Obesity In Prader-Willi Syndrome Research Articles

Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

1318-P: Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is the most common syndromic type of human obesity. Multiple endocrine abnormalities due to hypothalamic dysfunction as well as cognitive and behavioral disorders occur in PWS. Hypothalamic dysfunction, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex (PFC) function are implicated in the pathophysiology of hyperphagia and obesity in PWS. All available therapeutic tools have not fully targeted at counteract the mechanisms underlying obesity in PWS. Previously, we demonstrated the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing weight loss in obesity by modulating the brain dopaminergic system and enhancing the inhibitory activity of the PFC on eating behaviour (Ferrulli et al, DOM 2019) . In this case-report, for the first time, we tested the efficacy and safety of rTMS in a 23-year-old patient with PWS, in whom repeated interventions aimed at inducing weight loss have failed. A 5-week high frequency (18 Hz) rTMS treatment, associated with diet, resulted in a 3.5% weight loss (127.4 vs. 123 Kg, BMI: 50.4 vs. 48.6 Kg/m2, WHR: 1.14 vs. 1.12) . Concerning the metabolic parameters, an improvement in lipid profile has been shown (CHO/HDL/LDL/TG: 212/40/142/152 vs. 190/40/124/131 mg/dL) . While no significant changes emerged in the psychometric assessment of food craving, impulsiveness, quality of life, self-esteem, interestingly, a robust improvement in the Mini-Mental State Examination score (corrected for age and schooling) has been found [from 22 (severe impairment) to 27 (moderate impairment) ]. The improvement in the cognitive status assessed through the Montreal Cognitive Assessment was weaker (17/30 to 19/30) . In view of the urgent need of novel effective interventions for obesity in PWS, these findings support a potential role of rTMS in reducing food drive and behaviors impacting hyperphagia and obesity in PWS, with a possible impact also on cognitive functions. Disclosure A.Ferrulli: None. D.Cannavaro: None. C.Macrì: None. S.Massarini: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker’s Bureau; Eli Lilly and Company, Novo Nordisk. Funding IRCCS Multimedica - Ricerca Corrente

Serum Asprosin Concentrations in Children with Prader-Willi Syndrome: Correlations with Metabolic Parameters.

Children with Prader–Willi syndrome (PWS) are characterized by severe obesity. Asprosin is a newly discovered protein hormone produced by the white adipose tissue and is correlated with insulin resistance. The aim of our study was to describe the concentrations of serum asprosin in children with PWS compared to those with overweight/obesity and normal weight, and to explore the postprandial change in asprosin concentrations in participants with PWS and BMI-z matched controls. We enrolled 52 children, 23 with PWS, 8 with overweight/obesity, and 21 with normal weight. Fasting levels of asprosin, glucose, and insulin were collected in all children, and postprandial asprosin and fasting levels of acyl ghrelin (AG) and leptin were also determined in a subsample of participants. There were no significant differences among groups in fasting levels of asprosin, glucose, insulin, and HOMA-IR. Fasting serum asprosin and 1-h post-meal serum asprosin did not differ in children with PWS nor in BMI-z matched controls. Fasting asprosin showed an adjusted positive correlation with glucose in children with obesity (r = 0.93, p = 0.007) but not in children with PWS nor children with normal weight. Circulating asprosin might be a predictor of early alterations in glucose metabolism in children with obesity. More research is needed to further explain the association between asprosin, food intake, metabolism, and obesity in PWS.

The effects of glucagon-like peptide (GLP)-1 receptor agonists on weight and glycaemic control in Prader-Willi syndrome: A systematic review.

