Journal Article

Sapropterin Dihydrochloride Responsiveness in Phenylketonuria: A Case Series Exploring Gaps in Comprehensive Patient Monitoring

Iacobacci, Riccardo, Polizzi, Agata, Sciacca, Monica, Moliteo, Evelina, La Spina, Luisa, Ruggieri, Martino, Meli, Concetta, Migliore, Alessia, Messina, Marianna, Pappalardo, Maria Grazia, Leonardi, Roberta, Lo Bianco, Manuela, Rinella, Sergio

2025

Overview

Background: Phenylketonuria (PKU) is a rare autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to hyperphenylalaninemia (HPA). Untreated, elevated phenylalanine (Phe) levels cause severe neurocognitive, developmental, and psychiatric complications. Management relies on a Phe-restricted diet, which is challenging to maintain, particularly in adolescents and adults. Sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), can enhance residual PAH activity, lowering blood Phe levels and increasing dietary tolerance in responsive patients. However, real-world alignment with best practices remains underexplored. This study aims to report a tertiary referral center’s experience with sapropterin treatment in PKU and assess adherence to international guidelines. Methods: We retrospectively analyzed 23 PKU patients treated with sapropterin from 2007 to 2025. Patients with baseline Phe levels of 360–2000 µmol/L underwent a 10 mg/kg/day loading test over two weeks. Responsiveness was defined as a ≥30% reduction in blood Phe levels. Phe levels were measured pre- and post-test, and dietary tolerance was evaluated. Adherence to best practices was critically reviewed. Results: All patients showed significant Phe reductions (mean 71.43%, p < 0.0001), exceeding responsiveness thresholds. Most achieved substantial increases in dietary Phe tolerance, with three patients partially responsive (800–1200 mg/day). Responsiveness was unrespectful of the patient’s genotype, for those individuals for whom this was known (8/23 patients). Although effective, the test dose and duration differed from guideline recommendations (20 mg/kg/day). Neuropsychological and QoL assessments were not systematically performed, representing a key limitation. Conclusions: Sapropterin dihydrochloride effectively identified responders and improved dietary flexibility even with lower dosing protocols. Greater adherence to international standards, particularly regarding long-term neuropsychological monitoring, is needed to optimize patient care.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Adolescent / Adult / Amino acids / Biopterins - administration & dosage / Biopterins - analogs & derivatives / Biopterins - therapeutic use / Child / Child, Preschool / Classification / Diet / Dietary restrictions / Enzymes / Evidence-based medicine / Female / Genetic aspects / Humans / Male / Metabolism / Mutation / Patient compliance / Patient monitoring equipment / Patients / Performance evaluation / Phenylalanine / Phenylalanine - blood / Phenylalanine Hydroxylase - genetics / Phenylketonuria / Phenylketonurias - blood / Phenylketonurias - diet therapy / Phenylketonurias - drug therapy / Proteins / Retrospective Studies / Sapropterin dihydrochloride / Statistical analysis / Teenagers / Treatment Outcome / Young Adult