Phenylketonuria classic

Infants with classic phenylketonuria (PKU) are normal at birth but if untreated show slow development, severe mental retardation, autistic symptoms, and loss of motor control. Children may have pale skin and white-blonde hair. The neurotoxic effects relate to high levels of phenylalanine and not to the phenylketones from which the name of the disease derives. Infants are routinely screened a few days after birth for blood phenylalanine level. Treatment consists of a life-long semisynthetic diet restricted in phenylalanine (smalt quantities are necessary because it is an essential amino acid). Aspartame (N-aspartyl-phenylalanine methyl ester), which is widely used as an artificial sweetener, must be strictly avoided by phenyiketonurics. 

Classic phenylketonuria (PKU) is due to deficiency of phenylalanine hydroxylase, which leads to brain damage due to the neurotoxic effects of accumulated Phe or its metabolites. 

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-... 

Figure 20.22 Catabolism of phenylalanine and tyrosine. A indicates the lesion in classic phenylketonuria B indicates a tyrosinemia caused by tyrosine transaminase deficiency C indicates a tyrosinemia caused by p-hydroxyphenylpyruvate oxidase deficiency and the lesion in neonatal tyrosinemia D indicates alcaptonuria.

The same pool of tetrahydrobiopterin and the same dihydrobiopterin reductase are involved in the central nervous system in the hydroxylation of all three aromatic amino acids. Classical phenylketonuria, which involves a defect... 

Specifically, the deflciency of certain enzymes of tetrahydrobiopterin biosynthesis (GTP cyclohydrolase 1, pymvoyltetrahy-drobiopterin synthase. Fig. 3) result in severe neurological and developmental deflcits designated as atypical phenylketonuria caused by the ensuing deflciency in catecholamine type neurotransmitter biosynthesis. The condition can be treated with some success by the oral application of synthetic tetrahydrobiopterin in large amounts. More recently, tetrahydrobiopterin therapy has also been advocated for certain patients with classic phenylketonuria that results from mutations of phenylalanine hydroxylase... 

This therapeutic approach is based on the concept that the function of certain defective phenylalanine hydroxylases can be bolstered by increased amounts of the cognate coenzyme tetrahydrobiopterin. In fact, the relatively large number of patients with classic phenylketonuria may provide an economic incentive for the development of a biotechnological process for the bulk production of the coenzyme. 

Children with classical phenylketonuria (PKU) have reduced levels of DHA in plasma cholesterol esters (0.25 vs. 0.54 wt%) and membrane phospholipids compared with nonaffected controls (Sanjuro et al., 1994 Poge et al., 1998). It appears, however, that the reduced levels of DHA in PKU patients occur only in patients with strict diet therapy and are most probably caused by a reduced intake of omega-3 fatty acids (Poge et al., 1998). Studies are underway and planned on the effects of DHA supplementation in pregnant women with PKU and children with PKU (Giovannini et al., 1995). 

A liver biopsy was sent to the special chemistry research laboratory, where it was determined that the level of activity of phenylalanine hydroxylase (PAH) in Piquet s blood was less than 1% of that found in normal infants. A diagnosis of "classic" phenylketonuria (PKU) was made. 

Legido A, Tonyes L, Carter D, Schoemaker A, Di George A, Grover WD. Treatment variables and intellectual outcome in children with classic phenylketonuria CUn Pediatrics (PhQa) 1993 32 417-425. 

McDonald ID. Postnatal growth rates in a mouse genetic model of classical phenylketonuria. Contemp Top Lab Amin Sci 2000 39 54—56. 

Fig. 5.2 Microcephaly in a newborn with maternal PKU syndrome (MPKU) born from a mother with classical phenylketonuria treated since 33 weeks gestation (Photo courtesy of Dr. Maria Gizewska)...

Weglage J, et al. Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria. J Inherit Metab Dis. 2002 25(6) 431-6. 

MUd phenylketonuria Moderate phenylketonuria Severe (classical) phenylketonuria... 

Huemer M et al. Growth and body composition in children with classical phenylketonuria results in 34 patients and review of the literature. J Inherit Metab Dis. 2007 30(5) 694-9. 

Classical phenylketonuria is an hereditary defect in the synthesis of Phe hydroxylase (the enzyme may be absent or inactive), which affects about 1 infant in 10,000. These individuals are unable to convert Phe into tyrosine, and the major route of Phe metabolism is thus blocked. Phenylpyruvate and phenylacetic acid are excreted in the urine. The condition is accompanied by defective pigmentation and, if untreated, by severe mental retardation (hence the other name, phenylpyruvic oligophrenia, also known as Polling s syndrome). Tlie urine of newborn infants is now routinely tested (Guthrie test) for the presence of phenylketones the condition can be compensated by a diet low in phenylalanine, and the typic mental retardation is thereby avoided. Other types of phenylketonuria are due to defective reduction or synthesis of dihydrobiopterin (see Inborn errors of metabolism). 

Fig. 16.12 Chromatogram of organic acids extracted using DEAE-Sephadex from the urine of a patient with untreated classical phenylketonuria, separated as their ethoxime and trimethylsilyl derivatives on 10 per cent OV-101 on HP Chromosorb W (80-100 mesh) by temperature programming from 110°C to 285°C at 4°C min" with a 5 min initial isothermal delay. Peak identifications are 1, sulphate 2, benzoate 3, phosphate 5, mandelate 6, 2-hydroxyphenylacetate 7, phenyl-lactate 8, phenylpyruvate 9, hippurate 10, citrate 11, 4-hydroxyphenyl-lactate 12, 4-hydroxyphenylpyruvate 13, undecanedioate (internal standard) 14, urate 15, indole-3-lactate 16.5-hydroxyindole-3-acetate 17, n-tetracosane (standard) 18, -hexacosane (standard). The position of phenylacetate is arrowed (peak 4) but free phenylacetate has never been observed by the authors in the urine of untreated phenylketonuric patients. (From Chalmers, 1974).

Koepp, P. and Hoffmann, B. (1974), Aromatic acid excretion in classical phenylketonuria and hyperphenylalaninaemia variants. Helv. Paediatr. Acta, 29,489. 

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