The normal HGD enzyme is a hexamer (it has six subunits) that are organized in two groups of three (two trimers) and contains an iron atom. Different mutations may affect the structure, function, or solubility of the enzyme. Very occasionally, the disease appears to be transmitted in an autosomal-dominant fashion, where a single abnormal copy of HGD from a single parent is associated with alkaptonuria;  other mechanisms or defects in other genes possibly are responsible in those cases. The HGD enzyme is involved in the metabolism (chemical processing) of the aromatic amino acids phenylalanine and tyrosine. Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body. Tyrosine is specifically required for a number of functions, such as hormones (e.g. thyroxine, the thyroid hormone), melanin (the dark pigment in the skin and hair), and certain proteins, but the vast majority (over 95%) is unused and is metabolized through a group of enzymes that eventually generate acetoacetate and malate. In alkaptonuria, the HGD enzyme cannot metabolize the homogentisic acid (generated from tyrosine) into 4-maleylacetoacetate, and homogentisic acid levels in the blood are 100-fold higher than would normally be expected, despite the fact that a substantial amount is eliminated into the urine by the kidneys.The homogentisic acid is converted to the related substance benzoquinone acetic acid  which forms polymers that resemble the skin pigment melanin. These are deposited in the collagen, a connective tissue protein, of particular tissues such as cartilage.
Alkaptonuria is a rare inherited genetic disease which is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5); if a person inherits an abnormal copy from both parents (it is a recessive condition), the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth. Apart from treatment of the complications (such as pain relief and joint replacement for the cartilage damage), the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more common in Slovakia and the Dominican Republic. Signs and symptoms
Patients with alkaptonuria are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear and other cartilage, and the sclera and corneal limbus of the eye.After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees.