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Alkaptonuria
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Alkaptonuria
Classification and external resources
Homogentisic acid
ICD-10 E70.2
ICD-9 270.2
OMIM 203500
DiseasesDB 409
eMedicine ped/64
MeSH D000474

Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic

disorder of 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, a toxic tyrosine
byproduct called homogentisic acid (or alkapton) accumulates in the blood, and is
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]
Contents
[hide]

* 1 Signs and symptoms

* 2 Diagnosis
* 3 Pathophysiology
* 4 Treatment
* 5 Epidemiology
* 6 History
* 7 See also
* 8 References
* 9 External links

[edit] Signs and symptoms

Alkaptonuria itself is asymptomatic, but the sclera of the eyes may be pigmented
(often only at a later age)[1] and the skin is darkened in sun-exposed areas as
well as around sweat glands; sweat may be coloured brown. Urine may turn brown on
standing, especially when left for a period of time (which may alert parents of
children using diapers).[citation needed] 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 and leading to low back pain at a young age in most cases, but also of 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]

[edit] Diagnosis

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 and plasma. In alkaptonuria, plasma levels are 6.6
micrograms/ml on average, and urine levels are on average 3.12 mmol/mmol of
creatinine.[1]

[edit] Pathophysiology

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 from both parents. 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]

[edit] Treatment

No treatment modality has been unequivocally demonstrated to reduce the

complications of alkaptonuria. Commonly recommended treatments include dietary
restriction of phenylalanine and tyrosine and large doses of ascorbic acid
(vitamin C). Dietary restriction may be effective in children, but benefits in
adults have not been demonstrated.[6]

The insecticide 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]

[edit] 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]

[edit] 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,[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 HGO mutations were
demonstrated.[12]
A 1977 study showed that an ochronotic Egyptian mummy had probably suffered from
alkaptonuria.[13]

[edit] See also

* Ochronosis
* Tyrosinemia

[edit] References

1. ^ 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.
2. ^ a b Zatkov� A, de Bernab� DB, Pol�kov� 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. 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.
PMID 17948450. Full text at PMC: 1932065
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.
PMID 16371803.
6. ^ 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. PMID 9870204.
7. ^ 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.
8. ^ Clinical trial NCT00107783
9. ^ Garrod AE (1902). "The incidence of alkaptonuria: a study in clinical
individuality". Lancet 2: 1616-1620. doi:10.1016/S0140-6736(01)41972-6.
Reproduced in Yale Journal of Biology and Medicine 75:221-31 (2002). PMID
12784973.
10. ^ Garrod AE (1908). "The Croonian lectures on inborn errors of metabolism:
lecture II: alkaptonuria". Lancet 2: 73�79.
11. ^ La Du BN, Zannoni VG, Laster L, Seegmiller JE (1958). "The nature of the
defect in tyrosine metabolism in alcaptonuria" (PDF). Journal of Biological
Chemistry 230 (1): 251�60. PMID 13502394.
12. ^ Fern�ndez-Ca��n JM, Granadino B, Beltr�n-Valero de Bernab� D, et al
(1996). "The molecular basis of alkaptonuria". Nature Genetics 14 (1): 19�24.
doi:10.1038/ng0996-19. PMID 8782815.
13. ^ 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.

[edit] External links

* Alkaptonuria Society (UK)

[hide]
v � d � e
Inborn errors of amino acid metabolism (E70-72, 270)
K
Lysine/straight chain
Glutaric acidemia type 1 - type 2 - Hyperlysinemia - Pipecolic acidemia -
Saccharopinuria
Leucine

Maple syrup urine disease - Isovaleric acidemia - 3-Methylcrotonyl-CoA carboxylase

deficiency - 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
G?pyruvate
Glycine

Sarcosinemia - D-Glyceric acidemia - Glutathione synthetase deficiency

G?alpha-ketoglutarate
Glutamate/glutamine

SSADHD
Proline

Hyperprolinemia - Prolidase deficiency

Histidine

Carnosinemia - Histidinemia - Urocanic aciduria

G?succinyl-CoA
Methionine

Hypermethioninemia - Homocystinuria - Cystathioninuria

Valine

Maple syrup urine disease - Hypervalinemia - Isobutyryl-CoA dehydrogenase

deficiency
Isoleucine

Maple syrup urine disease - Beta-ketothiolase deficiency - 2-Methylbutyryl-CoA

dehydrogenase deficiency
General BC/OA

Propionic acidemia - Methylmalonic acidemia

G?fumarate
Phenylalanine/tyrosine

Phenylketonuria: Tetrahydrobiopterin deficiency - 6-Pyruvoyltetrahydropterin

synthase deficiency
Tyrosinemia: Type II tyrosinemia - Type III tyrosinemia/Hawkinsinuria -
Alkaptonuria/Ochronosis - Type I tyrosinemia
G?oxaloacetate
Urea cycle/Hyperammonemia
(arginine, aspartate)

N-Acetylglutamate synthase deficiency - Carbamoyl phosphate synthetase I

deficiency - Ornithine transcarbamylase deficiency/translocase deficiency -
Citrullinemia - Argininosuccinic aciduria - Argininemia
Transport
Cystinuria - Hartnup disease - Oculocerebrorenal syndrome - Lysinuric protein
intolerance - Inborn errors of renal tubular transport (Cystinosis, Fanconi
syndrome)
Tyrosine?Melanin
Albinism: Ocular albinism - Oculocutaneous albinism (Hermansky-Pudlak syndrome) -
Waardenburg syndrome
Glycine?Creatine
GAMT deficiency
Other
Trimethylaminuria - 2-Hydroxyglutaric aciduria - Fumarase deficiency
see also Amino acid metabolism enzymes, Urea cycle enzymes, intermediates
Retrieved from "http://en.wikipedia.org/wiki/Alkaptonuria"
Categories: Metabolic disorders | Genetic disorders | Autosomal recessive
disorders
Hidden categories: All articles with unsourced statements | Articles with
unsourced statements since December 2007
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