RARE DISEASE
Prader-Willi syndrome
Prader-Willi syndrome
Prader-Willi syndrome
Synonyms: Prader-Labhart-Willi syndrome
Synonyms: Prader-Labhart-Willi syndrome
Synonyms: Prader-Labhart-Willi syndrome
Drug discovery
32
drugs
With orphan designations
Overview
Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder caused by loss of paternal chromosome 15q11-q13 expression. It presents with neonatal hypotonia, feeding difficulties, and failure to thrive, progressing to hyperphagia-driven obesity, developmental delays, endocrine dysfunction (growth hormone deficiency, hypogonadism), and behavioral challenges (skin picking, temper outbursts). Management requires multidisciplinary care focusing on nutritional control, hormone replacement, and behavioral interventions [1][3][6].
Burden
Clinical: 93% develop obesity-related comorbidities (diabetes, obstructive sleep apnea) [6][13]; 44.4 average caregiver ZBI score reflecting severe burden [14]
Economic: Annual US healthcare costs ~$26,887/patient excess vs non-PWS peers [19]
Psychosocial: 60–70% exhibit obsessive-compulsive behaviors; 10–20% develop psychosis [6][17][18]
Citations embedded per formatting rules
Therapies
Growth hormone therapy: Improves lean mass, mobility, and metabolic parameters (initiated in infancy) [1][3][18]
Behavioral/environmental: Strict calorie-controlled diets (≤60% typical intake), food security protocols, cognitive behavioral therapy [1][13][18]
Multidisciplinary care: Endocrinology, nutrition, physical/occupational therapy, and psychopharmacology (e.g., SSRIs for OCD) [3][11][16]
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
1,046 drug discovery papers about Prader-Willi syndrome, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,046 drug discovery papers about Prader-Willi syndrome, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-17 | Sustained weight loss exceeding 100 kg with sequential incretin-based therapy in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by hyperphagia, severe obesity, and early-onset metabolic complications, in which durable weight loss is rarely achieved. We report a 29-year-old man with genetically confirmed maternal uniparental disomy PWS who presented with severe obesity (185 kg; body mass index [BMI] 59.7 kg/m2) and newly diagnosed type 2 diabetes (glycated hemoglobin [HbA1c], 8.3% [SI: 67 mmol/mol] [reference range, <5.7% (SI: <39 mmol/mol)]). He received sequential incretin-based therapy, initiated with retatrutide (1-12 mg weekly) within a clinical trial, followed by oral semaglutide and then dulaglutide after retatrutide became unavailable, together with a structured hypocaloric diet and supervised exercise. At 18 months, total weight loss reached 58.8% (-108.7 kg), with HbA1c of 4.9% (SI: 30 mmol/mol), consistent with diabetes remission after discontinuation of all glucose-lowering medications. Mild transient gastrointestinal symptoms occurred during dose escalation, with no serious adverse events. Follow-up bioimpedance showed a skeletal muscle mass of 38.5 kg after a 58.8% reduction in total body weight.
2026-09-08 | Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.
