Projects

In PWS, a cluster of small nucleolar RNAs (snoRNAs), the SNORD116 cluster, appears to be of critical importance, but the SNORD116 targets have yet to be identified. Dr. Carmichael and his team have engineered neurons that mimic naturally-occurring PWS deletions and are using them to look for alterations in gene expression and regulation. In year...

Dr. Rice and colleagues have shown that there is a decrease in GABA (a compound that helps turn brain activity off) in the brains of individuals with PWS, and this is associated with emotional problems, including a tendency for temper outbursts. In this project, the team will use brain imaging (fMRI) to examine whether a GABA-modulating drug...

Social cognition, or the ability to understand the thoughts and feelings of others, is impaired in Prader-Willi syndrome. Social reward circuitry (which places value on things in our environment) may also be altered. This impairment may contribute to oppositional behavior and ASD symptoms, which are common in PWS.

Genetic therapy has the potential to address the root cause of PWS, however, several feasibility questions need to be answered before we can consider genetic therapy for PWS. For example: Does activation of the PWS genes reverse symptoms in models of PWS? Which genes must be turned on? Does gene activation need to occur before a specific age in...

Lack of satiety, or feeling 'full', is a hallmark characteristic of PWS. Satiety mechanisms are not well understood, and it is not clear how the stomach signals the brain to stop eating. It is believed, however, that the vagus nerve to hind brain connection (NTS) may be a key part of this mechanism. In this project, Dr. Edward Fox will...

While we know the loss of SNORD116 (a gene that encodes many snoRNA molecules on Chromosome 15) leads to characteristics of PWS, we do not know how this exactly works. We need to understand how SNORD116 functions normally in order to understand why the loss of this region leads to PWS. It is likely that the snoRNAs in the SNORD116 region modify...

Dr. Reiter is analyzing neurons, made from stem cells from individuals with PWS. He has noted disruptions in the circadian rhythm of these cells (day/night cycle) that may reflect sleep problems in PWS. His work will identify how the circadian rhythms are disrupted in PWS cells, and pave the way for identifying new drugs to normalize circadian...

This grant supports a new collaboration between two scientists with complimentary expertise. Drs. Sebastian Bouret and Francoise Muscatelli will work to define critical periods for oxytocin use in PWS models, and optimize this therapeutic approach. Mouse models will be used to define the critical period during which oxytocin might provide the...

Dr. Kurrasch is studying whether inflammation in the brain, mediated by special immune cells called microglia, might contribute to hyperphagia and obesity in PWS. Using a mouse model of PWS, she will examine microglia activity and explore whether eliminating microglia improves energy regulation. Funding provided by FPWR – Canada.

Universal newborn screening for PWS will ensure that all babies with PWS are diagnosed at birth. Dr. Godler has developed a sensitive, accurate and cost-effective DNA test for detection of PWS and Angelman syndrome using the bloodspots (“heelprick”) obtained in all newborns. In the study, FPWR is collaborating with with the Angelman Syndrome...

This grant will support a small clinical trial evaluating the impact of cannibidiol cannabidivarin (CBDV) on hunger and behavior. CBDV is a compound similar to CBD, but with potential advantages over CBD for PWS. In this study, Dr. Hollander’s group will investigate a form of CBDV, a non-psychoactive drug that has anti-inflammatory,...

Dr. Lee’s group is exploring the use of a novel gene transfer vehicle, exosomes, to deliver missing portions of the PWS genes to the hypothalamus. In this pilot study, they seek to develop PWS-specific exosomes and test how well these can deliver genes to neurons and other cells.

Families of those with PWS experience a great deal of stress, particularly during adolescence. In this study, we are funding the development of a new behavioral intervention, aimed at developing more effective coping skills in fathers of adolescents with PWS, as a means to improve overall family well being. Dr. Forster will work with fathers of...

