Deficiency of homogentisic acid oxidase leads to
discoloration and staining of tissues. Sudden dark urine 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; Alcaptonuria; Hereditary Ochronosis.
1:250,000 live births, with a higher incidence reported
from Slovakia and the Dominican Republic.
Autosomal recessive. The mutation has been
mapped to the homogentisate 1,2-dioxygenase locus on 3q21-q23. Both sexes
are equally affected, but the course of the disease is more severe in men.
The enzyme homogentisic acid oxidase is required
to crack open the benzol ring of phenylalanine and tyrosine to allow for
further degradation. Lack of this enzyme leads to increased amounts of
homogentisic acid (ortho-meta-dihydroxyphenylacetic acid), which is mainly
excreted in high concentrations in the urine; 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
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. 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 and/or
arthrotic symptoms. Yet a brown-black discoloration of the diapers most
often is the first sign of this disorder. Rapid renal clearance of
homogentisate does not prevent it (and related metabolites) from slow
deposition in cartilage and connective tissues throughout the body. However,
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, called ochronosis, and affects the
intervertebral discs, tendons, and cartilage of the (large) joints. After
age 30 years, these depositions may lead to degeneration of the cartilage
and a clinical picture similar to that of rheumatoid arthritis.
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 occurs in
joints, which later in life may lead to periarticular calcifications.
Radiologic changes of the spine (including ruptured intervertebral discs)
have been reported and may resemble osteoarthritis. The presence of pigments
can be detected in sweat and on clothes.
The only manifestation in childhood is darkening
of urine upon standing. In adulthood, there is progressive darkening of
collagenous tissues and cartilage (ochronosis), including the sclerae.
Osteoarthritic signs, a sign of premature cartilage degeneration in these
patients, usually begin in the fourth decade of life. Arthritis involves the
spine, hips, and knees and is progressively disabling. There may be a higher
incidence of ...