2026-09-06 | Young Boy’s Battle with Childhood Obesity: Unmasking A Rare Case of Prader-Willi-Syndrome
Prader-Willi syndrome (PWS) is one of the most prevalent causes of syndromic obesity. This genetic disorder begins with hypotonia and poor feeding in the neonatal period, later evolving into hyperphagia and rapid weight gain during early childhood, frequently leading to severe obesity in adolescence and adulthood. We report a case of a 14-year-old boy presenting with morbid obesity (BMI: 47.4) and related complications. Before admission, he was not properly evaluated for obesity. Along with obesity, the presence of hypogonadism, undescended testes since childhood, learning difficulties, poor academic performance, and behavioral abnormalities, including temper tantrums and emotional outbursts, raised a strong suspicion of Prader–Willi syndrome (PWS). We used the consensus criteria for the diagnosis of PWS clinically and focused on managing obesity with a dual GIP/GLP-1 receptor agonist; the patient achieved a remarkable weight loss of 25 kg over one year and marked reversal of obesity–related complications, significantly improving the patient’s overall health and quality of life. J MEDICINE 2026; 27(2): 151-154
2026-08-01 | EP1441 - ECE_1387 - Prader–willi syndrome—from diagnosis to substitution therapy
Abstract Prader–Willi syndrome is a rare genetic disorder involving chromosome 15, characterized by hypotonia, a characteristic facial appearance (reduced bifrontal diameter), convergent strabismus, and intellectual disability. In boys, it is usually accompanied by cryptorchidism and a hypoplastic scrotum. We present the case of a patient who initially consulted a urologist due to priapism, after which further endocrinological evaluation was recommended. Hormonal testing revealed elevated estradiol levels with low testosterone levels, while clinical examination showed obesity and cryptorchidism. Due to cryptorchidism, urological treatment was performed, followed by repeat endocrinological evaluation, after which testosterone replacement therapy was initiated. This led to a reduction in body weight, voice deepening, development of male-pattern body hair, and overall clinical improvement. Review of the patient’s medical documentation revealed that genetic testing had been performed at birth and the diagnosis of Prader–Willi syndrome had already been established; however, appropriate therapy had not been initiated at that time. This case highlights the importance of early detection and appropriate long-term follow-up by an endocrinologist, as this enables timely initiation of adequate substitution therapy as well as prompt urological surgical intervention when indicated.
2026-07-23 | Carbetocin Nasal Spray for the Treatment of Hyperphagia in Prader-Willi Syndrome: Results From the Randomized, Placebo-Controlled, Phase 3 Compass PWS Study.
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. The oxytocinergic system represents one of the key neural circuits that is dysfunctional in PWS, making it an attractive therapeutic target. The oxytocin analog carbetocin has a longer half-life and greater receptor selectivity than oxytocin and showed therapeutic potential in the phase 3 CARE-PWS study (ClinicalTrials.gov NCT03649477) based on nominally significant improvements in hyperphagia and anxiousness with the 3 times daily (TID) 3.2-mg dose of intranasal carbetocin over placebo. The phase 3 placebo-controlled COMPASS PWS study was conducted to confirm the potential benefit observed with carbetocin in the CARE-PWS study. In the 12-week COMPASS PWS study (ClinicalTrials.gov NCT06173531), 175 participants were randomized 1:1 to carbetocin 3.2 mg TID nasal spray (n = 85) and placebo (n = 90). The primary efficacy endpoint was the change from baseline at week 12 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Secondary efficacy endpoints were the change in the Clinical Global Impression-Severity (CGI-S) score for PWS, and in the CGI-S for hyperphagia in PWS score from baseline at week 12, the CGI-Change for PWS score at week 12, and the percentage of participants with a treatment response (defined as improvement from baseline ≥8 points) based on the HQ-CT at week 12. Exploratory efficacy endpoints included the change from baseline at week 12 in scores for the PWS Anxiousness and Distress Behaviors Questionnaire. The least squares mean change (standard error) from baseline at week 12 in the HQ-CT was -4.8 (0.8) and -5.1 (0.8) in the carbetocin and placebo groups, respectively; the treatment difference of 0.3 (95% confidence interval: -1.8, 2.4; P = 0.79) was not statistically significant. There was no separation between carbetocin and placebo for any secondary or exploratory endpoint. The most frequently reported treatment-emergent adverse events in the carbetocin-treated participants were headache (n = 6 [7.2%]) and pyrexia (n = 5 [6.0%]). Carbetocin nasal spray did not demonstrate efficacy compared with placebo for hyperphagia in PWS in the 12-week COMPASS PWS study.
proteins
2026-09-06 | Case report: Tirzepatide-responsive refractory diabetes mellitus in an adult female with prader-willi syndrome.
