RARE DISEASE
Prader-Willi-like syndrome
Prader-Willi-like syndrome
Prader-Willi-like syndrome
Synonyms: PWS-like
Synonyms: PWS-like
Synonyms: PWS-like
Drug discovery
0
drugs
With orphan designations
Overview
Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder caused by loss of paternal gene expression on chromosome 15q11-q13. It features neonatal hypotonia, hyperphagia-driven obesity, developmental delay, endocrine dysfunction (growth hormone deficiency, hypogonadism), and behavioral challenges. Management requires multidisciplinary care focusing on nutritional control, hormone replacement, and behavioral interventions to mitigate complications [1][6][12].
Burden
Medical: High rates of obesity-related complications (diabetes, sleep apnea), scoliosis, and premature mortality [1][6][12].
Economic: Annual costs exceed €58,890 per individual (EU data), driven by hospitalizations and social services [4][14].
Caregiver impact: Significant psychosocial strain, with 87% reporting disrupted sleep/work and ZBI scores indicating severe burden [4][14].
Therapies
Growth hormone therapy: Improves lean mass, mobility, and metabolic parameters; initiated in infancy [3][8][17].
Strict dietary supervision: Calorie-restricted diets with environmental controls to prevent obesity [3][6][8].
Behavioral/multidisciplinary care: Includes SSRIs, cognitive-behavioral therapy, and structured routines to manage hyperphagia, skin-picking, and psychiatric comorbidities [3][8][14].
Categories: rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders, rare neurological diseases
Research Papers
48 drug discovery papers about Prader-Willi-like syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
48 drug discovery papers about Prader-Willi-like syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-01-30 | Case report of a patient with Prader-Willi-like syndrome with 6q16.1-16.3 microdeletion
Prader-Willi -like syndrm zaha geneticky heterognnu skupinu syndrmov s fenotypom iastone podobnm pacientom s Praderovm-Williho syndrmom. Ide najm o hypotonus, zaostvanie v psychomotorickom vvoji, niektor endokrinopatie alebo ochorenia inch orgnovch systmov. Autori prezentuj kazuistiku dievatka s diagnostikovanou mikrodelciou 6q16.1-16.3, ktor patr do skupiny Prader-Willi-like syndrmov V klinickom obraze dominoval globlny hypotonick syndrm, psychomotorick zaostvanie a od veku 18 mesiacov postupn zvyovanie telesnej hmotnosti vzhadom k aktulnej telesnej vke. Vo veku 4 rokov mala telesn vku 94,9 cm (-2,1 SD) a v dvoch stimulanch testoch bol potvrden deficit rastovho hormnu. Bola z aat lieba rastovm hormnom, ktor je prospen nielen z hadiska rastovch prrastkov, ale aj z hadiska formovania svalovej hmoty a zlepenia hrubej motoriky. Pacienti s Prader-Willi-like syndrmom vyaduj multidisciplinrny prstup a sledovanie viacermi pecialistami poda konkrtnych klinickch symptmov.
2025-11-01 | Long-term growth hormone effects in Prader-Willi syndrome
To assess the long-term effects and mortality rates associated with GH therapy in patients with Prader-Willi Syndrome (PWS). Prader-Willi Syndrome is a rare genetic disease characterized by growth hormone (GH) deficiency among other endocrine disorders. A systematic literature search was carried out on 4 databases including PubMed, Scopus, Web of Science, and Cochrane databases. The search was based on two keywords: “Growth hormone” AND “Prader-Willi Syndrome”. Outcome data included height-standard deviation score (SDS), weight SDS, body mass index (BMI)-SDS, insulin like growth factor 1 (IGF1), mortality, low density lipoprotein (LDL)-cholesterol, and blood glucose. A total of 41 studies were included, of which 30 were involved in the meta-analysis. Following treatment with GH, height-SDS showed a significant increase compared to baseline in two timeline subgroups (≤2 years and >2 years), with a mean difference (MD) of 1.05 (95% CI: 0.92–1.18, p<0.00001) and 1.53 (95% CI: 1.23–1.82, p<0.00001), respectively. Patients on GH experienced a more pronounced increase in height-SDS compared to those who have not received GH. This was further associated with a lower BMI-SDS among GH-treated patients compared to their counterparts, with an MD of -1.02 (95% CI: -1.76 to -0.28, p=0.007; I²=84%, p=0.0003). Additionally, IGF1-SDS showed a marked increase after GH. Other metabolic effects include significant increase in LDL and blood glucose levels after GH treatment. The mortality rate in PWS patients undergoing GH treatment is estimated at 1.5% (95% CI: 0.8–2.2%), with causes including respiratory issues, cardiac arrest, infections, accidents, and gastrointestinal complications. GH therapy in PWS significantly improves height and IGF-1 SDS, while relatively decreasing BMI compared to no-GH, indicative of lean mass growth and healthy development. Nonetheless, GH therapy requires careful metabolic monitoring due to its mixed effects on cholesterol and glucose levels. PROSPERO Reg. number: CRD420250649945
2024-10-19 | Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model.
