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

The correct diagnosis of tetrahydrobiopterin (BH₄, sapropterin dihydrochloride)-responsive phenylketonuria (PKU) and treatment with BH₄ are important for prognosis and quality of life. We examined whether age affects biopterin bioavailability following oral BH₄ administration in PKU and whether this influences BH₄ responsiveness. A retrospective analysis was conducted in 255 Japanese PKU patients who underwent a 24-h BH₄ 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 BH₄ 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 BH₄ 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 BH₄ responsiveness and age-appropriate dose adjustment should be considered when necessary.