This project takes the first steps towards developing a primate (macaque) model of PWS. Animal models of PWS are currently limited and are not able to replicate some important aspects of PWS, such as intellectual disability, as well as behavioral and social impairments. These aspects of PWS may be more effectively studied in a primate model. Our...

This study will combine advanced brain imaging technology with other assessments to examine how hormonal, cognitive, and psychological factors are interrelated in PWS. Results from this study will increase the understanding of how brain regions involved in food intake are related to appetite hormones, hair cortisol, and neuropsychological...

This grant supports the development of a new drug to tackle hunger and obesity with PWS. Inversago, a newly started, specialized biotech company, proposes that its CB1 blockers would treat a wider spectrum of symptoms than anything presently in development for PWS. The drug targets the endocannabinoid pathway, which is known to be altered in PWS....

Overcoming the strong drive to overeat and obesity with negative impacts on life expectancy and life quality is of upmost and crucial importance for individuals with Prader-Willi syndrome (PWS) and their families. Despite advances in understanding the genetic causes of PWS and the establishment of different mouse models that mimic some clinical...

MAGEL2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL2’s link to PWS has been determining its function within cells. Recently, my group has solved this enigmatic question. We...

Prader-Willi syndrome individuals show impaired social behaviors and altered oxytocin levels in the brain, but the reason for this remains unknown. Here we will test whether changes in the gut bacterial content in PWS could perturb social behaviors and related changes in oxytocin. In addition, we will examine whether a probiotic bacteria strain...

SNORD116 is a C/D box small nucleolar RNA that is critical for the etiology of PWS, as microdeletions encompassing only SNORD116 cause a PWS-like phenotype. The molecular functions of SNORD116 have been elusive, preventing therapy design. We showed that SNORD116 is not a typical snoRNA, as it associates with different proteins and has a different...

Prader-Willi syndrome (PWS) traits are genetically determined by the loss of expression of genes from the paternally inherited small region located on chromosome 15. These genes are transcribed to brain-specific small nucleolar RNAs (snoRNAs) whose function is still unknown. snoRNAs were traditionally assigned a role in ribosomal RNA processing...

Social isolation and impaired social cognition underpins loneliness, depression and anxiety, contributes to poor health and reduced longevity. They also are associated with such cognitive consequences as impaired executive functioning, cognitive decline, a bias towards negative, depressive thinking, and oversensitivity to perceived social...

PWS is caused by the loss of function of a set of genes. One of these genes, named MAGEL2, produces a protein that is important for the normal development of the brain, muscles and the endocrine system. Loss of function of MAGEL2 alone causes a disorder that is related to PWS, called Schaaf-Yang syndrome (SYS). To date, researchers have only...

The role of the brain in controlling food intake is increasingly apparent, with studies finding that genes related to obesity often play a role in brain regions crucial for feeding, appetite, and satiety. Prader-Willi syndrome, one of the most common forms of genetic obesity, results increased food intake (hyperphagia) leading to severe obesity,...

Neuropsychological studies have detailed several cognitive deficits in Prader-Willi Syndrome (PWS), among which the observation of altered social interactions, with notable difficulty in interpreting and responding to social information. The integration of the information from the face and the voice is important for our social communication as...

Neuropsychological studies have detailed several cognitive deficits in Prader-Willi Syndrome (PWS), among which the observation of altered social interactions, with notable difficulty in interpreting and responding to social information. The integration of the information from the face and the voice is important for our social communication as...

For Year 1, our project aims were: 1) to characterize the social, cognitive, and affective processes in preschoolers with PWS (by genetic subtype), in comparison to preschoolers with ASD and typically developing children, and 2) to pilot a remotely delivered parent education program to determine if it would be feasible and effective for families...

This project uses infant mice to understand the mechanism of a promising treatment for PWS. Oxytocin (OXT) regulates feeding and social behavior. In mouse research and recent clinical trials with infants and young children, OXT seems to improve the core feeding and social behavior disturbances of PWS. In humans, OXT is effective when it is given...

