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alkaptonuria

Saturday 28 January 2006

Definition: Alkaptonuria is an autosomal recessive disorder in which the lack of homogentisate 1,2-dioxygenase (EC 1.13.11.5) blocks the metabolism of phenylalanine-tyrosine at the level of homogentisic acid.

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Alkaptonuria was the first human inborn error of metabolism to be discovered by Garrod. The gene encoding homogentisic oxidase, mapped to 3q21, was cloned in 1996, 64 years after the initial description of the disease by Garrod.

Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which participates in the degradation of tyrosine.

As a result, a toxic tyrosine byproduct called homogentisic acid (or alkapton) accumulates in the blood and is excreted in urine in large amounts(hence -uria).

Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones. Treatment with nitisinone, which suppresses homogentisic acid production, is being studied. Alkaptonuria is more common in Slovakia and the Dominican Republic than in other countries.

Pathophysiology

Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid. Hepatic homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate.

Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified.

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.

Homogentisic acid accumulates in the body. A large amount is excreted, imparting a black color to the urine if allowed to stand and undergo oxidation.

The retained homogentisic acid selectively binds to collagen in connective tissues, tendons, and cartilage, imparting to these tissues a blue-black pigmentation (ochronosis) most evident in the ears, nose, and cheeks.

The most serious consequences of ochronosis, however, stem from deposits of the pigment in the articular cartilages of the joints. In some obscure manner, the pigmentation causes the cartilage to lose its normal resiliency and become brittle and fibrillated.

Wear-and-tear erosion of this abnormal cartilage leads to denudation of the subchondral bone, and often tiny fragments of the fibrillated cartilage are driven into the underlying bone, worsening the damage.

The vertebral column, particularly the intervertebral disc, is the prime site of attack, but later the knees, shoulders, and hips may be affected. The small joints of the hands and feet are usually spared.

The metabolic defect is present from birth, but the degenerative arthropathy develops slowly and usually does not become clinically evident until the thirties. Although it is not life-threatening, it may be severely crippling.

See also

- ochronosis
- tyrosinemia