Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rare hereditary metabolic disorder alcaptonuria is characterized by the inability to metabolize homogentisic acid, an intermediary compound in the catabolism of the aromatic amino acids phenylalanine and tyrosine. The essentially complete deficiency of homogentisic acid oxidase causes a striking accumulation of homogentisic acid and a derived melanin-like pigment in the connective tissues; the latter is termed ochronosis. Urinary homogentisic acid is oxidized rapidly and becomes a brown or black pigment if alkali is added. Older alcaptonurics have intensely pigmented (ochronotic) connective tissues, primarily the cartilaginous joint surfaces, ribs, intervertebral disks, ear cartilage, etc. They also have an unusual type of arthritis affecting the large weight-bearing joints, i.e. hips, knees and spine, but not the small joints of the hands and feet, as in rheumatoid arthritis. A mechanistic explanation for ochronotic arthritis has not been worked out, but it is clear that accumulation of homogentisic acid in the connective tissues directly or indirectly leads to the arthritic changes. A detailed analysis of the events leading to alcaptonuric arthritis should be worthwhile since it is a model form of arthritis secondary to a well-defined metabolic disorder that must persist for many years before the arthritic complications appear. Possibly other, more common types of arthritis, develop secondarily to metabolic disturbances that involve chemical mediators less obvious, or less easily detected, than homogentisic acid.
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PMID:Alcaptonuria and ochronotic arthritis. 194 88

Alkaptonuria is a rare, hereditary, metabolic disease in which homogentisic acid, an intermediary product in the metabolism of phenylalanine and tyrosine, cannot be further metabolized. The metabolic defect causes a characteristic triad of homogentisic aciduria, ochronosis, and arthritis. The cause of this disease is a constitutional lack of the enzyme homogentisic acid oxidase. The condition is inherited as an autosomal recessive disease. The ochronotic arthritis affects mainly male subjects after fourty. Authors present a case of a 60 years old man suffering from a generalized ochronotic arthritis since 1976. From 1992 summer to the beginning of 1993 the patient developed a progressive weakness in the lower limbs associated with thoracic back pain and subsequently a spastic paraparesis. These symptoms were related to a vertebral compression due to D4-D5 pathologic fracture. In spite of a decompressive operation the neurologic symptoms didn't improve.
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PMID:[A rare case of high dorsal radicular-medullary compression in a patient with ochronotic arthropathy. Clinico-radiological features]. 775 41

Alcaptonuria is a rare (incidence approx. 1:10(6)), autosomal-recessive transmitted metabolic disease. The basic defect is a lack of the enzyme homogentisic acid oxidase. During metabolism of phenylalanin and tyrosin to fumaric acid and acetoacetic acid this enzymatic defect causes an accumulation of the intermediate breakdown product homogentisic acid in bradytrophic tissues resulting in pigmentation and calcification of the intervertebral disks. We present a 57 year old female patient in whom we diagnosed alcaptonuria by the appearance of the typical symptom trias homogentisic acid excretion in the urine, ochronosis and arthritis. The anamnesis and results of a knee arthroscopy, radiographic and laboratory examinations as well as the intraoperative and histological findings during implantation of a knee joint surface replacing prosthesis (Gemini-System, Link Co., Hamburg, Germany) are reported.
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PMID:[Alkaptonuria and ochronotic arthropathy. Arthroscopic and intraoperative findings in implantation of a knee joint surface replacing prosthesis]. 782 Oct 69

Homogentisic acid (HGA) spontaneously starts to undergo oxidation and polymerization soon after the beginning of incubation in human blood or plasma at 37 degrees C, and forms plasma soluble melanins (PSM). Haemolysis accompanies this process in blood. The addition of equimolar quantities of antioxidants delays this oxidation significantly (isoascorbic acid by 2:30-4:00 h; glutathione by 3:20-4:05 h; D-penicillamine by 5:00-5:45 h). HGA is a phenylalanine and tyrosine metabolite, related structurally to the catecholamines and other precursors of melanins. HGA is normally metabolized by the enzyme homogentisic acid oxidase. When this enzyme is genetically missing, part of HGA is excreted in the urine, another part polymerizes darkens many tissues (ochronosis), and produces widespread degenerative changes in cartilage and other connective tissues, joints, blood vessels, heart valves, kidneys and in other tissues. Collectively this disorder is known as alcaptonuria, for which no satisfactory treatment is known. The causes of both alcaptonuric arthritis and rheumatoid arthritis are thought to involve increased oxidative stress. Inflammation of joints and connective tissue damage are involved in both diseases. Oxygen radicals are suspected to cause inflammation and cellular damage. Hydroxyl radicals degrade hyaluronic acid (the viscous synovial fluid of joints). High levels of products of free radical reactions, with fluorescence excitation (ex) and emission (em) maxima in the wavelength ranges of those of PSM (ex 320-400 and em 400-470) were reported in the blood sera and synovial fluids of patients with rheumatoid arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Homogentisic acid and structurally related compounds as intermediates in plasma soluble melanin formation and in tissue toxicities. 800 39

An eight year old wild caught Cynomolgus monkey was diagnosed as having alkaptonuria, a condition characterized by the passage of a normal-colored urine which darkens upon standing. The underlying cause is the congenital lack of homogentisic acid oxidase with subsequent passage of homogentisic acid in the urine. No other clinical manifestations, such as deposition of pigment in the skin or mucous membranes or development of an ochronitic arthritis, were observed in this animal.
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PMID:Alkaptonuria in a cynomolgus monkey (Macaca fascicularis). 816 45

