Alkaptonuria (AKU) is a rare autosomal recessive disorder with an incidence of 1:250 000 to 1:1000 000 live births. AKU is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGO). This enzyme converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. Accumulated HGA is rapidly cleared in the kidney and excreted in the urine. HGA blood levels are kept very low through rapid kidney clearance, but over time HGA is deposited in cartilage throughout the body and converted to a pigment-like polymer. This occurs through an enzyme-mediated reaction in collagenous tissues like ligaments, tendons, cartilage, and sclera.
As a result, AKU has three major features:
- Darkening of the urine upon contact with air. HGA is oxidized to form a pigment-like polymeric material responsible for the black color of standing urine, or after exposure to an alkaline agent.
- Ochronosis (bluish-black pigmentation of connective tissue). Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis
- Brown pigmentation of the sclera which does not affect vision, blue or gray discoloration and calcification of ear cartilage, possible discoloration on the skin of the hands, corresponding to underlying tendons and gray and black discoloration of cartilages in the joints.
- Arthritis. It often begins in the spine. Degenerative changes, mainly in intervertebral disks, may be seen throughout the entirety of the vertebral column, where the lumbar spine is the most commonly affected region. With progression of the disease it may cause changes resembling those of ankylosing spondylitis. Patients may complain of stiffness in their lower back with no other symptoms or signs of lumbar spine disease. The culprit of spinal abnormalities could possibly be disk space narrowing, widespread disk calcifications and mild osteophytosis with minimal calcification of the intervertebral ligaments. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and infrequent osteophyte formation. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years.
Pigment deposition can be also seen in heart endocardium, valves, and kidneys. Therefore, patients may have valvular disease, nephrolithiasis, and other renal complications in the advanced age.
Impaired renal function can accelerate the development of arthritis and ochronosis due to inability to excrete HGA and worsen the progression of the disease. By around age 60, 50% of individuals with alkaptonuria have a history of renal stones.