Deletions on chromosome 15 in the bands labeled 15q11.2-q13 on the chromosome inherited from a subject’s father cause Prader-Willi syndrome (PWS). The unique nature of this causative genetic event has been known for many years, but the precise manner in which it causes the developmental abnormalities of PWS is not completely understood since the...

Prader-Willi Syndrome (PWS) is a genetic condition resulting from paternal inheritance of a deletion within an imprinted region of chromosome 15q. The smallest known deleted region encompasses a small nucleolar non-coding RNA locus called SNORD116 (SNORD116), but very little is known about how deletion of SNORD116 leads to PWS. As shown using...

There is currently no cure for Prader-Willi syndrome (PWS). PWS is a complex and debilitating disorder that significantly impacts the lives of not only affected patients, but their families, as well. Recent work has revealed a genetic basis for PWS, and a number of the genes affected are known to have unique expression patterns throughout the...

Orthopedic anomalies are common in patients with Prader-Willi syndrome (“PWS”). Surveys suggest that roughly 19% of individuals with PWS may be diagnosed with knock knees, 10% with hip dysplasia, 7% with patellofemoral instability, and 3% with bowlegs. Yet, there is little consensus among orthopedists about how best to address these issues in...

Temper outbursts are one of the most commonly reported behavior problems of children, adolescents and adults with PWS. Outbursts cause increased stress for families and costs for the community. Despite this, there is currently no known treatment. Meditation on the Soles of the Feet (SoF) is a mindfulness-based intervention designed specifically to...

Our goal is to understand the molecular pathways disrupted in Prader-Willi syndrome (PWS) and to develop therapeutic interventions for this disorder. Through the biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that is switched on while the same set of genes on the chromosome 15...

Recent studies with oxytocin treatment in PWS have yielded inconsistent results. Intranasal administration of oxytocin by the Toulouse group decreased disruptive behaviors in patients with PWS, but a recent randomized trial in Australia of adolescents and adults of intranasal oxytocin (IN-OT) found no effect on syndrome-specific behavior in...

There are two goals to this study: 1) To identify differences between individuals with PWS with autism from those who have PWS without autism using technology that analyzes how genes are expressed and 2) To identify a new role for SNORD115 and SNORD116 which may help explain the PWS condition or how other very small molecules that do not make...

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Previous neuroanatomical studies in PWS have examined cells in the hypothalamus. To date, no data are available on the cellular structure of the brain in PWS in the frontal lobe where executive function...

Hyperphagia is one of the distinctive features of Prader-Willi syndrome (PWS), and when not carefully monitored or controlled, can be life threatening. It emerges in early childhood and remains a life-long challenge for individuals with PWS and their caregivers. To effectively manage and, in the future, treat hyperphagia, it is important to be...

Prader-Willi syndrome (PWS) is a severe neurodevelopmental disorder found in ~1 in 15,000 to 20,000 births. PWS phenotype caused by the loss of function of several genes located on chromosome 15. These genes are usually ‘switched on’ on the chromosome 15 that is inherited from the father and ‘switched off’ on the chromosome 15 inherited from the...

Osteoporosis is characterized by weakened and fragile bones and considered one of the major health abnormalities associated with Prader-Willi syndrome (PWS). This problem affects almost 90% of patients with PWS and has a negative impact on their quality of lives by causing physical and functional limitations that could also affect longevity. In...

Hyperphagia (extreme overeating) is the most significant factor contributing to obesity in Prader-Willi syndrome (PWS) and considered a cardinal feature. PWS is recognized as the most common syndromic cause of life-threating obesity, but no medications are currently available to decrease appetite or lessen obesity in PWS.

The hypothesis set out in our original application is that t-VNS given over time and following a protocol established for its use in epilepsy, will prevent the prolonged and debilitating temper outbursts and associated emotional dysregulation that characteristically affect people with PWS. We further propose that any improvements in behavior are...

