Alkaptonuria is a rare autosomal recessive inherited disorder caused by defects in the gene encoding an enzyme, homogentisic acid oxidase, involved in the catabolism of phenylalanine and tyrosine. As a consequence of this gene defect the catabolism of these two amino acids is inhibited and the intermediate homogentisic acid is excreted in the urine. If the urine of an individual with alkaptonuria is allowed to stand exposed to the air it will gradually turn dark brown-black as a result of the conversion of homogentisic acid to a melanin-like compound. The presence of alkali speeds up the conversion process and explains why washing of diapers of afflicted infants makes the stains more pronounced instead of removing them. This striking visual sign of alkaptonuria was key to the initial recognition of the disorder which was first described in detail in 1859. Archibald E. Garrod, in his seminal 1909 publication (Inborn Errors of Metabolism), described the inherited nature of alkaptonuria. In fact, alkaptonuria was not only the first characterized inborn error of metabolism but the first ever disease identified as being inherited. Alkaptonuria is characterized by homogentisic aciduria, ochronosis (a bluish-black discoloration of tissues) and arthritis. The exact mechanisms by which alkaptonuria results in ochronosis and arthritis are still not fully understood.
The homogentisic acid oxidase gene (HGD: homogentisate 1,2-dioxygenase) is found on chromosome 3q13.33 spanning 60 kb and encompassing 16 exons that encode a protein of 445 amino acids. A number of single nucleotide changes, insertions, deletions, and mutations in introns have been identified in alkaptonuric patients. In all, mutations have been found in 11 of the 16 exons of the HGD gene.