Alkaptonuria is a genetic disorder in which the urine of the patient turns black once exposed to air. One of its important characteristic is Ochronosis, a condition that leads to dark pigment accumulation in connective tissues like cartilage and skin.
The disease is also referred to by the following names:
- Homogentisic Acid Oxidase Deficiency
- Black Urine Disease
- Homogentisic Acidura
The condition was first described by English physician Sir Archibald Edward Garrod, who stated that it results from intermediate buildup due to metabolic deficiencies. A 1977 study found evidences of the disorder in an ochronotic Egyptian mummy.
The disorder arises in approximately 1 in every 250,000 to 1,000,000 people all over the world. The condition can affect individuals from any country and ethnic group. However, its prevalence statistics shows that it is more common among the population of Dominican Republic and Slovakia. One in every 19,000 Slovak is affected by Black Urine Disease.
Family history is the only known risk factor for Homogentisic Acidura. Mutations in the HGD gene are the principal cause of this hereditary disease. The mutation causes defects in the homogentisate 1,2-dioxygenase enzyme which hampers the breakdown of tyrosine. Due to these factors, the homogentisic acid, along with its oxide named alkapton, starts accumulating in the blood of patients and are passed in considerable amounts with urine.
The HGD gene controls the instruction for making the homogentisate Oxidase enzyme. This enzyme plays an important role in breaking down the important protein building blocks tyrosine and the amino acids phenylalanine. The HGD gene mutations impair the functioning of the enzyme. Consequently, the homogentisic acid that is produced as tyrosine and phenylalanine (that are broken down) builds up inside the body. The excessive homogentisic acid and other similar compounds accumulate in the connective tissues, leading to darkening of the cartilage and skin. It can result in various other health problems over time. The acid is also passed along with urine which makes the urine turn dark once exposed to air.
It follows an autosomal recessive inheritance pattern, meaning that a patient inherits one copy of the abnormal gene from each parent which causes the disorder. Although parents of Alcaptonuria patients are carriers of the mutated gene, they do not usually develop the symptoms themselves.
Alkaptonuria Signs and Symptoms
The symptoms depend on the severity of the condition and also the age of the patient. In many cases, it remains asymptomatic. The common signs and symptoms include:
- Pigmentation of the sclera of eyes (usually at an advanced age) leading to dark blots on the white area of the eyes
- Skin darkening, especially in around the sweat glands and in the sun-exposed areas
- Brown colored sweat
- Arthritis (especially of the spine)
- Brown or black coloration of urine if left exposed in air after collecting it
- Darkening of ears
- Kidney stone formation
- Stone in the prostate
The homogentisic acid buildup in tissues and cartilage leads to several serious symptoms and health problems. It leads to cartilage damage in various parts of the body including the spine, shoulder and hip which result in lower back pain in young individuals. Black Urine Disease can cause mild to moderate mental retardation in some rare cases.
The condition can lead to various valvular heart problems such as regurgitation and calcification of the aortic valve and the mitral valve. This disease may also accelerate the development of coronary artery disease in the patients.
Physicians perform a thorough physical examination and ask various questions to patients regarding the symptoms present in them. Diagnostic tests used for this purpose include thin layer chromatography and paper chromatography. Both the urine and blood plasma are used for making the diagnosis. Urinalysis and blood tests are performed to detect any sign of homogentisic acid in the patient’s urine. Homogentisic acid is completely absent from both urine and blood plasma if the individual does not have Alcaptonuria. However, people with the disorder have average urine levels of 3.12 mmol/ mmol of creatinine. Their average plasma levels are 6.6 micrograms/ ml.
Sometimes, ferric chloride is added to the urine sample to check if it turns black after coming in contact with compound. This test is very useful for making the diagnosis. Other diagnostic procedures like radiology and x-ray may also be useful for detecting spinal and other abnormalities. Newborn screening is usually not done for AKU.
Alkaptonuria Differential Diagnosis
A diagnostician should eliminate the possibility of the conditions mentioned below during the diagnosis of Black Urine Disease, as they can give rise to similar symptoms and make detection confusing for physicians:
- Mitral Valve Insufficiency
- Acute Porphyria
- Degenerative Osteoarthritis
- Lumbosacral Arthritis
It is not possible to treat the underlying causes of this genetic condition. Patients are generally prescribed high dosages of Vitamin C (ascorbic acid) as it has been proved to be useful for reducing the accumulation of homogentisic acid in cartilage. Vitamin C may also decelerate the progress of Arthritis.
Some patients may require physical therapy for maintaining the flexibility and strength of the muscles. Physiotherapy is also necessary for long term management of the joint pain resulting from Alcaptonuria. Non-weight-bearing exercises like swimming can also be beneficial. It is advisable for the patients to avoid putting stress and pressure on the spine and the major joints. Due to this reason, it is never recommended for AKU patients to take part in high-impact sports. Individuals with severely damaged joints require joint replacement therapy while kidney and prostate stones are treated with stone elimination surgery.
Dietary restrictions of tyrosine and phenylalanine also help to manage this disorder. However, these dietary restrictions have been proven to be more effective in children compared to adult patients.
Nitisinone therapy is another possible treatment option. The herbicide nitisinone suppresses the functioning of 4-hydroxyphenylpyruvate dioxygenase, an enzyme responsible for producing homogentisic acid from the 4-hydroxyphenylpyruvic acid. In this way, it reduces the amount of homogentisic acid in the body of a patient. However, the usefulness of this treatment is still under scrutiny as it leads to various side effects.
Current research suggests that gene therapy can be a useful treatment procedure for AKU.
The prognosis is usually positive with proper and timely treatment. Patients are allowed to participate in all normal daily activities after the treatment completes. Individuals with the disease generally have a normal life expectancy. However, Alcaptonuria is also associated with considerable morbidity due to the serious complications arising from it. The spinal disks and large joints of the patient suffer gradual degeneration, which may result in physical disability and loss of mobility.
No preventive measures are known to help avoid the development of this condition. This is because the exact etiology behind the gene mutation is not known. Research is being carried out by experts to determine whether it possible to prevent it. Couples with a family history of the condition should consider genetic counseling and gene reviews to understand the chances of having a child with AKU.
Alkaptonuria Support Groups
Various organizations have been established to provide facts and information regarding AKU to help the patients fight with the genetic condition properly. Some of these are mentioned below:
The Alkaptonuria Society
Room 2354B, 4th floor
Duncan Building Royal Liverpool University Hospital
Daulby Street, Liverpool L69 3GA
Phone: 011 44 151 706 4387 (from U.S.)
The Genetic and Rare Diseases Information Center
P.O. Box 8126
Gaithersburg, MD 20898-8126
Fax: (301) 251-4911
Phone: (888) 205-2311
Alkaptonuria is a rare and potentially fatal health disorder that leads to a number of serious symptoms. Timely treatment along with a proper and nutritional diet allows the patients to have a normal lifespan. Individuals with this condition develop symptoms of reduced mobility and severe back pain at an early age; but proper treatment helps them to lead a long and normal life.
The following pictures show how the homogentisic acid deposits affect the human body.
Picture 1 – Alkaptonuria
Picture 2 – Alkaptonuria Image