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

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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).