Alkaptonuria is a human hereditary metabolic disease characterized by a very high urinary excretion of homogentisic acid, an intermediary product in the metabolism of tyrosine, in association with ochronosis and arthritis. This disease is due to a deficiency in the enzyme homogentisic acid oxidase and is inherited as an autosomal recessive condition. We have found a new recessive mutation (aku) in the mouse that is homologous to human alkaptonuria, during a mutagenesis program with ethylnitrosourea. Affected mice show high levels of urinary homogentisic acid without signs of ochronosis or arthritis. This mutation has been mapped to Chr 16 close to the D16Mit4 locus, in a region of synteny with human 3q.
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PMID:aku, a mutation of the mouse homologous to human alkaptonuria, maps to chromosome 16. 818 36

Alkaptonuria (AKU; McKusick No. 203500), a rare hereditary disorder of the phenylalanine catabolism, was the first disease to be interpreted as an inborn error of metabolism (A. E. Garrod, 1902, Lancet 2: 1616-1620). AKU patients are deficient for homogentisate 1,2-dioxygenase (HGO; EC 1.13.11.5). This enzymatic deficiency causes homogentisic aciduria, ochronosis, and arthritis. Recently we cloned the human HGO gene and showed that AKU patients carry two copies of a loss-of-function HGO allele. Here we describe the complete nucleotide sequence of the human HGO gene and the identification of its promoter region. The human HGO gene spans 54,363 bp and codes for a 1715-nt-long transcript that is split into 14 exons ranging from 35 to 360 bp. The HGO introns, 605 to 17,687 bp in length, contain representatives of the major classes of repetitive elements, including several simple sequence repeats (SSR). Two of these SSRs, a (CT)n repeat in intron 4 and a (CA)n repeat in intron 13, were found to be polymorphic in a Spanish population sample. The HGO transcription start site was determined by primer extension. We report that sequences from -1074 to +89 bp (relative to the HGO transcription start site) are sufficient to promote transcription of a CAT reporter gene in human liver cells and that this fragment contains putative binding sites for liver-enriched transcription factors that might be involved in the regulation of HGO expression in liver.
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PMID:The human homogentisate 1,2-dioxygenase (HGO) gene. 924 27

In a 3-year-old boy alkaptonuria was diagnosed. From early age on gradual dark discoloration of his urine had been noticed in the diapers, but routine urinalysis had not revealed abnormalities. Alkaptonuria is a rare metabolic disease in which homogentisic acid cannot be metabolised, due to a lack of the enzyme homogentisic acid oxidase. The disease often manifests itself in childhood by darkening of urine on standing. The excretion of homogentisic acid in urine in these patients is increased. The disease leads to serious consequences, such as ochronosis of cartilage and connective tissues with arthritis. It is expected that treatment with ascorbic acid and a dietary restriction of protein (1 g/kg/day) can decrease the late and serious consequences by diminishing the serum concentration of the metabolite benzoquinone acetic acid.
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PMID:[A child with dark discoloration of urine]. 1049 97

In alkaptonuria, homogentisate 1,2-dioxygenase deficiency causes tissue accumulation of homogentisic acid (HGA), followed by signs and symptoms of ochronosis. These include massive urinary excretion of HGA, arthritis and joint destruction, pigmentation of cartilage and connective tissue, and cardiac valve deterioration. We describe a 46-year-old man with alkaptonuria and diabetic renal failure whose plasma HGA concentration was twice that of any other alkaptonuria patient, and whose ochronosis progressed much more rapidly than that of his two alkaptonuric siblings. After renal transplantation, the plasma HGA normalized, and the daily urinary excretion of HGA decreased by 2-3g. This case illustrates the critical role of renal tubular secretion in eliminating HGA from the body, and suggests that renal transplantation in a uremic patient not only restores HGA excretion, but may also provide homogentisate 1,2-dioxygenase activity for the metabolism of HGA.
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PMID:Exacerbation of the ochronosis of alkaptonuria due to renal insufficiency and improvement after renal transplantation. 1235 41

Alkaptonuria (AKU) is a rare metabolic disorder of phenylalanine catabolism that is inherited as an autosomal recessive trait. AKU is caused by loss-of-function mutations in the homogentisate 1,2-dioxygenase (HGO) gene. The deficiency of homogentisate 1,2-dioxygenase activity causes homogentisic aciduria, ochronosis and arthritis. We present the first molecular study of the HGO gene in Turkish AKU patients. Seven unrelated AKU families from different regions in Turkey were analysed. Patients in three families were homozygous for the R58fs mutation; another three families were homozygous for the R225H mutation; and one family was homozygous for the G270R mutation. Analysis of nine intragenic HGO polymorphisms showed that the R58fs, R225H and G270R Turkish AKU mutations are associated with specific HGO haplotypes. The comparison with previously reported haplotypes associated with these mutations from other populations revealed that the R225H is a recurrent mutation in Turkey, whereas G270R most likely has a Slovak origin. Most interestingly, these analyses showed that the Turkish R58fs mutation shares an HGO haplotype with the R58fs mutation found in Finland, Slovakia and India, suggesting that R58fs is an old AKU mutation that probably originated in central Asia and spread throughout Europe and Anatolia during human migrations.
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PMID:Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations. 1287 36


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