The defect lies in the catabolic pathway of tyrosine, which contains a

parahydroxylated ring structure. In a poorly understood complex reaction, the

enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic
acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the
ring. The product, homogentisic acid, is actually ortho-meta-dihydroxyphenylacetic
acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase (HGO)
forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney
and excreted.[2, 3]
Upon contact with air, homogentisic acid is oxidized to form a pigmentlike polymeric
material responsible for the black color of standing urine. Although homogentisic
acid blood levels are kept very low through rapid kidney clearance, over time
homogentisic acid is deposited in cartilage throughout the body and is converted to
the pigmentlike polymer through an enzyme-mediated reaction that occurs chiefly
in collagenous tissues. As the polymer accumulates within cartilage, a process that
takes many years, the normally transparent tissues become slate blue, an effect
ordinarily not seen until adulthood.
The earliest sign of the disorder is the tendency for diapers to stain black.
Throughout childhood and most of early adulthood, an asymptomatic, slowly
progressive deposition of pigmentlike polymer material into collagenous tissues
occurs.
In the fourth decade of life, external signs of pigment deposition, called ochronosis,
begin to appear.
The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative
of widespread staining of the body tissues, particularly cartilage. The hips, knees,
and intervertebral joints are affected most commonly and show clinical symptoms
resembling rheumatoid arthritis. Because of calcifications that occur in these sites,
however, the radiologic picture is more consistent with osteoarthritis.
Despite many speculations that this polymer deposition is associated with cardiac
pathology, no reports of mortality directly related to the homozygous state for
alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus
leading to coronary artery disease, and the risk of myocardial infarction is higher
than normal in older patients with ochronosis. [4]
Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although
no correlation has so far been made between the molecular nature of
theHGO mutation and its clinical phenotype, the wide variability of mutational
phenomena could certainly help explain the clinical variability in this disease.
Approximately 70 separate mutations have thus far been reported.
Frequency
United States
As Garrod suggested, alkaptonuria is an autosomal recessive genetic trait, although
an autosomal dominant transmission pattern in 3 generations in a
nonconsanguineous family has been reported. [5] The true frequency of alkaptonuria
cannot be given with certainty for numerous reasons. These include the fact that
newborn screening for alkaptonuria is much less widely practiced than that
for phenylketonuria. Guidelines for phenylketonuria screening have been well
established.[6]
Also, some carriers express 50% or more of normal enzyme activity and do not
manifest abnormal findings even with tyrosine loading. To further complicate this

picture, reports in the literature indicate wide variability in incidence, particularly

where gene pools are highly restricted. In certain areas, an incidence rate as high as
1 in every 25,000 live births has been reported; worldwide it is certainly far lower.
Mortality/Morbidity
Life expectancy is normal; however, associated morbidity can be significant. Early
involvement of the intervertebral discs at the thoracic and lumbar levels is very
common, occurring in approximately 50% of affected individuals. Typically,
significant back pain begins from age 30 years. The large joints (knee, shoulder and
hip) are very frequently involved; at least half of all patients undergo joint
replacement by the middle of the sixth decade of life. Achilles tendon involvement
is also common and may result in tearing. Involvement of the aortic leaflets, mitral
valve leaflets, or both is common, and calcifications of the coronary arteries occurs
in one half of all patients prior to age 60 years.
Sex
The distribution of this disease is equal in males and females because it is an
autosomal recessive or autosomal dominant trait. Males tend to have an earlier
onset of arthritic symptoms with a greater degree of severity than females,
although the reason for this difference is unclear.

Age
Because alkaptonuria is a genetic disorder, the deficiency of the HGO enzyme is
present from conception. Clinical symptoms, aside from dark-stained diapers, are
generally present only after the third decade of life.
WORK UP

In patients with alkaptonuria, homogentisic acid can be identified in urine

using gas chromatography mass spectroscopy. Spectrophotometric quantitation
shows 2 orders of magnitude elevations above normal.
Because many patients present without dark urine, looking for homogentisate
in all patients with radiographic evidence of osteoarthritis may be advisable.
After DNA extraction from whole blood, screening for mutations can be
performed with polymerase chain reaction (PCR) technique.
Spinal radiography reveals disk degeneration combined with dense
calcification, particularly in the lumbar area.
Chest radiography is advised to assess for possible involvement of aortic or
mitral valves.
In affected individuals older than 55 years, CT scanning may provide
evidence of coronary artery calcifications.
Electrocardiography may be advisable, with particular attention directed at
any signs of myocardial insufficiency.
Other studies and procedures should be directed at the joint disease itself.
Joint replacements may become necessary in severely affected larger joints.

In association with the gross visual finding of black-stained cartilage in

various areas of the body (eg, larynx, costochondral junctions, trachea), microscopic
examination reveals pigment deposition within and outside cells in these tissues.
No specific stain is available to distinguish homogentisate-derived pigment
from melanin, and the 2 compounds have similar solubility characteristics.
In infancy, a history of dark-stained diapers should alert the physician to
alkaptonuria.[7]
Infants, young children, and asymptomatic young adults can be evaluated
with simple urine testing on an outpatient basis.
Medical therapy is used to ameliorate the rate of pigment deposition. This
minimizes articular and cardiovascular complications in later life.
Reduction of phenylalanine and tyrosine has reportedly reduced homogentisic
acid excretion. Whether a mild dietary restriction from early in life would avoid or
minimize later complications is not known, but such an approach is reasonable.
Vitamin C, as much as 1 g/d, is recommended for older children and adults.
The mild antioxidant nature of ascorbic acid helps to retard the process of
conversion of homogentisate to the polymeric material that is deposited in
cartilaginous tissues.
Limited use of nitisinone, an inhibitor of the enzyme 4hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic
acid, has been reported. Urinary homogentisate excretion was markedly reduced,
but safety of prolonged use is still an open question.
Reduction of phenylalanine and tyrosine reportedly reduced homogentisic
acid excretion in the urine of a child. In an adult, a similar restriction reportedly had
no effect on excretion of the abnormal metabolite. Whether a mild dietary
restriction from early in life would avoid or minimize later complications is not
known, but such an approach is reasonable.
Vitamin C, as much as 1 g/d, is recommended for older children and adults.
No medications are known to be useful in managing alkaptonuria. Vitamin C, as
much as 1 g/d, is recommended for older children and adults.

