Phenylketonuria pathogenesis

Metabolic Alterations, Many of the biochemical anomalies of phenylketonuria can be explained by the inhibition or absence of phenylalanine hydroxylase. The evidence in favor of this mode of pathogenesis is both direct and indirect. The indirect evidence is based on the metabolic experiments of Jervis, who administered a variety of amino acids to phenylketonuric patients and demonstrated that only phenylalanine increases the urinary excretion of phenylalanine and all its derivatives phenylpyruvic, phenyllactic, and phenylacetic acids. These experiments suggest that the block in the phenylalanine-tyrosine pathway is located beyond phenylalanine. Since tyrosine administration to phenylketonuric patients did not produce such effects, the block was assumed to be located between phenylalanine and tyrosine. This was confirmed by isotope experiments. When labeled phenylalanine is administered to normal patients, radioactivity is soon recovered in tyrosine and in proteins. In phenylketonuric patients, most of the radioactivity is recovered in the urine, and practically none is found in the protein. The administration of phenylpyruvic acid and phenylacetic acid demonstrated that in the phenylketonuric patient there is no block in the conversion of these compounds into phenylalanine. However, the most conclusive evidence was obtained when Jervis studied autopsy specimens from normal and phenylketonuric individuals and demonstrated that phenylalanine hydroxylase activity is practically nonexistent in phenylketonuric patients [76]. 

Menkes, J.H. The pathogenesis of mental retardation in phenylketonuria and other inborn errors of amino acid metabolism. Pediatrics 39, 297-308 (1967)... 

The problem of pathogenesis has received more attention in the case of phenylketonuria than in most other inborn errors of metabolism. As soon as the intoxication theory was put forward, and supporting evidence in the results of dietary treatment accumulated, the search began. Early hypotheses incriminated one or other of the abnormal metabolites of phenylalanine, e.g. phenylacetic acid [63], known to affect the C.N.S., o-tyramine [64] (which probably does not occur). Several of these metabolites can inhibit such enzymes as DOPA-decarboxylase, tryptophan hydroxylase and glutamic decarboxylase of brain [65]. In fact, the concentrations of serotonin, noradrenaline and adrenaline in the blood are low in phenylketonuria [65, 66] and some theories of pathogenesis have considered that lack of these and other neurotransmitter substances at the synapses, caused by inhibition of the relevant enzyme, was the cause of the neurological disease. This was difficult to combine with the demonstrable deficiencies in... 

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