Genotype-phenotype correlations in phenylketonuria

Trefz, Friedrich K.; Burgard, Peter; König, Thomas; Goebel-Schreiner, B.; Lichter‐Konecki, Uta; Konecki, David; Schmidt, Enrico; Schmidt, H; Bickel, Horst

doi:10.1016/0009-8981(93)90233-t

Cited by 32 publications

(20 citation statements)

References 6 publications

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“…The results presented above, namely the inhibition of I NMDA caused by high concentrations of L-Phe, may provide a cellular mechanism whereby hyperphenylalaninemia contributes to the development of mental retardation during PKU. In support of this contention, it is interesting to note that concentrations of L-Phe (0.4-0.7 mM), which are associated with a lower risk of brain damage during hyperphenylalaninemia, 38 only slightly attenuated I NMDA . If our hypothesis that impaired NMDA receptor contributes to the development of mental retardation in patients with PKU is correct, it may promote the development of specific therapeutic strategies (ie, use of glycine-binding site agonists or glycine transporter antagonists) aimed at mitigating PKU-related cognitive problems.…”

Section: Implications Of I Nmda Regulation By L-phementioning

confidence: 83%

Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

et al. 2002

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Section: Implications Of I Nmda Regulation By L-phementioning

confidence: 83%

Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

et al. 2002

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“…A portion of this work was presented at the 8th annual meeting of mine the molecular basis for the phenotypic heterogeneity of this disorder (3,4). Classic PKU is observed in 1 in 7000 to 1 in 15 000 births in most white populations.…”

mentioning

confidence: 99%

In Vivo Measurement of Phenylalanine in Human Brain by Proton Nuclear Magnetic Resonance Spectroscopy

et al. 1995

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“…As discussed previously (2,43), in general, in vitro estimates of residual hydoxylase activity of PAH mutants tend to be higher than those observed in liver biopsies. At least one reason for this tendency is that in vitro PAH activities are customarily measured by using saturating concentrations of phenylalanine and BH 4 , as was done for mutant R261Q (44). Given this situation, it is possible that residual PAH activities estimated with the use of Eq.…”

Section: ϫDphe͞dt ϭ ϫVmentioning

confidence: 99%

“…The system is complex, consisting of phenylalanine hydroxylase (PAH), the pterin coenzyme tetrahydrobiopterin (BH 4 ), and several enzymes that serve to regenerate BH 4 , i.e., dihydropteridine reductase and pterin 4␣-carbinolamine dehydratase (1,2).…”

mentioning

confidence: 99%

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Kaufman

1999

Proc. Natl. Acad. Sci. U.S.A.

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The derivation of a quantitative model of phenylalanine metabolism in humans is described. The model is based on the kinetic properties of pure recombinant human phenylalanine hydroxylase and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agree well with data from normal as well as from phenylketonuric patients and obligate heterozygotes. These calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in classical patients and in those with milder forms of the disease.The initial and rate-limiting step in the complete catabolism of phenylalanine to CO 2 and water is its hydroxylation to tyrosine, a reaction catalyzed by the phenylalanine hydroxylating system. The system is complex, consisting of phenylalanine hydroxylase (PAH), the pterin coenzyme tetrahydrobiopterin (BH 4 ), and several enzymes that serve to regenerate BH 4 , i.e., dihydropteridine reductase and pterin 4␣-carbinolamine dehydratase (1, 2).Although the benzene ring of phenylalanine cannot be ruptured without first being hydroxylated in the para position, the alanine side-chain of the amino acid can be metabolized even in the absence of the ring-hydroxylation step. This alternate pathway is initiated by transamination of phenylalanine to phenylpyruvate followed by conversion of the latter compound to metabolites such as phenyllactate, phenylacetate, and o-hydroxyphenylacetate.

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Genotype-phenotype correlations in phenylketonuria

Cited by 32 publications

References 6 publications

Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria

In Vivo Measurement of Phenylalanine in Human Brain by Proton Nuclear Magnetic Resonance Spectroscopy

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

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