Alkaptonuria Health Article

Definition

Alkaptonuria is a rare, inherited disorder characterized by urine that turns dark when exposed to air, dark pigmentation of the cartilage and other tissues, and arthritis.

Description

Alkaptonuria (AKU) (sometimes spelled alcaptonuria) is a disorder in which a substance called homogentisic acid (HGA) accumulates in cells and connective tissues throughout the body. Large amounts of HGA also are excreted in the urine. In a process known as ochronosis, deposits of HGA form dark pigments in the skin, joints, and other tissues of the body. Over the long term, ochronosis leads to ochronotic arthritis, which is a painful inflammation and stiffening of the joints. AKU is also known as homogentisic acid oxidase deficiency, ochronosis, alkaptonuria ochronosis, or ochronotic arthritis.

History

The black urine that characterizes AKU has been recognized throughout history. It sometimes was considered to be a bad omen. The dark pigmentation of ochronosis has been identified in an Egyptian mummy from 1500 B.C.

AKU was one of the first inherited disorders to be identified as a deficiency in a single enzyme in one pathway of the body's metabolism. In 1902, Sir Archibald Garrod, after consultation with the famous geneticist William Bateson, proposed that the inheritance of AKU could best be described by Gregor Mendel's theory of the inheritance of recessive characteristics. These are inherited traits expressed in some of the offspring of parents who both carry the trait. The parents may or may not express the trait. In 1908, Garrod coined the term "inborn error of metabolism" to describe AKU and three other metabolic disorders. Furthermore, he suggested that AKU was due to a deficiency in a specific enzyme, a protein that catalyzes one step of a metabolic pathway.

Homogentisic acid

During normal metabolism, the 20 common amino acids, that are the building blocks of enzymes and other proteins, are broken down into simpler substances. This process provides energy for the body. The amino acids phenylalanine and tyrosine are converted to simpler substances in a series of eight steps. Each step in this pathway occurs through the action of a different enzyme. The first step in the pathway converts phenylalanine to tyrosine. The inherited disorder known as phenylketonuria results from a deficiency in the enzyme that carries out this first step.

AKU results from a deficiency in an enzyme called homogentisate 1,2-dioxygenase (HGD). This enzyme also is called homogentisic acid oxidase. It is responsible for the fourth step in the breakdown of phenylalanine and tyrosine, the conversion of HGA to 4-maleylacetoacetic acid. When there is a deficiency in active HGD, as in AKU, HGA cannot be broken down further. It accumulates in cells and tissues throughout the body, and large amounts of HGA are excreted in the urine.

Oxygen causes HGA molecules to combine with each other to form a very large molecule called a polymer. This polymer is a dark pigment similar to melanin, the pigment responsible for skin color. This pigment is formed in the tissues of the body, as well as in urine exposed to the oxygen in air. Oxygen can also convert HGA into a toxic substance called benzoquinone acetic acid.

HGA is excreted very quickly. In general, levels of HGA are kept quite low in individuals with AKU. Nevertheless, over time, large quantities of HGA, either as individual molecules or as a polymer, are deposited in the cartilage (the flexible tissue of the joints and other bony structures) and in other connective tissues of the body.

Granules of HGA pigment collect around collagen. This is the protein that makes up the fibers of connective tissues. Collagen is the most abundant protein in the body. It is a major structural component of cartilage, bone, tendons, ligaments, and blood vessels. Collagen also forms an important structural layer beneath the skin, and it holds together the cells of various tissues. The accumulation of HGA in connective tissues interferes with the body's ability to make new collagen. As a result, collagen fibers throughout the body are weakened. In particular, HGA weakens the collagen fibers in the cartilage of the joints.

Ochronosis

Most treatment of AKU is directed at the diseased joints. The treatment for ochronosis is the same as for other forms of degenerative arthritis. Treatments include painkillers, physical therapy, rehabilitation, orthopedic supports, and rest. Chiropractic manipulations and exercise regimens also are utilized.

Treatment of ochronotic arthritis eventually may require hip and/or knee joint replacements with artificial materials. In older individuals, fusion of the lumbar discs of the lower spine may be necessary. Aortic valve replacement may be necessary to treat heart disease.