Confronting oxytocin and vasopressin deficits in autism spectrum disorders and rare syndromes brought promises and disappointments for the treatment of social disabilities. We searched downstream of oxytocin and vasopressin for targets alleviating social deficits in a mouse model of Prader-Willi syndrome and Schaaf-Yang syndrome, both associated with high prevalence of autism. We found a population of neurons in the lateral septum-activated on termination of social contacts-which oxytocin and vasopressin inhibit as per degree of peer affiliation. These are somatostatin neurons expressing oxytocin receptors coupled to GABA-B signaling, which are inhibited via GABA-A channels by vasopressin-excited GABA neurons. Loss of oxytocin or vasopressin signaling recapitulated the disease phenotype. By contrast, deactivation of somatostatin neurons or receptor signaling alleviated social deficits of disease models by increasing the duration of contacts with mates and strangers. These findings provide new insights into the treatment framework of social disabilities in neuropsychiatric disorders.
2024-02-26 | The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.
Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.
2024-01-10 | Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader–Willi syndrome: a one-year retrospective cohort study
Abstract Background Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader–Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. Methods A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. Results The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea–hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO 2 ), lowest SpO 2 , duration when SpO 2 is lower than 90%, or proportion of the patients with SpO 2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. Conclusion Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.
oligonucleotides
2026-07-18 | Spectrum of genetic forms of obesity and related disorders: Prader-Willi-like syndromes (part 1)
Prader–Willi–like syndromes (PWLS) represent a heterogeneous group of disorders characterized by a set of key clinical features, including muscular hypotonia, obesity, psychomotor and speech developmental delay, and behavioral problems, in the absence of methylation abnormalities within the chromosomal region 15q11.2q13. The phenotypic manifestations of PWLS show substantial overlap with the classical Prader–Willi syndrome (PWS), a disorder belonging to the group of imprinting disorders. PWLS include certain chromosomal syndromes (deletions of 1p36, 2pter, 3p26.3, 6q, 10q26, 19p, subtelomeric deletion of 12q, paracentric inversion Xq26q28, Xq27–qter disomy, duplications of 6q, 15q, Xq21.1q21.31, Xq23q25), imprinting disorders (Angelman syndrome, Temple syndrome, pseudohypoparathyroidism types 1A and 1C, pseudopseudohypoparathyroidism, Schaaf–Yang syndrome), and monogenic syndromic forms of obesity (Fragile X syndrome, Bardet–Biedl syndrome, Alström syndrome, Cohen syndrome, Börjeson–Forssman–Lehmann syndrome, MYT1L -related syndrome, SIM1 -associated PWS-like obesity, GNAI1 -associated neurodevelopmental disorder). The combination of the genetic heterogeneity of PWLS and the absence of the specific genetic defect observed in PWS creates significant challenges for differential diagnosis in clinical practice. This literature review systematizes current research data aimed at refining the phenotypic characterization, management approaches, and treatment strategies for syndromes within the Prader–Willi–like spectrum.
2026-05-07 | Mechanisms of USP7/MAGEL2 Complex Assembly and Its Mutational Disruption in Neurodevelopmental Diseases.
The WASH complex regulates endosomal trafficking and is linked to several neurodevelopmental diseases, including Prader-Willi syndrome, Schaaf-Yang syndrome, and Hao-Fountain syndrome. Its function is tightly controlled by ubiquitination, maintained by the multi-subunit MUST complex containing both a ubiquitin ligase (MAGEL2/TRIM27) and a deubiquitinase (USP7). However, the mechanism underlying the MUST complex assembly remains poorly understood. In this study, we investigate the assembly of USP7 and MAGEL2 components of the MUST complex using NMR spectroscopy, isothermal titration calorimetry, X-ray crystallography, and cellular assays. We show that the USP7/MAGEL2 interaction is bipartite and multivalent. Two distinct domains of USP7, TRAF and UBL1-2, recognize two unstructured but evolutionarily conserved regions of MAGEL2, one of which contains multiple TRAF-binding sites. Furthermore, we determine the high-resolution crystal structure of the TRAF/MAGEL2 complex and identify Hao-Fountain syndrome-linked mutations in USP7 that disrupt USP7/MAGEL2 complex formation in vitro and in cells. These findings provide mechanistic insight into the pathogenic basis of Hao-Fountain syndrome and related Schaaf-Yang and Prader-Willi syndromes.
2026-01-10 | Novel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity.
Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader-Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein-protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity.
2025-06-24 | Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome.
Biallelic variations in SREK1 reduce SNORD115/116 expression, linking severe obesity and Prader-Willi-like traits, offering genetic and molecular insights into a new form of syndromic obesity.
2024-07-01 | MAGEL2 (patho-)physiology and Schaaf-Yang syndrome.