Prader-Willi syndrome (PWS) is a complex genetic disorder that affects multiple systems and results from loss of expression of paternally inherited genes in the 15q11.2-q13 region. It is characterized by severe hypotonia and feeding difficulties during infancy, followed by hyperphagia in later childhood and adolescence, which, without strict control of excessive eating behaviors, ultimately leads to severe obesity associated with type 2 diabetes mellitus. We present the case of a woman who was diagnosed with PWS and diabetes mellitus in adulthood. She had a history of hypotonia, developmental delay, intellectual disability, hyperphagia, and morbid obesity since childhood, with gonadal dysplasia emerging during puberty. She presented with long-term poorly controlled blood glucose levels. Genetic testing revealed a heterozygous deletion in the 15q11.2-q13.1 region on chromosome 15, and DNA methylation analysis confirmed the diagnosis of PWS. The distinctiveness of this case lies in the patient's uncontrollable food-seeking behavior combined with PWS-related severe insulin resistance and β-cell dysfunction, which together resulted in refractory diabetes. Initial combination therapy using multiple glucose-lowering agents, including insulin, metformin, chiglitazar sodium, a glucagon-like peptide-1 receptor agonist, and a sodium-glucose cotransporter-2 inhibitor, demonstrated limited efficacy. Subsequent substitution of the glucagon-like peptide-1 receptor agonist with the dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide led to notable improvements in appetite suppression, body weight reduction, and glycemic control. This case underscores the importance of considering genetic syndromes in patients with diabetes presenting with early-onset severe obesity and developmental abnormalities and emphasizes the potential therapeutic value of novel antidiabetic agents such as tirzepatide for managing PWS-associated metabolic disturbances. These findings provide important insights into the diagnosis and treatment of diabetes complicated by PWS.
2026-09-06 | Cognitive development in children with Prader-Willi syndrome receiving early growth hormone therapy.
Prader‒Willi syndrome (PWS) is a genetic disorder characterized by hypotonia, feeding difficulties in infancy, excessive eating in childhood, intellectual disability and short stature. Growth hormone therapy (GHT) improves body composition and decreases fat percentage in patients with PWS. However, the effect of GHT on cognitive function is not clear. The aim of this study was to evaluate the beneficial effects of GHT on cognition in younger patients with PWS. A retrospective analysis of patients with PWS who received GHT in four hospitals was conducted in Taiwan. Patient demographics, molecular diagnosis, age at GHT initiation, GHT dose, developmental quotient/full-scale intelligence quotient (DQ/FSIQ) scores, and verbal intelligence quotient/verbal comprehension index (VIQ/VCI) scores were analyzed. This retrospective study included a total of 61 patients. Seven patients who did not receive growth hormone treatment were assigned to the control group, while the remaining 54 patients composed the treatment group. After applying the exclusion criteria, 47 patients were ultimately included in the analysis. Twenty-nine patients were treated before 3 years of age, and eighteen patients were treated after 3 years of age. The DQ/FSIQ score was significantly greater in the younger age group (p < 0.05). Specifically, in the nondeletion type and female groups, younger patients presented significantly higher DQ/FSIQ scores (p < 0.05). Compared with the untreated group, the early GH treatment group had significantly higher VIQ/VCI scores (p < 0.05). According to linear regression, the age at GHT initiation was significantly negatively correlated with the DQ/FSIQ score (β1 = -1.264, R2 = 0.184, F = 4.16, p < 0.05) and the VIQ/VCI score (β(VIQ)1 = -1.981, R2 = 0.242, F = 4.09, p < 0.05). The initiation of GHT before 3 years of age and as early as possible had a significant effect on cognitive development after adjustments were made for sex and molecular type.
2026-08-27 | A Clinical Genetics-Driven Dual Diagnosis of Prader-Willi Syndrome Due to Mosaic Maternal UPD(15) and NOTCH3-Related CADASIL.
Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader-Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis. He presented with very mild neurodevelopmental impairment. Following the detection of proteinuria and microalbuminuria from age 22 years, focal segmental glomerulosclerosis was diagnosed upon renal biopsy. A family history of cerebrovascular events was recorded. Combined SNP-array and MS-MLPA analyses across tissues established a diagnosis of PWS due to mosaic UPD(15)mat. The mosaic fraction, estimated by SNP-array, was approximately 10% in peripheral blood and 40% in buccal cells; MS-MLPA detected abnormal methylation only in buccal cells, explaining the previous negative blood-based results. Exome sequencing identified the paternally inherited pathogenic NOTCH3 variant NM_000435.2:c.3016C>T, p.(Arg1006Cys). Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL, despite the absence of overt ischemic events in the proband. Collectively, these investigations established a dual molecular diagnosis of PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL. This report highlights the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases. With respect to PWS, it demonstrates that mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood. In addition, following the diagnosis of CADASIL, and based on the available evidence linking NOTCH3 to renal physiology and disease, we discuss whether NOTCH3-related renal microangiopathy may have contributed to the renal phenotype. However, given the patient's multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case.
2026-08-24 | Failure to thrive (FTT) in infants with Prader-Willi syndrome and long-term effects of GH-treatment on FTT.
Failure to thrive (FTT) with feeding difficulties and hypotonia are well-known features in infants with Prader-Willi syndrome (PWS). Limited studies reported the percentage of infants with FTT and it is unknown whether growth hormone (GH)-treatment affects body composition of infants with or without FTT differently. To evaluate the percentage of infants with PWS with FTT from birth to age 6 months and to investigate the 5-year GH effects on body composition in infants with or without FTT at GH-start. We defined FTT as weight-for-length <-2 SDS and evaluated the percentage of infants with FTT in a group of 54 infants from birth to age 6 months. In addition, we investigated in 166 children the 5-year GH effects on body composition, comparing children with and without FTT at GH-start. All infants were treated with 1.0 mg GH/m2/day (~0.035mg/kg/day). Body composition was determined by Dual energy X-ray Absorptiometry (DXA). From birth to age 6 months, 29% of infants had FTT at 1 month, 20% at 3 months, and 16% at 6 months. At GH-start, at a median age of 1.03 (IQR 0.45,1.89) year, 12% (20/166) had FTT (FTTGH-start). Infants with FTTGH-start had a lower lean body mass index (LBMI) compared to non-FTTGH-start, but a greater catch-up in LBMI in the first year of GH, resulting in a similar LBMI as the non-FTTGH-start after 5 years of GH-treatment. Children with FTTGH-start had lower FM% after 5 years of GH-treatment, but this difference disappeared after including covariates. Twenty-nine percent of infants had FTT at 1 month, 20% at 3 months, and 16% at 6 months. Twelve percent had FTT at the start of GH-treatment. Children with FTT at GH-start showed greatest LBM improvement during GH-treatment, resulting in a similar LBM after 5 years of GH-treatment as those without FTT at GH-start.
2026-08-01 | P260 - ECE_1902 - Effect of growth hormone treatment on muscle strength in adults with Prader-Willi syndrome (PWS)
Abstract Introduction Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hypothalamic dysfunction, intellectual disability, hypotonia and hyperphagia. Individuals with PWS display features of growth hormone (GH) deficiency, including short stature, increased fat mass, and low muscle mass and strength. Reduced muscle mass results in a low basal metabolic rate (BMR). Combined with hyperphagia, this often results in severe obesity. As obesity is the primary contributor to increased morbidity and mortality in adults with PWS, addressing it is essential for long-term health in this population. GH treatment improves body composition and muscle strength in children with PWS. Smaller studies suggest similar improvements in body composition in adults. However, the effect of GH treatment on muscle strength in adults with PWS has not yet been demonstrated. We have studied the effect of GH treatment on muscle strength in a Dutch population of GH-naïve adults with PWS. Methods At the Dutch Center of Reference for PWS, 24 GH-naïve patients with PWS were included in this open-label prospective cohort study. We measured muscle strength before the start of GH treatment (0.6 mg once daily) and after 3, 6 and 12 months of therapy. Muscle strength was quantified using a handgrip dynamometer for hand and forearm strength, as well as the 30-second sit-to-stand test and the 5× sit-to-stand test for leg muscle strength. In addition, subjective improvements in muscle and side-effects were assessed. All tests were validated for adult individuals with an intellectual disability. Results Ten females and fourteen males were included (17 deletion and 7 mUPD, age range 22-63 years, BMI range 23-38 kg/m2). Overall, patients, parents and caregivers reported notable improvements in muscle strength. Most remarkable subjective changes were increased walking speed and increased ability to get out of chairs, walk without help or climb the stairs. They also reported a decrease in fatigue and daytime sleepiness. Objective improvements were significant increases in muscle strength as measured by the handgrip dynamometer (P = .042), the 30-second sit-to-stand test (P = .002), and the 5× sit-to-stand test (P = .032). Conclusions GH treatment significantly improves muscle strength in adults with PWS. As improved muscle strength improves exercise tolerance, it enables a healthier lifestyle needed to reduce obesity and cardiovascular complications in this vulnerable population.
