Genotyping of the phenylalanine hydroxylating system offers a new way of characterizing patients with phenylalanine hydroxylase (PAH) deficiency. This paper investigates the power of genotyping as a parameter for differential diagnosis and as a measure of the risk factor of brain damage in well-treated patients with phenylketonuria (PKU). Thirty-three PKU patients were followed up over 9 years and the quality of dietary treatment, plasma phenylalanine (phe) in the newborn period before treatment and intellectual outcome at the age of 9 years were measured and correlated with the predicted residual activity (PRA) of the phe hydroxylase system as estimated from mutation analysis of the PAH gene. Patients were grouped in group Ia (PRA = 0%), group Ib (PRA = 5-15%) and group II (PRA > or = 25% of the normal activity). Mean plasma phe levels in the newborn in group Ia were 37.9 +/- 6.5 (2296 +/- 394), in group Ib 40.8 +/- 15.9 (2472 +/- 963) and in group II 16.2 +/- 4.2 (981 +/- 254) mg/dl (mumol/l). Difference in mean plasma values of groups Ia and Ib on the one hand and group II on the other were highly significant (P < 0.0001). No difference could be seen between groups Ia and Ib. There was a higher mean IQ at the age of 9 years in group II (97.4 +/- 5.4) in comparison with groups Ia (92.7 +/- 12.8) and Ib (85.0 +/- 14.4). The difference between group Ib and group II was significant (P < 0.040).(ABSTRACT TRUNCATED AT 250 WORDS)