Schaaf-Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader-Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss-of-function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation.
small molecules
2026-06-22 | Efficacy and safety of semaglutide for obesity and hyperphagia in adults with Prader-Willi syndrome
ABSTRACT Context Prader-Willi syndrome is a genetic neurodevelopmental disorder characterized by hyperphagia and early-onset obesity from hypothalamic dysfunction with endocrinopathies and learning disability. Management is challenging with strict control of the food environment needed. While newer glucagon-like peptide-1 receptor agonists, such as semaglutide, have efficacy in non-PWS obesity, there have been limited case reports in PWS. Objective/Design/Setting Retrospective records review of 12 adults with PWS and overweight/obesity treated with semaglutide at a UK academic hospital centre specialist clinic. Patients mean ± SD age 28.3 ± 10.1 years, 83% female, BMI 46.6 ± 8.2kg/m², 75% type 2 diabetes mellitus. Intervention Median follow-up 17.2 months (range 8.7-36.1) with median semaglutide dose 2.4mg once weekly (1.0-2.4). Results Although there was no significant weight loss on semaglutide, there was stabilisation of the weight gain prior to treatment over previous 12.4 months (7.6-23.0) (post −3.1 ± 9.9% vs. pre +5.7 ± 5.6%: d −0.72, P=0.037). There was a significant decrease in hyperphagia on semaglutide from Hyperphagia Questionnaire for Clinical Trials (n=11, −7.3 ± 6.1 (max 36), d −1.19, P=0.003), having been stable before treatment. HbA1c improved in those with elevated baseline levels (n=6, −4.2 ± 4.9%, d −0.74, P=0.13). Mild gastrointestinal side effects were seen in 25% but did not lead to discontinuation. Conclusions In adults with PWS, semaglutide produced weight maintenance, reduced hyperphagia, and improved glycaemic control, with good tolerability. Larger placebo-controlled trials are needed to confirm these findings in adults and adolescents with PWS, especially in those without T2DM, where efficacy may be greater.
2026-06-19 | Beyond the GH–IGF-1 Axis: A Network Perspective Integrating Clinical Observations and Mechanistic Insights
Background: Obesity encompasses a heterogeneous group of conditions that include not only simple obesity, but also genetic and endocrine disorders. The growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis plays a central role in body composition, insulin sensitivity, and metabolic regulation. We encountered three patients in whom the clinical courses highlighted distinct interactions between obesity and the GH-IGF-1 axis. Methods: We reviewed three representative cases. Case 1 involved acromegaly improved by the peroxisome proliferator-activated receptor-α (PPAR-α) agonist pemafibrate. Case 2 involved Prader-Willi syndrome (PWS) with severe obesity treated using dulaglutide. Case 3 involved severe obesity managed with behavioral therapy. Clinical characteristics and therapeutic responses were analyzed. Results: In Case 1, pemafibrate administration resulted in a marked and sustained reduction in IGF-1 levels despite ongoing lanreotide therapy, suggesting a potential hepatic or pituitary interaction between PPAR-α signaling and GH-IGF-1 regulation. In Case 2, dulaglutide induced weight loss and reduced insulin requirements in a patient with PWS, a condition characterized by high levels of ghrelin. The therapeutic effect may involve modulation of ghrelin, an upstream regulator of GH secretion. In Case 3, behavioral therapy stabilized metabolic deterioration in a patient with a body mass index of 50.7 kg/m2, even though GH and IGF-1 levels remained low after weight reduction, suggesting mechanisms independent of the GH-IGF-1 axis. Conclusion: These findings support a conceptual shift from a linear GH-IGF-1 axis to an integrated GH-IGF-1 network that connects peripheral signals, hypothalamic regulation, and higher brain functions, offering a novel framework for personalized obesity management.
2026-03-12 | Low dose systemic AAV-exendin-4 gene therapy for Prader-Willi syndrome and dietary obesity
Prader-Willi syndrome (PWS) patients display developmental delays, endocrine dysfunction, excessive eating, central obesity, and various behavioral abnormalities. Effective and sustained treatments are limited, highlighting the need for new therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have revolutionized obesity treatment while their efficacy in PWS population remains inconsistent and data in PWS animal models are lacking. Here, we assessed the efficacy of a newly developed AAV platform to deliver a GLP-1RA exendin-4 via an engineered hybrid capsid Rec2. Intraperitoneal administration of Rec2-exendin-4 at the dose of 2 × 10 10 viral genome per mouse normalized metabolic dysfunction in the Magel2 -null mouse model of PWS. Systemic Rec2-exendin-4 treatment reversed genotype-driven excessive adiposity, impaired glycemic control, hyperleptinemia, and adipose gene expression signatures. Moreover, intraperitoneal injection of Rec2-exendin-4 (4 × 10 10 viral genome/mouse) exerted high levels of efficacy in diet-induced obesity model—decreasing food intake; preventing excessive weight gain and obesity; improving glucose metabolism and insulin sensitivity; and reversing fatty liver. Metabolic improvements were maintained at least 5 months. These data demonstrate the therapeutic potential of a systemic AAV-mediated exendin-4 gene therapy for PWS-related metabolic abnormalities in Magel2 -null model and dietary obesity.
