Growth failure is a major complication of Rett Syndrome (RS). It is our hypothesis that dietary energy insufficiency relative to energy needs is the primary cause of growth failure. Altered partitioning of energy balance, i.e., increased energy expenditure due to involuntary motor activity, is the suspected mechanism of the greater energy needs. Thus, the long-term objective of this proposal is to identify the mechanism by which the partitioning of energy balance in RS girls is altered and to estimate its contribution to the overall energy requirement of these childred.
The specific aims of the proposal are: 1) to determine whether total daily energy expenditure in RS girls is higher than that in healthy girls; 2) to determine whether the components of energy expenditure, measured by sleeping and quietly and actively awake metabolic rates, in RS girls are increased compared with those in healthy controls; 3) to determine whether dietary energy intakes in RS girls are sufficient to meet the energy demands of involuntary motor activity compared with those of healthy girls; and 4) to determine whether dietary energy in an amount that exceeds measured total daily energy expenditure is sufficient to reverse a)growth failure, measured by height and weight velocities, skinfold thicknesses, and muscle circumferences, and b)the abnormalities in the components of energy expenditure measured by sleeping and quickly and actively awake metabolic rates, after nutritional intervention in RS girls; and 5) to determine whether the absolute amount or proportion of energy expended in repetitive motor activity increases after nutritional rehabilitation in RS girls. Energy balance will be studied in 2 groups of subjects: 1) RS girls and 2) healthy controls. RS girls also will be studied after one year of nutritional rehabilitation via enteral tube feedings. To date, we studied 11 RS girls and 9 healthy controls. The results of the energy studies in RS and healthy girls are summarized as follows: 1) The clinical features of growth failure and malnutrition were present in all Rett girls. The Rett girls were stunted and wasted by Z-score criteria and fit the classification for first degree acute and chronic malnutrition by Waterlow's criteria. The growth and nutritional characteristics differed significantly between the RS girls and the healthy controls. 2) Body weight was significantly lower in RS girls than in healthy controls. This difference was the result of a significant reduction of the lean body mass, particularly the muscle of the lower, but not upper, extremities, as opposed to body fat. The pronounced reduction of lean body mass in the absence of equal or greater losses of body fat in the RS girls, was an unexpected finding of this project. 3) TDEE and SMR, measured by whole room calorimetry were 33% lower in RS girls than in healthy age-matched, as well as lean body mass-matched, controls. 4) Energy expenditure during REM sleep was slightly less, albeit not significant, than that measured during NREM sleep or in the basal state. 5) The ratio of TDEE to SMR, an indicator of daily physical activity, and the amount of awake time spent in activity, determined by 24-hr activity records, were not significantly different between the RS girls and the healthy controls. 6)Dietary energy intakes were significantly lower in the RS girls than in the healthy controls. 7) Nitrogen intakes and urinary nitrogen losses were significantly lower in the RS girls than in the healthy controls. Urinary nitrogen loses showed a significant positive linear relationship with dietary nitrogen and energy intakes in both groups of girls. Although apparent nitrogen balance was lower in the RS girls than in the healthy controls, these differences were not significantly different. RS girls were in positive apparent nitrogen balance despite that pronounced wasting of lean body mass, particularly the muscle of the lower extremities. At present, 11 RS girls have entered the refeeding phase of the study: 7 receive supplemental feedings through a gastrostomy button and 4 receive oral supplementation alone. The results of the refeeding studies are summarized as follows:1)Height (or length) velocities were 33% greater and weight velocities were at least threefold greater during the post than pre-supplmentation period. Although linear growth rates were similar between both feeding groups, the rate of weight gain was two-fold greater in the RS girls who received enteral (gastrostmy button), as opposed to oral, supplementation. 2)Weight gain was comprised equally of lean body mass and body fat, regardless of the mode of refeeding. Lean body mass, expressed as a proportion of body weight, decreased by 4% to 9% with nutritional supplementaion, while body fat, expressed as a proportion of body wieght, increased by the same percentage. The significance of our study is that it is the first to establish the nutritional basis of growth failure in RS girls. Our findings thus far demonstrate that the repetitive, involuntary motor movements of RS girls do not increase their total daily energy expenditure, and therefore, are not casually related to their growth failure. Of interest to us, however, is the apparent positive nitrogen balance in the presence of pronounced wasting of lean body mass, particularly the muscles of the lower extremities. We presume that the reductions of total daily energy expenditure, sleeping metabolic rates, and urinary nitrogen losses serve as compensatory mechanisms that permit the channeling of available, albeit reduced, dietary energy and protein into metabolic pathways that support essential physiologic functions of the body. Thus, our studies suggest that energy and protein are limiting nutrients in RS girls because of inadequeste dietary intakes. The observation that dietary energy and protein supplementation improved linear growth and led to the deposition of lean body mass and body fat in the RS girls supports our suppositions. We anticipate that early, aggressive nutritional intervention will optimize the nutritional stuatus and physical performance of these girls, as well as reduce the morbidity and mortality associated with nutritional deprivation.

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