phenylketonuria (PKU) is limited. Understanding its effects on dietary restrictions, growth in children, and caregiver burden is essential to optimize PKU management. Methods: This prospective, two-year longitudinal study with a comparison group followed 33 children with PKU after sapropterin responsiveness assessment (21 responsive, 12 non-responsive). Outcomes included metabolic control, prescribed protein intake, dietary patterns, growth, psychological measures, and caregiver burden. Results: Sapropterin-responsive children increased natural protein intake from 10 g to 28 g/day at 2 years (p < 0.001), with reduced protein substitute intake (60 g [56-63] to 45 g [40-60], p < 0.05); no changes occurred in non-responsive children (p > 0.05). Animal-based foods (cheese, eggs, meat, fish) were introduced in 52% (11/21) of responsive children once tolerance exceeded approximately 25 g/day. The caregivers of responsive children reported reduced financial, familial-social, and personal burden (all p ≤ 0.05), alongside decreased food neophobia (p = 0.005) and caregiver depression (p = 0.013). In sapropterin-responsive children, weight and BMI z-scores remained stable, while height z-score increased over 24 months (p = 0.03); non-responsive children had higher weight and BMI z-scores than responsive children at 24 months (p = 0.037 and p = 0.026). Blood phenylalanine concentrations remained within recommended target ranges overall, with lower median values in responsive children at several time points. Conclusions: Sapropterin enabled more flexible, sustainable dietary management in responsive children with PKU, supporting metabolic control, growth, and improved family well-being and social participation. Equitable access to therapies and long-term dietetic support remain essential to optimize outcomes.