Alkaptonuria

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at January 5, 2017
StartDiseasesAlkaptonuria

Alkaptonuria is a rare, hereditary genetic disorder also known as AKU, onchorosis or black urine disease. The most noticeable outward symptoms of the disease include inky blue or black urine and darkening of the skin, cartilage of the ears, and whites of the eyes (sclera).

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Definition & Facts

In most cases, symptoms and complications of the disease do not begin to appear until adulthood. Generally, the only noticeable symptom in childhood is urine which becomes dark or discolored when exposed to air. Occasionally, infants will be asymptomatic and patients will be unaware of the disease until complications arise in adulthood. This disease is incurable, but there are several treatment options available to help manage the symptoms of AKU. 

Alkaptonuria is rare, and numbers of those affected vary by country. It is, however, estimated that only 1 in 1 million births worldwide are affected by the disorder. It is known that people of Slovakian or Dominican descent may be four times more likely to be affected at a rate of 1 in 250,000 births.

The disease is not gender specific and both males and females are affected in equal numbers. Alkaptonuria is an inherited disorder in which mutated genes result in the inability of the body to break down homogentisic acid. The buildup of this acid in the body causes the symptoms and complications associated with AKU. Since it is hereditary, a family history of AKU also increases risk.

Symptoms & Complaints

Alkaptonuria causes a myriad of symptoms. While generally not life threatening, these symptoms can have a profound effect on the quality of a patient's life. Symptoms of AKU usually appear in patients over 30 years of age.

Some who are affected are asymptomatic and unaware they suffer from the disorder until adulthood. Urine that turns dark blue or black when exposed to air is usually the only symptom present in children and young adults. As people with Alkaptonuria age, they may notice darkening of the skin, ears and parts of the eye.

In addition to primary symptoms, Alkaptonuria also has secondary complications. AKU can cause arthritis, joint pain, and limited joint mobility due to calcification of cartilage. This can also lead to difficulty breathing as the synovial joints in the rib cage become less mobile. Other complications include:

Causes

AKU is caused by a mutation of the HGD gene. A single copy of this recessive gene can be passed on to offspring with no effect on the genetic carrier. However, if both parents are carriers, there is a 1:4 chance that offspring will be born with two copies of the genetic mutation. This results in alkaptonuria. This gene mutation impairs the ability of homogentisate oxidase in the body to break down homogentisic acid.

High levels of homogentisic acid cause the symptoms such as brittle bones, heart disease, and kidney stones associated with AKU. As this acid builds up, it accumulates in the connective tissues of the body causing the characteristic discoloration of the bones, skin, cartilage and whites of the eyes. 

Diagnosis & Tests

Alkaptonuria can cause complications similar to symptoms of other disorders, so diagnosis cannot be based on these symptoms alone. For instance, there is a form of onchorosis - related to the use of certain substances but unrelated to alkaptonuria - in which the skin and cartilage will darken. Unlike onchorosis occurring in Alkaptonuria, this form of onchorosis is reversible.

Bone and joint symptoms, such as reduced mobility and pain, may also appear similar to those of ankylosing spondylitis, osteoarthritis or rheumatoid arthritis. To diagnose AKU, a patient will need to see his primary physician for a physical examination and thorough evaluation of medical history.

A urinalysis can be ordered to test the urine for the presence of homogentisic acid which indicates alkaptonuria. Various medical imaging tools may be used to indicate whether a patient shows additional symptoms common to AKU such as cardiac or joint disease. DNA testing can also be done to determine whether the gene mutations that cause AKU are present. 

Treatment & Therapy

AKU is incurable, but those affected can expect longevity comparable to normal life expectancy rates. Quality of life, however, may be profoundly affected. Treatments and therapies for Alkaptonuria focus on symptom management and maintaining quality of life for patients. The disease is most frequently managed through diet, though some studies cast doubt on the efficacy of this method. Patient therapies are tailored to treat the symptoms of individual patients and may include:

Prevention & Prophylaxis

There is currently no way for carriers of the mutated HGD gene to reliably prevent passing on this gene defect to offspring. If both parents are carriers, any offspring produced have a 1:4 chance of being born with alkaptonuria.

Genetic testing for prospective parents and prenatal and fetal testing can help parents assess risks and make informed decisions based on that information. A genetic counselor can help parents sort through family planning options based on genetic testing results and assessed risk.