2025-12-31 | Managing Hyperphagia, Obesity, and Hyperglycemia in Prader-Willi Syndrome: A Meta-Analysis of GLP-1 Agonists and SGLT2 Inhibitors
Background: Prader-Willi Syndrome (PWS) is a genetic disorder caused by a deletion, mutation, or imprinting error of the paternal 15q11-13 region or by maternal uniparental disomy of chromosome 15. One of the disorder's most noticeable characteristics is the development of a constant insatiable appetite, which often results in hyperphagia, hyperglycemia and severe obesity. Hyperphagia related incidents and obesity complications are the leading cause of death for individuals with PWS. Effective treatments for hyperphagia, obesity, and hyperglycemia are needed to improve the quality of life and life expectancy for patients with PWS. Methods: This meta-analysis aims to assess changes in weight, HbA1c, and hyperphagia after the commencement of GLP-1 agonists and SGLT2 inhibitors in individuals with PWS. A review of the literature was conducted by searching Scopus, PubMed, clinicaltrials.gov, and Cochrane to identify relevant case studies, case series, retrospective studies, non-randomized clinical trials, and randomized clinical trials that involved treating PWS patients with any GLP-1 agonists or SGLT2 inhibitors. A total of 224 records were screened with 45 studies meeting inclusion criteria. Studies involving monotherapy and combination therapy regimens were included, and studies of all ages were included. Case and retrospective studies must have quantitative data on changes in weight, hyperphagia, BMI, or HbA1c to be included in the meta-analysis, and a meta-analysis of raw data extracted from these studies was conducted. For the studies involving trials, a fixed-effect meta-analytic model was used. Results: Preliminary analysis of the studies showed promising results that indicated that GLP-1 agonists and SGLT2 inhibitors could help PWS patients with weight management, reduction of hyperphagia, and glycemic control. However, most of the studies were retrospective case reviews rather than trials, and the trials had less favorable results. The two clinical trials, which looked at the GLP-1 agonists exenatide and liraglutide, showed limited improvement in HbA1c and hyperphagia, but there were no clinically significant changes in weight in either trial. Conclusions: Emerging evidence indicates that GLP-1 agonists and SGLT2 inhibitors may provide meaningful benefits for individuals with Prader-Willi Syndrome by reducing hyperphagia, improving glycemic control, and supporting weight management. Nonetheless, the current literature is limited primarily to case reports and small observational studies, and only two trials have been published. Future clinical trials are needed to assess the efficacy and safety of newer GLP-1 medications such as semaglutide and tirzepatide. In studies of the broader population, these newer drugs have demonstrated greater weight loss than older drugs in their class like liraglutide and exenatide. Additionally, further investigation into combination strategies, particularly pairing GLP-1 agonists or SGLT2 inhibitors with diazoxide choline, are needed. Diazoxide choline was recently approved for treating PWS-associated hyperphagia, but one adverse effect reported for this drug was hyperglycemia. Since GLP-1 agonists and SGLT2 inhibitors are effective glycemic control drugs, investigation into their interactions with diazoxide choline should be undertaken. These additional clinical trials are essential to improve the treatment options and ultimately improve both quality of life and long-term health outcomes in patients with PWS.
2025-07-14 | Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice
Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the Magel2 gene is considered a significant contributor to the etiology of the syndrome. The loss of the Magel2 gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the Magel2 gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS). Both male and female mice lacking the Magel2 gene in MeA-innervating ARCPomc neurons display no alterations in anxiety-like behavior during the open field test, light/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a Magel2 gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the Magel2 gene in ARCPomc neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward. With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARCPomc neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.
gene therapies
2025-11-12 | Oxytocin neurons drive melanocortin circuit maturation via vesicle release during a neonatal critical period
The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system in mice. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.
2024-03-04 | Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editing
Summary Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.
other
2025-11-14 | Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice
Introduction Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the Magel2 gene is considered a significant contributor to the etiology of the syndrome. The loss of the Magel2 gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the Magel2 gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS). Methods In this study, we used a retrograde AAV containing the Cre recombinase under the control of neuronal Pomc enhancers to genetically eliminate the Magel2 gene in MeA-innervating ARCPomc neurons. Results Both male and female mice lacking the Magel2 gene in MeA-innervating ARC Pomc neurons display no alterations in anxiety-like behavior during the open field test, light/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a Magel2 gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the Magel2 gene in ARC Pomc neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward. Discussion With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARC Pomc neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.
proteins
2026-01-30 | Case report of a patient with Prader-Willi-like syndrome with 6q16.1-16.3 microdeletion
Prader-Willi -like syndrm zaha geneticky heterognnu skupinu syndrmov s fenotypom iastone podobnm pacientom s Praderovm-Williho syndrmom. Ide najm o hypotonus, zaostvanie v psychomotorickom vvoji, niektor endokrinopatie alebo ochorenia inch orgnovch systmov. Autori prezentuj kazuistiku dievatka s diagnostikovanou mikrodelciou 6q16.1-16.3, ktor patr do skupiny Prader-Willi-like syndrmov V klinickom obraze dominoval globlny hypotonick syndrm, psychomotorick zaostvanie a od veku 18 mesiacov postupn zvyovanie telesnej hmotnosti vzhadom k aktulnej telesnej vke. Vo veku 4 rokov mala telesn vku 94,9 cm (-2,1 SD) a v dvoch stimulanch testoch bol potvrden deficit rastovho hormnu. Bola z aat lieba rastovm hormnom, ktor je prospen nielen z hadiska rastovch prrastkov, ale aj z hadiska formovania svalovej hmoty a zlepenia hrubej motoriky. Pacienti s Prader-Willi-like syndrmom vyaduj multidisciplinrny prstup a sledovanie viacermi pecialistami poda konkrtnych klinickch symptmov.
