alkaptonuria
Alkaptonuria was the first human inborn error of metabolism to be discovered by Garrod. It is an autosomal recessive disorder in which the lack of homogentisic oxidase blocks the metabolism of phenylalanine-tyrosine at the level of homogentisic acid.
Thus, 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 gene encoding homogentisic oxidase, mapped to 3q21, was cloned in 1996, 64 years after the initial description of the disease by Garrod.
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.