Effect of Phenylalanine on Brain Maturation: Implications for the Treatment of Patients with Phenylketonuria

Hommes, F. A.; Matsuo, Kiyosato

doi:10.1007/978-1-4615-9821-3_28

Cited by 2 publications

(2 citation statements)

References 18 publications

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“…In this hypothesis, the phenylalaninesensitive ATP-sulphurylase (ATP:sulphate adenylyl transferase, EC 2.7.7.4) is the enzyme inhibited by phenylalanine, ultimately leading to demyelination. The apparent K i of phenylalanine for this enzyme was found to be 0.9mmol/L (Hommes and Matsuo 1988).…”

Section: Discussionmentioning

confidence: 98%

Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse

Hommes

Moss

1991

J of Inher Metab Disea

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Myelin turnover has been studied in the 25-day-old HPH-5 mouse, a phenylalanine hydroxylase-deficient mouse mutant. The half-life of the fast component of myelin decreased from 15 days in control mice to 4.5 days at blood phenylalanine levels of 2.5 mmol/L. The slow component of myelin seems also to be affected by the high phenylalanine level. These observations confirm similar observations obtained with chemically induced models of hyperphenylalaninaemia and are therefore due to the hyperphenylalaninaemia per se, independently of the inhibitors of phenylalanine hydroxylase. An intermediate blood level of phenylalanine (0.7 mmol/L) likewise seems to interfere with myelin metabolism, although to a lesser degree.

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Section: Discussionmentioning

confidence: 98%

Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse

Hommes

Moss

1991

J of Inher Metab Disea

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“…A hypothesis that could explain these diverse observations has been proposed (Hommes and Matsuo 1987;Hommes 1991). Central in this hypothesis is the inhibition of phenylalanine of ATP-sulphurylase (ATP:sulphate adenylyltransferase, EC 2.7.7.4; Hommes, 1985;Hommes and Matsuo, 1988), leading to a decreased synthesis of sulphatides. A lower level of sulphatides provides a lower degree of protection for myelin basic protein towards proteolytic degradation, resulting in an increased turnover of myelin, not compensated by an increased rate of synthesis (Hommes and Moss 1992).…”

mentioning

confidence: 99%

The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH‐5 mouse brain

Hommes

1993

J of Inher Metab Disea

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Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using alpha-methylphenylalanine-induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH-5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemia per se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus). The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days. Since the hippocampus has been shown to be involved in the long-term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.

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Effect of Phenylalanine on Brain Maturation: Implications for the Treatment of Patients with Phenylketonuria

Cited by 2 publications

References 18 publications

Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse

Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse

The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH‐5 mouse brain

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