2025-11-01 | Long-term growth hormone effects in Prader-Willi syndrome
To assess the long-term effects and mortality rates associated with GH therapy in patients with Prader-Willi Syndrome (PWS). Prader-Willi Syndrome is a rare genetic disease characterized by growth hormone (GH) deficiency among other endocrine disorders. A systematic literature search was carried out on 4 databases including PubMed, Scopus, Web of Science, and Cochrane databases. The search was based on two keywords: “Growth hormone” AND “Prader-Willi Syndrome”. Outcome data included height-standard deviation score (SDS), weight SDS, body mass index (BMI)-SDS, insulin like growth factor 1 (IGF1), mortality, low density lipoprotein (LDL)-cholesterol, and blood glucose. A total of 41 studies were included, of which 30 were involved in the meta-analysis. Following treatment with GH, height-SDS showed a significant increase compared to baseline in two timeline subgroups (≤2 years and >2 years), with a mean difference (MD) of 1.05 (95% CI: 0.92–1.18, p<0.00001) and 1.53 (95% CI: 1.23–1.82, p<0.00001), respectively. Patients on GH experienced a more pronounced increase in height-SDS compared to those who have not received GH. This was further associated with a lower BMI-SDS among GH-treated patients compared to their counterparts, with an MD of -1.02 (95% CI: -1.76 to -0.28, p=0.007; I²=84%, p=0.0003). Additionally, IGF1-SDS showed a marked increase after GH. Other metabolic effects include significant increase in LDL and blood glucose levels after GH treatment. The mortality rate in PWS patients undergoing GH treatment is estimated at 1.5% (95% CI: 0.8–2.2%), with causes including respiratory issues, cardiac arrest, infections, accidents, and gastrointestinal complications. GH therapy in PWS significantly improves height and IGF-1 SDS, while relatively decreasing BMI compared to no-GH, indicative of lean mass growth and healthy development. Nonetheless, GH therapy requires careful metabolic monitoring due to its mixed effects on cholesterol and glucose levels. PROSPERO Reg. number: CRD420250649945
2024-10-19 | Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model.
Confronting oxytocin and vasopressin deficits in autism spectrum disorders and rare syndromes brought promises and disappointments for the treatment of social disabilities. We searched downstream of oxytocin and vasopressin for targets alleviating social deficits in a mouse model of Prader-Willi syndrome and Schaaf-Yang syndrome, both associated with high prevalence of autism. We found a population of neurons in the lateral septum-activated on termination of social contacts-which oxytocin and vasopressin inhibit as per degree of peer affiliation. These are somatostatin neurons expressing oxytocin receptors coupled to GABA-B signaling, which are inhibited via GABA-A channels by vasopressin-excited GABA neurons. Loss of oxytocin or vasopressin signaling recapitulated the disease phenotype. By contrast, deactivation of somatostatin neurons or receptor signaling alleviated social deficits of disease models by increasing the duration of contacts with mates and strangers. These findings provide new insights into the treatment framework of social disabilities in neuropsychiatric disorders.
2024-02-26 | The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.
Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.
2024-01-10 | Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader–Willi syndrome: a one-year retrospective cohort study
Abstract Background Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader–Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. Methods A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. Results The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea–hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO 2 ), lowest SpO 2 , duration when SpO 2 is lower than 90%, or proportion of the patients with SpO 2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. Conclusion Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.
oligonucleotides
2026-07-18 | Spectrum of genetic forms of obesity and related disorders: Prader-Willi-like syndromes (part 1)
Prader–Willi–like syndromes (PWLS) represent a heterogeneous group of disorders characterized by a set of key clinical features, including muscular hypotonia, obesity, psychomotor and speech developmental delay, and behavioral problems, in the absence of methylation abnormalities within the chromosomal region 15q11.2q13. The phenotypic manifestations of PWLS show substantial overlap with the classical Prader–Willi syndrome (PWS), a disorder belonging to the group of imprinting disorders. PWLS include certain chromosomal syndromes (deletions of 1p36, 2pter, 3p26.3, 6q, 10q26, 19p, subtelomeric deletion of 12q, paracentric inversion Xq26q28, Xq27–qter disomy, duplications of 6q, 15q, Xq21.1q21.31, Xq23q25), imprinting disorders (Angelman syndrome, Temple syndrome, pseudohypoparathyroidism types 1A and 1C, pseudopseudohypoparathyroidism, Schaaf–Yang syndrome), and monogenic syndromic forms of obesity (Fragile X syndrome, Bardet–Biedl syndrome, Alström syndrome, Cohen syndrome, Börjeson–Forssman–Lehmann syndrome, MYT1L -related syndrome, SIM1 -associated PWS-like obesity, GNAI1 -associated neurodevelopmental disorder). The combination of the genetic heterogeneity of PWLS and the absence of the specific genetic defect observed in PWS creates significant challenges for differential diagnosis in clinical practice. This literature review systematizes current research data aimed at refining the phenotypic characterization, management approaches, and treatment strategies for syndromes within the Prader–Willi–like spectrum.
