NUTRITION IN RETT SYNDROME

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The OBJECTIVE of this proposal is to characterize the components of protein and calcium metabolism that are altered and to estimate their contribution to the overall protein and calcium requirements of RS girls. The SPECIFIC AIMS for this project are:1)to determine if rates of body protein degradation, leucine oxidation, and urea production are higher and body protein synthesis, net protein retention, and the splanchnic extraction of lysine are lower in RS than in healthy girls, using a primed, constant infusion of [1-13C]leucine, [d4,4,5,5]lysine, and [15N2]urea to calculate rates of whole body protein synthesis, degradation, leucine oxidation, net protein retention, the splanchnic extraction of lysine, and urea production; 2)to determine if fractional rates of intestinal calcium absorption are lower and rates of diet-and bone-derived urinary calcium excretion are higher in RS than in healthy girls, using a single bolus dose of 42Ca and 46Ca to calculate fractional rates of calcium absorption, total absorption, net balance, and diet- and bone-derived urinary calcium; 3)to determine if serum insulin, IGF-1, growth hormone, and osteocalcin levels are lower and urinary cortisol outputs are higher in RS than in healthy girls. To test our hypotheses, two groups of SUBJECTS, RS and healthy girls, will be studied during controlled dietary conditions. METHODS: Body protein and calcium metabolism will be examined using state-of-the-art stable isotope mass spectrometry techniques. Rates of body protein synthesis, degradation, net retention, and urea production will be determined using primed, constant infusions of [1-13C]leucine, [d4,4,5,5]lysine, and [15N2]urea. Rates of intestinal absorption and diet- or bone-derived urinary losses of calcium will be determined by intravenous/oral single bolus doses of 42Ca and 46Ca. Body composition will be determined using whole body potassium (40K) counting and duel-energy x-ray absorptiometry. Hormone profiles (plasma insulin, IGF-1, growth hormone, osteocalcin, and urinary cortisol) will be measured using radioimmunoassay techniques. Analysis of covariance and linear regression will be used to detect differences in the outcome variables of body protein and calcium metabolism and hormone profiles between RS and healthy girls. PROGRESS: To date, we studied three RS girls, two who were fed via gastrostomy button and one who fed orally. The results of the protein and calcium metabolic studies of RS girls are summarized below and are compared with measurements of body protein metabolism in children with Crohn disease. The major points to be made from these observations are: 1)In the postabsorptive state, rates of endogenous body protein degradation exceeded rates of body protein synthesis, such that net protein retention was negative and reflected the expected catabolic state during postabsorptive conditions. 2)In the fed state, leucine flux was 2.5-fold greater than that obtained in the postabsorptive state. However, this difference was explained entirely by the intake of dietary leucine, resulting in no net difference of endogenous body protein degradation between the postabsorptive and fed state. 3)In the fed state, rates of endogenous body protein degradation approximated rates of body protein synthesis, such that net protein retention was neutral and reflected the reversal of the catabolic state with feeding. 4)In the fed state, rates of body protein synthesis and oxidation were 2- to 3-fold greater than those obtained in the postabsorptive state; nevertheless, protein oxidation, as a proportion of total flux, was disproportionately greater (2-fold) than the proportion of flux represented by protein synthesis. 5)In the fed state, rates of urea production were double those obtained in the postabsorptive state. Assuming that 75% of all urea nitrogen was excreted, dietary nitrogen was utilized with 79% efficiency, a value that compared favorably with that of healthy children. 6)When the variables of body protein metabolism of RS girls were compared with those of children with Crohn disease, the striking features were the disproportionately greater rates of endogenous protein breakdown, as well as the increased rates of protein synthesis and oxidation, in the RS girls. More importantly, as a proportion of total flux, endogenous body protein degradation was 3-fold greater, body protein synthesis was 25% lower, and protein oxidation was 25% higher in RS girls than in children with Crohn disease. 7)The fractional absorption of dietary calcium and vitamin D and parathyroid hormone levels were normal in RS girls. The SIGNIFICANCE of these preliminary observations is that muscle wasting in RS girls may be the consequence of a heightened catabolic state in which rates of endogenous body protein degradation markedly exceed rates of body protein synthesis. Feeding does not suppress the high rates of endogenous body protein degradation. The disproportionately high rates of protein oxidation, particularly as a proportion of total flux, also may account for reduced protein availability and further aggravate muscle wasting. In contrast, bone demineralization in RS girls does not appear to be the result of a defect in the intestinal absorption of dietary calcium nor a deficiency of vitamin D dietary intake or its metabolism. These preliminary results are important because they provide further insight into the metabolic mechanisms that lead to muscle wasting and bone demineralization in RS girls and may result in more rational therapeutic strategies that enhance the functional outcome and quality of life in RS girls with growth arrest. If these preliminary findings are consistently present in RS girls, these abnormalities in body protein metabolism may be responsive to dietary or hormonal intervention. Further studies will be necessary to examine the dietary and/or hormonal factors that regulate body protein metabolism in RS girls.