Figure 1. A, Appearance of the urine at the time of the initial void; B, at 24 hours postvoid; C, at 48 hours postvoid.
Alkaptonuria is a rare disorder of tyrosine metabolism inherited as an autosomal recessive trait, with an incidence of 1 in 200 000.1 A deficiency of homogentisic acid oxidase, the cause of this disorder, leads to the accumulation of large amounts of homogentisic acid in the body with subsequent excretion of the acid in the urine. The gene responsible for alkaptonuria has been mapped to the long arm of chromosome 3, 3q2.2
The only clinical sign of this disorder in the pediatric age group is the darkening of urine to an almost black color on standing. The change in coloration, the result of oxidation and polymerization of homogentisic acid, is enhanced in an alkaline urine. An acid urine may not become darkened after standing many hours.
The major clinical features of alkaptonuria are not evident until mid adulthood and are the result of deposition of a blue-black pigment, derived from oxidation of homogentisic acid, in cartilage and connective tissue. The pigment results in degeneration of cartilage, particularly that of the spine and large joints (hips and knees). The arthritis, known as ochronotic arthritis because of the color of the pigment in cartilage, has clinical characteristics of rheumatoid arthritis, but radiologic findings are typical of osteoarthritis.2 Stiffness and discomfort of the back are usually the initial symptoms of the arthritis.
The first evidence of pigment deposition in cartilage and connective tissue is noted in adults in the third and fourth decades of life. A faint slate-gray coloration may be perceived through the skin overlaying the cartilage of the nose and ears.3 Discoloration of the sclera of the eyes may also be noted. Patients with homogentisic acid oxidase deficiency have a higher incidence of heart disease, particularly calcification of the mitral and aortic valves and myocardial infarctions.3
A presumptive diagnosis of alkaptonuria may be made by demonstrating the change in color of standing urine over time. Confirmation is made by measuring the excretion of homogentisic acid in the urine. The addition of oxidizing agents such as silver nitrate, ferric chloride, or Benedict reagent to the urine will enhance the color change to brown-black in less than 48 hours.1 Since homogentisic acid is a strong reducing agent, it will cause a positive reaction with Fehling or Benedict reagent, whereas it will not result in a positive reaction with glucose oxidase. Phenol poisoning and malignant melanoma may result in the passage of dark-colored urine, which is present at the time of voiding rather than developing on standing.
There is no specific treatment for alkaptonuria. Theoretically, the deposition of pigment could be prevented by dietary restriction of phenylalanine and tyrosine to minimal daily requirements. Large doses of ascorbic acid could possibly impede oxidation and polymerization of homogentisic acid. To date, these treatments have not proven efficacious.1
Accepted for publication May 5, 2000.
Reprints: Keith Ancona, MD, Department of Pediatrics, HSC 11 Room 040, SUNY Stony Brook, Stony Brook, NY 11794-8111.
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