Plasma phenylalanine

Fig. 2.1.1 Tandem mass spectrometry analyses of plasma phenylalanine (phe) and tyrosine (tyr) in a patient with phenylketonuria (PKU left panel phe 793 pmol/1, tyr 70 pmol/1) and in a control (right panel phe 27 pmol/1, tyr 28 pmol/1). The stable-isotope-labelled internal standards are D4-tyrosine (D4-tyr), containing four deuterium atoms and D5-phenylalanine (D5-phe), which has five deuterium atoms.

Screening for a BH4 deficiency should be done in all newborns with plasma phenylalanine levels higher than 120 pmol/1, as well as in older children with neurologic signs and symptoms [10]. The following tests are recommended (1) analysis of pterins in urine, (2) measurement of DHPR activity in blood from a Guthrie card,... 

Stegink LD, Koch R, Blaskovics ME, Filer LJ Jr, Baker GL, McDonnell JE. Plasma phenylalanine levels in phenylketonuric heterozygous and normal adults administered aspartame at 34 mg/kg body weight. Toxicology 1981 20(l) 81-90. 

Routine liver function tests do not rehably indicate hver damage, and they may not become abnormal until there is already considerable hver damage. It is therefore common practice to monitor patients by conducting annual liver biopsies. Measurement of the serum amino-terminal propeptide of type III procoUagen (PHI PI) has been used as an alternative to hver biopsy high concentrations correlate with fibrosis on liver biopsy (49). No patient with a normal serum concentration had an abnormal biopsy. An increase in the plasma phenylalanine/tjrosine ratio in children and adolescents can provide chnical evidence of liver damage before the appearance of symptoms in patients who have taken high doses of methotrexate (50). 

Hilton M A, Bertolone S, Patel CC. Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue. Med Pediatr Oncol 1989 17(4) 265-70. 

The criteria for a biochemical diagnosis of untreated classic PKU are (1) a plasma phenylalanine level above 20 mg/dL (1.2mmol/L) (Figure 55-6, A) (2) a phenylalanine/ tyrosine ratio >3 (3) increased urinary levels of metabolites of phenylalanine (i.e., phenylpyruvic and 2-hydroxyphenyl-acetic acids) and (4) a normal concentration of the cofactor... 

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. 

A small subset of patients with hyperphenylalaninemia show an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) activity but have a deficiency in dihy-dropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydro-biopterin (BH4), a cofactor of PAH (see Fig. 39.18). Less frequently, DHPR activity is normal but a defect in the biosynthesis of BH4 exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, BH4 is also a cofactor for two other hydroxy-lations required in the synthesis of neurotransmitters in the brain the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa (see Chapter 48). It has been suggested that the resulting deficit in central nervous system neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. 

Phenylketonuria is an inherited disorder caused by the deficient function of the enzyme phenylalanine hydroxylase this results in increased phenylalanine levels, which damage the developing brain and result in mental retardation. The aim of dietary management is to maintain a normal plasma phenylalanine level by restricting the routine... 

These patients can be diagnosed by administration of tetrahydrobiopterin, which will cause a fall in the plasma phenylalanine level. Evidence thus far marshaled seems to support a defect in biosynthesis of biopterin, the precursor to tetrahydrobiopterin and the active cofactor for phenylalanine hydroxylase (Kure... 

Krause W, Halminski M, McDonald L, Dembme P, Salvo R, Freides D, Elsas L. Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria a model for the study of phenylalanine and brain function in man. J Clin Invest 1985 75 40-48. 

Paddon-Jones et al. reported optimal protein synthesis when dietary protein was provided three times per day compared with the same total amount of protein given in various amounts [26, 29]. In patients with PKU, providing amino acid-based medical food throughout the day compared to a single dose of similar protein equivalents had a positive effect on protein synthesis [30]. A positive effect on plasma phenylalanine concentrations was also reported [30]. For patients with a metabolic disorder, providing medical food along with limited whole protein foods is most beneficial to optimize synthesis. 

MacDonald A, Rylance G, Hall SK, AspUn D, Booth IW. Factors affecting the variation in plasma phenylalanine in patients with phenylketonuria on diet. Arch Dis Child. 1996 74 412-7. 

Plasma phenylalanine concentration of a neonate on a phe-free diet... 

Goal Reduce plasma phenylalanine concentrations to between 120 and 360 pmol/L. Step by step ... 

The only way to know if a diet prescription needs to be adjusted is to measure blood or plasma phenylalanine concentrations. The recommended frequency of monitoring is provided in guidelines developed by Genetic Metabolic Dietitians International [10]. Figure 10.3 shows the diet adjustments that will need to be made whether the infant is receiving phenylalanine from infant formula or from breast-feeding. 

In a classic double-bUnded crossover cUnical trial, Schindeler and colleagues reported a positive effect on executive function in 16 subjects with treated PKU [26]. Either placebo or LNAA supplementation (250 mg/kg/day) was given over four 2-week phases, with a 4-week washout period. Results showed positive impact of LNAA supplementation on several spedlic executive functions, especially on measures of attention. Higher plasma phenylalanine concentrations were reported in phases where LNAA intakes were lowest. A secondary effect was noted in that subjects given the most LNAA, by supplement and medical food, had the lowest blood phenylalanine concentrations (24.9 % reduction). 

Hoeksma M, et al. Phenylketonuria high plasma phenylalanine decreases cerebral protein synthesis. Mol Genet Metab. 2009 96(4) 177-82. 

Sanjutjo P, et al. Dietary threonine reduces plasma phenylalanine levels in patients with hyperphenyltil-aninemia. J Pediatr Gastroenterol Nutr. 2003 36(1) 23-6. 

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. 

Observational studies In 80 patients aged at least 8 years, who had taken part in a 6-week, randomized, placebo-controlled study of sapropterin, and who were enrolled in a 22-week, multicenter, open, extension study there were dose-related reductions in plasma phenylalanine concentrations from 844 to 645 pmol/l 68 patients had at least one adverse event, all but one of which were mild or moderate in intensity [34 ]. Neither the one severe event nor any of the three serious events was considered related to sapropterin. No adverse event led to treatment withdrawal. 

Enzymes. The clinical utility of L-asparaginase has acted as a stimulus for the evaluation of other enzymes for possible antitumor activity. A phenylalanine ammonia-lyase from yeast rapidly decreased the plasma phenylalanine and tyrosine... 

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