Age‐Dependent Variation in Blood Biopterin Peaks Following Oral Tetrahydrobiopterin Administration in Phenylketonuria

ABSTRACT The correct diagnosis of tetrahydrobiopterin (BH 4 , sapropterin dihydrochloride)‐responsive phenylketonuria (PKU) and treatment with BH 4 are important for prognosis and quality of life. We examined whether age affects biopterin bioavailability following oral BH 4 administration in PKU and whether this influences BH 4 responsiveness. A retrospective analysis was conducted in 255 Japanese PKU patients who underwent a 24‐h BH 4 loading test (mostly ≤ 2 months old) and/or a 1‐week test (all ≥ 5 months) between 2008 and 2023. Correlations were evaluated among age, peak blood biopterin, and the phenylalanine (Phe) reduction rate. In the 24‐h test, analyses of day‐of‐age versus peak biopterin after oral BH 4 showed that peak levels were highest during the early neonatal period and declined significantly with age ( p = 0.008). In the 1‐week test, peak levels increased during school age through adolescence (6–19 years) ( p = 0.001), with no material age trend in adults (≥ 20 years). In the 24‐h test, peak biopterin correlated positively with the Phe reduction rate ( p = 0.029), and baseline Phe correlated negatively with peak biopterin ( p = 0.001). These findings indicate that BH 4 loading tests performed in infants and preschool‐aged children (1 month–5 years)—in whom biopterin peaks tend to be low—or in patients with high baseline Phe levels may yield suppressed biopterin peaks and false‐negative results. Reassessment of BH 4 responsiveness and age‐appropriate dose adjustment should be considered when necessary.