Energy Homeostasis in children with Prader- Willi syndrome

Obesity is a common component of NIDDM and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi Syndrome(PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. In order to shed light on the glucoregulatory mechanisms in PWS, we studied pediatric and adult PWS with normoglycemia. The objectives of this study were 1) to examine glucose (glu), insulin (ins) and c-peptide (cpep) responses to OGTT and IVGTT 2) to characterize first and second phases ins secretion 3) to assess hepatic ins extraction (HIE) in PWS subjects and 4) to determine whether beta cell function in PWS is age-dependent.. Group I consisted of 9 pediatric (PED) PWS and 22 age-, weight- and puberty stage-matched obese subjects who had OGTT. Group II consisted of 14 adult (AD) PWS and 10 age-, weight-, and BMI-matched obese AD who had OGTT. Group III consisted of 9 AD PWS and 8 age- and weight-matched obese AD who had FSIVGTT. During the OGTT in the PED group, glu levels were not significantly (sig) different in PWS vs. obese children. In contrast, the fasting, (20±6 vs. 37±4uU/ml), peak (114±24 vs. 214±23uU/ml) and total AUC for ins (12,673±2176 vs. 26,734±2608uU/ml × min) were sig lower in the PED PWS. During the OGTT in the AD groups, ins levels were not sig different in the AD PWS and obese groups. During IVGTT in AD, both the first (138±42 vs. 454±102uU/ml × min) and second (295±66 vs. 1015±231uU/ml × min) phase ins release were sig reduced in the PWS. Similarly, first and second phase cpep responses were also sig reduced in the PWS. In contrast, the mean HIE was 33% higher in PWS vs. obese group(15.4±1.5 vs. 10.3±1.6). Similarly, the post-stimulation HIE was sig greater (5.2±0.8 vs. 2.4±0.4) in the PWS group when compared to obese group. In summary, PWS manifest a) reduced β-cell responses b) increased HIE and c) a dissociation of obesity and ins resistance in contrast to obese subjects. Increased ins sensitivity as well as enhanced HIE appear to be compensatory mechanisms for the reduced β-cell function in PWS.

Individuals with Prader-Willi syndrome (PWS) are commonly restricted to 60-75% of height-appropriate calorie intake because they rapidly become obese on a normal diet. This study measured changes in energy expenditure, glucose and lipid homeostasis, and metabolic flexibility in response to a meal in PWS adults. 11 adults with PWS were compared with 12 adiposity-matched and 10 lean subjects. Indirect calorimetry was conducted at baseline and 210 min after a standardized 600 kCal breakfast to assess energy expenditure and substrate utilization. Circulating glucose, insulin, C-peptide, glucagon, nonesterified fatty acids, and triglycerides were measured up to 240 min. Insulin sensitivity and insulin secretion rate were assessed by HOMA-IR and C-peptide deconvolution, respectively. Body composition was determined by dual-energy X-ray absorptiometry. The PWS group had lower lean mass than the obesity control group. Corrected for lean mass, there were no differences between the PWS and obesity groups in resting metabolic rate or metabolic flexibility. Total and abdominal fat mass, insulin sensitivity, and insulin secretion rate were also similar between these groups. This study did not detect an intrinsic metabolic defect in individuals with PWS. Rather, lower lean mass, combined with lower physical activity, may contribute to weight gain on an apparent weight-maintenance diet.

Influence of age, gender, and glucose tolerance on fasting and fed acylated ghrelin in Prader Willi syndrome

