GENOTYPE-PHENOTYPE CORRELATIONS IN PHENYLKETONURIA

Genotyping of the phenylalanine hydroxylating system offers a new way of characterizing patients with phenylalanine hydroxylase (PAH) defici ency. This paper investigates the power of genotyping as a parameter f or differential diagnosis and as a measure of the risk factor of brain damage in well-treated patients with phenylketonuria (PKU). Thirty-th ree PKU patients were followed up over 9 years and the quality of diet ary treatment, plasma phenylalanine (phe) in the newborn period before treatment and intellectual outcome at the age of 9 years were measure d and correlated with the predicted residual activity (PRA) of the phe hydroxylase system as estimated from mutation analysis of the PAH gen e. Patients were grouped in group Ia (PRA = 0%), group Ib (PRA = 5-15% ) and group II (PRA greater-than-or-equal-to 25% of the normal activit y). 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 grou p II 16.2 +/- 4.2 (981 +/- 254) mg/dl (mumol/l). Difference in mean pl asma values of groups Ia and Ib on the one hand and group II on the ot her 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 y ears 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 gr oup II was significant (P < 0.040). Although intellectual outcome may be influenced by many factors, there is evidence that genotyping of th e PAH gene may not only be useful as a better tool for differential di agnosis of PKU but also as a predictive parameter for the risk of brai n damage in well-treated and early treated patients with PKU.