The mainstay management of hyperphagia and obesity in Prader-Willi syndrome (PWS) relies on dietary restrictions, strict supervision and behavioural modifications, which can be stressful for the patient and caregiver. There is no established pharmacological strategy to manage this aspect of PWS. Theoretically, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RA) used in patients with obesity and type 2 diabetes mellitus (T2DM) may be efficacious in weight and glycaemic control of PWS patients. We conducted a systematic review of the literature to summarize the evidence on the use of GLP1-RA in PWS patients. Primary studies were searched in major databases using key concepts 'Prader-Willi syndrome' and 'GLP1 receptor agonist' and outcomes, 'weight control OR glycaemic control OR appetite regulation'. Ten studies included, summarizing GLP1-RA use in 23 PWS patients (age, 13-37 years), who had used either exenatide (n = 14) or liraglutide (n = 9) over a duration of 14 weeks to 4 years. Sixteen (70%) of these patients had T2DM. Ten patients experienced improvement in body mass index, ranging from 1.5 to 16.0 kg/m2 , while improvement in HbA1c was seen in 19 of 23 cases, ranging between 0.3% and 7.5%. All five studies reporting appetite or satiety showed improvement in satiety levels. There were no reported serious side effects. GLP1-RA appears safe in PWS patients and may have potential benefits for weight, glycaemic and appetite control. Nonetheless, we also highlight a significant gap in the literature on the lack of well-designed studies in this area, which limits the recommendation of GLP1-RA use in PWS patients at present.

Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: A narrative review.

In early childhood, individuals with Prader-Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: "PWS" AND "therapy" OR "[drug name]"; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long-term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off.

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader–Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11–q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy.

Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model.

In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hypogonadism, and accelerated mortality. Although the hyperphagia and obesity in PWS have been attributed to elevated levels of the orexigenic hormone ghrelin, this link has never been firmly established, nor have ghrelin's potentially protective actions to increase GH secretion, blood glucose, and survival been investigated in a PWS context. In the current study, we show that placing Snord116del mice modeling PWS on ghrelin-deficient or ghrelin receptor [GH secretagogue receptor (GHSR)]-deficient backgrounds does not impact their characteristically reduced body weight, lower plasma IGF-1, delayed sexual maturation, or increased mortality in the period prior to weaning. However, blood glucose was further reduced in male Snord116del pups on a ghrelin-deficient background, and percentage body weight gain and percentage fat mass were further reduced in male Snord116del pups on a GHSR-deficient background. Strikingly, 2 weeks of daily administration of the GHSR agonist HM01 to Snord116del neonates markedly improved survival, resulting in a nearly complete rescue of the excess mortality owing to loss of the paternal Snord116 gene. These data support further exploration of the therapeutic potential of GHSR agonist administration in limiting PWS mortality, especially during the period characterized by failure to thrive.

Obesity management in Prader-Willi syndrome: current perspectives.

Prader–Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). The syndrome is considered the most common genetic cause of obesity, occurring in 1:10,000–1:30,000 live births. Its main characteristics include neonatal hypotonia, poor feeding, and lack of appetite in infancy, followed by weight gain, lack of satiety, and uncontrolled appetite, frequently after the age of 2–3 years. The clinical picture includes short stature, multiple endocrine abnormalities (hypogonadism, growth hormone/insulin-like growth factor-I axis dysfunction, hypothyroidism, central adrenal insufficiency), dysmorphic features, scoliosis, osteoporosis, mental retardation, and behavioral and psychiatric problems. Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake. In fact, PWS subjects die prematurely from complications conventionally related to obesity, including diabetes mellitus, metabolic syndrome, sleep apnea, respiratory insufficiency, and cardiovascular disease. The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. Consequently, dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS. In spite of all available therapeutic tools, however, successful weight loss and maintenance are hardly accomplished. In this context, clinical trials with new drugs have been initiated in order to find new possibilities of a therapy for obesity in these patients. The preliminary results of these studies seem to be encouraging. On the other hand, until well-proven medical treatments are available, bariatric surgery can be taken into consideration, especially in PWS patients with life-threatening comorbidities.

The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways.

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.

Growth Hormone Treatment in Children With Prader-Willi Syndrome: Three Years of Longitudinal Data in Prepubertal Children and Adult Height Data From the KIGS Database.

Longitudinal data of children with Prader-Willi syndrome (PWS) treated with genotropin were registered in the Pfizer International Growth Database (KIGS). To evaluate efficacy and safety of growth hormone (GH) treatment in a large group of children with PWS. Data registered in KIGS from 1987 to 2012. Worldwide retrospective cohort study. Patients included 522 prepubertal children treated with GH for three years and 173 children who had reached adult height. Safety analysis included 2332 children. Intervention involved GH treatment. Height standard deviation score (SDS), body mass index (BMI) SDS, occurrence of serious adverse events, and deaths reported in KIGS. In prepubertal children, mean (standard deviation) height SDS improved to -0.31 (1.34) (P < 0.05) during three years of GH treatment. In the adolescent group, height SDS improved until the start of puberty to -0.22 (1.31) (P < 0.05) but had a loss of -0.77 (0.81) during puberty, resulting in a mean adult height SDS of -1.19 (1.37). Total height gain was 0.95 (1.32) SDS. BMI SDS increased in the prepubertal group from 1.11 (2.09) to 1.53 (1.43) (P < 0.05) and did not significantly change in the adolescent group, who had a BMI SDS at an adult height of 1.78 (1.26). KIGS contained 12 death reports. GH treatment in children with PWS significantly improves linear growth. BMI remains on average below +2 SDS, in contrast to the natural course of increasing obesity in PWS. Safety should be closely monitored in children with PWS, with and without GH treatment.