Prader-Willi syndrome (PWS) is one of the most commonly recognized causes of early-onset childhood obesity. Individuals with PWS have significant hyperphagia and decreased recognition of satiety. The exact etiology of the hyperphagia remains unknown and, therefore, untreatable. We conducted a pilot, open-label study of response to metformin in 21 children with PWS and six with early morbid obesity (EMO). Participants had significant insulin resistance and glucose intolerance on oral glucose tolerance testing (OGTT) and were started on metformin for these biochemical findings. We administered the Hyperphagia Questionnaire to parents of patients before and after starting metformin treatment. Both the PWS and EMO groups showed significant improvements in food-related distress, anxiety, and ability to be redirected away from food on the Hyperphagia Questionnaire. In the PWS group, improvements were predominantly seen in females. Within the PWS group, responders to metformin had higher 2-h glucose levels on OGTT (7.48 mmol/L vs. 4.235 mmol/L; p=0.003) and higher fasting insulin levels (116 pmol/L vs. 53.5 pmol/L; p=0.04). Additionally, parents of 5/13 individuals with PWS and 5/6 with EMO reported that their child was able to feel full while on metformin (for many this was the first time they had ever described a feeling of fullness). Metformin may improve sense of satiety and decrease anxiety about food in some individuals with PWS and EMO. Positive response to metformin may depend on the degree of hyperinsulinism and glucose intolerance. Nonetheless, the results of this pilot study bear further investigation.

Energy expenditure at rest and during sleep in children with Prader-Willi syndrome is explained by body composition

Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome

Compare behavioral and emotional problems of children and adolescents with Prader-Willi Syndrome (PWS) and clients consulting mental health centers (MHC) and related behavioral and emotional problems to the children's personality in the PWS group. Participants were 39 children with PWS and 585 matched MHC clients. Child Behavior Checklist (CBCL) syndromes were related to the Big-Five personality factors measured with the California Child Q-sort (CCQ). Mean CBCL Total Problems scores were not different for the PWS and MHC groups, but differences were found for several of the CBCL subscales. Patterns of correlations among CBCL scales were similar in both groups, although coefficients were generally higher in the PWS group, indicating higher comorbidity or co-absence of CBCL syndromes in children and adolescents with PWS. Personality profiles were specific for internalizing and Externalizing problems of children and adolescents with PWS.

Grey matter volume and cortical structure in Prader-Willi syndrome compared to typically developing young adults.

Prader‐Willi Syndrome (PWS) is a complex genetic disorder caused by a deletion of the paternal chromosome 15. PWS is characterized by increased body fat, hypotonia, growth hormone (GH) deficiency, motor and cognitive disabilities, and hyperphagia, potentially resulting in obesity. This study measured and compared calorie expenditure while walking in PWS and controls. Participants included 8 children with PWS (7 were on GH replacement therapy; mean age = 11.1±0.8 y; body mass = 44.7±11.7 kg; body fat = 37.2±11.4 %; lean mass = 26.4±4.3 kg), 9 lean children (mean age = 9.8±2.0y; body mass = 35.4±11.3 kg; body fat = 22.2±8.6 %; lean mass = 25.5±11.6 kg), and 10 obese children (mean age = 10.6±1.1 y; body mass = 62.1±14.6 kg; body fat = 44.4±3.7 %; lean mass = 33.3±5.1 kg). Fat free mass (FFM) and body fat % were measured with dual x‐ray absorptiometry (DXA). Participants walked for three 5‐minute bouts on a treadmill at 2.0, 2.5, and 3.0 mph, with a 6‐minute seated rest period in between speeds. Expired gases were analyzed for minutes 4–5 of each speed. There were no group by time interactions for any of the variables of interest. PWS children had a higher VO2 ml/kg/min than obese children (p=0.04), but were similar to lean children (p=1.00); PWS children exhibited a greater caloric expenditure in kcal/kg/min than obese (p=0.03), but similar to lean (p=1.00). No other differences were found among the PWS and control groups during walking for VO2 when expressed in L/min or ml/FFM/min, caloric expenditure when expressed in kcal/min or kcal/FFM/min, or metabolic equivalents. The results of this study suggest that children with PWS are expending similar calories as lean controls of comparable body mass while walking. Thus, the difference in body fat does not appear to affect calories spent doing the same absolute work in PWS.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder characterized by hypotonia, suck and feeding difficulties, hypogonadism, small hands and feet, developmental delay, hyperphagia and early childhood obesity and a particular facial appearance. The obesity associated with PWS is the result of a chronic imbalance between energy intake and energy expenditure (EE) due to hyperphagia, decreased physical activity, reduced metabolic rate and an inability to vomit. EE is affected by body composition as well as exercise. Individuals with PWS have a lower lean body mass (LBM) compared with controls which may contribute to reduced basal level EE. To determine the relationship among body composition, activity levels and metabolic rates, dual energy X-ray absorptiometry (DEXA) and a whole-room respiration chamber were used to measure body composition, total EE (TEE), resting EE (REE), physical activity, and mechanical work (MW) during an 8 hr monitoring period. The chamber consisted of a live-in whole-room indirect calorimeter equipped with a force platform floor to allow simultaneous measurement of EE, physical activity, and work efficiency during spontaneous activities and standardized exercise. Participants with PWS (27 with 15q11-q13 deletion and 21 with maternal disomy 15 with an average age of 23 years) had significantly decreased TEE by 20% and reduced LBM compared to 24 obese subjects. Similarly, REE was significantly reduced by 16% in the individuals with PWS relative to the comparison subjects. Total MW performed during the 8 hr monitoring period was significantly reduced by 35% in the PWS group. The energy cost of physical activity is related to the duration, intensity and type of activity and the metabolic efficiency of the individual. After adjusting group differences in LBM by analysis of variance, TEE and REE were no longer different between the two groups. Our data indicate that there is a significant reduction of EE in individuals with PWS resulting from reduced activity but also from lower energy utilization due to reduced LBM which consists primarily of muscle.

