Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

Lykkelund, C.; Nielsen, Jens Bo; Hc, Lou; Rasmussen,; Gerdes, Anne–Marie; Christensen, Ernst; Güttler, Flemming

doi:10.1007/bf00441411

Cited by 65 publications

(40 citation statements)

References 42 publications

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“…Decreased cerebral concentrations of tyrosine and tryptophan may result in insufficient synthesis of dopamine and serotonin, respectively. In cerebrospinal fluid and brain of untreated and treated PKU, patients the concentrations of neurotransmitters are clearly decreased (Antoshechkin et al 1991;Burlina et al 2000;Butler et al 1981;Guttler and Lou 1986;Lykkelund et al 1988;McKean 1972). Similar observations were made in brain tissue of PKU mice (Pascucci et al 2002;Puglisi-Allegra et al 2000).…”

Section: Effects Of Decreased Cerebral Concentrations Of Large Neutrasupporting

confidence: 76%

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

Spronsen

Hoeksma

Reijngoud

2009

J of Inher Metab Disea

114

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In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

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Section: Effects Of Decreased Cerebral Concentrations Of Large Neutrasupporting

confidence: 76%

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

Spronsen

Hoeksma

Reijngoud

2009

J of Inher Metab Disea

114

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“…It has been shown for the tyrosine-derived neurotransmitters (Krause et al, 1985(Krause et al, , 1986 and for tyrosine supplementation (Lou et al, , 1987Lou, 1985Lou, , 1988Lykkelund et al, 1988) that an increased flux through tyrosine hydroxylase is associated with changes in parameters of brain function, but such an effect has not been demonstrated with tryptophan supplementation (Nielsen, 1988). The tryptophan hydroxylase flux is less sensitive to changes in the blood tryptophan level than the tyrosine hydroxylase flux is to changes in the blood tyrosine level.…”

Section: Discussionmentioning

confidence: 96%

The control of 5‐hydroxytryptamine and dopamine synthesis in the brain: A theoretical approach

Hommes

Lee

1989

J of Inher Metab Disea

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The transport of the eight amino acids (phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine and methionine) using the large neutral amino acid transporter of the blood-brain barrier (BBB) has been calculated using published kinetic data. The fate of the amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for tyrosine and tryptophan, the hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non-homogeneous system. At physiological levels of these eight amino acids, the largest contribution to the control of the flux of tyrosine is given by the hydroxylase step, followed by the diffusional component of the transport across the BBB. For tryptophan it is the hydroxylase step, followed by the carrier-mediated transport across the BBB. For the other amino acids it is the metabolism, followed by the diffusional component of the BBB transport. These parameters for tyrosine and tryptophan were determined at increased levels of blood phenylalanine, tyrosine or histidine. The flux through tryptophan hydroxylase can be affected by high blood levels of tyrosine and histidine to values also observed in hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with mental retardation, it is concluded that interference with transport across the BBB of tyrosine and tryptophan, as well as the flux through tryptophan hydroxylase leading to the synthesis of 5-hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in hyperphenylalaninaemia. It can be calculated that addition of tyrosine to the diet to raise the blood tyrosine level in phenylketonuria patients may have a beneficial effect for the synthesis of neurotransmitters derived from tyrosine.

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“…The above arguments suggest that competing effects of brain Phe on DOPA decarboxylase and BBB efflux may fortuitously cancel, such that adequate dopamine synthesis is maintained in the present PKU patients. Nonetheless, reduced dopamine metabolite levels are reported in the cerebrospinal fluid of PKU patients (Lykkelund et al, 1988), suggesting that cerebral dopamine synthesis is actually impaired, but to an extent falling below a threshold for emergence of motor symptoms. An additional compensating mechanism could be an upregulation of postsynaptic dopamine receptors, as occurs in patients suffering from untreated Parkinson's disease.…”

Section: Discussionmentioning

confidence: 99%

Reduced Cerebral Fluoro-l-Dopamine Uptake in Adult Patients Suffering from Phenylketonuria

Landvogt¹,

Mengel

Bartenstein³

et al. 2007

J Cereb Blood Flow Metab

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Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. To test this hypothesis, we used positron emission tomography (PET) to measure the utilization of 6-[ 18 F]fluoro-L-dopamine (FDOPA) in the brain of adult patients suffering from PKU and in healthy controls. Dynamic 2-h long FDOPA emission recordings were obtained in seven adult PKU patients (five females, two males; age: 21 to 27 years) with elevated serum Phe levels, but lacking neurologic deficits. Seven age-matched, healthy volunteers were imaged under identical conditions. The utilization of FDOPA in striatum was calculated by linear graphical analysis (k 3 S , min À1 ), with cerebellum serving as a nonbinding reference region. The time to peak activity in all brain time-radioactivity curves was substantially delayed in the PKU patients relative to the control group. The mean magnitude of k 3 S in the striatum of the PKU patients (0.0052 ± 0.0004 min À1 ) was significantly lower than in the control group (0.0088±0.0009 min À1 ) (P < 0.001). There was no significant correlation between individual serum Phe levels and k 3 S . The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe. Assuming this competition to be spatially uniform, the relationship between striatum and cerebellum time-activity curves additionally suggests inhibition of DOPA efflux, possibly also due to competition from Phe. The linear graphical analysis shows reduced k 3 S in striatum, indicating reduced DOPA decarboxylase activity.

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Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine

Cited by 65 publications

References 42 publications

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

The control of 5‐hydroxytryptamine and dopamine synthesis in the brain: A theoretical approach

Reduced Cerebral Fluoro-l-Dopamine Uptake in Adult Patients Suffering from Phenylketonuria

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