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

## TL;DR

This study shows that age affects how well tetrahydrobiopterin (BH4) works in phenylketonuria patients, with younger children and those with high phenylalanine levels showing lower biopterin peaks.

## Contribution

The study reveals age-dependent variations in BH4 bioavailability and their impact on BH4 responsiveness in PKU patients.

## Key findings

- Peak biopterin levels are highest in the early neonatal period and decline significantly with age.
- In school-age children through adolescence, peak biopterin levels increase, but no age trend is seen in adults.
- Higher baseline phenylalanine levels correlate with lower biopterin peaks after BH4 administration.

## Abstract

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.