Alkaptonuria is often asymptomatic, but the sclera of the eyes may be pigmented (often only at a later age),^[1] and the skin may be darkened in sun-exposed areas and around sweat glands; sweat may be coloured brown. Urine may turn brown or even inky black if collected and left exposed to open air, especially when left standing for a period of time. Kidney stones and stone formation in the prostate (in men) are common and may occur in more than a quarter of cases.^[1]

The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in tissues. In the joints this leads to cartilage damage, specifically in the spine, leading to low back pain at a young age in most cases. Cartilage damage may also occur in the hip and shoulder. Joint replacement surgery (hip and shoulder) is often necessary at a relatively young age.^[1]

Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases valve replacement may be necessary. Coronary artery disease may be accelerated in alkaptonuria.^[1]

A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black (depending on diet) after several hours because of the accumulation of homogentisic acid.^[4]

The diagnosis of alkaptonuria needs to be suspected before diagnostic testing can be performed using paper chromatography and thin layer chromatography. Both blood plasma and urine can be used for diagnosis. In healthy subjects, homogentisic acid is absent in both blood plasma and urine. In alkaptonuria, plasma levels are 6.6 micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of creatinine.^[1]

Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid. Hepatic homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate. Alkaptonuria arises in people who have inherited two abnormal HGD genes: one from each parent. Numerous different HGD mutations have been identified.^[1]

In a patient who underwent a liver transplant for an unrelated problem, alkaptonuria resolved and joint disease stabilised after the transplant, confirming that the liver is the main site of homogentisic acid production in alkaptonuria.^[5]

Treatment

No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Commonly recommended treatments include large doses of ascorbic acid (vitamin C)and dietary restriction of phenylalanine and tyrosine. Dietary restriction may be effective in children, but benefits in adults have not been demonstrated.^[6]

The herbicide nitisinone inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that generates homogentisic acid from 4-hydroxyphenylpyruvic acid. This reduces homogentisic acid. The main side-effect is irritation of the cornea, and there is a concern that it will cause the symptoms of hereditary tyrosinaemia type III because of the possible accumulation of tyrosine or other intermediaries.^[7] Further studies are being conducted in the USA ^[8] and Europe. ^{[9] [10]}

Epidemiology

In Slovakia the disease occurs in 1:19,000 people. In other ethnic groups, the normal prevalence is between 1:100,000 and 1:250,000.^[2] It is reported frequently in the Dominican Republic, but exact prevalence there is not known.^[3]

History

Alkaptonuria was one of the four diseases described by Sir Archibald Edward Garrod, as being the result of the accumulation of intermediates due to metabolic deficiencies. He linked ochronosis with the accumulation of alkaptans in 1902,^[11] and his views on the subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at the Royal College of Physicians.^[12] The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958.^[13] The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.^[14]

A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.^[15]

In 2003, The AKU Society was founded to support patients diagnosed with the disease.^[16]