A genetic metabolic disorder due to deficiency of the enzyme homogentisic acid (HGA) dioxygenase. Deficiency of this enzyme leads to the three cardinal features of alkaptonuria –the presence of homogentisic acid in the urine, ochronosis (bluish-black pigmentation in connective tissue), and arthritis. The presence of HGA in the urine causes it to turn black upon standing when exposed to air. Alkaptonuria was easily diagnosed among the nomadic Bedouin peoples because people with the disease left a characteristic dark spot in the sand marking the spot where they had urinated. Ochronosis is due to the accumulation of a bluish-black pigment in connective tissues that darkly discolors them. Ochronosis occurs only after age 30. The pigment also accumulates in the cartilage of the joints and results in early-onset osteoarthritis. The arthritis often begins in the twenties. Other less common features of the alkaptonuria include pigment deposition (aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation), renal stones, and prostate stones. Diagnosis is based upon the detection of excess HGA in the urine by gas chromatography and mass spectrometry analysis.
Alkaptonuria results from mutations in the gene called HGD which encodes the enzyme homogentisic acid dioxygenase. This gene has been mapped to chromosome 3 in the region of bands 3q21-q23. More than 40 mutations in the HGD gene have been identified in people with alkaptonuria. Many of these mutations change single amino acids in the homogentisate oxidase protein. Mutations in the HGD gene probably inactivate the enzyme by changing its structure. Alkaptonuria is inherited in an autosomal recessive manner.
Alkaptonuria was one of the conditions for which autosomal recessive inheritance was first proposed. This prescient proposal was made in 1902 by the English physician Archibald Garrod, later Sir Archibald. In a series of brilliant lectures in 1908 Garrod set forth the charter group of what he called “inborn errors of metabolism.” The 4 conditions he labeled as inborn errors were albinism, cystinuria, pentosuria and, of course, alkaptonuria.