2026-05-07 | Mechanisms of USP7/MAGEL2 Complex Assembly and Its Mutational Disruption in Neurodevelopmental Diseases.
The WASH complex regulates endosomal trafficking and is linked to several neurodevelopmental diseases, including Prader-Willi syndrome, Schaaf-Yang syndrome, and Hao-Fountain syndrome. Its function is tightly controlled by ubiquitination, maintained by the multi-subunit MUST complex containing both a ubiquitin ligase (MAGEL2/TRIM27) and a deubiquitinase (USP7). However, the mechanism underlying the MUST complex assembly remains poorly understood. In this study, we investigate the assembly of USP7 and MAGEL2 components of the MUST complex using NMR spectroscopy, isothermal titration calorimetry, X-ray crystallography, and cellular assays. We show that the USP7/MAGEL2 interaction is bipartite and multivalent. Two distinct domains of USP7, TRAF and UBL1-2, recognize two unstructured but evolutionarily conserved regions of MAGEL2, one of which contains multiple TRAF-binding sites. Furthermore, we determine the high-resolution crystal structure of the TRAF/MAGEL2 complex and identify Hao-Fountain syndrome-linked mutations in USP7 that disrupt USP7/MAGEL2 complex formation in vitro and in cells. These findings provide mechanistic insight into the pathogenic basis of Hao-Fountain syndrome and related Schaaf-Yang and Prader-Willi syndromes.
2026-01-10 | Novel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity.
Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader-Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein-protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity.
2025-06-24 | Biallelic variants in SREK1 downregulating SNORD115 and SNORD116 cause a Prader-Willi-like syndrome.
Biallelic variations in SREK1 reduce SNORD115/116 expression, linking severe obesity and Prader-Willi-like traits, offering genetic and molecular insights into a new form of syndromic obesity.
2024-07-01 | MAGEL2 (patho-)physiology and Schaaf-Yang syndrome.
Schaaf-Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader-Willi syndrome (PWS) locus on chromosome 15. In this review, we consolidate decades of research on MAGEL2 to elucidate its physiological functions. Moreover, we synthesize current knowledge on SYS, suggesting that while MAGEL2 loss-of-function seems to underlie several SYS and PWS phenotypes, additional pathomechanisms probably contribute to the distinct and severe phenotype observed in SYS. In addition, we highlight recent therapeutic advances and identify promising avenues for future investigation.
small molecules
2026-06-22 | Efficacy and safety of semaglutide for obesity and hyperphagia in adults with Prader-Willi syndrome
ABSTRACT Context Prader-Willi syndrome is a genetic neurodevelopmental disorder characterized by hyperphagia and early-onset obesity from hypothalamic dysfunction with endocrinopathies and learning disability. Management is challenging with strict control of the food environment needed. While newer glucagon-like peptide-1 receptor agonists, such as semaglutide, have efficacy in non-PWS obesity, there have been limited case reports in PWS. Objective/Design/Setting Retrospective records review of 12 adults with PWS and overweight/obesity treated with semaglutide at a UK academic hospital centre specialist clinic. Patients mean ± SD age 28.3 ± 10.1 years, 83% female, BMI 46.6 ± 8.2kg/m², 75% type 2 diabetes mellitus. Intervention Median follow-up 17.2 months (range 8.7-36.1) with median semaglutide dose 2.4mg once weekly (1.0-2.4). Results Although there was no significant weight loss on semaglutide, there was stabilisation of the weight gain prior to treatment over previous 12.4 months (7.6-23.0) (post −3.1 ± 9.9% vs. pre +5.7 ± 5.6%: d −0.72, P=0.037). There was a significant decrease in hyperphagia on semaglutide from Hyperphagia Questionnaire for Clinical Trials (n=11, −7.3 ± 6.1 (max 36), d −1.19, P=0.003), having been stable before treatment. HbA1c improved in those with elevated baseline levels (n=6, −4.2 ± 4.9%, d −0.74, P=0.13). Mild gastrointestinal side effects were seen in 25% but did not lead to discontinuation. Conclusions In adults with PWS, semaglutide produced weight maintenance, reduced hyperphagia, and improved glycaemic control, with good tolerability. Larger placebo-controlled trials are needed to confirm these findings in adults and adolescents with PWS, especially in those without T2DM, where efficacy may be greater.
