Ochronosis- hereditary


Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC, 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]


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]


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]


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]