Aromatic amino acid metabolism in the pathogenesis of kwashiorkor

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DESCRIPTION (provided by applicant): Protein-energy malnutrition (PEM) presents with marasmus or kwashiorkor. While wasting characterizes marasmus, in kwashiorkor, anorexia, edema, lower plasma proteins, dermatitis, hypopigmented skin, impaired immune and anti-oxidant capacities, neurological abnormalities, and hepatic steatosis are additional features. The pathogenesis of these signs, and optimal diets for rehabilitation remain unclear. We propose that decreased supply of aromatic amino acids (AAAs) is a factor. Because phenylalanine and tyrosine are precursors for dopamine, melanin and the catecholamines, and tryptophan is the precursor of serotonin and niacin, a shortage of the AAAs may underlie most of the signs and symptoms of kwashiorkor. We also propose that infection-induced synthesis of positive acute phase proteins further limits the availability of AAAs for synthesis of other proteins, hence replenishment of nutrient transport proteins (NTPs) and lean tissues. Stable isotope tracer methods will be used to test these hypotheses in children with PEM. Protocol #1 will determine differences in AAA and whole body protein kinetics in children with kwashiorkor and marasmus. The hypothesis tested is that children with kwashiorkor but not marasmus, have decreased availability of the AAAs because of decreased release from an impaired protein breakdown. Protocol #2 will determine the AAA requirements of children with marasmic-kwashiorkor during treatment to test the hypothesis that the amount of AAAs supplied by the therapeutic diets is limited for optimal synthesis of proteins. Protocol #3 will determine the effect of supplementation with either AAAs or alanine on protein kinetics and the synthesis of selected NTPs in children with kwashiorkor. Mental state, appetite and skin changes will also be monitored. The hypotheses tested are, 1) providing adequate amounts of AAAs during nutritional rehabilitation will stimulate NTPs and whole body protein synthesis rates to a greater extent than in alanine controls, 2) AAA supplements will shorten the time taken for anorexia and mental abnormalities to disappear and for normal pigmented skin and hair to appear. This research may explain whether a shortage of three special compounds called aromatic amino acids is responsible for the severe illness and high death rate of children with the kwashiorkor type of malnutrition and whether supplying adequate amounts of these compounds in the treatment diet will speed up recovery from this condition.