2026-06-19 | Beyond the GH–IGF-1 Axis: A Network Perspective Integrating Clinical Observations and Mechanistic Insights
Background: Obesity encompasses a heterogeneous group of conditions that include not only simple obesity, but also genetic and endocrine disorders. The growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis plays a central role in body composition, insulin sensitivity, and metabolic regulation. We encountered three patients in whom the clinical courses highlighted distinct interactions between obesity and the GH-IGF-1 axis. Methods: We reviewed three representative cases. Case 1 involved acromegaly improved by the peroxisome proliferator-activated receptor-α (PPAR-α) agonist pemafibrate. Case 2 involved Prader-Willi syndrome (PWS) with severe obesity treated using dulaglutide. Case 3 involved severe obesity managed with behavioral therapy. Clinical characteristics and therapeutic responses were analyzed. Results: In Case 1, pemafibrate administration resulted in a marked and sustained reduction in IGF-1 levels despite ongoing lanreotide therapy, suggesting a potential hepatic or pituitary interaction between PPAR-α signaling and GH-IGF-1 regulation. In Case 2, dulaglutide induced weight loss and reduced insulin requirements in a patient with PWS, a condition characterized by high levels of ghrelin. The therapeutic effect may involve modulation of ghrelin, an upstream regulator of GH secretion. In Case 3, behavioral therapy stabilized metabolic deterioration in a patient with a body mass index of 50.7 kg/m2, even though GH and IGF-1 levels remained low after weight reduction, suggesting mechanisms independent of the GH-IGF-1 axis. Conclusion: These findings support a conceptual shift from a linear GH-IGF-1 axis to an integrated GH-IGF-1 network that connects peripheral signals, hypothalamic regulation, and higher brain functions, offering a novel framework for personalized obesity management.
2026-03-12 | Low dose systemic AAV-exendin-4 gene therapy for Prader-Willi syndrome and dietary obesity
Prader-Willi syndrome (PWS) patients display developmental delays, endocrine dysfunction, excessive eating, central obesity, and various behavioral abnormalities. Effective and sustained treatments are limited, highlighting the need for new therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have revolutionized obesity treatment while their efficacy in PWS population remains inconsistent and data in PWS animal models are lacking. Here, we assessed the efficacy of a newly developed AAV platform to deliver a GLP-1RA exendin-4 via an engineered hybrid capsid Rec2. Intraperitoneal administration of Rec2-exendin-4 at the dose of 2 × 10 10 viral genome per mouse normalized metabolic dysfunction in the Magel2 -null mouse model of PWS. Systemic Rec2-exendin-4 treatment reversed genotype-driven excessive adiposity, impaired glycemic control, hyperleptinemia, and adipose gene expression signatures. Moreover, intraperitoneal injection of Rec2-exendin-4 (4 × 10 10 viral genome/mouse) exerted high levels of efficacy in diet-induced obesity model—decreasing food intake; preventing excessive weight gain and obesity; improving glucose metabolism and insulin sensitivity; and reversing fatty liver. Metabolic improvements were maintained at least 5 months. These data demonstrate the therapeutic potential of a systemic AAV-mediated exendin-4 gene therapy for PWS-related metabolic abnormalities in Magel2 -null model and dietary obesity.
2025-12-31 | Managing Hyperphagia, Obesity, and Hyperglycemia in Prader-Willi Syndrome: A Meta-Analysis of GLP-1 Agonists and SGLT2 Inhibitors
Background: Prader-Willi Syndrome (PWS) is a genetic disorder caused by a deletion, mutation, or imprinting error of the paternal 15q11-13 region or by maternal uniparental disomy of chromosome 15. One of the disorder's most noticeable characteristics is the development of a constant insatiable appetite, which often results in hyperphagia, hyperglycemia and severe obesity. Hyperphagia related incidents and obesity complications are the leading cause of death for individuals with PWS. Effective treatments for hyperphagia, obesity, and hyperglycemia are needed to improve the quality of life and life expectancy for patients with PWS. Methods: This meta-analysis aims to assess changes in weight, HbA1c, and hyperphagia after the commencement of GLP-1 agonists and SGLT2 inhibitors in individuals with PWS. A review of the literature was conducted by searching Scopus, PubMed, clinicaltrials.gov, and Cochrane to identify relevant case studies, case series, retrospective studies, non-randomized clinical trials, and randomized clinical trials that involved treating PWS patients with any GLP-1 agonists or SGLT2 inhibitors. A total of 224 records were screened with 45 studies meeting inclusion criteria. Studies involving monotherapy and combination therapy regimens were included, and studies of all ages were included. Case and retrospective studies must have quantitative data on changes in weight, hyperphagia, BMI, or HbA1c to be included in the meta-analysis, and a meta-analysis of raw data extracted from these studies was conducted. For the studies involving trials, a fixed-effect meta-analytic model was used. Results: Preliminary analysis of the studies showed promising results that indicated that GLP-1 agonists and SGLT2 inhibitors could help PWS patients with weight management, reduction of hyperphagia, and glycemic control. However, most of the studies were retrospective case reviews rather than trials, and the trials had less favorable results. The two clinical trials, which looked at the GLP-1 agonists exenatide and liraglutide, showed limited improvement in HbA1c and hyperphagia, but there were no clinically significant changes in weight in either trial. Conclusions: Emerging evidence indicates that GLP-1 agonists and SGLT2 inhibitors may provide meaningful benefits for individuals with Prader-Willi Syndrome by reducing hyperphagia, improving glycemic control, and supporting weight management. Nonetheless, the current literature is limited primarily to case reports and small observational studies, and only two trials have been published. Future clinical trials are needed to assess the efficacy and safety of newer GLP-1 medications such as semaglutide and tirzepatide. In studies of the broader population, these newer drugs have demonstrated greater weight loss than older drugs in their class like liraglutide and exenatide. Additionally, further investigation into combination strategies, particularly pairing GLP-1 agonists or SGLT2 inhibitors with diazoxide choline, are needed. Diazoxide choline was recently approved for treating PWS-associated hyperphagia, but one adverse effect reported for this drug was hyperglycemia. Since GLP-1 agonists and SGLT2 inhibitors are effective glycemic control drugs, investigation into their interactions with diazoxide choline should be undertaken. These additional clinical trials are essential to improve the treatment options and ultimately improve both quality of life and long-term health outcomes in patients with PWS.
