Phenylketonuria phenylalanine concentration

The concentration of phenylalanine in the blood of neonates is used to screen for phenylketonuria (PKU). Explain the biochemical basis for the correlation of elevated blood phenylalanine concentration and PKU. Explain why restriction of dietary phenylalanine is critically important for youngsters with PKU. 

Extrapyramidal symptoms developed with co-trimox-azole in a girl with dihydropteridine reductase deficiency and rapidly disappeared after withdrawal. This variant of phenylketonuria should be considered in all infants found to have raised phenylalanine concentrations during the neonatal period (46). 

The detection of phenylketonuria was the first screening programme to be established. The screening test is based on the detection of increased phenylalanine concentration in the blood spot. 

The mainstay of the management of phenylketonuria is to reduce the plasma phenylalanine concentration by dietary control. Mental retardation is not present at birth, and can be prevented from cKcurring if plasma phenylalanine concentrations are kept low in the early years of life. It was thought that dietary control need only be follow ed for ten years or so but current views arc that lifelong therapy is neces.sary. 

Phenylketonuria, an inborn error of phenylalanine metabolism, occurs with a frequency of about 1 in 10,000 births and is treated with a strict dietary regimen. Recently, some patients with PKU have been found to show increased tolerance towards phenylalanine intake, while receiving tetrahydrobiopterin (BH ) supplementation. We have treated two infants with BH -responsive PKU with BH for more than 2 years. No additional dietary control was required to maintain blood phenylalanine concentrations in the desired range. Both children have shown normal development. Generally, these results suggest that BH treatment might be an option for some patients with mild PKU, as it frees them from dietary restriction and thus improves their quality of life. 

Classification of the severity of phenylketonuria is based on the type of the genetic mutations in phenylalanie hydroxylase (PAH) gene, dietary phenylalanine tolerance, and prelreatment blood phenylalanine concentrations. 

Cleary M, et al. Fluctuations in phenylalanine concentrations in phenylketonuria a review of possible relationships with outcomes. Mol Genet Metab. 2013 110(4) 418-23. 

The goal of nutrition management of phenylketonuria (PKU) is to maintain blood phenylalanine concentrations between 120 and 360 pmol/L. 

Moats RA KR, Moseley K, Guldberg P, Guttler F, Boles RG, Nelson MD. Brain phenylalanine concentration in the management of adults with phenylketonuria. J Inherit Metab Dis. 2000 23(1) 7-14. 

Moats RA, et al. Brain phenylalanine concentrations in phenylketonuria research and treatment of adults. Pediatrics. 2003 112(6 Pt 2) 1575-9. 

In clinical trials, 20-61 % of individuals with phenylketonuria (PKU) have been found to respond to tetrahydrobiopterin (BH4) as demonstrated by a decrease in blood phenylalanine concentration. 

Levy HL, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria a phase 111 randomised placebo-controlled study. Lancet. 2007 370(9586) 504-10. 

Acosta PB, et al. Intake of major nutrients by women in the Maternal Phenylketonuria (MPKU) Study and effects on plasma phenylalanine concentrations. Am J CMn Nutr. 2001 73(4) 792-6. 

Systematic reviews In a review of a placebo-controlled trial of sapropterin in 89 children and adults with phenylketonuria whose diets were not restricted and who had previously responded to sapropterin and a trial in 90 children aged 4-12 years with phenylketonuria whose diet was restricted, there was a significant fall in blood phenylalanine concentration with sapropterin in the first and a non-significant fall in the second no serious adverse events were associated with short-term sapropterin... 

Systematic reviews The efficacy and safety of sapropterin dihydrochloride in lowering phenylalanine concentration in patients with phenylketonuria has been systematically reviewed [21 ]. Two trials including a total of 135 participants were included in the analysis. No serious adverse events were associated with the use of sapropterin on the short-term. 

Because treatment is most effective if started in earliest infancy, it is necessary to make the diagnosis of phenylketonuria before any clinical signs appear, i.e. from the biochemical changes. Every newborn infant must be tested and, therefore, the test used must be inexpensive, simple and reliable [70, 71]. The available methods are determination of phenylalanine concentration in the blood, o-hydroxyphenyl-acetic acid in urine or phenylpyruvic acid in urine. The third method, once widely used, has now been largely abandoned the first and, to a lesser extent, the second are used on a very large scale in many countries. Sometimes tests for other conditions, such as homocystinuria, galactosaemia and maple syrup urine disease, are combined with the test for phenylketonuria. 

Pish protein concentrate and soy protein concentrate have been used to prepare a low phenylalanine, high tyrosine peptide for use with phenylketonuria patients (150). The process includes pepsin hydrolysis at pH 1.5 ptonase hydrolysis at pH 6.5 to Hberate aromatic amino acids gel filtration on Sephadex G-15 to remove aromatic amino acids incubation with papain and ethyl esters of L-tyrosine and L-tryptophan, ie, plastein synthesis and ultrafiltration (qv). The plastein has a bland taste and odor and does not contain free amino acids. Yields of 69.3 and 60.9% from PPG and soy protein concentrate, respectively, have been attained. 

Phenylketonuria (PKU) is a group of inherited disorders caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that catalyses the conversion of phenylalanine to tyrosine, the first step in the pathway for catabolism of this amino acid. As a result, the concentration of phenylalanine in the liver and the blood increases. This high concentration in the liver increases the rate of a side reaction in which phenylalanine is converted to phe-nylpyruvic acid and phenylethylamine, which accumulate in the blood and are excreted in the urine. 

Similarly, lysine has been incorporated into gluten hydrolyzate and lysine, threonine and tryptophan have been individually incorporated into zein hydrolyzates. Lysine, methionine, and tryptophan were incorporated simultaneously into hydrolyzates of protein from photosynthetic origin. A very interesting application of this procedure involved the preparation of low-phenylalanine plasteins from a combination of fish protein concentrate and soy protein isolate by a partial hydrolysis with pepsin then pronase to liberate mainly phenylalamine, tyrosine, and tryptophan, which were then removed on sephadex G-15. Desired amounts of tyrosine and tryptophan were added back in the form of ethyl esters and a plastein suitable for feeding to infants afflicted with phenylketonuria was produced. 

DISCUSSION. The concentrations of six unconjugated aromatic acids in urine of 12 cases of phenylketonuria on normal and phenylalanine-restricted diets are shown in Table 10.4. The amounts were calculated as mg/g creatinine (done on an aliquot by established procedures). An example of the separation of six individual known aromatic acids carried through the procedure is seen in Figure 10.12. An example of the normal profile of the acids in a normal urine is also shown. 

TABLE 10.4 CONCENTRATION OF UNCONJUGATED AROMATIC ACIDS IN URINE SPECIMENS OF 12 CASES OF PHENYLKETONURIA ON NORMAL AND PHENYLALANINE-RESTRICTED DIETS... 

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