Mechanisms of obesity in Prader-Willi syndrome.

Obesity is the most common cause of metabolic complications and poor quality of life in Prader-Willi syndrome (PWS). Hyperphagia and obesity develop after an initial phase of poor feeding and failure to thrive. Several mechanisms for the aetiology of obesity in PWS are proposed, which include disruption in hypothalamic pathways of satiety control resulting in hyperphagia, aberration in hormones regulating food intake, reduced energy expenditure because of hypotonia and altered behaviour with features of autism spectrum disorder. Profound muscular hypotonia prevents PWS patients from becoming physically active, causing reduced muscle movements and hence reduced energy expenditure. In a quest for the aetiology of obesity, recent evidence has focused on several appetite-regulating hormones, growth hormone, thyroid hormones and plasma adipocytokines. However, despite advancement in understanding of the genetic basis of PWS, there are contradictory data on the role of satiety hormones in hyperphagia and data regarding dietary intake are limited. Mechanistic studies on the aetiology of obesity and its relationship with disease pathogenesis in PWS are required. . In this review, we focused on the available evidence regarding mechanisms of obesity and potential new areas that could be explored to help unravel obesity pathogenesis in PWS.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

ObjectiveExtreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. MethodsWe studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. ResultsIndividuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. ConclusionsDysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Profiles of obesity in Prader-Willi syndrome

Profiles of obesity in Prader-Willi syndrome

A short clinical overview of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a multifaceted developmental disorder most commonly associated with extreme hyperphagia and life-threatening obesity. PWS is a genetic disorder of imprinting with almost all cases occurring spontaneously. Behavioural and imaging studies have shown that obesity in PWS arises from overeating driven by a faulty satiety mechanism which manifests as an almost permanent state similar to starvation. With no available treatments, management of the eating behaviour is the only option and has two main strategies: restrict access to food and distract thoughts from food. In this mini review, which we have aimed at clinicians, we outline the main aspects of PWS including genetics, development of the eating behaviour and best practice approaches to management.

“Efficacy of Laparoscopic Sleeve Gastrectomy as a Stand-alone Technique for Children with Morbid Obesity” and “BioEnterics® Intragastric Balloon for Treatment of Morbid Obesity in Prader-Willi Syndrome: Specific Risks and Benefits”

“Efficacy of Laparoscopic Sleeve Gastrectomy as a Stand-alone Technique for Children with Morbid Obesity” and “BioEnterics® Intragastric Balloon for Treatment of Morbid Obesity in Prader-Willi Syndrome: Specific Risks and Benefits”

BioEnterics Intragastric Balloon for Treatment of Morbid Obesity in Prader–Willi Syndrome: Specific Risks and Benefits

Obesity in Prader-Willi Syndrome (PWS) is progressive, severe, and resistant to dietary, pharmacological, and behavioral treatment. A body weight reduction is mandatory to reduce the risk of cardio-respiratory and metabolic complications. The aim of the study was to assess risks and benefits of BioEnterics Intragastric Balloon (BIB) for treatment of morbid obesity in PWS patients. Twenty-one BIB were positioned in 12 PWS patients (4 M, 8 F), aged from 8.1 to 30.1 years, and removed after 8 +/- 1.4 months (range: 5-10 months). Auxological, clinical, and nutritional evaluations were performed every 2 months. Variations in body composition were analysed by dual energy X-ray absorbiometry (DXA). One patient (28.5 years, BMI: 59.3 kg/m(2)) died 22 days after BIB positioning because of gastric perforation. In another case (26.2 years, BMI: 57.6 kg/m(2)), BIB was surgically removed after 25 days because of symptoms suggesting gastric perforation (not confirmed). The remaining ten patients showed a significant decrease of BMI (p = 0.005) and of fat tissue as measured by DXA (p = 0.012). No significant modifications in bone mineral density (BMD) occurred, but a slight loss in lean body mass (p = 0.036) was documented. In five patients, BIB treatment was repeated more than once. This study shows that when noninvasive pharmacological therapies fail, BIB may be effective to control body weight in PWS patients with morbid obesity, particularly when treatment is started in early childhood. However, careful clinical follow-up and close collaboration with parents are crucial to avoid severe complications, which can be caused by persisting unrestrained food intake.

