Alkaptonuria:

Alkaptonuria:

·     It was the first described  inborn error of metabolism by Garrod in 1902.

·     Rare disorder of autosomal recessive inheritance. It is caused by mutation in a gene that results in the accumulation of homogentisic acid (HGA).

·     Characteristically, the excess HGA means sufferer pass dark urine, which upon standing turns black. This is a feature present from birth.

·     Other manifestation occur due to deposition of HGA in collagenous tissues, namely ochronosis and ochronotic osteoarthropathy.

·     Does not reduce life expectancy, but significantly affects quality of life.

·     It results from the absence of homogentisate 1,2- dioxygenase (HGD), the enzyme, predominantly produced by hepatocytes in the liver and within the kidney, is responsible for the breakdown of HGA; an intermediate in the tyrosine degradation pathway.

·     Deficient HGD activity within the liver causes HGA levels to arise. Large quantities of HGA are removed by urinary excretion on a daily basis.

·     Urine darkens because the HGA polymerize. Over time the HGA polymer is deposited within connective tissue, causing ochronosis (darkening of collagenous tissue). Long-term ochronosis results in the development of ochronotic osteoarthropathy.

·     Clinical features :

·     homogentisic aciduria, ochronosis, ochronotic osteoarthropathy (OAA).

·     Earliest feature is detection of HGA in urine. The darkening of urine occurs because the HGA pigment oxidizes to benzoquinone-acetate (BQA), which forms a melanin-like polymer that slowly turns urine black.

·     Dark spots in the sclera (white) of eye.

·     Ochronosis develops as the BQA accumulates both intra- and extracellularly in connective tissue. Typically this pigment is seen clearly in eyes and ears of patients, also present in bodily fluids, including perspiration, which often results in skin discoloration.

·     Organs affected are : large joints, cardiovascular system, kidney, skin and glands. Other manifestations include renal, prostate, gallbladder and salivary gland stones, rupture of tendons and ligaments, osteopenia and fractures.

·     Aortic valve stenosis is common, often requiring surgical replacement.

·     Development of OAA is the result of deposition of HGA polymer within hyaline articular cartilage.

·     The affected tissue become weak, brittle and prone to fracturing and cracking, causing rapid joint degeneration.

·     Therapies:

·     Physiotherapy, joint replacement surgery

·     Ascorbic acid is an antioxidant that reduce the conversion of HGA to BQA via oxidation, but it did not affect HGA urinary excretion. Moreover, vit.C is cofactor for 4-hydroxyphenylpyruvate dioxygenase, which causes increased HGA production this contributes to formation of renal oxalate stones.

·     Low protein diet: but tissue catabolism contribute to raised HGA plasma levels within patient.

·     Liver transplantation

·     Enzyme replacement

·     Anti-inflammatory medication.