Life expectancy is normal.

Risk of myocardial infarction later in life is increased.
No treatment modality has been unequivocally demonstrated to reduce the
complications of alkaptonuria. Commonly recommended treatments include large
doses of ascorbic acid(vitamin C)and dietary restriction of phenylalanine and
tyrosine. Dietary restriction may be effective in children, but benefits in adults have
not been demonstrated.
The herbicide nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme
that generates homogentisic acid from 4-hydroxyphenylpyruvic acid. This reduces
homogentisic acid. The main side-effect is irritation of the cornea, and there is a
concern that it will cause the symptoms of hereditary tyrosinaemia type III because
of the possible accumulation of tyrosine or other intermediaries.

In a patient who underwent a liver transplant for an unrelated problem, alkaptonuria

resolved and joint disease stabilised after the transplant, confirming that the liver is
the main site of homogentisic acid production in alkaptonuria
Alkaptonuria, an autosomal recessive disorder, was first described by Garrod in
1902.[2] In 1908, Garrod coined the term inborn error of metabolism and proposed
that alkaptonuria resulted from the deficiency of an enzyme that normally splits the
aromatic ring of homogentisic acid. The deficient enzyme was identified by La Du et
al. in 1958.[3] Pollak et al. mapped the alkaptonuria gene to the chromosome 3q2.
Sixty-seven mutations of the alkaptonuria gene have been identified upto date.
Alkaptonuria is due to the deficiency of homogentisic acid oxidase, resulting in
accumulation in the tissues of homogentisic acid, an intermediate metabolite of
phenylalanine and tyrosine metabolism. As homogentisic acid accumulates both
intracellularly and extracellularly, it is oxidized to benzoquinone acetate, which
polymerizes to form melanin-like polymers, resulting in widespread deposition in
fibrous tissue and cartilage. Some of the homogentisic acid is excreted in the urine.
Since homogentisic acid has affinity to alkalis, it was named as alkapton and the
condition as alkaptonuria.[4]
One of the first symptoms of alkaptonuria is darkening of urine on standing (due to
the oxidation of homogentisic acid). In most pediatric patients, darkening of urine is
the only feature suggesting alkaptonuria.[5] The patients are usually asymptomatic
until the 3rd decade. Scleral pigmentation (Osler's sign) usually starts around the
3rd decade. Skin pigmentation becomes obvious in the 4 thdecade. Pigmentation is
more in areas exposed to light and where sweat glands are located. One of the first
sites to be affected is the ear cartilage. There may be discoloration of the forehead,
cheeks, axilla, genitalia, palms, and soles.[4] Brown staining of the nails is seen.
Histopathology shows ochronotic pigment deposits within collagen bundles, leading
to swelling and homogenization of the bundles. Some bundles show jagged or
pointed ends. The ochronotic pigment deposits in the dermis show a yellow or ochre
color in sections stained with hematoxylin and eosin, from where ochronosis derives
its name.
Ochronotic arthropathy starts around the 4th decade. Weight-bearing joints like the
knees and the intervertebral joints in the spine, as well as the shoulder joints, are
involved, with narrowing of joint spaces and disc calcifications. Arthritis is the only
disabling effect of this condition and occurs in almost all patients as age advances.
[4] Ochronotic arthropathy can be so severe as to require total joint replacement.
Pigment deposits can be seen in the larynx, tonsils, esophagus, dura mater,
eardrums, trachea, and bronchi. Aortic or mitral valvulitis, calcification of coronary
arteries and atherosclerotic plaques are seen after the age of 50 years. Pigment
deposits can form stones in the prostate, urethra, and kidneys due to high urinary
homogentisic acid excretion. The endocrine organs, central nervous system and
teeth can also be affected.
The diagnosis is confirmed by the identification and quantification of homogentisic
acid in urine using gas-liquid chromatography. The levels of homogentisic acid are
increased in the blood, urine, and tissues. Screening for mutations is done after
extracting the genomic DNA from whole blood and subjecting it to PCR.[1]

Active surveillance for cardiac, renal, and prostate complications should be done
after the 4th decade. No effective therapy is available for the treatment of
alkaptonuria at present. Dietary restriction of phenylalanine and tyrosine play a
limited role in reducing the excretion of homogentisic acid. Foods to be avoided
include milk, meat, poultry, egg, cheese, and nuts. Diet may prevent further
progression of arthropathy.
Vitamin C (ascorbic acid), an antioxidant given in the dose of 500 mg twice daily,
inhibits the polymerization of homogentisic acid and can be prescribed, but its
efficacy has not been proven.
Nitisinone, a triketone herbicide, has shown to significantly reduce the excretion of
homogentisic acid by inhibiting the enzyme 4-hydroxy phenylpyruvate dioxygenase
that is responsible for the synthesis of homogentisic acid. Side effects include
elevated levels of tyrosine and corneal irritation. Long-term studies are needed
regarding its safety profile and efficacy.