Abordagem terapêutica da obesidade na Síndrome de Prader-Willi

Prader-Willi Syndrome (PWS) is a multisystemic genetic disease characterized by hypotonia, mental retardation, characteristic facial appearance, hyperphagia, and compulsive eating due to hypothalamic dysfunction. PWS is caused by loss of function of genes located in chromosome 15q11-q13, an area subject to genomic imprinting. Obesity is a major cause of increased morbidity and mortality among patients with PWS. The objective of this study was to analyze the therapeutic options available for the treatment of the obesity in PWS including pharmacological and surgical strategies.

Free and total leptin serum levels and soluble leptin receptors levels in two models of genetic obesity: the Prader-Willi and the Down syndromes

Alterations in energy balance and feeding behavior and the subsequent high frequency of obesity are hallmarks of 2 chromosomal diseases: the Prader-Willi syndrome (PWS) and the Down syndrome (DS). Leptin, an important regulator of food intake and energy homeostasis, circulates in 2 forms: a free, therefore active, fraction and a fraction bound to the soluble leptin receptor, whose bioavailability consequently participates in the regulation of leptin action. To investigate the possible role of the free-bound leptin balance in the pathogenesis of obesity in PWS and DS, we enrolled 7 obese women with DS, 5 obese women with PWS, 7 obese women, and 7 normal-weight healthy control women. Basal hormonal concentrations, total and free leptin levels, and leptin receptors levels were measured in plasma samples obtained from the 4 groups. No significant differences were observed in the hormonal milieu. Women with DS exhibited lower total leptin concentrations ( P < .01), comparable leptin receptor level and, therefore, lower free leptin values ( P < .01) when compared with obese controls, then resembling the profile peculiar to normal-weight control women. At variance, subjects with PWS did not differ from obese controls regarding both leptin and leptin receptor levels. Our data suggest that, whereas subjects with PWS have a leptin assessment corresponding to their degree of obesity, subjects with DS may have a defect in the secretion of leptin that could at least partially account for this form of syndromal obesity.

Management of obesity in Prader–Willi syndrome

Prader–Willi syndrome (PWS) is associated with uncontrolled appetite and morbid obesity. Management of PWS is particularly challenging and requires the involvement of both the family and health-care providers, as well as the affected individual. In this Viewpoint the efficacy of the strategies currently used to control obesity in PWS is discussed.

Ghrelin levels in young children with Prader-Willi syndrome

To explore the hypothesis that high ghrelin levels contribute to obesity in Prader-Willi syndrome (PWS), we assessed whether the increased levels observed in older persons with PWS exist in very young children, before the onset of hyperphagia. We measured ghrelin levels in nine children with PWS (17-60 months of age) and eight healthy control subjects of equivalent body mass index (BMI), age, and sex. PWS and control groups had equivalent BMI (16.8 +/- 1.4 vs 16.1 +/- 0.9 kg/m(2), respectively; P = .24), age (37.8 +/- 15.4 vs 50.3 +/- 17.7 months; P = .14), and sex. PWS and control groups also had equivalent fasting levels of total ghrelin (787 +/- 242 vs 716 +/- 135 pg/mL, respectively; P = .24), bioactive ghrelin (102 +/- 35 vs 91 +/- 23 pg/mL; P = .45), insulin, and glucose. Ghrelin correlated negatively with BMI among controls (r = -0.760, P = .029) but not PWS (r = 0.015, P = .97). Children <5 years of age with PWS, who had not yet developed hyperphagia or excessive obesity, had normal ghrelin levels, in contrast with the hyperghrelinemia of older, hyperphagic people with PWS. It is possible that ghrelin levels increase suddenly before hyperphagia develops.