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

Novotny, Edward J.; Avison, Malcolm J.; Herschkowitz, N; Petroff, Ognen A. C.; Prichard, James W.; Seashore, Margretta R.; Rothman, Douglas L.

doi:10.1203/00006450-199502000-00020

Cited by 59 publications

(32 citation statements)

References 32 publications

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“…The individual time courses of our measured brain versus plasma Phe levels (not shown) appear to confirm a large individual spread in kinetic parameters. 1 H-MRS. As in earlier studies (8,9,11), it was possible to quantitate by 1 H-MRS cerebral Phe concentrations in patients with PKU, thereby confirming the usefulness of 1 The preload values of Phe were somewhat different between the two series. It seems quite possible that this small difference is caused by the first dose of LNAAs taken before the baseline measurement.…”

supporting

confidence: 49%

“…In earlier studies, it was demonstrated that cerebral Phe can be readily detected noninvasively by proton magnetic resonance spectroscopy ( 1 H-MRS) (8,9) and that quantitative 1 H-MRS can be applied to reliably determine its concentrations (9,10). It was also shown that the influx of Phe through the blood-brain barrier (BBB) during an oral Phe challenge can be monitored by 1 H-MRS (11).…”

Section: Introductionmentioning

confidence: 99%

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

Pietz¹,

Kreis²,

Rupp³

et al. 1999

J. Clin. Invest.

250

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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supporting

confidence: 49%

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.

250

178

View full text Add to dashboard Cite

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“…It is known to be a precursor for catecholamine synthesis, and normally present in human brain at approximately 0.2 mM. 144 Its concentration is elevated in phenylketonuria (PKU), an inborn error of phenylalanine metabolism, and can reach 5 mM. In PKU patients, the hydroxylation of phenylalanine to tyrosine is disturbed due to an absence or deficiency of the liver enzyme phenylalanine hydroxylase, or rarely, of its tetrahydrobiopterin cofactor.…”

Section: Phenylalanine (Phe)mentioning

confidence: 99%

Proton NMR chemical shifts and coupling constants for brain metabolites

2000

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“…One case of atypical PKU will be described separately. Mean age was 14.3 (12)(13)(14)(15)(16)(17) years. Start of dietary treatment was early (mean 21.5 (range 11-45) days after birth).…”

Section: Methodsmentioning

confidence: 99%

Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6-pyruvoyl tetrahydropteridine synthase deficiency

1996

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White matter abnormalities on MRI have been observed in phenylketonuria (PKU) patients with late onset neurological symptoms as well as in neurologically inconspicious patients. We investigated 14 early treated adolescents at an age between 12 and 17 years (mean age 14.3 years) with classical PKU as well as one retarded patient with atypical PKU by cranial MRI with spinecho T1-, T2- and proton density sequences. Clinical examination was normal. Visual evoked potential (VEP) examination showed a prolonged latency of peak P100 (mean 122.6 ms; control mean 115.9) and IQ testing showed a mean IQ of 101.1. To investigate the influence of plasma phenylalanine (Phe) levels three approaches were used: Phe was determined for the day of MRI, for a period of 6 months prior to MRI and for lifetime up to 12 years. MRI scans revealed areas of abnormally increased signal intensity on T2-weighted and proton density images in 12 (86%) patients, preferably involving the parieto-occipital lobes. MRI of the patient with atypical PKU was normal. MRI findings correlated most strongly to long-term dietary control up to 12 years. We found no correlation with the other parameters of biochemical control, IQ or VEP latency. The nature and prognosis of MRI abnormalities in neurologically normal PKU patients remain unclear although abnormalities in VEPs which were not associated with the degree of MRI abnormalities in our sample indicate a disturbance in myelination along the visual pathways.

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

Cited by 59 publications

References 32 publications

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

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

Proton NMR chemical shifts and coupling constants for brain metabolites

Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6-pyruvoyl tetrahydropteridine synthase deficiency

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