Two-Year Outcomes of Sapropterin Treatment in Children with Phenylketonuria: A Longitudinal Observational Study of Metabolic, Dietary, and Psychosocial Effects

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> Sapropterin-responsive children increased natural protein intake from 10 g to 28 g/day at 2 years (<i>p</i> < 0.001), with reduced protein substitute intake (60 g [56-63] to 45 g [40-60], <i>p</i> < 0.05); no changes occurred in non-responsive children (<i>p</i> > 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 <i>p</i> ≤ 0.05), alongside decreased food neophobia (<i>p</i> = 0.005) and caregiver depression (<i>p</i> = 0.013). In sapropterin-responsive children, weight and BMI z-scores remained stable, while height z-score increased over 24 months (<i>p</i> = 0.03); non-responsive children had higher weight and BMI z-scores than responsive children at 24 months (<i>p</i> = 0.037 and <i>p</i> = 0.026). Blood phenylalanine concentrations remained within recommended target ranges overall, with lower median values in responsive children at several time points. <b>Conclusions:</b> 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.