Glutamine Depletion in Phenylketonuria

Two adult brothers with untreated phenylketonuria, one with a severe mental defect and the other with superior intelligence, were compared biochemically. No significant differences were found in their degree of hyperphenylalaninemia, nor in their urinary excretion of phenylalanine metabolites. A striking difference between the two, however, was a significant reduction in concentration of glutamine in the plasma of the defective brother, but not in the intelligent brother. A second adult with untreated phenylketonuria and normal intelligence, as well as a group of phenylketonuric children who were receiving a low-phenylalanine diet, also had plasma glutamine concentrations within the normal range. Twelve mentally defective untreated patients with phenylketonuria all showed a significant reduction in plasma glutamine. These findings cast doubt on some proposed mechanisms for the mental defect in phenylketonuria, and suggest that chronic insufficiency of glutamine may play a part in damaging the growing human brain.