Randomized investigation to evaluate phenylalanine fluctuation after overnight fasting in PKU patients treated with prolonged-release versus standard amino acid protein substitute.

backgroundEffective management of phenylketonuria (PKU) requires consistent blood phenylalanine (Phe) control. However, patients, particularly those with classical PKU, often experience diurnal fluctuations, particularly with early morning Phe levels after an overnight fast. These fluctuations have been linked to neurocognitive and psychological impairments. This 4-week, randomized, controlled crossover study evaluated the efficacy of a prolonged-release amino acid (PR-AA) compared to a conventional free amino acid-based protein substitute (AA) in reducing early morning blood Phe levels in patients with classical PKU.

methodsParticipants on a low-Phe diet supplemented with protein substitutes were randomly assigned to one of two treatment arms: Arm A, participants received the PR-AA as a single evening dose for 7 days, followed by a 2-week washout period, then crossed over to receive their usual AA protein substitute for all daily doses for another 7 days. Arm B, the order was reversed. All other daily protein substitute doses remained unchanged, using the patients’ usual Phe-free L-AA protein substitute throughout the study. Blood Phe and tyrosine (Tyr) levels, Phe/Tyr ratio, branched-chain amino acids (BCAAs), urinary nitrogen and creatinine excretion, tolerability, and patient acceptability were assessed.

resultsFrom 16 eligible patients, 13 children with classical PKU (n= 8 females, 62%) with a mean age of 11.8 ± 3.2 years completed the study. Administration of the PR-AA significantly reduced early morning Phe levels compared to AA (mean difference from baseline to the end of treatment with PR-AA: 63.6 ± 28.93 µmol/L; −17.8%; p = 0.0484; with AA: 95.5 ± 28.9 µmol/L; +27.6%; p = 0.0063). Subgroup analyses indicated greater benefit in patients < 12 years and in those with higher baseline Phe level (>360 μmol/L). PR-AA also significantly increased blood Tyr levels, and improved the Phe/Tyr ratio. No significant differences were observed for other parameters. PR-AA was well tolerated, with high adherence.

conclusionsPR-AA demonstrated improved metabolic control, particularly in reducing early morning Phe levels. PR-AA may be a useful alternative protein substitute for patients with classical PKU, particularly those with poor metabolic control. Further long-term studies are warranted to assess sustained efficacy, adherence, and neurocognitive outcomes.