The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: evaluation of response and subsequent treatment.

The response to tetrahydrobiopterin (BH4) in patients with phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (OMIM 261600) has been widely reported. Here we report results of the BH4 loading test (20 mg/kg per day) in a group of 36 patients with PAH deficiency and phenotype of mild hyperphenylalaninaemia (HPA), mild phenylketonuria (PKU) or classic PKU. The patients ranged from neonates aged 7-15 days, detected in the Newborn Screening Programme for PKU in the population of Galicia (NW Spain), to adults aged up to 32 years who had been receiving a low-phenylalanine (Phe) diet for a period of years. Ten of the 36 patients showed a reduction of more than 30% in plasma Phe levels within 24 h of BH4 loading (ranging from 33.7% to 90.2%, mean 59.2%, SD 19.8%). All the patients with mild HPA (100%) showed a positive response; 57% of patients with mild PKU (4 of 7) showed a positive response. Of particular interest were positive responses in two patients with classic PKU, and in one patient with mutations of the phenylalanine hydroxylase (PAH) gene that have not to date been reported to be BH4-responsive (p.S303A and p.G46S). BH4 treatment (5-8 mg/kg per day) was commenced in 9 of the 10 BH4-responsive patients. The observed responses to treatment argue for application of the BH4 loading test in all patients with HPA or PKU, independently of genotype, phenotype or age.