Lipid metabolism is closely linked to adiposity. Prader-Willi syndrome (PWS) is a typical genetic disorder causing obesity; however, the distinct lipidomic profiles in PWS children have not been thoroughly investigated. Herein, serum lipidomics analyses were simultaneously explored in PWS, simple obesity (SO), and normal children (Normal). Results indicated that the total concentration of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in the PWS group were significantly deceased compared with both the SO and the Normal group. In contrast, compared with the Normal group, there was an overall significant increase in triacylglycerol (TAG) levels in both the PWS and the SO groups, with the highest found in SO group. Thirty-nine and 50 differential lipid species were screened among 3 groups: between obesity (PWS and SO) and the Normal group. Correlation analysis revealed distinct profiles in PWS that was different from other 2 groups. Notably, PC (P16:0/18:1), PE (P18:0-20:3), PE (P18:0-20:4)) showed significant negative correlation with body mass index (BMI) only in the PWS group. PE (P16:0-18:2) showed a negative association with BMI and weight in the PWS group, but significant positive correlation in the SO group; no statistically significant association was found in the Normal group. We also found a significant negative correlation between Blautia genus abundance and several significantly changed lipids, including LPC (14:0), LPC (16:0), TAG (C50:2/C51:9), TAG (C52:2/C53:9), TAG (C52:3/C53:10), and TAG (C52:4/C53:11), but no significant correlation in the Normal group and the SO group. Similarly, in the PWS group, the Neisseria genus was significantly negatively associated with acylcarnitine (CAR) (14:1), CAR (18:0), PE (P18:0/20:3), and PE (P18:0/20:4), and extremely positively associated with TAG (C52:2/C53:9); no obvious correlations were observed in the Normal group and the SO group.

The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. To explore effects of varying dietary macronutrients on appetite-regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and insulin] in children with PWS and healthy children (HC). Randomized, cross-over experiments compared two test diets [high protein-low carbohydrate (HP-LC) and high protein-low fat (HP-LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63years; BMI z 1.05); experiment 2 had seven HC (median age 12.54years; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4hours. Independent linear mixed models were adjusted for age, sex and BMI z-score. Fasting and post-prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP-1 levels were higher in PWS after the HP-LC and HP-LF meals than the STANDARD meal (P=.02-0.04). The fasting proinsulin to insulin ratio (0.08 vs 0.05) was higher in children with PWS (P=.05) than in HC. Average appetite scores in HC declined after all three meals (P=.02) but were lower after the HP-LC and HP-LF meals than the STANDARD meal. Altered processing of proinsulin and increased GLP-1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake.

Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of expression of maternally imprinted genes on the long arm of chromosome 15 (15q 11-13). There are two main genetic sub-types: (1) deletion, caused by the absence of paternally derived genetic material; and (2) uniparental disomy (UPD), where two copies of maternally derived chromosome 15 are present. In addition to generally mild/borderline intellectual disability (ID) and the almost universal feature of hyperphagia, PWS is associated with high rates of behaviour problems including temper tantrums, compulsive behaviour, perseverative speech, skin picking and rigid thinking. The present study seeks to explore whether these behaviours are associated with relative deficits in executive function (EF), which comprises the set of non-automatic processes utilized by an individual when faced with a novel situation. Eighteen adult participants with a clinical diagnosis of PWS (12 with deletion sub-type, 6 with UPD) were recruited from a UK Health Service PWS clinic, and compared with 15 participants of similar age and verbal ability on a series of EF tasks and also Digit Span Forwards. An informant completed two ratings of behaviour, the Aberrant Behavior Checklist (ABC) and the Dysexecutive Questionnaire (DEX). The PWS group had significantly higher scores on the ABC but not on the DEX. There were no significant differences between the whole PWS group and the comparison group on any of the EF tasks. The deletion sub-type group was significantly poorer at a non-executive task, Digit Span Forwards. There was an unexpected trend for the deletion sub-type group to show more efficient performance on a visuospatial planning task, the Tower of London (TOL), but this trend did not reach significance. The lack of relative deficits in EF task performance does not support the hypothesis that EF differences could account for the high levels of behaviour problems found in PWS. Applying the Baddeley and Hitch model of working memory it is suggested that the PWS group have a relatively intact central executive and visuospatial sketchpad but a relative impairment in the phonological loop, perhaps relating to the capacity of the phonological store. This latter finding seems to be particularly salient for those with a deletion. As differences in EF ability were not found, it is suggested that a region of the brain involved in the modulation of emotion but not particularly with EF, the orbitofrontal cortex (OFC), may be implicated in the behaviour problems reported in PWS.

Context: Low bone mineral density (BMD) is the most important risk factor for fragility fracture. Body weight is a simple screening predictor of difference in BMD between individuals. However, it is not clear which component of body weight, lean (LM), or fat mass (FM), is associated with BMD. People with the genetic disorder of Prader-Willi syndrome (PWS) uniquely have a reduced LM despite increased FM.Objective: We sought to define the individual impact of LM and FM on BMD by investigating subjects with and without PWS.Design, Setting and Participants: This cross-sectional study was conducted at the Clinical Research Facility of the Garvan Institute of Medical Research, with PWS and control participants recruited from a specialized PWS clinic and from the general public by advertisement, respectively. The study involved 11 adults with PWS, who were age- and sex-matched with 12 obese individuals (Obese group) and 10 lean individuals (Lean group).Main Outcome Measures: Whole body BMD was measured by dual-energy X-ray absorptiometry. Total body FM and LM were derived from the whole body scan. Differences in BMD between groups were assessed by the analysis of covariance model, taking into account the effects of LM and FM.Results: The PWS group had significantly shorter height than the lean and obese groups. As expected, there was no significant difference in FM between the Obese and PWS group, and no significant difference in LM between the Lean and PWS group. However, obese individuals had greater LM than lean individuals. BMD in lean individuals was significantly lower than in PWS individuals (1.13 g/cm2 vs. 1.21 g/cm2, p < 0.05) and obese individuals (1.13 g/cm2 vs. 1.25 g/cm2, p < 0.05). After adjusting for both LM and FM, there was no significant difference in BMD between groups, and the only significant predictor of BMD was LM.Conclusions: These data from the human genetic model Prader-Willi syndrome suggest that LM is a stronger determinant of BMD than fat mass.

The characteristics of scoliosis in Prader-Willi syndrome (PWS): analysis of 58 scoliosis patients with PWS.