Phenylketonuria pathology

Errors in amino acid metabolism served as sources of some of the first insights into the correlation between pathology and biochemistry. Although there are many hereditary errors of amino acid metabolism, phenylketonuria is the best known. This condition is the result of the accumulation of high levels of phenylalanine in the body fluids. By unknown mechanisms, this accumulation results in mental retardation unless the afflicted are placed on low phenylalanine diets immediately after birth. 

Rutter By normal I mean that they occur commonly in the general population without being associated with the disease. In a sense all allelic variations are mutations, but in medical genetics one would tend to make a distinction between a gene for phenylketonuria which is obviously causing pathology, as opposed to ApoE4 which is a normal variation but nevertheless carries with it an increased statistical risk for Alzheimer s. 

PKU Phenylketonuria the pathologic condition of increased excretion of phenylketones in the urine because of impaired conversion of phenylalanine to tyrosine. Classical PKU is because of a genetic deficiency of phenylalanine hydroxylase however, other causes are deficiencies in dihydropteridine reductase or in the biosynthesis of tetrahydrobiopterin. 

EXAMPLE 14.8 The first enzyme activity (dihydrobiopterin reductase) in Fig. 14-14 catalyzes the transfer of hydrogen to dihydrobiopterin which is thereby reduced to tetrahydrobiopterin. The second enzyme activity is a hydroxylase containing two Fe + atoms, and this catalyzes the reduction of Oj such that one oxygen atom is incorporated into phenylalanine to form tyrosine, and the second is incorporated into water. At the same time tetrahydrobiopterin is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is an example of a mixed-function oxidase. A deficiency of phenylalanine hydroxylase results in an accumulation of phenylalanine which is not converted to tyrosine but is excreted as phenylpy-ruvate. This pathological condition is known as phenylketonuria and is associated with severe mental retardation. 

Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010 99 Suppl LS3-9. 

Some inherited metabolic disorders are extremely damaging while the effects of others are so mild that they can hardly be called diseases. For example, alkaptonurics are usually quite healthy although in later life they are prone to a particular form of arthritis. Similarly the conditions of fructosuria and pentosuria, in which fructose and pentose sugars respectively appear in the urine, have no pathological consequences. At the other end of the scale is phenylketonuria in which the enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine, is lacking. In this condition phenylpyruvic acid and other intermediate products of phenylalanine metabolism accumulate in the blood and tissues and are so injurious to the central nervous system that, although physical development is essentially normal, there is severe mental retardation. 

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