2025-07-14 | Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice
Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the Magel2 gene is considered a significant contributor to the etiology of the syndrome. The loss of the Magel2 gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the Magel2 gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS). Both male and female mice lacking the Magel2 gene in MeA-innervating ARCPomc neurons display no alterations in anxiety-like behavior during the open field test, light/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a Magel2 gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the Magel2 gene in ARCPomc neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward. With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARCPomc neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.
gene therapies
2025-11-12 | Oxytocin neurons drive melanocortin circuit maturation via vesicle release during a neonatal critical period
The hypothalamus is crucial for regulating essential bodily functions, including energy balance. It is an exceedingly complex and heterogeneous brain region that contains a variety of neuronal systems that are interconnected with each other. Among these, the melanocortin system, which comprises pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons, displays a remarkable anatomical relationship with oxytocin (OT) neurons in the paraventricular nucleus (PVH). Here, we demonstrate that OT neurons are instrumental in the development of the melanocortin system in mice. Chemogenetic inhibition of OT neurons during the first postnatal week selectively disrupts POMC and AgRP projections to the PVH, without affecting other target nuclei like the dorsomedial nucleus. This developmental role is age-dependent, as silencing OT neurons in juvenile or adult stages has no impact on melanocortin circuits. OT neurons release various neuropeptides and neurotransmitters, and their secretion can be modulated by chemogenetic manipulation. Expressing the botulinum toxin serotype B light chain in OT neurons reveals that their developmental actions rely on SNARE-mediated exocytosis. Moreover, administering an OT receptor antagonist during the first postnatal week leads to similar melanocortin circuit defects and long-term metabolic effects. Furthermore, neonatal chemogenetic activation of OT neurons rescues POMC circuit deficits in a mouse model of Prader-Willi Syndrome. These findings reveal that OT acts as a paracrine neurotrophic factor orchestrating the development of melanocortin circuits during a restricted neonatal critical period.
2024-03-04 | Activation of the imprinted Prader-Willi Syndrome locus by CRISPR-based epigenome editing
Summary Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi Syndrome (PWS) is caused by loss of paternally expressed imprinted genes on chromosome 15q11.2-q13.3, although the maternal allele is intact but epigenetically silenced. Using CRISPR repression and activation screens in human induced pluripotent stem cells (iPSCs), we identified genomic elements that control expression of the PWS gene SNRPN from the paternal and maternal chromosomes. We showed that either targeted transcriptional activation or DNA demethylation can activate the silenced maternal SNRPN and downstream PWS transcripts. However, these two approaches function at unique regions, preferentially activating different transcript variants and involving distinct epigenetic reprogramming mechanisms. Remarkably, transient expression of the targeted demethylase leads to stable, long-term maternal SNRPN expression in PWS iPSCs. This work uncovers targeted epigenetic manipulations to reprogram a disease-associated imprinted locus and suggests possible therapeutic interventions.
other
2025-11-14 | Magel2 in hypothalamic POMC neurons influences the impact of stress on anxiety-like behavior and spatial learning associated with a food reward in male mice
Introduction Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the Magel2 gene is considered a significant contributor to the etiology of the syndrome. The loss of the Magel2 gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the Magel2 gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS). Methods In this study, we used a retrograde AAV containing the Cre recombinase under the control of neuronal Pomc enhancers to genetically eliminate the Magel2 gene in MeA-innervating ARCPomc neurons. Results Both male and female mice lacking the Magel2 gene in MeA-innervating ARC Pomc neurons display no alterations in anxiety-like behavior during the open field test, light/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a Magel2 gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the Magel2 gene in ARC Pomc neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward. Discussion With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARC Pomc neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.
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