Alkaptonuria (AKU), or Black Urine/Bone Disease, is caused by the mutation of the HGD gene for the homogentisate 1, 2-dioxygenase enzyme, which maps to chromosome 3 (3q21-3q23). Alkaptonuria is a rare autosomal recessive disorder. Each person carries two HGD genes in their body, which has information to create the homogentisate 1, 2-dioxygenase enzyme (HGD).

HGD is normally found in tissues in the body (ex. liver, kidney, intestines). In Alkaptonuria cases, both copies of the HGD gene inherited by their parents contain abnormalities that result in the body not producing a properly functioning HGD enzyme. Abnormalities can be numerous in the chromosome to stop it from functioning properly. This HGD enzyme is responsible for the metabolism of the chemical alkapton, which darkens upon exposure to air. In alkaptonuria, people have inherited the inability to make a functioning HGD enzyme, which result in the alkapton not being metabolized, and seeps into the body’s cartilage and urine track. There are no environmental influences upon this disease, and it is purely genetic. Patients are usually asymptomatic as children, but black urine can be present from birth.

Pigmentation can also be seen in the cartilage of the ear and around the eye as one grows older. It is not until a patient reaches their thirties that actual symptoms can be seen- such as joint pain, breathing problems and bone mineral deficiency. Alkaptonuria patients are also prone to valvular heart disease, irregular heart rhythms, heart failure, hearing loss, and the development of kidney stones.      Alkaptonuria was the first genetic disease ever identified, and was discovered by Sir Achibald E.

Garrod in 1901. By using urine samples from test subjects and measuring the amount of HGA in them, Garrod recognized Mendel’s principles of heredity (which were new and unproven to relate with humans at the time) could be seen in the case of Alkaptonuria. The heredity hypotheses that Alkaptonuria based on was later proven to be true as biochemists gathered evidence that cells synthesize and degrade most organic molecules through metabolic pathways. The name Alkapturnia is derived from the Arabic word ‘alkali’, which means ‘to suck up oxygen greedily’, and coined by Boedeker in 1859 after discovering unusual properties in the urine of a patient. The oldest case of Alkaptonuria has been diagnosed in the ancient egyptian mummy of Harwa, which dates back to 1500 BCE.      If Alkaptonuria is suspected in a patient, a urine sample can be collected and the amount of homogentisic acid in it can be measured by gas chromatography. Doctors can also use DNA testing to to check for a mutated HGD gene.

Severity of symptoms can be recorded by the AKU Severity Score Index. Levels of seriousness typically depend on how bad patients experience joint pains, as well as the existence of heart and kidney stone problems. Alkaptonuria affects a patient’s bones and cartilage, making them black and brittle. This usually leads to osteoarthritis, also known as degenerative joint disease. Since patients are in constant pain without the help of medication, this can result in them often being in bad or irritable moods.

There is no specific cure for Alkaptonuria, but patients typically undergo joint replacement surgery by age fifty in the shoulder, hip, and knee areas due to the brittleness of the bone and cartilage. Nearly half of Alkaptonuria patients undergo some type of surgery that involve these symptoms. Surgery might also be needed to replace heart valves and to treat kidney or prostate stones. Vitamin C rich diets are recommended and said to lessen the amount of homogentisic acid in the body, but it has not been proven to provide long term safety. Anti-inflammatory medications and narcotics are often prescribed to prevent joint pain, as well as recommendations to see a physical therapist regularly to help maintain flexibility in these problem areas. These treatments can prove costly, as surgeries run around $40,000, not including the added therapy needed to fully recover, which averages to around $100 per session. Insurance ranges from coverages, since some might dent coverage on the disease because it is a pre-existing condition. This could put the financial weight on the patient and family’s shoulder, and make them unable to provide the proper treatment for them.

However, these treatments are proven to help prevent the common issues found in alkaptonuria patients- arthritis, heart disease, and kidney stones.     The normalcy of an AKU patient is affected greatly due to their chronic pain. This can make even the simplest of tasks impossible to do, and can affect sleeping patterns with the amount of discomfort they are in. This can also restrict them in the type of jobs they can pursue, as well as simple household tasks that require too much strain on their joints.

This can be handicapping, and can cause patients to become reliant on other forms of assistance so they can get through their day, such as medications or a human helper. This can take a toll on the individual and family alike, as the patient will always need to be monitored to make sure their symptoms don’t get too much for them to tolerate. As patients age, they will also be prone to become more dependent on their medication, since symptoms worsen as time goes on. This is stressful for the family of course, since there is little they can do to help.

The search for a cure for Alkaptonuria is always ongoing, and being handled by the National Human Genome Research Institute (NHGRI). The National Organization for Rare Diseases also tries to spread awareness and funds for AKU research. AKU has recently been tested with the drug NTBC by the NHGRI, for it has been shown to reduce the amount of HGD in the body.

Research is still being done on this drug to see if it can provide any long lasting effects. There are no specialty AKU treatment centers in the US currently. However, there is one specialty center that is housed in Liverpool, England. The Robert Gregory National Alkaptonuria Centre specializes in treating people with AKU. Organizations such as the Alkaptonuria Society also gives patients a chance to talk with AKU experts if they have any questions regarding their disease.      AKU is a recessive disorder, which means both parents would have to be carriers of an abnormal HGD gene to produce a child with AKU. Because of this, the disease is very rare.

The risk factor that AKU brings in terms of bearing children is the increased risk of offspring getting two recessive abnormal HGD genes, so parents are advised to get DNA tested before they have children to see how likely their child is to develop this disease. Once a child is born, there is no way to prevent Alkaptonuria. Alkaptonuria is estimated to occur in 1 of every 250,000-1 million births.

AKU occurs equally in males and females, but symptoms tend to develop sooner and more severe in males than females. The disease has been reported in all ethnic groups, but is more common in areas of Germany, Slovakia, and the Dominican Republic. It is assumed that there are higher levels of this disease in this area because of its smaller gene pool, but it is still ongoing to find concrete evidence on such.

Risk factors of AKU are purely genetic, and are not influenced by any outside source. Alkaptonuria is a nonfatal disease, with only a handful of deaths being associated to its symptoms.      Support groups for AKU include the Alkaptonuria Society, the Alkaptonuria Society of North America, Children Living with Inherited Metabolic Diseases and Genetic and Rare Diseases Information Center. These groups gather funding for AKU research, as well as raise awareness of the disease. Since it is so rare, there seems to be a low public awareness on AKU, which is why these organizations make it their mission to have AKU patients be heard and provide them the assistance to live a better life. 

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