Phenylketonuria: Biochemical Mechanisms

Kaufman, Seymour

doi:10.1007/978-1-4615-8237-3_1

Cited by 79 publications

(57 citation statements)

References 313 publications

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“…Besides several other important aspects, inhibition of enzymes involved in cerebral energy production has been shown for Phe in in vitro studies (4 -7). However, no clear evidence could be established to prove that impaired cerebral energy metabolism represents a key explanatory factor for PKU-related brain damage or dysfunction in vivo (8).…”

Section: In Vivomentioning

confidence: 99%

Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

et al. 2003

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Both severe impairments of brain development in untreated infants and acute reversible neurotoxic effects on brain function are clinical features of phenylketonuria (PKU). For determining whether impairments of cerebral energy metabolism play a role in the pathophysiology of PKU, quantitative in vivo 31 P magnetic resonance spectroscopy (MRS) was performed in a supratentorial voxel of 11 adult PKU patients and controls. Peak areas of inorganic phosphate; phosphocreatine; ␣-, ␤-, and ␥-ATP; NAD; phosphomonoesters; phosphodiesters; and a broad phospholipid signal were converted to millimolar concentrations. Mg 2ϩ , pH, ADP, the phosphorylation potential, and the relative velocity of oxidative metabolism V/V max were derived. Clinical evaluation included mutation analysis, neurologic investigation, intelligence testing, magnetic resonance imaging, and concurrent plasma and brain phenylalanine (Phe), the last by 1 H-MRS. Phe loading was performed in five patients with an oral dose of 100 mg/kg body wt L-Phe monitored by spectral EEG analysis. Under steadystate conditions, 31 P-MRS revealed normal values for ATP, phosphocreatine, NAD, phosphomonoesters, phosphodiesters, Mg 2ϩ , and pH in PKU. ADP (ϩ11%) and the phosphorylation potential (ϩ22%) were increased. Peak areas of inorganic phosphate (Ϫ22%) and phospholipid (Ϫ8%) were decreased. ADP correlated with concurrent plasma (r ϭ 0.65) and brain (r ϭ 0.55) Phe. During the Phe load, blood Phe levels increased steeply.EEG revealed slowing of background activity. The phosphorylation potential decreased, whereas ADP and V/V max increased. In vivo31 P-MRS demonstrated subtle abnormalities of cerebral energy metabolism in PKU in steady-state conditions that were accentuated by a Phe load, indicating a link between Phe neurotoxicity and imbalances of cerebral energy metabolism. Abbreviations 1 H-MRS, proton magnetic resonance spectroscopy IDC, index of dietary control MPF, mean power frequency MRI, magnetic resonance imaging P I , inorganic phosphate PAH, phenylalanine hydroxylase PCr, phosphocreatine PDE, phosphodiesters Phe, phenylalanine PL, phospholipids PME, phosphomonoesters 31 P-MRS, phosphorus-31 magnetic resonance spectroscopy PKU, phenylketonuria PP, phosphorylation potential Phenylketonuria (PKU) is the most frequent inborn disorder of amino acid metabolism. PKU is caused by an autosomal recessively transmitted deficiency of hepatic phenylalanine (Phe) hydroxylase (PAH; enzyme commission 1.14.16.1). In untreated PKU patients, Phe accumulates to plasma levels exceeding 1500 M; normal plasma Phe in fasting adults is 60 M. The characteristics of untreated PKU result from disturbed brain development and include microcephaly, epilepsy, severe mental retardation, and behavior problems (1).Through the early start of a Phe-restricted diet, the phenotype of untreated PKU can be widely prevented. However, elevated plasma concentrations of Phe, which usually occur in adolescence because of a relaxed diet, are known to cause acute impairments of brain function. Reduced atten...

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Section: In Vivomentioning

confidence: 99%

Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

et al. 2003

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“…Direct effects of Phe, as well as imbalances of the large neutral amino acids (LNAAs) in brain, are thought to be major causes (6,7).…”

Section: Introductionmentioning

confidence: 99%

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria

Pietz¹,

Kreis²,

Rupp³

et al. 1999

J. Clin. Invest.

255

178

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Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1 H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was ∼1,000 µmol/l and brain Phe was ∼250 µmol/l in both series. Without LNAA supplementation, brain Phe increased to ∼400 µmol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

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“…Prolidase deficiency appears to be an inborn error of metabolism in the general category of disorders such as phenylketonuria, wherein the biochemical aberrations are mesent from birth and produce subclinical damage before clinical abnormalities are recognized (12). If proposed therapies for prolidase deficiency are to be optimally effective they probably will need to be initiated during early infancy (5,9).…”

Section: Discussionmentioning

confidence: 99%

Congenital Expression of Prolidase Defect in Prolidase Deficiency

et al. 1984

Pediatr Res

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Phenylketonuria: Biochemical Mechanisms

Cited by 79 publications

References 313 publications

Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

Cerebral Energy Metabolism in Phenylketonuria: Findings by Quantitative In Vivo 31P MR Spectroscopy

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria

Congenital Expression of Prolidase Defect in Prolidase Deficiency

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