Different Phenotypes for Phenylalanine Hydroxylase Deficiency

Abstract

Abnormalities related to the hydroxylation of phenylalanine to tyrosine are classified into three phenotypes based on the amount of dietary phenylalanine tolerated to keep serum phenylalanine within therapeutic levels, i.e., 180–425 μmol/l (3–7 mg/100 ml): (1) Classical phenylketonuria (PKU) tolerating approximately 17% of a normal intake of phenylalanine or approximately 0.12 mmol per kg body weight; (2) mild PKU with a tolerance some 50% higher; and (3) persistent hyperphenylalaninaemia (HPA) with serum phenylalanine values within therapeutic levels on a daily intake of geqslant 0.7 mmol phenylalanine per kg body weight. Oral phenylalanine loading was performed on 100 heterozygotes for these abnormalities and 33 normal homozygotes. The slope of the rise in serum tyrosine multiplied by the maximum serum tyrosine concentration over the maximum phenylalanine concentration was the most powerful discriminant (D/_s, 3.54; overlapping 2.4%). Three heterozygous phenotypes were distinguished by this discriminant, and a significant correlation was observed between the phenotypic combination of the parents and the phenotype of their affected child. In particular, parents of children with classical PKU were clearly distinguished from heterozygotes for the other two abnormalities.