Alkaptonuria

Alkaptonuria is an inherited condition characterized by the buildup of dark pigment in connective tissues, leading to arthritis, dark urine, and potential complications in the heart and kidneys.

Overview

Alkaptonuria is an inherited condition that causes arthritis, kidney stones, spots of dark pigmentation, and dark urine. Ochronosis, a buildup of dark (blue-black) pigment in certain tissues, is a characteristic feature of the condition. The first symptom is often urine that turns black or very dark when exposed to air (oxidation), though this color change may not occur immediately after urination.

Symptoms

Pigment changes are usually evident after age 30 and can be seen in the whites of the eyes (sclera), the ears, and the hands. Dark pigment can also be found in earwax and sweat. Other symptoms include:

• Arthritis: Typically develops in early adulthood, affecting the spine and large joints like the hips and knees.
• Calcification: Pigment deposits can harden, making joints and ligaments rigid, brittle, and prone to damage.
• Heart Valve Issues: Calcification of the cartilage in heart valves can lead to stenosis (narrowing) and regurgitation (leaking).
• Kidney and Prostate Issues: The body’s attempt to remove excess pigment can strain the kidneys, potentially leading to renal failure or the development of calcium stones.

With appropriate medical management, people with alkaptonuria generally have a normal life expectancy.

Frequency

Alkaptonuria is rare, affecting 1 in 250,000 to 1 million people in the United States. It is more common in certain areas of Slovakia (incidence of about 1 in 19,000) and in the Dominican Republic.

Causes

Variants in the HGD gene cause alkaptonuria. This gene provides instructions for making an enzyme called homogentisate 1,2-dioxygenase, which is responsible for breaking down the amino acids phenylalanine and tyrosine.

• Variants in the HGD gene result in an enzyme that does not function well.
• Homogentisic acid accumulates in the body instead of being broken down.
• Excess acid settles in connective tissues, forming ochronotic pigment, which darkens skin and cartilage and leads to calcification.

Inheritance

This condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell must have a variant to cause the disorder. Parents of an affected individual each carry one copy of the altered gene but typically do not show symptoms.