Alkaptonuria is a rare inherited genetic disease which is caused by a mutation in the HGD gene for the enzyme homogentisate 1,2-dioxygenase (); if a person inherits an abnormal copy from both parents (it is a recessive condition), the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves, as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth.
Apart from treatment of the complications (such as pain relief and joint replacement for the cartilage damage), the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more common in Slovakia and the Dominican Republic.
Signs and symptoms
thumb|Intervertebral discs calcification due to ochronosis
Patients with alkaptonuria are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear and other cartilage, and the sclera and corneal limbus of the eye.
After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees. The pain can be severe to the point that interferes with activities of daily living and may affect the ability to work. Joint-replacement surgery (hip and shoulder) is often necessary at a relatively young age. HGD mutations are generally found in certain parts (exons 6, 8, 10, and 13), but a total of over 100 abnormalities has been described throughout the gene.
The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones. caused by elevated levels of the amino acid tyrosine. Hypertyrosinaemia can lead to serious symptoms including corneal keratopathy, dermal toxicity, neurodevelopment delay issues in children, and alterations of wider metabolism. There is currently no effective treatment for hypertyrosinaemia other than limiting protein intake. Due to the potential side-effects of nitisinone treatment it is currently only prescribed to children aged 16 and above in Europe and patients will then have to follow a protein restricted diet and closely manage their tyrosine levels through frequent monitoring.
Prognosis
Alkaptonuria does not appear to affect life expectancy, although the latest study on the topic is from 1985. and his views on the subject, including its mode of heritance, were summarized in a 1908 Croonian Lecture at the Royal College of Physicians. The genetics of it was also studied by William Bateson in 1902.
The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958. The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.
A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.
Society and culture
The AKU Society is a charity which support all people affected by AKU. Based in the UK, the charity can be contacted here. It has a number of international AKU sister societies who provide support across the world.
The AKU Society works to provide information, education, support, and helps people to access treatment for their condition. A number of support resources are available here and they have also been translated into all major languages here
As part of the DevelopAKUre consortium, the AKU Society successfully proved the effectiveness of nitisinone to treat AKU, leading to the drug receiving approval from the European Medicines Agency in 2020. The AKU Society continues to drive research into developing potential treatments and cures for AKU working closely with a number of universities across the world.
Research directions
Research collaborations by several national centres have been established to find a more definitive treatment for alkaptonuria. This has included studies on the use of nitisinone and investigations into antioxidants to inhibit ochronosis.