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Classification and external resources
Homogentisic acid.svg
ICD-10 E70.2 (ILDS E70.210)
ICD-9 270.2
OMIM 203500
DiseasesDB 409
MedlinePlus 001200
eMedicine ped/64
MeSH D000474

Alkaptonuria (black urine disease, black bone disease, or alcaptonuria) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC, which participates in the degradation of tyrosine. As a result, homogentisic acid and its oxide, called alkapton, accumulate in the blood and are excreted in urine in large amounts (hence -uria). Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones. Treatment with nitisinone, which suppresses homogentisic acid production, is being studied.[1] Alkaptonuria is more common in Slovakia and the Dominican Republic than in other countries.[2][3]

Signs and symptoms[edit]

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]

Intervertebral discs Calcification

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 alkaptonuria patients, plasma levels of homogentisic acid (HGA) are on average 6.6 micrograms/ml; normally HGA levels are undetectable.[1] Urinary HGA levels are increased 300 fold in alkaptonuria patients, between 0.4 and 12.4 g per day (on average 3.12 mmol HGA/mmol of creatinine).[1]


Alkaptonuria is caused by a mutation in the gene encoding the enzyme, Hepatic homogentisate 1,2-dioxygenase (HGD). Numerous mutations have been identified in this gene.[1][2] These mutations can affect the protein’s structural and enzymatic properties, thereby resulting in its reduced catalytic efficiency.[2] A 99% decrease in function is necessary before any alkaptonuria-related symptoms can be seen.[2] Patients need to inherit two mutant copies (alleles) of the HGD gene (one from each parent) in order to develop alkaptonuria; alkaptonuria is therefore an autosomal recessive disorder.

HGD activity is required to convert homogentisic acid (HGA), a biochemical intermediate product in tyrosine metabolism and degradation, to another intermediary, 4-maleylacetoacetate. HGD activity is typically found in the liver [5] . In the absence of HGD function, HGA is oxidized and polymerized to melanin-like pigments, which deposit in and bind to cartilage and connective tissues.[6][7] Excess accumulation of HGA and its metabolite products in tissues can ultimately cause ochronosis, with darkening of cartilaginous tissues and bone, arthritis, and the deterioration of joints and cardiac valves.[1][2]

Pathophysiology of alcaptonuria, which is due to the absence of functional homogentisate dioxygenase in the liver.


No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria. Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of ascorbic acid (vitamin C) or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment has not shown to be effective,[1] while reported benefits from protein dietary restriction has been shown to only apply to children, and not in adults.[8]

Recent studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitrisinone inhibits the enzyme, 4-hydroxyphenylpyruvate dioxygenase, responsible for converting tyrosine to homogentisic acid (HGA), thereby blocking the production and accumulation of HGA.[9] Nitisinone treatment has been shown to cause a 95% reduction in plasma and urinary HGA.[1] The main side-effect is corneal irritation.[10] Due to the possible accumulation of tyrosine or other intermediaries, there is additional concern of developing symptoms typical of hereditary tyrosinaemia type III.[10] Further studies are being conducted in the USA [11] and Europe.[12][13]


DevelopAKUre[14] is a series of international clinical trials to study the effect of nitisinone for the treatment of alkaptonuria. The studies will recruit in Europe [15] and in the USA.[16] The trials are funded by the European Commission.[17]


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]


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,[18] and his views on the subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at the Royal College of Physicians.[19] The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958.[20] The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.[21]

A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.[22]

In 2003, The AKU Society was founded to support patients diagnosed with the disease.[23]

See also[edit]


