Deficiency of homogentisic acid oxidase leads to discoloration and staining of tissues. Dark discoloration of the urine when exposed to air should alert the clinician of the possible presence of homogentisic acid. Valvular heart disease and myocardial ischemia may occur in adults.
Homogentisic Acid Oxidase Deficiency; Homogentisate 1,2-Dioxygenase Deficiency; Alcaptonuria; Hereditary Ochronosis.
1:250,000 live births, with a higher incidence reported from Slovakia (approximately 1:20,000) and the Dominican Republic.
Autosomal recessive. The mutation has been mapped to the homogentisate 1,2-dioxygenase locus on chromosome 3q21-q23. Both sexes are equally affected, but the course of the disease is more severe in males.
Homogentisic acid is an intermediary compound in the metabolism of tyrosine and phenylalanine. The missing enzyme homogentisic acid oxidase is required to crack open the benzol ring of phenylalanine and tyrosine to allow for further degradation. The lack of this enzyme leads to increased amounts of homogentisic acid (ortho-meta-dihydroxyphenylacetic acid), which are mainly excreted in high concentrations in the urine, while the rest is oxidized and polymerized by polyphenol oxidase to toxic benzoquinone acetic acid that irreversibly binds to collagen. Exposition of the urine to air results in slow oxidation of homogentisate to a pigment-like substance, which is responsible for the color change to brown-black. This reaction can be significantly accelerated by alkalinization of the urine and blocked by large doses of ingested vitamin C. However, if the urine is sufficiently acidotic, the discoloration can be so subtle and slow that the disease is not recognized until the affected patient presents with ochronosis (black-bluish discoloration of skin, sclerae and cartilage) and/or arthrotic symptoms. Yet, a brown-black discoloration of the diapers often is the first sign of this disorder. Rapid renal clearance of homogentisate does not prevent it (and its related metabolites) from slow deposition in cartilage and connective tissues throughout the body. Nonetheless, the sclerae and the cartilage of ears and nose usually do not show a detectable blue-black discoloration until adulthood. Polymerization of homogentisate to benzoquinone acetic acid and its deposition into these tissues is responsible for the dark staining (ochronosis) and affects the intervertebral discs, tendons, and cartilage of the (large) joints. After the age of about 30 years, these depositions may lead to degeneration of the cartilage and a clinical picture similar to that of rheumatoid arthritis.
The urine turns black upon exposition to air secondary to the high concentration of homogentisic acid. A pathognomonic sign of this disorder is the dark blue (or brown-black) staining of the sclerae and cartilage, which is most obvious on nose and ears, but also involves larynx, trachea, and joints, which later in life may lead to periarticular calcifications. Radiologic changes of the spine (including narrowed, ruptured, and calcified intervertebral discs ...