ALKAPTONURIA GENETICS PDF

Alkaptonuria is a rare inherited disorder. This enzyme is used to break down a toxic substance called homogentisic acid. The buildup of homogentisic acid causes your bones and cartilage to become discolored and brittle. This typically leads to osteoarthritis, especially in your spine and large joints. There are few other symptoms during childhood. Symptoms become more obvious as you age.

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Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine , which occur in protein. Homogentisic acid and its oxidized form alkapton are excreted in the urine, giving it an unusually dark color.

The accumulating homogentisic acid causes damage to cartilage ochronosis , leading to osteoarthritis and heart valves , as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over 30 years old, although the dark discoloration of the urine is present from birth. Apart from treatment of the complications such as pain relief and joint replacement for the cartilage damage , the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms.

Alkaptonuria is a rare disease ; it occurs in one in , people, but is more common in Slovakia and the Dominican Republic. Patients with black bone disease are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. After the age of 30, people begin to develop pain in the weight-bearing joints of the spine, hips, and knees.

The pain can be severe to the point that interferes with activities of daily living and may affect ability to work. Joint-replacement surgery hip and shoulder is often necessary at a relatively young age.

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. Also, a propensity to developing kidney stones exists, and eventually also gallstones and stones in the prostate and salivary glands sialolithiasis can occur.

All people carry in their DNA two copies one received from each parent of the gene HGD , which contains the genetic information to produce the enzyme homogentisate 1,2-dioxygenase HGD which can normally be found in numerous tissues in the body liver, kidney, small intestine, colon, and prostate.

In people with alkaptonuria, both copies of the gene contain abnormalities that mean that the body cannot produce an adequately functioning enzyme. Different mutations may affect the structure, function, or solubility of the enzyme. The HGD enzyme is involved in the metabolism chemical processing of the aromatic amino acids phenylalanine and tyrosine.

Normally, these enter the bloodstream through protein-containing food and the natural turnover of protein in the body.

Tyrosine is specifically required for a number of functions, such as hormones e. The homogentisic acid is converted to the related substance benzoquinone acetic acid which forms polymers that resemble the skin pigment melanin. These are deposited in the collagen , a connective tissue protein, of particular tissues such as cartilage.

This process is called ochronosis as the tissue looks ochre ; ochronotic tissue is stiffened and unusually brittle, impairing its normal function and causing damage. If the diagnosis of alkaptonuria is suspected, it can be confirmed or excluded by collecting urine for 24 hours and determining the amount of homogentisic acid by means of chromatography. No assay of HGA in blood has been validated.

The severity of the symptoms and response to treatment can be quantified through a validated questionnaire titled the AKU Severity Score Index. This assigns scores to the presence of particular symptoms and features, such as the presence of eye and skin pigmentation, joint pain, heart problems, and organ stones. No treatment modality has been unequivocally demonstrated to reduce the complications of alkaptonuria.

Main treatment attempts have focused on preventing ochronosis through the reduction of accumulating homogentisic acid. Such commonly recommended treatments include large doses of ascorbic acid vitamin C or dietary restriction of amino acids phenylalanine and tyrosine. However, vitamin C treatment does not have definitively proven effectiveness [1] and protein restriction which can be difficult to adhere to has not shown to be effective in clinical studies.

Several studies have suggested that the herbicide nitisinone may be effective in the treatment of alkaptonuria. Nitisinone inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase , responsible for converting tyrosine to homogentisic acid, thereby blocking the production and accumulation of HGA. Nitisinone has been used for some time at much higher doses in the treatment of type I tyrosinemia.

Long-term use requires frequent monitoring for complications. Alkaptonuria does not appear to affect life expectancy, although the last study on the topic is from These generally start in the fourth decade. The typical age at requiring joint replacement surgery is 50—55 years. In most ethnic groups, the prevalence of alkaptonuria is between , and , Alkaptonuria was one of the four diseases described by 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 , [4] [6] and his views on the subject, including its mode of heritance, were summarized in a Croonian Lecture at the Royal College of Physicians.

The defect was narrowed down to homogentisic acid oxidase deficiency in a study published in A study showed that an ochronotic Egyptian mummy had probably suffered from alkaptonuria. Research collaborations by several national centres have been established to find a more definitive treatment for alkaptonuria.

This has included studies on the use of nitisinone and investigations into antioxidants to inhibit ochronosis. From Wikipedia, the free encyclopedia. Pigment Cell Melanoma Res. BMC Ophthalmology. Retrieved 17 April Reproduced in Garrod AE Yale Journal of Biology and Medicine.

Oxford University Press. Journal of Biological Chemistry. Nature Genetics. Bibcode : Sci Jul ICD - 10 : E Inborn error of amino acid metabolism E70—E72 , Glutaric acidemia type 1 type 2 Hyperlysinemia Pipecolic acidemia Saccharopinuria. Carnosinemia Histidinemia Urocanic aciduria. Hyperprolinemia Prolidase deficiency. Hypervalinemia Isobutyryl-CoA dehydrogenase deficiency Maple syrup urine disease. Cystathioninuria Homocystinuria Hypermethioninemia.

Methylmalonic acidemia Methylmalonyl-CoA mutase deficiency Propionic acidemia. Dopamine beta hydroxylase deficiency reverse: Brunner syndrome. Solute carrier family : Cystinuria Hartnup disease Iminoglycinuria Lysinuric protein intolerance Fanconi syndrome : Oculocerebrorenal syndrome Cystinosis. Categories : Amino acid metabolism disorders Autosomal recessive disorders Skin conditions resulting from errors in metabolism.

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In other projects Wikimedia Commons. By using this site, you agree to the Terms of Use and Privacy Policy. Histidine Carnosinemia Histidinemia Urocanic aciduria.

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Alkaptonuria

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Making a diagnosis for a genetic or rare disease can often be challenging. The following resources provide information relating to diagnosis and testing for this condition.

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Genetics of Alkaptonuria

Alkaptonuria is an inherited condition that causes urine to turn black when exposed to air. Ochronosis, a buildup of dark pigment in connective tissues such as cartilage and skin, is also characteristic of the disorder. This blue-black pigmentation usually appears after age People with alkaptonuria typically develop arthritis, particularly in the spine and large joints, beginning in early adulthood. Other features of this condition can include heart problems, kidney stones , and prostate stones. This condition is rare, affecting 1 in , to 1 million people worldwide.

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