  1. ^ a b c d e f g h i j k Phornphutkul C, Introne WJ, Perry MB, et al. (2002). "Natural history of alkaptonuria". New England Journal Medicine 347 (26): 2111–21. doi:10.1056/NEJMoa021736. PMID 12501223. 
  2. ^ a b c d e f Zatková A, de Bernabé DB, Poláková H, et al. (2000). "High Frequency of Alkaptonuria in Slovakia: Evidence for the Appearance of Multiple Mutations in HGO Involving Different Mutational Hot Spots". American Journal of Human Genetics 67 (5): 1333–9. doi:10.1016/S0002-9297(07)62964-4. PMC 1288576. PMID 11017803. 
  3. ^ a b Milch RA (1960). "Studies of Alcaptonuria: Inheritance of 47 Cases in Eight Highly Inter-related Dominican Kindreds". Am. J. Hum. Genet. 12 (1): 76–85. PMC 1932065. PMID 17948450. 
  4. ^ Srsen S (1978). "Dark pigmentation of ear cerumen in alkaptonuria". Lancet 2 (8089): 577. doi:10.1016/S0140-6736(78)92912-4. PMID 79943. 
  5. ^ Kobak AC, Oder G, Kobak S, Argin M, Inal V (2005). "Ochronotic arthropathy: disappearance of alkaptonuria after liver transplantation for hepatitis B-related cirrhosis". Journal of Clinical Rheumatology 11 (6): 323–5. doi:10.1097/01.rhu.0000191157.25894.55. PMID 16371803. 
  6. ^ Zannoni, V. G., Malawista, S. E., & La Du, B. N. (1962). Studies on ochronosis. II. Studies on benzoquinoneacetic acid, a probable intermediate in the connective tissue pigmentation of alcaptonuria. Arthritis & Rheumatism, 5(6), 547–556. doi:10.1002/art.1780050603
  7. ^ Milch, R. A., & Murray, R. A. (1961). Studies of alcaptonuria : Mechanisms of swelling of homogentisic acid-collagen preparations. Arthritis & Rheumatism, 4(3), 253–267. doi:10.1002/art.1780040304
  8. ^ de Haas V, Carbasius Weber EC, de Klerk JB, et al. (1998). "The success of dietary protein restriction in alkaptonuria patients is age-dependent". Journal of Inherited Metabolic Disease 21 (8): 791–8. doi:10.1023/A:1005410416482. PMID 9870204. 
  9. ^ Y. Anikster, W.L. Nyhan, W.A. Gahl NTBC and alkaptonuria. American Journal of Human Genetics, 63 (1998), pp. 920–921
  10. ^ a b Suwannarat P, O'Brien K, Perry MB, et al. (2005). "Use of nitisinone in patients with alkaptonuria". Metabolism: Clinical and Experimental 54 (6): 719–28. doi:10.1016/j.metabol.2004.12.017. PMID 15931605. 
  11. ^ NCT00107783
  12. ^ NCT01916382
  13. ^
  14. ^
  15. ^
  16. ^
  17. ^
  18. ^ Garrod AE (1902). "The incidence of alkaptonuria: a study in clinical individuality". Lancet 2 (4137): 1616−1620. doi:10.1016/S0140-6736(01)41972-6.  Reproduced in Garrod AE (2002). "The incidence of alkaptonuria: a study in chemical individuality. 1902 classical article". Yale Journal of Biology and Medicine 75 (4): 221–31. PMC 2588790. PMID 12784973. 
  19. ^ Garrod AE (1908). "The Croonian lectures on inborn errors of metabolism: lecture II: alkaptonuria". Lancet 2 (3): 73–79. PMID 20992918. 
  20. ^ La Du BN, Zannoni VG, Laster L, Seegmiller JE (1 January 1958). "The nature of the defect in tyrosine metabolism in alcaptonuria" (PDF). Journal of Biological Chemistry 230 (1): 251–60. PMID 13502394. 
  21. ^ Fernández-Cañón JM, Granadino B, Beltrán-Valero de Bernabé D, et al. (1996). "The molecular basis of alkaptonuria". Nature Genetics 14 (1): 19–24. doi:10.1038/ng0996-19. PMID 8782815. 
  22. ^ Stenn FF, Milgram JW, Lee SL, Weigand RJ, Veis A (1977). "Biochemical identification of homogentisic acid pigment in an ochronotic egyptian mummy". Science 197 (4303): 566–8. doi:10.1126/science.327549. PMID 327549. 
  23. ^ "AKU Society". 

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