There is some data suggesting that one of the systems that regulates appetite and weight in the brain, the melanocortin-4 receptor pathway, may be disrupted in PWS. This study will examine a new class of drugs targeting this pathway, in a mouse model of PWS. The drugs will be tested alone and in combination with other drugs currently being...

Dr. Tucci’s group has shown that mice with the SNORD116 deletion have sleep abnormalities and increased body temperature. They hypothesize that environmental temperature may play a crucial role in the pathophysiology of PWS symptoms including sleep and obesity. They will use PWS mice that will be maintained under different temperature regimens and...

Caregivers, physicians and patients with PWS report that daytime sleepiness in PWS significantly disrupts daily life. However, the underlying cause of excessive daytime sleepiness in PWS is unknown. Dr. Scammell’s group is exploring the contribution of reduced neuronal function in the hypothalamus region of the brain, specifically, oxytocin/orexin...

Although it is well established that deletion of SNORD116 contributes to PWS in humans, mice missing Snord116 don’t display hyperphagia and obesity. This makes it very difficult to study the biology of SNORD116 and test anti-obesity drugs. In a major breakthrough, Dr. Yeo’s group has shown that if Snord116 is deleted in adult mice, a percentage of...

People with intellectual or developmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for social exclusion and isolation. This underpins loneliness, depression and anxiety, contributes to poor health and reduced longevity. This project will recruit 50 young adults with PWS into an intensive, 10-week group...

Numerous hormone levels are deficient in PWS. However, the underlying biology and how the altered hormone levels contribute to the characteristics of PWS is not well understood. Dr. Nicholls’ group has developed a novel cell culture model system to study how PWS genes regulate hormone production and release. This model system will advance our...

The loss of two snoRNAs, SNORD115 and SNORD116, plays a central role in the development of Prader-Willi syndrome. However, the normal function of SNORD116 is still unclear, making it difficult to understand what goes wrong when SNORD116 is lost. Dr. Stamm’s group is exploring how SNORD116 influences other genes, and their preliminary studies...

Ghrelin levels are elevated in PWS, but why, how, and whether it plays a role in hyperphagia or other aspects of PWS are all still unanswered questions. This project will explore if ghrelin plays a protective role in PWS with regards growth hormone deficiency, hypoglycemia and mental health issues, but a detrimental role with regards to extreme...

Despite the significant progress in understanding the molecular basis underlying Prader-Willi syndrome, little advance has been achieved in developing the treatment specifically targeting to the molecular defect. The SNORD116 between the SNRPN and UBE3A genes is important for the major features of PWS. The host transcripts and SNORD116 in the...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

Prader-Willi syndrome (PWS) is a genetically and clinically complex disorder. From a molecular standpoint, a major question has been the contribution of individual genes within the Prader-Willi domain on chromosome 15 to the overall clinical phenotype. Many animal models have attempted to address this question, but have not been able to fully...

Children with PWS are hypotonic (floppy) at birth. Their poor muscle tone causes delays in sitting and walking and contributes to orthopedic problems such as scoliosis. Reduced endurance lowers the number of calories they can consume per day to manage their body weight, and impairs their quality of life. Treatments that build muscle mass or...

Children with Prader-Willi syndrome suffer from very low muscle tone, growth delay, short stature, developmental delay, muscle weakness and exercise intolerance. Studies have suggested that there is a problem with energy metabolism in PWS but what kind of problem this is and how this leads to PWS is not clear at the present time. Many PWS patients...

Although PWS is best known for hypothalamic obesity and hyperphagia, the cognitive and behavioral issues are the most challenging for families. Brain difference is the underpinning of the characteristics that define the Prader-Willi personality: food related behaviors, excessive/repetitive behaviors, stress sensitivity/mood disorder, cognitive...

Task switching is a cognitive process important for regulating behaviour. People with PWS generally show impaired switching and this difficulty is linked to people resisting change and showing temper outbursts triggered by changes.

