| Alkaptonuria Classification and external resources |
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| 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. Homogentisic acid is the common name for 25-dihydroxyphenylacetic acid The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize 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. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Homogentisate 12-dioxygenase is an Enzyme, which catalyzes the conversion of Homogentisate to 4-maleylacetoacetate. This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize 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). Homogentisic acid is the common name for 25-dihydroxyphenylacetic acid Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones. Cartilage is a type of dense Connective tissue. It is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix Ochronosis, often called alkaptonuric ochronosis, is an Autosomal recessive Metabolic disorder that causes an excess of Homogentisic acid Osteoarthritis ( OA, also known as degenerative Arthritis, degenerative joint disease) is a clinical syndrome in which low-grade inflammation In Anatomy, the heart valves are Valves in the Heart that maintain the unidirectional flow of blood by opening and closing depending on the difference Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form Treatment with nitisinone, which suppresses homogentisic acid production, is being studied. Nitisinone (also known as NTBC, an abbreviation of its full chemical name is a drug originally developed as an herbicide now used in the treatment of hereditary tyrosinemia [1] Alkaptonuria is more common in Slovakia and the Dominican Republic than in other countries. Slovakia (long form Slovak Republic; Slovak:, long form, is a Landlocked country in Central Europe with a population of over five million The Dominican Republic ( Spanish: República Dominicana;) is a nation located in the Caribbean region and shares the island of Hispaniola with [2][3]
Contents |
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. The sclera, called the white or white of the eye, is the opaque (usually white though certain animals such as horses and lizards can have black sclera fibrous The skin contains two different groups of sweat glands: Apocrine sweat glands and Merocrine sweat glands. Urine may turn brown on standing, especially when left for a period of time (which may alert parents of children using diapers). Kidney stones and stone formation in the prostate (in men) are common, and may occur in more than a quarter of cases. Kidney stones, also called renal calculi, are solid concretions (crystal aggregations of dissolved minerals in Urine; calculi typically form The prostate (from Greek προστάτης - prostates, literally "one who stands before" "protector" "guardian" is a [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. A joint is the location at which two or more Bones make contact Cartilage is a type of dense Connective tissue. It is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix Low back pain (sometimes referred to generally as lumbago) is a common symptom of musculoskeletal disorders or of disorders involving the Lumbar vertebrae. Joint replacement surgery (hip and shoulder) is often necessary at a relatively young age. Joint replacement is one of the most common and successful operations in modern Orthopaedic surgery. [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. Valvular heart disease is any disease process involving one or more of the valves of the heart (the aortic and mitral valves on the left and the pulmonary The miter valve (also known as the bicuspid valve or left atrioventricular valve) is a dual flap (bi = 2 valve in the Heart that lies between Coronary artery disease may be accelerated in alkaptonuria. Coronary artery disease (CAD (or atherosclerotic Heart disease) is the end result of the accumulation of atheromatous plaques within the walls [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
The diagnosis of alkaptonuria needs to be suspected before diagnostic testing can be performed, using paper chromatography and thin layer chromatography. Paper chromatography is an analytical technique for separating and identifying mixtures that are or can be coloured especially Pigments This can also be used Thin layer chromatography (TLC is a Chromatography technique used to separate mixtures 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]
Pathophysiology
Homogentisic acid is a natural intermediary of the metabolism of tyrosine, an amino acid. Homogentisic acid is the common name for 25-dihydroxyphenylacetic acid Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Hepatic Homogentisate 1,2-dioxygenase (coded by the HGD gene) metabolises homogentisic acid into 4-maleylacetoacetate. The liver is a vital organ in the human body and is present in Vertebrates and some other animals Homogentisate 12-dioxygenase is an Enzyme, which catalyzes the conversion of Homogentisate to 4-maleylacetoacetate. 4-Maleylacetoacetate is an intermediate in the metabolism of Tyrosine. 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. Liver transplantation or hepatic transplantation is the replacement of a diseased Liver with a healthy liver Allograft. [5]
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). Phe redirects here For the BitTorrent feature see PHE. For the constellation see Phoenix (constellation. Tyrosine (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine, is one of the 20 Amino acids that are used by cells to synthesize This article deals with the molecular aspects of ascorbic acid 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. Nitisinone (also known as NTBC, an abbreviation of its full chemical name is a drug originally developed as an herbicide now used in the treatment of hereditary tyrosinemia 4-Hydroxyphenylpyruvate dioxygenase HPD is a Cu -containing Enzyme, that catalyzes the third Reaction in the Catabolism of Phenylalanine 4-Hydroxyphenylpyruvic acid is an intermediate in the metabolism of Phenylalanine. 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. The cornea is the transparent front part of the Eye that covers the iris, Pupil, and Anterior chamber. Tyrosinemia (or "Tyrosinaemia" is an error of Metabolism, usually inborn in which the body cannot effectively break down the Amino acid Tyrosine [7] Further studies are being conducted. [8]
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. The Dominican Republic ( Spanish: República Dominicana;) is a nation located in the Caribbean region and shares the island of Hispaniola with [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. Sir Archibald Edward Garrod was an English Physician who pioneered the field of inborn errors of metabolism. 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. Ochronosis, often called alkaptonuric ochronosis, is an Autosomal recessive Metabolic disorder that causes an excess of Homogentisic acid The Royal College of Physicians of London was the first medical institution in England to receive a Royal Charter [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. A mummy is a Corpse whose Skin and Flesh have been preserved by either intentional or Incidental exposure to Chemicals extreme [13]
See also
References
- ^ a b c d e f g Phornphutkul C, Introne WJ, Perry MB, et al (2002). Ochronosis, often called alkaptonuric ochronosis, is an Autosomal recessive Metabolic disorder that causes an excess of Homogentisic acid Tyrosinemia (or "Tyrosinaemia" is an error of Metabolism, usually inborn in which the body cannot effectively break down the Amino acid Tyrosine "Natural history of alkaptonuria". New England Journal Medicine 347 (26): 2111–21. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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. 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. PMID 17948450. Full text at PMC: 1932065
- ^ Srsen S (1978). PubMed Central is a free digital database of full-text Scientific literature in biomedical and life sciences "Dark pigmentation of ear cerumen in alkaptonuria". Lancet 2 (8089): 577. 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. 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. 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:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15931605.
- ^ Clinical trial NCT00107783
- ^ Garrod AE (1902). In health care clinical trials are conducted to allow safety and Efficacy data to be collected for new drugs or devices "The incidence of alkaptonuria: a study in clinical individuality". Lancet 2: 1616−1620. Reproduced in Yale Journal of Biology and Medicine 75:221-31 (2002). PMID 12784973.
- ^ Garrod AE (1908). "The Croonian lectures on inborn errors of metabolism: lecture II: alkaptonuria". Lancet 2: 73–79.
- ^ 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.
- ^ 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:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 327549.
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