gene therapies
2026-09-29 | Modeling the Prader-Willi Syndrome Associated Growth Phases in Snord116 KO Mice
Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by distinctive developmental transition from neonatal hypotonia and poor feeding to pro-gressive weight gain and, later, hyperphagia and obesity. The paternally expressed SNORD116 cluster is critical for postnatal growth, but how its deficiency shapes this progression remains unclear. Here, we analyzed day-over-day growth rates in 351 mice carrying Snord116 deletion or altered Snord116 dosage, including wild-type littermates, across both sexes and two genetic backgrounds. Snord116 expression increased markedly during early brain development. Snord116-deficient mice exhibited a distinct three-stage growth trajectory: impaired growth until approximately P16, normalization between P17 and P21, followed by transient accelerated weight gain until approximately P30. Alt-hough growth rates subsequently normalized, the accumulated deficit was not fully compensated, and adult Snord116KO mice remained smaller than wild-type controls. These developmental transitions broadly parallel early nutritional phases of human PWS, although mice did not progress to persistent obesity-associated growth. Reactivation of the maternal Snord116 cluster partially rescued the growth phenotype, whereas activation of both parental alleles produced a modest growth advantage, most evident in males. These findings identify early postnatal development as a critical window of Snord116-dependent growth regulation and provide a framework for investigating mechanisms underlying PWS progression.
2026-09-22 | Targeted Epigenetic Reactivation strategies as new treatments for Prader-Willi Syndrome: Achievements and Challenges.
Prader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder caused by the loss of expression of paternal genes in the 15q11-q13 locus. The same genes on the maternal allele are present but are epigenetically silenced. This genetic alteration causes a spectrum of symptoms associated with hypothalamic dysfunction. Research is increasingly focused on setting strategies aiming to reactivate the maternal locus and restore the expression of that critical gene cluster. Early therapeutic efforts explored broad-spectrum epigenetic drugs, such as DNA- and histone-methyltransferase inhibitors. While these compounds demonstrated some efficacy in preclinical models, their lack of genomic specificity limits their clinical viability. To overcome this barrier, high-precision epigenome editing tools, most notably dCas9-based systems, have emerged as highly promising strategies capable of inducing site-specific demethylation and stable reactivation of the silenced maternal allele. However, translating these targeted strategies into clinical practice requires overcoming major therapeutic hurdles. This review discusses these key translational challenges, focusing on the imperative to optimize delivery vectors for widespread central nervous system distribution, the necessity of advanced human-derived neuronal models to validate functional recovery, and the critical need to prevent iatrogenic Angelman Syndrome caused by UBE3A imprinting. Finally, we explore future therapeutic horizons, highlighting how newly identified epigenetic regulators and non-coding RNAs could serve as alternative targets to unlock the maternal PWS locus.
2026-07-01 | 10031 Prader willi syndrome(PWS) genetics: connecting the dots to attempt to explain variation in phenotype
Why did you do this work?
PWS is the first disorder attributed to genomic imprinting and caused by absent expression of paternally active genes on chromosomal region 15q11.2q13. Genomic imprinting is a complex concept, where one set of genes (paternally or maternally derived) are silenced and the other is expressed in normal individuals. This work endeavours: To discuss various genes affected in PWS and demonstrate association with individual disorders and syndromes through genetic similarities. To associate phenotypic variation in PWS patients to different genes being affected.
What did you do?