There is increasing evidence that Prader-Willi Syndrome is associated with high rates of psychosis, a serious mental disorder that profoundly disrupts thought and emotion. However, little is known about the early or ‘prodromal’ phase of illness and the risk factors that predict the emergence of psychosis in PWS patients. This is a critical gap in...

The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice...

A hallmark symptom of PWS is extreme, unrelenting hyperphagia associated with obesity. Other medical characteristics of individuals with PWS include low circulating growth hormone, short stature, adrenal insufficiency, hypothyroidism, and hypogonadism. Additionally, individuals with PWS have decreased levels of circulating fasting insulin compared...

This project centers on better understanding the social-cognitive characteristics of Prader-Willi syndrome (PWS) in early childhood and providing education and training to parents of children with PWS to optimize learning and joint engagement between parent and child. There are two goals of this research:

The genetic causes of Prader-Willi syndrome (PWS) are known, including as a complex disorder involving imprinted genes that normally only function after inheritance from the father. A dozen genes contribute to the clinical problems in PWS, although what most of these genes do is poorly understood. Additionally, although numerous mouse models that...

This proposed proof of concept study follows an earlier trial of vagus nerve stimulation, using a surgically implanted medical device, in three people with PWS to investigate whether such treatment might reduce the over-eating behaviour characteristic of people with PWS. Whilst the effects on eating were equivocal, two of the three participants,...

Recent technological developments have ushered in a new era for the medical research field based on our ability to generate stem cells (called induced pluripotent stem cells or iPSCs) out of adult patient cells, such as blood or skin fibroblasts. There are two important benefits of this technology relevant for research into Prader Willi Syndrome...

Current evidence suggests that most Prader-Willi syndrome (PWS) traits result from loss of paternally inherited SNORD116 gene group. SNORD116 belong to a class of small nucleolar RNAs (snoRNAs), which are involved in modification of other RNA species. snoRNAs act as guides to define sites of target RNA modification by partner enzymes. Typically, a...

Study one: There is a reduction in the number of neurons that produce oxytocin in people with PWS. This, along with a range of other evidence supports the likelihood that abnormalities in the oxytocin system are key to the problems of PWS. However, studies examining the levels of oxytocin in PWS as well as clinical trials evaluating the effect...

There are two goals to this study: 1) To identify differences among individuals with PWS and autism from those who have PWS without autism by analyzing gene expression and 2) To identify new patterns of gene expression which may help explain the PWS condition or how other very small molecules that do not make protein (non-coding RNAs) implicated...

Obesity and insatiable appetite (hyperphagia) are among the most serious symptoms experienced by Prader-Willi syndrome (PWS) patients. While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in...

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis. PWS is an imprinted disorder, meaning that the genes implicated in PWS are expressed only on the paternal but not the maternal chromosome 15q11-13. At the heart of the minimally deleted region in PWS are several processed...

Prader-Willi Syndrome (PWS) is a rare genetic disorder with symptoms that typically include obesity, severe appetite and impaired reproductive function. It is thought that dysfunction of the hypothalamus, a part of the brain that controls body weight and reproduction, underlies some of these symptoms. Our goal is to understand what is...

Excessive eating (hyperphagia) is one of the most challenging features of Prader-Willi Syndrome (PWS) and currently there are no medications available for effective appetite regulation. Hyperphagia is most likely to be driven by elevated levels of the appetite-stimulating hormone ghrelin in patients with PWS. The underlying cause of this elevated...

Paying attention to communicative faces is essential for our understanding of the social world. Indeed, faces provide observers rich and complex information about the identity (gender, age, etc), the socio-emotional state (eye-brows movements, eye-gaze) and the linguistic message (auditory speech sounds/mouth movements) of our social partners. The...

The loss of two regulatory RNAs is critical for the development of Prader-Willi syndrome. One of these RNAs prevents the formation of a truncated serotonin receptor. We will test the role of this truncated serotonin receptor in the production of growth hormones and determine whether it is a 'master regulator' for other receptors. Based on our...

