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Alkaptonuria (MIM 203500; gene symbol AKU) is a rare, hereditary, metabolic disease in which homogentisic acid, an intermediary product in the metabolism of phenylalanine and tyrosine, cannot be further metabolized. The metabolic defect causes a characteristic triad of homogentisic aciduria, ochronosis, and arthritis.
The cause of the disease is a constitutional lack of the enzyme homogentisic acid oxidase. This enzyme normally exists primarily in the liver and kidney. It requires oxygen, ferrous iron, and sulfhydryl groups to open the ring of homogentisic acid.
The condition is inherited as an autosomal recessive disease. No metabolic method for the detection of heterozygotes has been devised; mutation analysis for this purpose is feasible. The molecular basis of alkaptonuria has been demonstrated to be defects in the gene coding for homogentisic acid oxidase (symbol HGO). The AKU and HGO genes are the same and map to human chromosome 3q21-q23; the nucleotide sequence (GenBank U63008) is divided into 14 exons over 60 kb of genomic DNA.
The relationships between the metabolic defect and the complications ochronosis and arthritis remain a challenging research problem of the future. Even though the lack of homogentisic acid oxidase is the ultimate cause of these complications, the mechanisms that bring them about are unknown.
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Alkaptonuria is a rare, hereditary, metabolic disease in which the enzyme homogentisic acid oxidase is missing. Because of this defect, homogentisic acid produced during the metabolism of phenylalanine and tyrosine cannot be further metabolized; instead, it accumulates and is excreted in the urine.
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If urine containing homogentisic acid is allowed to stand for some time, it gradually turns dark as the acid is oxidized to a melaninlike product (Fig. 121-1). The polymerization is speeded by alkali, which explains why washing diapers of alkaptonuric infants with soap tends to make the stains more intense instead of removing them.
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It is not surprising that such an obvious sign as dark urine led to the early recognition of this disease. Several persons reported in the medical literature of the sixteenth and seventeenth centuries who continually passed dark urine are presumed to have had alkaptonuria.1 It is of interest that an Egyptian mummy dated approximately 1500 BC showed the characteristic x-ray changes of alkaptonuria—that is, extensive intervertebral disk calcification and narrowing of the hip and knee joints. Spectral analysis of pigment obtained from the hip region of the mummy resembled closely the reference pigment obtained by oxidation of homogentisic acid.2 Although it was not possible to identify homogentisic acid in the tissues, this may well be the earliest case of alkaptonuria.
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Boedeker described the first patient in whom the diagnosis was made ...