Somatic growth failure is a major aspect of the developmental arrest of Rett syndrome (RS). Although reduced dietary energy intake may account for somatic growth failure, nutritional repletion does not normalize this problem. This project will examine metabolic and hormonal factors that may provide clues to the pathophysiology of somatic growth arrest in RS girls. We HYPOTHESIZE that, in the presence of positive energy balance, altered partitioning of protein and calcium balance, i.e., increased body protein degradation relative to synthesis, decreased intestinal absorption and increased urinary excretion of calcium, in the presence of reduced serum IGF-1 levels, are the mechanisms that account for persistent somatic growth failure in RS girls. The OBJECTIVE of this proposal is to identify the metabolic and/or hormonal mechanisms by which the partitioning of protein and calcium balance is altered and to estimate the contribution of these abnormalities to the protein and calcium requirements of RS girls.
The SPECIFIC AIMS of this proposal are 1) to compare in RS and healthy girls: a) rates of body protein degradation, synthesis, leucine oxidation, net retention, the splanchnic extraction of lysine, and urea production; b) rates of intestinal absorption and diet- and bone-derived urinary excretion of calcium; c) insulin, IGF-1, cortisol, growth hormone, and osteocalcin levels; and 2) to determine if the abnormalities of: a) protein and calcium metabolism; b) hormone profiles, and c) somatic growth of RS girls can be reversed with dietary protein and calcium intakes in excess of recommended allowances. Two groups of SUBJECTS, RS and healthy girls, will be studied at baseline. Subsequently, RS girls will be randomized into one of two dietary protein/calcium treatment groups or a no-treatment group and studied after 1 yr. Untreated RS girls will be treated thereafter and studied a third time 1 yr. later. METHODS: Rates of body protein synthesis, degradation, net retention, and urea production will be determined using primed, constant infusions of [1-/13C] leucine, [d/4,4,5,5] lysine, and [15/N/2] urea. Rates of intestinal absorption and diet- or bone-derived urinary losses of calcium will be determine by intravenous/oral single bolus doses of 42/Ca and 46/Ca. Insulin, IGF-1, growth hormone, cortisol, and osteocalcin levels will be determined by radioimmunoassay. Body composition will be determined by 40/K counting and DEXA. Analysis of covariance without/with repeated measures will be used to determine significant differences in outcome variables between RS and healthy girls and among the high vs. usual vs. no dietary protein/calcium treatment groups. SIGNIFICANCE: The information obtained from this study will provide further insight into the metabolic and/or hormonal mechanisms that lead to somatic growth arrest in RS. A better understanding of the partitioning of dietary protein and calcium balance during conditions of altered growth will permit a more rational approach to nutritional intervention and improve the clinical outcome and quality of life of RS girls.

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Baylor College of Medicine
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