Dr. Wendy Leu had the first correct answer.


Discussion: Alkaptonuria






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
<http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r1>  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
<http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r2>
CLINICAL FEATURES

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
<http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r2>  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
<http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r3>  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
<http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r3>
DIAGNOSIS

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 <http://archpedi.ama-assn.org/issues/v155n9/ffull/#rc2r1>
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.
TREATMENT

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.


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.