ALKAPTONURIA: THE RARE DISEASE THAT TURNS URINE BLACK
Have you ever wondered what causes black urine? If you have, you might be interested in learning about a rare genetic disorder called Alkaptonuria, alternatively known as black bone disease or black urine disease.
What is Alkaptonuria?
Alkaptonuria (AKU) is a very rare genetic disease that affects about 1 in 250,000 to 1 million people worldwide. People with Alkaptonuria lack an enzyme that breaks down a byproduct of tyrosine called homogentisic acid (HGA). As a result, HGA accumulates in the body and causes urine to darken or turn black when exposed to air for several hours.
The disease is inherited in an autosomal recessive manner, which means that both parents must carry a mutated copy of the gene. When this happens, there is a 25% chance that a child born of these parents will develop Alkaptonuria.
Black urine is the most distinctive symptom of Alkaptonuria, occurring when urine is exposed to air, allowing for HGA to oxidize. The urine color may vary depending on the amount of HGA and the pH of the urine.
Some of the HGA builds up in the system, turning cartilage and bones black (hence black bone disease). HGA depositions also increase bodily inflammation and can give rise to painful symptoms and other problems.
Other common symptoms of Alkaptonuria include:
- Blue, grey or blackish discoloration of the skin, outer ears or sclera (white part) of the eyes
- Joint pain and stiffness
- Reduced mobility
- Sleep problems
- Breathing issues
Long-term accumulation of HGA frequently leads to other comorbidities, the most common of which is osteoarthritis. This affects the joints, causing them to lose their protective features and ultimately reduces bone density and strength.
Secondary Amyloidosis is another possibility that may affect those with AKU later in life. HGA depositions in the blood vessels, heart wall and lungs can cause cardiac myopathy and breathing problems.
What Causes Black Urine Disease?
Black urine disease is caused by a specific gene mutation to the HGD gene located on chromosome 3. HGD stands for homogentisate 1,2-Dioxygenase, which is the enzyme responsible for the breakdown of HGA. There are more than 100 different mutations on the HGD gene that can cause Alkaptonuria.
In the usual scenario, HGA is broken down with HGD into maleylacetoacetate, which goes on to form fumarate, an intermediate involved in energy and protein metabolism. In AKU, HGD is ineffective, causing HGA to be excreted into urine or to buildup in the system. When oxidized, it is converted to benzoquinone acetic acid, which is responsible for the blue-black discoloration of the bones, joints, skin and eyes, as well as other symptoms and complications.
Diagnosis of Alkaptonuria
Diagnosis usually occurs when the patient first becomes aware of their symptoms. AKU may be suspected during early infancy or childhood due to darkening urine stains, although this is easy to overlook and may not affect all with the disorder. Discoloration of skin, nails and eyes is commonly recognized during the patient’s 20s-30s. Symptoms of pain may only present during the patient’s 30s or 40s.
Urine testing is the gold standard for diagnosing AKU and can be performed via gas chromatography. If HGA is found in the urine, the diagnosis can be confirmed through genetic testing. Blood tests may also confirm the diagnosis, as blood levels of HGA are known to rise up to 100-fold in those with AKU.
Alkaptonuria Treatment and Management
There is no cure for Alkaptonuria. Researchers are currently looking to develop novel therapeutics that aim to replace HGD or inhibit HGA oxidation. Due to the rarity of the disease, research efforts are slow.
Nitisinone is a drug recently approved to inhibit the enzyme that converts tyrosine to HGA, thus reducing the amount of HGA in the body. It has been shown to lower HGA levels by as much as 95% and improve urine color in people with Alkaptonuria. Nitisinone can cause side effects such as eye inflammation and skin light sensitivity. It may also increase the risk of depression and Parkinson’s disease.
Other treatment for Alkaptonuria includes:
- Low Tyrosine Diet: Reducing the intake of foods that contain tyrosine or phenylalanine (another amino acid that can be converted to tyrosine) can help lower the production of HGA and slow down its accumulation in the body. As tyrosine is found in many foods such as cheese, meat, nuts, and soy, this suggestion may be difficult to follow, although patients usually benefit from restricting protein-heavy foods. No dietary changes have been proven sufficient to prevent bone and cartilage damage in later life.
- Antioxidant Supplementation: Taking antioxidant supplements such as Vitamin C, zinc, selenium, and cysteine may help reduce the oxidation of HGA and prevent its deposition in the tissues. However, there is very little research available to support the effectiveness of these supplements.
- Symptom Relief: Some with Alkaptonuria require medications to combat transient symptoms associated with the condition, such as over-the-counter painkillers, anti-inflammatories, sleeping pills, and antidepressants.
- Joint and Valve Replacement Surgery: For people with severe arthritis and joint damage caused by Alkaptonuria, joint replacement surgery may be an option to restore function and mobility. If amyloidosis develops, patients may go on heart medication and eventually require valve replacement surgery.
AKU is not usually a life-threatening disease and those with the condition generally have a normal life expectancy. 
The disease may begin to catch up with them during their 40s and 50s, affecting the bones and joints and lowering the quality of life. They may require walking aids at younger ages than most individuals with osteoarthritis and could contract heart or lung comorbidities earlier than most as well.
Alkaptonuria is a rare disease that illustrates how a single gene mutation can have profound effects on the body. While not life-threatening, Alkaptonuria can lead to osteoarthritis and other diseases at earlier ages, which can greatly detract from the quality of life. Nitisinone is currently used to treat the condition with great success, alongside dietary changes and symptom management.
-  https://www.ncbi.nlm.nih.gov/books/NBK1454/
-  https://rarediseases.info.nih.gov/diseases/5775/alkaptonuria
-  https://pubmed.ncbi.nlm.nih.gov/37404676/
-  https://pubmed.ncbi.nlm.nih.gov/30049652/
-  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058836/
-  https://www.britannica.com/science/alkaptonuria
-  https://akusociety.org/information-and-support/nitisinone/
-  https://www.nhs.uk/conditions/alkaptonuria/
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