Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients

Abstract Background Hyperphenylalaninemia (HPA) is an inherited metabolic disorder due to deficiency of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH 4 ). BH 4 -responsiveness in PAH-deficient HPA is a recently described characteristic of most milder phenotypes. BH 4 -responsive patients show reduction of plasma phenylalanine (phe) levels after oral administration of BH 4 . Aim Determination of the incidence of BH 4 -responsiveness among a non-selected, cohort population of PAH-deficient hyperphenylalaninemic patients and evaluation of phenotype–genotype correlations. Patients and methods All patients born in Lombardy (Italy) between January 2000 and December 2004, and affected by HPA (107 patients) were classified after BH 4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH 4 -responsiveness. 6R-BH 4 (20mg/kg) was administered orally as a single dose and plasma samples were obtained at time-points 0, 4, 8, and 24h after BH 4 administration. In patients with basal plasma phe levels ⩽360mmol/L a combined phe (100mg phe/kg) and BH 4 (20mg/kg) loading test was performed. Patients were defined "responsive to BH 4 " when plasma phe levels decreased by 30% 8h after oral BH 4 administration. Results BH 4 significantly lowered blood phe levels in 91 (85%) of 107 patients affected by PAH-deficient HPA. Most responsive patients were affected by mild HPA (77%), a smaller percentage by mild (7%) and moderate (7%) phenylketonuria (PKU). One patient with classical PKU was responsive to BH 4 . Eighteen mutations were found to be associated to the BH 4 -responsive phenotype. Conclusions BH 4 -responsiveness is shown by a consistent number of PAH-deficient hyperphenylalaninemic patients and seems to be common in milder phenotypes. Genotype is not the only factor determining BH 4 -responsiveness.