For several decades the most extensively studied human DNA sequences were those generating messenger RNAs (mRNAs) which are used as templates for protein synthesis. The process decoding the genetic information from mRNAs to proteins is carried out by molecular machines named ribosomes and proteins are commonly perceived as essential molecules...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

Plasma levels of the peptide hormone ghrelin are markedly elevated in individuals with Prader-Willi Syndrome (PWS), however the functional consequences of this elevation have not yet been determined, nor are the mechanistic causes of ghrelin elevation known. Many attribute the characteristic, maladaptive PWS eating behaviors directly to ghrelin,...

Background: MAGEL-2 is a gene frequently deleted or mutated in individuals affected with PWS. Furthermore, mice lacking MAGEL-2 display symptoms similar to those seen in PWS children. However, a critical barrier to our understanding of MAGEL-2’s link to PWS has been determining its function within cells. Recently, my group has solved this...

Many individuals with PWS have sleepiness, abnormal rapid eye movement (REM) sleep, and falling episodes resembling cataplexy - episodes of muscle paralysis that are usually triggered by strong, positive emotions. Caregivers, physicians and patients with PWS report significant disruption of daily life as a result of these sleep-related symptoms....

A publication resulting from this project was highlighted in an FPWR Research Blog post “Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome” (December 2016)

Prader-Willi syndrome (PWS) is caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Temper outbursts are commonly shown by people with Prader-Willi syndrome (PWS) and can cause great problems for people with the syndrome, their family members and caregivers. One common reason for temper outbursts is that people with PWS find changes to routines or to plans very difficult. This difficulty with change is linked to impairment in a...

Prader-Willi Syndrome (PWS) is a complex genetic disorder characterized by an insatiable feeling of hunger and an irrepressible urge to overeat. If left uncontrolled, hunger and overeating can lead to morbid obesity, diabetes, cardiovascular disease and premature death. Why PWS causes hunger is an important question that must be answered in we...

Prader-Willi syndrome (PWS) is a rare genomic imprinting disorder caused by an abnormality in the PWS critical region (PWSCR), a particular region of 15th chromosome (15q11-q13). Genomic imprinting refers to a phenomenon in which genes from specific parent can be expressed. PWSCR contains several imprinted genes that are only expressed from either...

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety or behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

A remarkable clinical resemblance between Prader-Willi syndrome (PWS) and hypotonia-cystinuria syndrome (HCS) was observed in our multidisciplinary clinic for PWS in our center. All HCS patients were initially referred for genetic analysis of PWS. Patients with either syndrome suffer from weakness and poor sucking in the newborn period. This...

MAGEL2 is one of five genes in the Prader-Willi syndrome (PWS) critical domain on chromosome 15 that encodes a protein. Our group recently described a group of patients with mutations of MAGEL2 causing Prader-Willi features and autism. Autism spectrum disorder is seen in up to one third of individuals with PWS, and in all individuals with MAGEL2...

In Prader-Willi syndrome (PWS) the progression from poor appetite and failure-to-thrive (FTT) to obesity and voracious appetite is complex and takes several years. We have recently shown that there are 6 distinct post-natal nutritional phases in PWS. By looking at the end products of cellular processes in individuals with PWS before and after the...

Hyperphagia (extreme overeating) is the most significant factor contributing to obesity in Prader-Willi syndrome (PWS) and considered a cardinal feature. PWS is recognized as the most common syndromic cause of life-threating obesity, but no medications are currently available to decrease appetite or lessen obesity in PWS. Preliminary studies have...

Prader-willi syndrome is a genetic disorder caused by loss of a portion of a copy of chromosome 15. Common features include early problems with muscle weakness and feeding followed by occult weight gain without an increase in food consumption beginning during late infancy/early toddler period prior to the onset of hyperphagia. Recent research has...

