Studies on phenylketonuria. II. The excretion of o-hydroxyphenylacetic acid in phenylketonuria.

Phenylketonuria (phenylpyruvic oligophrenia) is an inherited condition in the human in which the ability of the liver to oxidize phenylalanine to tyrosine is impaired (2). Because this pathway represents the major, although not the only, manner in which phenylalanine is metabolized in mammals, considerable amounts of phenylalanine accumulate in the blood and tissues of affected individuals, and phenylalanine and abnormal metabolites derived from it are excreted in the urine. These metabolites are phenylpyruvic acid (3), p-phenyl-L-lactic acid (3), and phenylacetylglutamine (4), the conjugated form in which phenylacetic acid is excreted by the human. In addition to the biochemical abnormalities, most of the individuals who inherit the biochemical defect suffer a profound impairment of mental functioning. It has not been possible up to the present time to establish a connection between the biochemical abnormality and the development of the mental defect. Experiments in which the phenylalanine intake of phenylketonuric children was restricted until normal blood levels of phenylalanine were obtained and phenylpyruvic acid excretion ceased were carried out in this laboratory (5). The results indicated that the mental defect does not occur as the result of a simple interference with the functioning of an otherwise normal central nervous system, but many observations were made which were in agreement with the idea that toxic metabolites might be responsible for some of the mental symptoms; similar results have been reported by Bickel, Gerrard, and Hickmans (6). In the course of the metabolic experiments, qualitative reactions were obtained with phenylketonuric urine which were not observed in the urine of normal individuals. Ex-