Progress in experimental phenylketonuria: A critical review

Vorhees, Charles V.; Butcher, Richard E.; Berry, Helen K.

doi:10.1016/0149-7634(81)90041-5

Cited by 35 publications

(15 citation statements)

References 135 publications

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“…A theory supported by a substantial amount of experimental evidence is that overloading of a common carrier system for large neutral amino acids by excess phenylalanine interferes with transport of other essential amino acids into brain (5,20,21,27). The decreased availability of amino acids leads to depressed protein and lipoprotein synthesis both in vivo and in vitro (1,5,14,19,22,25,26).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

et al. 1982

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SummaryA supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluidserum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15-40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed. SpeculationThe branched chain amino acids and phenylalanine share a common transport system. High levels of phenylalanine in brain of children with phenylketonuria may be reduced by administration of a supplement of valine, isoleucine and leucine (VIL). Supplementation of the low-phenylalanine diet with VIL during the first 2 years of life may add a measure of protection to the developing brain beyond that which can be achieved by diet alone. In older children, VIL supplementation may permit liberalization of the diet without unfavorable behavioral consequences.Treatment for phenylketonuria (PKU) by means of a lowphenylalanine diet has become common practice since its first use in affected newborn infants (3). The treatment partially corrects the abnormal amino acid pattern, including the high concentration of phenylalanine and its metabolites, and allows relatively normal intellectual and physical development if the treatment is begun early enough (10). Initially it was assumed that treatment would be terminated when major phases of brain growth were completed. Evidence has accumulated which suggests that termination of treatment for the patient with classic PKU, at least during the school years, is unwise (13,15,16) and it may be prudent to continue the diet into adult years for women with PKU in order to avoid the teratogenic effects of phenylalanine (6).An animal model developed in this laboratory was used to demonstrate the effects of experimental hyperphenylalaninemia (PKU) (12). Methods to inhibit the deleterious effects of phenylalanine on the central nervous system were studied in the model. Administration of branched chain amino acids, valine, isoleucine, and leucine (VIL), to pregnant rats with experimentally induced PKU prevented the decrease in fetal brain weight characteristic of PKU animals (7). A striking finding was that phenylalanine levels in brain of PKU fetuses whose mothers received VIL supplement were lower than in PKU fetuses not exposed to VIL, although fetal blood phenylalanine levels were similar. Subsequent studies suggested that isoleucine was more effective than other amino acids in exerting a beneficial effect on fetal rat brain growth (1 1).Human trials followed. VIL was first used as a supplement to the low-phenylalanine diet of several older PKU children in w...

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Section: Discussionmentioning

confidence: 99%

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

et al. 1982

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“…The cause of the cerebral damage is probably multifactorial (Kaufman, 1977) since it may be secondary to a deficiency of, or interference with, myelin synthesis and/or myelin breakdown (Menkes, 1966(Menkes, , 1968Alvord et al, 1950;Shah et al, 1972); to impairment of neuronal protein synthesis caused by amino acid transport alteration (Berger et al, 1978;Herrero et al, 1983;McKean et al, 1968) or by direct interference (Barashnev and Korneichuk, 1982); and finally to abnormal metabolism of neurotransmitter amines (Nadler and Hsia, 1961;Vorhees et al, 1981). The myelinization defect suggested by anatomopathological (Shah et al, 1972), neurological (Behebehani et al, 1981) and biochemical (Hommes et al, 1982;Hommes, 1985;Shah et al, 1972) studies is undoubtedly very important.…”

Section: Introductionmentioning

confidence: 98%

Pattern reversal visual evoked potentials in phenylketonuria

Giovannini

Valsasina

Villani

et al. 1987

J of Inher Metab Disea

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The pathogenesis of brain dysfunction in phenylketonuria (PKU) is still under investigation. Hyperphenylalaninaemia results in increased turnover of myelin. In order to demonstrate the derangement of myelinization in PKU we studied the visual evoked potentials (VEP) in 14 PKU patients and in 20 normal subjects. VEP findings were correlated with the metabolic control of the disease and with the electroencephalographic findings. VEP were more sensitive than the EEG in detecting a neurological dysfunction. VEP are influenced by dietary control and are normal only in children with good metabolic control.

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“…It is therefore not surprising that these neurotransmitters have been implicated in the aetiology of the mental retardation observed in PKU (cf. Voorhees et al, 1981). Any condition associated with an increase in one or more of these neutral amino acids will similarly affect the uptake by the brain of the other neutral amino acids.…”

mentioning

confidence: 98%

The role of the blood‐brain barrier in the aetiology of permanent brain dysfunction in hyperphenylalaninaemia

Hommes

1988

J of Inher Metab Disea

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Calculations on the rate of entry of the neutral amino acids into the brain via the blood-brain barrier show that a considerable decrease in this rate, particularly for tryptophan and tyrosine, takes place in histidinaemia and tyrosinaemia, type II. These conditions are, however, not associated with mental retardation. It is therefore concluded that effects at the blood-brain barrier alone do not provide an adequate explanation for the aetiology of permanent brain dysfunction in hyperphenylalaninaemia.

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Progress in experimental phenylketonuria: A critical review

Cited by 35 publications

References 135 publications

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

Pattern reversal visual evoked potentials in phenylketonuria

The role of the blood‐brain barrier in the aetiology of permanent brain dysfunction in hyperphenylalaninaemia

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