Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Objective: Tetrahydrobiopterin (BH4) is known to normalize blood phenylalanine levels in BH4 deficiency, but not in phenylketonuria (PKU). Recently the patients with mild PKU who were responsive to BH4 were found in neonatal screening for PKU. This study aimed to investigate the effect of BH4 and phenylalanine hydroxylase (PAH) gene mutations in patients with BH4 responsive mild PKU and mild hyperphenylalaninemia (HPA). Methods: The responsiveness of the BH4 loading test was evaluated in HPA patients detected by neonatal PKU screening. All patients were normal in biopterin metabolism and were diagnosed as HPA with PAH gene mutations. A single-(10 mg/kg), and four-time-, one-week-BH4 [20 mg/(kg · day)] loading test and a long-term BH4 treatment were performed for them. Results: In a single BH4 loading test, no classic PKU patients demonstrated decreases in serum phenylalanine levels. The patients with a decrease greater than 20% in serum phenylalanine levels in the single-BH4-loading test showed a similar decrease in the four-dose-BH4 loading test. The one-week-BH4 administration test clarified the BH4 effect not only in responsive patients, but also in patients who showed low responsiveness in single- or four-dose-BH4 loading test. The majority of patients with mild HPA and mild PKU who had the R241C allele responded to BH4 administration. R241C, P407S and A373T mutation were never found in classic PKU patients without BH4 responsiveness. Conclusions: The one-week-BH4 administration test is the most effective for the diagnosis of the BH4 responsive PAH deficiency. R241C, P407S and A373T alleles represented the causes of mild HPA or mild PKU in patients with BH4 responsiveness. BH4 treatment is a new and effective pharmacotherapy which replaces the phenylalanine restricted diet for mild HPA and mild PKU patients.