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Reversible retardation of growth has recently been demonstrated to occur in children with hereditary fructose intolerance (HFI), an inborn error of fructose metabolism. This growth retardation is caused by ingestion of small amounts of fructose that do not cause symptoms. The pathogenesis of the growth retardation will be investigated in clinical studies on patients with HFI and in an animal model.

The animal model will be developed by pair feeding weanling rats on an otherwise adequate diet containing up to 80% of calories as either fructose or glucose. the adequacy of the model will be evaluated by 1) assessing the severity of the growth retardation by measuring body weight, tail length, and crown-rump length, and 2) demonstrating that the severity of growth retardation depends on the dose of fructose and 3) demonstrating reversibility of growth retardation.

This proposal seeks funding to test the following hypothesis: In patients with HFI, small amounts of dietary frunctose induce chronic fructose intoxication which is expressed biochemically as a detectable disorder of adenine nucleotode metabolism and physiologically as growth retardation. Further, the chronic metabolic disorder causes the growth retardation by one or more of the following mechanisms: 1) direct disturbance of an essential process such as protein synthesis 2) a disturbance in the metabolism of calcium, phosphate, or vitamin D or 3) a disturbance in the secretion of or responsiveness to growth hormone (GH) or somatomedin C SM-C.

This hypothesis will be tested by: 1) assessment of the magnitude of the disturbance of adenine nucleotide metabolism by measurement of serum concentrations and urinary excretion rates of the products of adenine nucleotide degredation (inosine, hyposanthine, xanthine, and uric acid), magnesium (released by ATP-Mg++ degradation), and inorganic phosphate (depletion of which triggers the degradation of preformed adenine nucleotides) in HFI patients consuming small amounts of fructose and in the rat model. 2) assessment of serum concentrations of calcium, phosphorus, 25 hydroxy Vit. D and 1,25 dihydroxy Vit. D, and urinary excretion of calcium in patients and in the rat model, and of bone mineral content and total body content of calcium and phosphorus in the rat model, and 3) measurement of basal and evoked serum concentrations of GH and Sm-C in patients with HFI and in the rat model and measurements of the effect of fructose on GH release by rat pituitary cells in vitro.

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