The MAGEL2 gene appears as one of the main genes involved in feeding and behavioral (autistic like behavior) alterations observed in Prader-Willi Syndrome. We showed that, in mouse, the deficiency of Magel2 results in a phenotype similar to the clinical description of patients with mutations in MAGEL2. Indeed, we showed that Magel2-deficient mice...

The identification of genetic loci conferring susceptibility to Prader-Willi Syndrome (PWS) provides valuable opportunities for understanding its biological basis. A powerful approach for probing the roles of genes within the nervous system is to introduce them into mice. The resulting mouse models may be studied in depth to determine how genes...

The genetic disorder Prader-Willi syndrome (PWS), results in debilitating physical, endocrine, cognitive, and behavioral symptoms. Many of the characteristics of PWS, such as uncontrollable food intake, stunted growth, and emotional problems suggest that disruptions in brain regions such as the hypothalamus may cause this. Recently, the gene...

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human chromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at a high risk of developing psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging study in...

Once Prader-Willi patients reach the stage where hyperphagia is a dominant characteristic of the disease, the progression to obesity, morbid obesity and diabetes and their complications reduces the quality of life of the patient and increases their risk of death from a number of causes. The constant food seeking and food obsession combined with...

Prader-Willi syndrome (PWS) is caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Obesity and insatiable appetite (hyperphagia) are among the most serious symptoms experienced by Prader-Willi syndrome (PWS) patients. While many of the causes underlying PWS symptoms remain unknown, the discovery of the protein hormone ghrelin and its role in controlling appetite has led researchers to investigate the possible role of ghrelin in...

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of inherited genes from fathers on chromosome 15. PWS is characterized by intellectual disabilities, repetitive and compulsive behaviors, social cognition deficits, increased eating and obesity. These individuals typically consume up to three times the normal caloric...

The vagus nerve is a major route of communication between the brain and the gut. Vagus nerve stimulation (VNS) is a procedure whereby a small implanted device placed under the skin on a patient’s chest delivers an intermittent electrical impulse to the vagus nerve, which will travel up and down the nerve and into the brain and to the gut. VNS has...

Dr. Jennifer Miller is assisting FPWR in identifying opportunities for clinical trials in PWS and developing recommendations for the conduct of such clinical trials. Among the issues to be addressed are target population, identification of informative surrogate endpoints, and assessment of recruitment challenges. In addition, she is providing...

This supplement will help Dr. M. Tauber complete the study awarded in 2011: Early to midterm oxytocin effects on the brain metabolism of adults with Prader-Willi syndrome. Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe disabilities such as morbid obesity, as well as behavioral and socialization problems. We are...

Dr. Tauber is leading a European effort to collect blood samples on infants and children with PWS to monitor changes in hormones over time. This funding will support a blood bank recruitment coordinator, who will work to collect clinical data on birth, growth, endocrine functions and feeding behavior in newly diagnosed patients with PWS.

Previous results showed that our physical rehabilitation program could induce weight loss in a group of adult PWS patients, but failed to improve their muscular mass (Grolla et al.2010). The loss of muscle mass affects elderly, obese and PWS patients leading to frailty and impaired quality of life. It is becoming apparent, using animal models,...

Prader-Willi Syndrome (PWS) is a complex genetic disorder associated with varied clinical findings, neurocognitive delay, and endocrine abnormalities. Clinically, individuals with PWS progress along a path marked by different nutritional stages. In infancy, children with PWS have hypotonia, poor feeding, excessive daytime sleepiness, and...

Individuals with Prader Willi Syndrome (PWS) are known to display frequent and severe temper outburst behaviours throughout their life. These behaviours can have a significant impact on the quality of life for the individual and their family. Prader Willi outbursts are reactive explosion of emotion that once provoked the individual has little...

Mental illness is a major problem in Prader-Willi syndrome (PWS). It prevents social interactions and seriously threatens the quality of life of the patient and of those around the patient. Mood swings, stereotyped repetitive behaviors, psychotic episodes are dependent on proper functioning of brain regions such as the prefrontal cortex. Activity...

