Alkaptonuria: Causes, Disease Mechanism, Symptoms, Diagnosis, Treatment, Prevention

Alkaptonuria is a condition, in which, urine of a person turns dark brownish or blackish in color when it gets exposed to air. It is a genetic condition and a form of disorder under the umbrella of inborn errors of metabolism.

Another characteristic feature of this disorder is the building up of a dark pigment in the connective tissues of the person. Tissues like the bone, cartilage and skin are affected in this. It causes blue black pigmentation in these parts and is usually seen occurring after 30 years of age.

Alkaptonuria is a genetic disorder, caused by defect in a gene responsible for breakdown of certain parts of proteins. The gene named HGD, controls and provides information to produce an enzyme called homogentisate oxidase. This enzyme performs the function of breaking down the amino acids namely phenylalanine and tyrosine that help to build up proteins. In this condition, there occur some genetic changes or mutations in this gene, which disturbs its normal functioning.

As a result of genetic mutations, the abnormal functioning or improper break down of these amino acids leads to excess formation of a substance called homogentisic acid, which further accumulates in the body. This substance or acid along with its related compounds gets deposited in tissues like skin and cartilage, which gives the tissues a characteristic bluish black pigmentation and the process called ochronosis. The excess acid is also excreted in the urine. When urine containing this acid is exposed to air, the acid comes in contact with the air and turns brownish black giving the urine its typical color.

The process of onchronosis, which causes pigmentation and deposition in tissues, makes the bone and the cartilage more susceptible to wear and tear of the joints. This leads to degradation of the cartilage and painful movements of the joints. Over a period of time, the degraded cartilage causes the bones to rub against each other and cause more friction and pain. It can further lead to painful osteoarthritis. Additionally, this excess homogentisic acid can get deposited in the cartilage and tissues of the blood vessels and valves. This can affect the blood flowing through the blood vessels and also increases the risk of heart diseases and related complications.

Alkaptonuria is an inherited condition, present since birth. However, during infancy only the symptom of black urine may be noted. In infants, the diaper with urine, when exposed to air, may appear dark. If allowed to remain for few hours it may even turn black. Sometimes, this typical feature may not be easily evident in all patients.

The other symptoms may begin by adulthood, which could be possibly because the excess accumulation of homogentisic acid in bones and cartilage takes some time, which then shows signs in the later years. These symptoms include:

• Dark pigmentation over skin
• Dark spots in the eye
• Darkening or grayish discoloration of the ear cartilage.
• Back pain
• Reduced joint movements
• Painful joints and arthritis, especially of the spine.
• Fusion of spinal bones with reduced ability to bend.
• Joint effusion or swelling, particularly knees.
• Cardiac involvement may be seen, for example, signs of valvulitis.

The condition can be confirmed by performing urine analysis. The urine test is done using gas chromatography, a specialized test. The urine of persons with this condition will turn black when agents like ferric chloride are added to it.

The complaints of dark urine may not be present in all, hence for suspected cases, a confirmatory test detecting the presence of the enzyme homogentisate may be required.

• Blood tests may be performed for screening of genetic mutations.
• Imaging studies like spinal x-rays to identify disc degeneration, chest radiographs to detect any valvular involvement and scans to detect calcification in arteries may be ordered.
• Electrocardiography may be able to detect abnormalities in functioning of the heart.

Treatment aims at reducing the pigment deposition, which is responsible for further complications. Vitamin C, with its antioxidant nature may play a role in delaying the process of homogentisic acid formation or may be helpful in reducing its deposition in the tissues and thus delay the arthritic process. High doses of vitamin C, around 1 g/d may be advised for adults and older children.

While the involvement of dietary restrictions remain unclear, it may be helpful to restrict the intake of proteins as the amino acids are not properly broken down. A mild dietary protein restriction to reduce the intake of phenylalanine and tyrosine, may be considered, especially in children.

Surgical intervention may be required in elderly patients for fusion of lumbar discs. Joint replacement and valve replacement surgeries may be considered in some patients as appropriate.

Observation of dark colored urine in infants or young children should be promptly evaluated. Genetic counseling for known cases and those with a family history can help. Prenatal tests to detect the condition in the womb may be considered.

For patients of alkaptonuria, following medical advice and regular monitoring can help in early detection and treatment of symptoms. Some of the possible complications include arthritis, heart diseases and kidney or prostate stones, mainly caused by deposition of the excess acid. Following a healthy routine with a balanced meal and restricting high protein intake can help. Regular exercise may be carried out with medical advice.