Special thanks to: 

Writer: Sissi Wang, Research Associate, RareShare

Reviewer: Lakshminarayan Ranganath, MD, Royal Liverpool University Hospital, and co-founder and Medical Director of the Alkaptonuria Society in the UK.

Alkaptonuria affects both males and females equally and the condition is very rare. On average, there is about 1 case per 250,000 to 1,000,000 people, but the condition is more common where intermarriage is prevalent.

Alkaptonuria is an autosomal recessive disease. This means that individuals must have two copies of the abnormal gene for the same trait, one from the mother and one from the father. If an individual receives one normal gene and one affected gene, the person will become a carrier for the condition but not affected with it. This case is known as a heterozygous gene pattern. Thus, the risk for two carrier parents to pass to gene and produce an affected offspring is 25% per pregnancy. The risk of inheritance is the same for both males and females. The specific gene that is mutated in the case of this condition is the HGD gene. Normally, HGD contributes to the making of an enzyme called homogentisate dioxygenase, which is responsible for breaking down HGA. With the mutation, however, the acid can not be broken down properly and as a result, accumulates within the body.

The symptoms of alkaptonuria are progressive and generally do not appear until adulthood thus individuals can lead normal childhoods. Generally, urine is dark or turns black with exposure to air. Unusual pigmentation of the ear cartilage and of the sclera (white portion of the eye) may develop. Kidney stones and prostate stones may also form. The disorder also manifests joint pain, causing stiffness and in later stages can cause arthritis. Vertebrae and other bones may fuse together, leading to immobility, a condition called ankylosis. Cardiac complications may also arise, such as arrhythmias and aortic stenosis.

Diagnosis of alkaptonuria is based on patient history, identification of symptoms, and clinical tests. High levels of homogentisic acid in urine and its characteristic dark color indicate the presence of the disease.

In individuals over 40, echocardiography may be recommended to detect potential cardiac complications, such as aortic dilatation or calcification.

Gas chromatography-mass spectroscopy or LC-Tandem mass spectrometry is used to measure the levels of HGA in urine. Molecular genetic testing may also be used to confirm the diagnosis. The clinical impact of alkaptonuria may be assessed with spinal x-rays, to show the calcification of bones and joints; various imaging techniques, to assess joint problems as well as artery calcification; and echocardiography for cardiac complications.

Treatment for alkaptonuria is palliative. Dietary restrictions are beneficial in order to minimize the levels of acid accumulating in the body. Joint pain can be treated with paracetamol and nonsteroidal anti-inflammatory drugs. In severe cases, spinal surgery or joint replacement surgeries are required.

Life expectancy is not significantly reduced, unless cardiac complications arise.

Alkaptonuria. Genetics Home Reference website. http://ghr.nlm.nih.gov/condition/alkaptonuria

Alkaptonuria. Genetic and Rare Diseases Information Center website. https://rarediseases.info.nih.gov/gard/5775/alkaptonuria/case/31676/case-questions

Alkaptonuria; AKU. Online Mendelian Inheritance in Man website. http://omim.org/entry/203500?search=Alkaptonuria&highlight=alkaptonuria

Alkaptonuria. The National Organization for Rare Diseases website. http://rarediseases.org/rare-diseases/alkaptonuria/

Alkaptonuria. OrphaNet website. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=56