Influence of Age on ortho-Hydroxyphenylacetic Acid Excretion in Phenylketonuria and Its Genetic Variants

Extract: Excretion in urine of o-hydroxyphenylacetic acid (o-OH-PAA) was measured quantitatively during a 24-hr period in 43 children ranging from 2 weeks to 12 years of age who were affected by different types of hyperphenylalaninemia (20 typical phenylketonuria (PKU) 7 atypical PKU, and 16 mild forms according to the classification of Auerbach et al.); 28 out of the 33 cases diagnosed at birth in the course of a screening program were examined before reaching 3 months of age. Phenylpyruvic acid (PPA) excretion was estimated at the same time semiquantitatively.It was found (1) that ferric chloride tests were negative constantly and the daily excretion of o-OH-PAA was always inferior to 5 μM/24 hr in the younger group when the level of phenylalanine in plasma was below 1.5 μmol/ml; (2) that o-OH-PAA excretion increased significantly as the children got older: 11.0 ± 3.8 before 3 months, 16.1 ± 15.9 at 6 months, 75.0 ± 48.5 at 1 year, and 122.1 ± 84.7 μM/24 hr at 2 years of age for levels of phenylalanine in plasma which ranged from 1.5 to 2.1 μmol/ml; (3) that the excretion thresholds for 0-OH-PAA and PPA reached adult values (0.4–0.5 and 0.7–0.9 μmol/ml, respectively) only after 2 years.In 16 cases, using intravenous perfusion of 0.06 M L-phenylalanine, we have shown also that the PPA and o-OH-PAA excretion was identical whatever the type of (PKU) or mild forms) insofar as the levels of phenylalanine in plasma reached (1.5–3.0 μmol/ml) were equal in both types.Speculation: This paper presents observations which demonstrate that only a minute amount of o-OH-PAA is excreted daily in the urine of both classic PKU and other forms of hyperphenylalaninemia during the first months of life. It is suggested that this very low excretion is caused by a delayed maturation of phenylalanine transaminase; it is further proposed that the different types of hyperphenylalaninemia, with the exception of those caused by a deficiency of the tyrosine-oxidizing system, are all secondary to mutations affecting the phenylalanine hydroxylase system.