Transport inhibition in the pathology of phenylketonuria and other inherited metabolic diseases

Abstract

Kinetic analysis of the rates of transport of amino acids and of sugars across the blood‐brain barrier shows how severe is the competition which commonly occurs between groups of chemically related substances in the blood plasma for one of a number of shared transport carriers. In view of the possible importance of such competition in causing brain damage in inherited metabolic diseases an example is given of the use of these kinetic data to work out the best way of ensuring an adequate supply of amino acids to the brain during the dietary treatment of phenylketonuria. Indications are obtained of the degree to which the supply of amino acids other than phenylalanine to the brain may be reduced and of the conditions which are likely to prove most dangerous. It is concluded that the supplementation of the diet with tyrosine alone cannot be expected to provide an effective alternative to phenylalanine restriction. The high level of phenylalanine found commonly in untreated phenylketonuria carries a risk of reducing the supply to the brain of up to eleven other amino acids which the brain cells need. A lack of any one of these may interfere with brain growth and development. The implications are considered for possible improvements in the treatment of phenylketonuria or other inherited metabolic diseases. It is concluded that there may well be some advantage in increasing the intake of amino acids other than the restricted phenylalanine which the brain has to obtain from the circulation above the amounts currently given in the treatment of phenylketonuria (or of analogous compensatory nutrition in the treatment of other metabolic defects by dietary restriction).

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

“…Thus, the increase of only one (Tyr) or three (VIL) AAs may even accentuate disturbances of neurotransmitter or protein synthesis (42). VIL therapy did not find acceptance in PKU treatment.…”

Transport of L‐phenylalanine and related amino acids at the ovine blood‐brain barrier.

“…The kh for histidine in the lamb and methionine in the sheep were estimated. In the adult rat these have been determined using the initial-rate, steady-state technique to be 500 + 80 ,smol 1`for histidine and 580 + 70 smol 1`for methionine (Pratt, 1982). In our study, half-maximal inhibition was observed at much lower concentrations of phenylalanine, suggesting a species difference in the relative affinities of these amino acids for the large neutral amino acid carrier.…”

“…In particular, the recognition that the affinity constants of blood-brain barrier amino acid transport are within the range of blood concentrations has led to the suggestion that the inhibition of influx of related amino acids may be a significant factor in the causation of cerebral damage in amino acidopathies such as phenylketonuria (Pratt, 1982). The developing brain is especially susceptible to the deleterious effects of a sustained increased in the circulating concentration of particular amino acids.…”

Phenylketonuria (PKU) – A Success Story

“…This influx is interfered with, especially in infancy, if one or more of the serum amino acid levels are exceptionally high. Pratt (Pratt, 1982) reviewed the evidence to date and predicted that adding tyrosine or leucine, valine and isoleucine only, would be ineffective. Despite this, several studies in rats and humans claimed neurological/psychometric improvement with the administration of the branch chain amino acids -valine, leucine and isoleucine (Jordan, 1985;Vorhees, 1989).…”