Alkaptonuria: Description, Causes and Risk Factors:Excretion of homogentisic acid (alkapton) in the urine due to congenital lack of the enzyme homogentisate 1,2-dioxygenase, which mediates an essential step in the catabolism of phenylalanine and tyrosine; urine turns dark if allowed to stand or is alkalinized (a result of formation of polymerization products of homogentisic acid); frequently occurs throughout relatively long periods or may recur and subside at irregular intervals; arthritis and ochronosis are late complications; autosomal recessive inheritance; caused by mutation in the homogentisate 1,2-dioxygenase gene (HGD) on chromosome 3q.alkaptonuriaThis is an autosomal recessive condition of homogentisic acid oxidase deficiency, resulting from a set of inherited alleles on chromosome 3 (3q21-q23). A whole spectrum of mutations has been identified. It was first described by Garrod in 1902 and was one of the first clinical descriptions to be identified as autosomal recessive.There is an underlying defect of tyrosine metabolism causing accumulation of homogentisic acid. This is rapidly cleared by the kidney but, if the urine is left standing, it is oxidized to form a pigmented polymer that colors the urine black. The kidneys keep blood levels of homogentisic acid very low but over time homogentisic acid deposited in cartilage throughout the body and it is converted to the polymer. As the polymer accumulates within cartilage, over the course of many years, the normally transparent tissues become slate blue but this does not occur before adulthood.Expression of the disease is multifactorial. A slightly raised occurrence of HLA-DR7 has been found. The disease loosens the cross-linking between collagen fibres and much of the pathology results from this.Deposits of pigmented polymers of homogentisic acid occur in many tissues, including cartilage, tendons, nail beds, eyelids, cheeks, axillae, genital regions, eardrums, larynx and buccal mucosa. The name alkaptonuria originates from the dark color of the urine due to the high level of 2,5-dehydroxyphenylacetic acid from the oxidation and polymerization of the homogentisic acid.Autopsy findings show that early changes include chondrocyte necrosis, pigment deposition in the cardiovascular system and fibrolipid components of atheromatous plaques. Pigmentation of the aortic and mitral valve cusps and valve rings is a result of intracellular and extracellular pigment deposition and is associated with calcification and clinically significant aortic stenosis.It occurs in 1:100,000 to 1:250,000 live births in the most European countries. There is an exceptionally high incidence in Slovakia at 1:19,000 but only about 10 of the chromosomal variations are present. This suggests inbreeding in a restricted gene pool. There is no difference in incidence between the sexes except that males tend to present sooner with more severe disease.Life expectancy is normal but there is considerable morbidity, with significant pain beginning as early as the age of 30. Slow degeneration of the spinal discs and the large joints are the main problems, with subsequent loss of agility and mobility.Symptoms:Symptoms may include:Arthritis (especially of the spine) that gets worse over time.
  • Darkening of the ear.
  • Dark spots on the white of the eye (sclera) and cornea.
  • People with this condition also can get arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria.
Diagnosis:The tests often used in diagnosis may include:Chromatographic examination of urine. This is the standard diagnostic test. Homogentisic acid can be identified using gas chromatography-mass spectroscopy. Plasma can also be used. There are reducing substances but not glucose present.
  • X-ray of the lumbar spine. This may show disc degeneration with calcification.
  • Chest X-ray. This is advisable if the condition is suspected, to exclude aortic or mitral valve involvement.
  • CT scanning. This should be performed in patients over the age of 55 to rule out coronary artery calcification.
  • Polymerase chain reaction (PCR) can identify gene mutations in DNA extracted from blood.
Treatment:Several therapeutic approaches have been used in patients with alkaptonuria. Treatment with vitamin C decreases urinary benzoquinone acetic acid but has no effect on HGA excretion, and no credible studies have shown that treatment with vitamin C is clinically effective. Two patients were also enrolled in a separate study of nitisinone (Investigational New Drug exemption number 46865, held by Swedish Orphan International), for which they also gave written informed consent. Capsules containing nitisinone were prepared by the Pharmaceutical Development Service of the National Institutes of Health.NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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