Phenylketonuria characterization

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

Phenylalanine hydroxylase (PH) which requires tetrahydrobiopterin (BH4) as a cofactor, is defective in cases of phenylketonuria (PKU). This is a rare (prevalence 1 / 15 000 in the United Kingdom) genetic condition characterized by fair complexion, learning difficulties and mental impairment. If PH is either not present in the hepatocytes or is unable to bind BH4 and is therefore non functional, phenylalanine accumulates within the cells. Enzymes in minor pathways which are normally not very active metabolize phenylalanine ultimately to phenylpyruvate (i.e. a phenylketone). To use the traffic flow analogy introduced in Chapter 1, the main road is blocked so vehicles are forced along side roads. Phenylpyruvate is excreted in the urine (phenyl-ketone-uria), where it may be detected but a confirmatory blood test is required for a reliable diagnosis of PKU to be made. 

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. 

For example, alkaponuria is characterized by homogentisic acid in urine phenylketonuria, which results in mental retardation, is characterized by quantities of phenylpyruvic acid in the urine. It is diagnosed in a suspected patient by determining the amount of this acid in the urine and the increased levels of phenylalanine in the plasma. Maple sugar disease is diagnosed the presence of large amounts of the branched chain amino acids, such as valine, leucine, and isoleucine in the blood and urine. 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

The disease phenylketonuria, which causes severe mental retardation, is characterized by the urinary excretion of phenylpyruvate. Why is this formed ... 

Both tyrosine and tryptophan hydroxylases belong to a small family of monooxygenases, that also includes phenylalanine hydroxylase all three enzymes require tetrahydro-biopterin as a substrate to drive the hydroxylation reaction." Deficiencies in the enzymes responsible for formation and recycling of tetrahydrobiopterin result in variant forms of phenylketonuria and hyperphenylalaninemia characterized by low levels of monoamine neurotransmitters and severe neurological abnormalities. "... 

The pathway leading to o-tyrosine is of little quantitative significance in normal individuals however, it becomes important in phenylketonuria, and we shall see later that this disease is characterized by a considerable increase in the elimination of o-hydroxyphenylacetic acid. This acid may be formed from o-tyrosine through a pathway suggested by Armstrong et al. (AlO), which is summarized in Fig. 10. 

The first evidences related to gene, nutrient, and disease interaction are emerged from single gene mutation originated metabolic diseases like phenylketonuria. Phenylketonuria is an inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase and characterized by mental retardation and is treatable by a low phenylalanine diet [71]. 

Phenylketonuria (PKU) is an inherited autosomal recessive metabolic disease characterized by characterized by decrease activity of enzyme phenylalanine hydroxylase (PAH) [1], The Norwegian biochemist and physician Asbjom Foiling discovered PKU in 1934 by detecting phenylketones in the urine of siblings with mental retardation, with subsequent identification of altered... 

Phenylketonuria or phenylpyruvic oligophrenia is a disease transmitted as a typical mendelian recessive character and manifested by a specific biochemical and neurological syndrome. Biochemically, phenylketonuria is characterized by increased levels of phenylalanine in the blood, cerebrospinal fluid, and urine. In addition to phenylalanine derivatives, a few indole derivatives are found in the urine of phenylketonuric patients. 

Whatever the mechanisms, the neurological findings are quite striking, as demonstrated by macroscopic and microscopic examinations of the central nervous system of patients affected with phenylketonuria. The disease is characterized by deficient myelination and gliosis. Several parts of the nervous system are in-... 

In cases of phenylketonuria (oligophrenia phenylpyruvica) a congenital anomaly of metabolism characterized by an incomplete oxidation of phenylalanine to /-tyrosine. Pare et and Sandler found a significant... 

Phenylalanine is hydroxylated to tyrosine by the enzyme phenylalanine hydroxylase. The inborn disease phenylketonuria is characterized by a deficiency of this enzyme. 

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