A 3-year-old girl with fair hair and blue eyes came under observation because of speech retardation. The patient was given a phenylalanine-free diet, since persistently positive urine tests with ferric chloride and reagent strips (Phenistix) were strongly suggestive of phenylketonuria. On further investigation she was found to be suffering from a totally different and not heretofore recognized condition, the salient features of which were an abnormally high concentration of histidine in the blood and an excessive output of histidine in the urine. The child's sister, one year older, presented the same metabolic anomaly. In each case both the concentration of histidine in plasma and the daily output were directly related to the amount of protein in the diet; but even at their lowest levels they greatly exceeded those of normal children of the same age. An oral load of histidine was followed by an increase of histidine in plasma much higher and more prolonged than that observed in controls, and by the excretion of a much larger fraction of the ingested dose.
The urine of each sister contained not only excessive amounts of histidine but also notable quantities of imidazole-pyruvic, imidazole-acetic, and imidazole-lactic acid, histidine derivatives of which normal urine contains only traces. It is concluded that in the two sisters the normally predominant pathway of histidine catabolism, which leads through urocanic acid to glutamic acid, was partially or completely blocked. Since, even after histidine loading, the urines never contained detectable amounts of urocanic acid, the block must precede the formation of that substance. The condition presented is therefore due primarily to a deficiency or total lack of histidine-alpha-deaminase; the enzyme which converts histidine to urocanic acid. As a result of this defect histidine is forced to take the alternative but less efficient pathway which begins with its transamination to imidazole-pyruvic acid. This substance is the one responsible for positive reactions in the ferric chloride and Phenistix tests.
All urine specimens examined, whether from the patient or from normal controls, contained considerable quantities of an unidentifiable imidazole compound ("X"), which does not appear to have been previously reported. The existence of this substance may call for some modification of current concepts of histidine metabolism in man.