Incidence of BH 4 -responsiveness in phenylalanine-hydroxylase-deWcient Italian patients

Background: Hyperphenylalaninemia (HPA) is an inherited metabolic disorder due to deWciency of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). BH4-responsiveness in PAH-deWcient HPA is a recently described characteristic of most milder phenotypes. BH4-responsive patients show reduction of plasma phenylalanine (phe) levels after oral administration of BH4. Aim: Determination of the incidence of BH4-responsiveness among a non-selected, cohort population of PAH-deWcient hyperphenylalaninemic patients and evaluation of phenotype–genotype correlations. Patients and methods: All patients born in Lombardy (Italy) between January 2000 and December 2004, and aVected by HPA (107 patients) were classiWed after BH4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH4-responsiveness. 6R-BH4 (20 mg/kg) was administered orally as a single dose and plasma samples were obtained at time-points 0, 4, 8, and 24 h after BH4 administration. In patients with basal plasma phe levels 6360 mmol/L a combined phe (100 mg phe/kg) and BH4 (20 mg/kg) loading test was performed. Patients were deWned “responsive to BH4” when plasma phe levels decreased by 30% 8 h after oral BH4 administration. Results: BH4 signiWcantly lowered blood phe levels in 91 (85%) of 107 patients aVected by PAH-deWcient HPA. Most responsive patients were aVected by mild HPA (77%), a smaller percentage by mild (7%) and moderate (7%) phenylketonuria (PKU). One patient with classical PKU was responsive to BH4. Eighteen mutations were found to be associated to the BH4-responsive phenotype. Conclusions: BH4-responsiveness is shown by a consistent number of PAH-deWcient hyperphenylalaninemic patients and seems to be common in milder phenotypes. Genotype is not the only factor determining BH4-responsiveness.