Alkaptonuria—

C. Excreted in the urine in the rare hereditary disease alkaptonuria. Homogentisic acid is easily oxidized in the air to dark-coloured polymeric products, so that urine from patients with alkaptonuria turns gradually black. It is formed from tyrosine and is an intermediate in tyrosine breakdown in the body. Alkaptonuria is due to the absence of the liver enzyme which cleaves the aromatic ring. 

Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in type II tyrosinemia neonatal tyrosinemia alkaptonuria and 0 type I tyrosinemia, or tyrosinosis.

Following transamination, the carbon skeleton of tyrosine is degraded to ftimarate and acetoacetate. Metabohc diseases of tyrosine catabohsm include tyrosinosis, Richner-Hanhart syndrome, neonatal ty-rosinemia, and alkaptonuria. 

G3. Garrod, A. E., The Croonian lectures on inborn errors of metabolism. II. Alkaptonuria. Lancet ii, 73-79 (1908). 

Alkaptonuria <0.4 Tyrosine degradation Homogentisate 1,2-dioxygenase Dark pigment in urine late-developing arthritis... 

Another inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase (Fig. 18-23). Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. Individuals with alkaptonuria are also prone to develop a form of arthri-... 

Correct answer = B. Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), a-ketoisovalerate (due to branched-chain a-ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening of the urine. 

Examples of other important genetic diseases associated with amino acid metabolism Other important genetic diseases associated with amino acid metabolism include albinism, homocystinuria, methylmalonyl CoA mutase deficiency, alkaptonuria, histidinemia, and cystathioninuria. 

DISCUSSION. Caution should be exercised when interpreting chromatograms from a complex mixture of aromatic compounds in urine. This is especially true when excretion of the catechols is very high. When the derivatives of the compound extracted from urine of patients with phenylketonuria are prepared decomposition products of the large amounts of phenylpyruvic acid present give rise to peaks which interfere with and resemble HVA. When difficulties of this type are suspected, differential extraction of the urine can be performed. When alkaptonuria urine is extracted with dichloromethane, homovanillic acid is extracted preferentially, leaving the spurious compounds behind. 

Figure 10.8 shows the results of analysis of authentic organic acids derivatized as described and separated on a column of 5% SE-52 on silanized Celite (5 ft). Figure 10.9 shows an example of a chromatogram of extracts from urine of patients with alkaptonuria. 

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

Amino acid abnormalities, such as phenylketonuria, tyrosinemla, alkaptonuria, albinism, histidinemiu, byperprolinemia. homocystin-aria, cyslinuria, and keloaciduria. Note that these names, in general, imply the germane amino acid. 

Tyrosine Alkaptonuria Homogentisic acid in urine darkens on standing in adult years, pigment deposits cause darkening of skin, cartilage arthritis develops Homogentisic acid oxidase... 

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

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