| Alkaptonuria |
| Classification and external resources |
Homogentisic acid |
| ICD-10 |
E70.2 (ILDS E70.210) |
| ICD-9 |
270.2 |
| OMIM |
203500 |
| DiseasesDB |
409 |
| MedlinePlus |
001200 |
| eMedicine |
ped/64 |
| MeSH |
D000474 |
| GeneReviews |
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Alkaptonuria (black urine 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 1.13.11.5), 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]
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Contents
- 1 Signs and symptoms
- 2 Diagnosis
- 3 Pathophysiology
- 4 Treatment
- 5 Epidemiology
- 6 History
- 7 See also
- 8 References
- 9 External links
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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]
Diagnosis[edit]
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]
Pathophysiology[edit]
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[edit]
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.[8]
Epidemiology[edit]
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[edit]
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,[9] and his views on the subject, including its mode of heritance, were summarised in a 1908 Croonian lecture at the Royal College of Physicians.[10] The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in 1958.[11] The genetic basis was elucidated in 1996, when HGD mutations were demonstrated.[12]
A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria.[13]
In 2003, The AKU Society was founded to support patients diagnosed with the disease.[14]
See also[edit]
- Ochronosis
- List of cutaneous conditions
- List of radiographic findings associated with cutaneous conditions
References[edit]
- ^ a b c d e f g 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.
- ^ a b 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.
- ^ 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.
- ^ Srsen S (1978). "Dark pigmentation of ear cerumen in alkaptonuria". Lancet 2 (8089): 577. doi:10.1016/S0140-6736(78)92912-4. PMID 79943.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ ClinicalTrials.gov NCT00107783
- ^ 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.
- ^ Garrod AE (1908). "The Croonian lectures on inborn errors of metabolism: lecture II: alkaptonuria". Lancet 2 (3): 73–79. PMID 20992918.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "AKU Society".
External links[edit]
- Alkaptonuria Society (UK)
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Inborn error of amino acid metabolism (E70–E72, 270)
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| K→acetyl-CoA |
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Lysine/straight chain
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- Glutaric acidemia type 1
- type 2
- Hyperlysinemia
- Pipecolic acidemia
- Saccharopinuria
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Leucine
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- Maple syrup urine disease
- Isovaleric acidemia
- 3-Methylcrotonyl-CoA carboxylase deficiency
- 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
- 3-Methylglutaconic aciduria 1
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Tryptophan
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| G |
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G→pyruvate→citrate
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Glycine
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- Sarcosinemia
- D-Glyceric acidemia
- Glutathione synthetase deficiency
- Glycine→Creatine: GAMT deficiency
- Glycine encephalopathy
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G→glutamate→
α-ketoglutarate
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Histidine
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- Carnosinemia
- Histidinemia
- Urocanic aciduria
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Proline
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- Hyperprolinemia
- Prolidase deficiency
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Glutamate/glutamine
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G→propionyl-CoA→
succinyl-CoA
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Valine
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- Maple syrup urine disease
- Hypervalinemia
- Isobutyryl-CoA dehydrogenase deficiency
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Isoleucine
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- Maple syrup urine disease
- Beta-ketothiolase deficiency
- 2-Methylbutyryl-CoA dehydrogenase deficiency
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Methionine
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- Hypermethioninemia
- Homocystinuria
- Cystathioninuria
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General BC/OA
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- Propionic acidemia
- Methylmalonic acidemia
- Methylmalonyl-CoA mutase deficiency
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G→fumarate
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Phenylalanine/tyrosine
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Phenylketonuria
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- Tetrahydrobiopterin deficiency
- 6-Pyruvoyltetrahydropterin synthase deficiency
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Tyrosinemia
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- Type II tyrosinemia
- Type III tyrosinemia/Hawkinsinuria
- Alkaptonuria/Ochronosis
- Type I tyrosinemia
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Tyrosine→Melanin
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- Albinism: Ocular albinism (1)
- Oculocutaneous albinism (Hermansky–Pudlak syndrome)
- Waardenburg syndrome
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Tyrosine→Norepinephrine
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- Dopamine beta hydroxylase deficiency
- reverse: Brunner syndrome
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G→oxaloacetate
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Urea cycle/Hyperammonemia
(arginine
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- N-Acetylglutamate synthase deficiency
- Carbamoyl phosphate synthetase I deficiency
- Ornithine transcarbamylase deficiency/translocase deficiency
- Citrullinemia
- Argininosuccinic aciduria
- Argininemia
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Transport/
IE of RTT |
- Solute carrier family: Cystinuria
- Hartnup disease
- Lysinuric protein intolerance
- Iminoglycinuria
- Fanconi syndrome: Oculocerebrorenal syndrome
- Cystinosis
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| Other |
- Trimethylaminuria
- 2-Hydroxyglutaric aciduria
- Fumarase deficiency
- Ethylmalonic encephalopathy
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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