What is alkaptonuria?

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Alkaptonuria is an inherited autosomal recessive disorder of the degradative metabolism of the amino acid tyrosine. Alkaptonuria describes the excretion in urine of homogentisate, a metabolic product of tyrosine. Urine turns black in air from the oxidation of homogentisate.
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Risk Factors

To have the disorder, a person must have received one defective copy of the gene for homogentisate 1,2-dioxygenase from each parent. The disorder is present from birth and is largely unaffected by treatment or lifestyle. The disease incidence is very rare, except in people whose ancestry is derived from Slovakia or the Dominican Republic.

Etiology and Genetics

In 1902, the physician Archibald E. Garrod called alkaptonuria an “inborn error of metabolism,” meaning an inherited disorder of normal metabolism. This statement for the first time linked human disease with the recently rediscovered rules for the inheritance of traits in pea plants, originally discovered by Gregor Mendel in 1865. Among the hundreds of human genetic diseases that also fit this description are phenylketonuria, galactosemia, and Tay-Sachs disease. Though the terms “gene,” “DNA,” and “enzyme” were unknown in 1902, Garrod correctly implied that a single human gene determined the enzymatic ability to metabolize “alkapton” (now called homogentisate) and that the disease was caused by a defect in the gene. By 1908, Garrod had further identified the human disorders albinism, cystinuria, and pentosuria as inborn errors of metabolism analogous to alkaptonuria.

Alkaptonuria is completely caused by the inherited inability to convert homogentisate, a degradative metabolic intermediate of tyrosine, to its product 4-maleylacteoacetate. The conversion normally occurs mostly in the liver. In persons with alkaptonuria, accumulation of homogentisate in the liver leads to excretion into the blood and ultimately into the urine. Homogentisate deposits may occur in joints and other tissues over time. The enzyme homogentisate 1,2-dioxygenase is responsible for the metabolic conversion. It is encoded by the HGD gene on the long arm of chromosome 3, band 3q13.33. The enzyme is inactive in persons with alkaptonuria as a consequence of defective alleles (gene copies) of the HGD gene, one from each parent. (Parents do not have the disorder, because they each have one normal functioning HGD allele.)

The HGD gene has been cloned and sequenced. Mutations in the form of altered DNA sequence of the coding portion of the HGD gene, leading to amino acid substitutions that alter and inactivate the homogentisate 1,2-dioxygenase protein, have been identified in persons with alkaptonuria. Mutations at different locations in the HGD gene have been found in alcaptonurics living in the United States, Slovakia, Spain, Finland, Iraq, and Turkey, clearly indicating that the mutations and the disease arose multiple times in human history independently.

In most of the world, the incidence of alkaptonuria is between 1 in 250,000 and 1 in 1 million births, as reported by geneticists Wendy Introne and William Gahl. The defective gene frequency is highest in populations whose ancestry is derived from Slovakia and the Dominican Republic. In Slovakia and the Dominican Republic, the disease occurs about once in 19,000 births, according to A. Zatkova et al.


The outstanding sign of the disease is urine that turns black shortly after excretion. Discolored urine may be the only sign in infants and young children. Homogentisate is colorless, but air oxidation leads to a melanin-like dark pigment. Other signs and symptoms, especially in older children and adults, derive from homogentisate deposits in cartilage (ochronosis) and include dark earlobes, dark sclera of the eyes, joint and lower back pain, and kidney stones. Homogentisate deposits damage cartilage, and joint deposits can cause osteoarthritis. Deposits may also damage heart valves.

Screening and Diagnosis

Infants may be diagnosed because of a black or brown urine-stained diaper. Confirmation requires measuring significant homogentisate levels in blood plasma or urine. As for many genetic disorders, one aid in diagnosis is another person in the same family or a close relative who has the disease.

Treatment and Therapy

No effective treatment has been demonstrated for alkaptonuria. Dietary restriction of phenylalanine (as for phenylketonuria) and tyrosine has been tried. Large doses of ascorbic acid (vitamin C) have been tried, on the idea that the vitamin can help prevent homogentisate deposits. Treatment with the herbicide nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, an enzyme that also generates homogentisate, has also been tried, but the drug may be toxic over the long term. Joint stiffness can be delayed by low- or moderate-impact exercise and physical training. Surgery can replace knee, hip, and shoulder joints damaged by arthritis in older adults. Monitoring can be done to check for cardiac or urologic complications.

Prevention and Outcomes

A family that already has a child with alkaptonuria identifies the parents as a “couple at risk,” who have a 25 percent chance with each pregnancy of having a child with alkaptonuria. Prenatal diagnosis and the option of abortion are feasible for these couples. Further pregnancies have a 75 percent chance of a child without alkaptonuria, which genetic testing can confirm. Prevention by routine genetic testing to identify couples at risk is not feasible in most populations, because the disease is so rare.


"Alkaptonuria." MedlinePlus. US National Library of Medicine, 7 May 2013. Web. 10 July 2014.

Bearn, A. G. “Inborn Errors of Metabolism: Garrod’s Legacy.” Molecular Medicine 2 (1996): 271–73. Print.

Garrod, Archibald E. “The Incidence of Alkaptonuria: A Study in Chemical Individuality.” Yale Journal of Biology and Medicine 75 (2002): 221–31. Print.

Introne, Wendy J., and William A. Gahl. "Alkaptonuria." GeneReviews. U of Washington, Seattle, 22 Aug. 2013. Web. 10 July 2014.

Korf, Bruce R., and Mira B. Irons. Human Genetics and Genomics. 4th ed. Oxford: Wiley-Blackwell, 2013. Print.

Zatkova, Andrea. "An Update on Molecular Genetics of Alkaptonuria (AKU)." Journal of Inherited Metabolic Disease 34.6 (2011): 1127–36. Print.

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