Studies on alcaptonuria

Abstract

Chemical and other findings are reported in a case of alcaptonuria. It was shown that, apart from homogentisic acid, no other aromatic substances likely to arise in the intermediary metabolism of tyrosine and phenylalanine are excreted in abnormal and detectable quantities. The variability of the daily excretion of homogentisic acid was investigated and it was found that even on a constant diet both the daily output of homogentisic acid and the H: N ratio vary considerably. It was shown that phenylalanine and tyrosine are converted to homogentisic acid by the alcaptonuric to the extent of probably about 80-85%. Neither the ingestion of ascorbic acid, nor of cysteine or methionine had any significant effect on the excretion of homogentisic acid. The alcaptonuric can deal with large doses of ascorbic acid in a normal manner. Ingestion of dl-2:5-dihydroxyphenylalanine produced an increased excretion of homogentisic acid; it is suggested that tyrosine is normally first oxidized to 2:5-dihydroxyphenylalanine which is then converted to homogentisic acid through the keto acid. The concn. of homogentisic acid in the plasma of the alcaptonuric was found to be very low, even after the giving of phenylalanine. The high renal clearance volumes found suggest that homogentisic acid is either formed in the kidney or actively excreted by the tubuli at a very high rate. The possibility that alcaptonuria may be due to an abnormality in the secretory function of the kidney is mentioned. No trace of homogentisic acid was detected in the urines of other members of the family. One relative, however, excreted small amts. of a reducing substance which was not homogentisic acid, but which increased on ingestion of phenylalanine.