Prader-Willi Syndrome (PWS) is a rare disorder, sharing common genes with autism and schizophrenia; patients with PWS are at very high risk of developing severe psychiatric illnesses and behavioral problems, however, the underlying neurobiology that places them at-risk is yet unknown. Here we propose a cross-sectional, multi-faceted brain imaging...

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder, predominantly caused by a deletion on the long arm of chromosome 15. This deletion eliminates a group of genes called HBII-85 whose function is currently unknown. Therefore, this proposal aims to investigate the underlaying molecular mechanisms behind the loss of HBII-85 and how this...

Extreme obesity is one of the major health problems related to Prader-Willi syndrome (PWS), yet there are few effective medications. Endocannabinoids (eCBs) are lipid signaling molecules that act on a cellular receptor, called the CB1 receptor. This receptor is present in the brain and in peripheral tissues, where it also recognizes the...

Prader-Willi syndrome is a multisystem disorder due to absence of paternally expressed imprinted genes at 15q11.2-q13. Diminished bone mineral density (BMD) and osteoporosis are common in PWS individuals, especially in adolescence and adulthood. The reasons for the increased prevalence of osteoporosis in PWS are not totally clear, but decreased...

: Prader-Willi Syndrome (PWS) is a genetic disease characterized by failure to thrive and low muscle tone during infancy, followed by food-seeking, insatiable appetite and progressive obesity in childhood. The resulting increases in total body fat and decreases in muscle mass lead to metabolic problems such as diabetes and heart disease.

Prader-Willi Syndrome (PWS), a complex genetic disorder that results from a failure to inherit a normal copy of the father’s chromosome 15. Key genes on the paternal chromosome are deleted, but how the deletion of this region leads to PWS is a complete mystery. In PWS, a normal copy of the mother’s chromosome 15 is inherited, but the genes are...

Among the many complications of Prader-Willi Syndrome (PWS), the increased food intake (hyperphagia) has serious long-term medical consequences. The goal of this proposal is to define novel brain regions that may contribute to this problem. Studies of brain activity suggest that the prefrontal cortex might be different in PWS patients. This is an...

Prader-Willi syndrome (PWS) is a genetic disease characterized by an insatiable appetite and a variety of behavioral dysregulations. It is known that the brain, and particularly a region of the brain called the hypothalamus, is important to regulating appetite and body weight. We also know that many key physiological processes, including appetite...

Many advances in recent years have added to our understanding of the genetic causes of PWS, including recognition of it as a disorder of genomic imprinting involving defective genes that normally only function after inheritance from the father. At least a dozen genes appear to contribute to the many clinical problems seen in PWS. Unfortunately the...

Prader-Willi syndrome (PWS) is caused by a loss of expression of specific genes normally expressed only from paternal alleles on chromosome 15. PWS patients display common symptoms, which include feeding difficulties in infancy, loss of muscle tone, rapid weight gain after two years of age, extreme hunger and unrelenting appetite, obesity, and...

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human cromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Like most genetic disorders, there is no specific therapeutic intervention targeted to the molecular defect for Prader-Willi syndrome (PWS). The clinical presentations of PWS are caused by paternal deficiency of genes in the chromosome 15q11-q13 region. Recent reports indicate a region between the SNRPN and UBE3A genes harboring SnoRNA clusters is...

The brain balances energy stores with energy expenditure with little conscious effort. The hypothalamus is a part of the brain that senses levels of a hormone called leptin, which is produced by fat. Excess leptin normally causes a decrease in appetite and increase in activity. This balance is disrupted in obese children who carry mutations in...

Early in infancy, babies with Prader-Willi syndrome (PWS) have no interest in feeding manifested by lack of crying for food and failure-to-thrive requiring assisted feeding with a G-tube, NG tube, or cross-cutting of bottle nipple (phase 1a). There is then a series of transition through five nutritional phases, ending in the classic PWS...