I assimilated information from electronic patient records, patient files and analysed well-researched publications regarding PWS and disorders with similar gene involvement. Two patients with PWS were followed up for more than fifteen years. They have very different medical problems and needs. While the affected boy has done well academically and has mild scoliosis, he has obesity, delayed puberty and some mental health struggles. He has been cooperative with his family to control hyperphagia. The girl with PWS does not have hyperphagia or obesity, but moderate scoliosis requiring spinal braces and learning difficulties in need of support. Such profound variation of phenotype may be related to environmental factors but also due to PWS gene variation among patients.
What did you find?
About 20 genes, all located in the PWS critical region, are defective in PWS.
What does it mean?
Many genes affected in PWS are discovered as causative factors in unrelated disorders. This may also contribute to PWS patients having different clinical presentations and symptom intensity varies among patients. Further research in this prospect may lead towards identifying gene modulation therapies which may help ameliorate major manifestations of PWS.
References
Eddiry S, Diene G, Molinas C, Salles J, Auriol FC, Gennero I, Bieth E, Skryabin BV, Rozhdestvensky TS, Burnett LC, Leibel RL, Tauber M, Salles JP. SNORD116 and growth hormone therapy impact IGFBP7 in Prader-Willi syndrome. Genetics in Medicine: Official Journal of the American College of Medical Genetics 2021;23(9):1664–1672. https://doi.org/10.1038/s41436-021-01185-y Spritz RA, Bailin T, Nicholls RD, Lee ST, Park SK, Mascari MJ, Butler MG. Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. American Journal of Medical Genetics 1997;71(1):57–62. https://doi.org/10.1002/(sici)1096-8628(19970711)71:1<57::aid-ajmg11>3.0.co;2-u
2026-05-15 | 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 × 1010 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 × 1010 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.
2026-05-14 | SMCHD1 is a novel target for gene-activation therapy to treat Prader-Willi Syndrome
ABSTRACT Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of gene expression from the active paternal allele at an imprinted gene cluster on chromosome 15. Current treatments have limited efficacy as they target individual symptoms rather than the underlying cause of disease. All patients preserve a normal, yet epigenetically-silenced, copy of the PWS cluster genes; activation of this imprinted copy to restore necessary gene expression is an appealing option for tackling the root of the disorder. Here we have addressed the potential to activate these silent maternal genes by targeting the epigenetic regulator Structural Maintenance of Chromosomes Hinge domain containing 1 (SMCHD1). First, we expanded the role of SMCHD1 in repressing the PWS cluster from mice to humans, a critical step if SMCHD1 is to be a drug target. Second, we discovered that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role at only half of the PWS genes. We show that deleting Smchd1 after early development in vivo is effective at causing PWS gene-activation in disease-relevant mouse tissues including hypothalamus, and that this has beneficial effects on phenotypes observed in a PWS mouse model. Despite SMCHD1 having a role in gene silencing elsewhere in the genome, our data suggest that targeting SMCHD1 after early development is remarkably safe. Taken together, these data propose SMCHD1 as a novel target for gene-activation therapy for PWS.
oligonucleotides
2022-08-25 | Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity.
Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of the Magel2 gene disrupts POMC neuronal circuits and functions. Here, we report that loss of the Magel2 gene exclusively in ARC POMC neurons innervating the medial amygdala (MeA) causes a reduction in body weight in both male and female mice fed with a high-fat diet. This anti-obesity effect is associated with an increased locomotor activity. There are no significant differences in glucose and insulin tolerance in mice without the Magel2 gene in ARC POMC neurons innervating the MeA. Plasma estrogen levels are higher in female mutant mice than in controls. Blockade of the G protein–coupled estrogen receptor (GPER), but not estrogen receptor-α (ER-α), reduces locomotor activity in female mutant mice. Hence, our study provides evidence that knockdown of the Magel2 gene in ARC POMC neurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.
2021-10-11 | Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia.
Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition, and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternally imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implications for potential therapeutic interventions.
2021-05-11 | Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells
ABSTRACT Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders such as Prader-Willi syndrome (PWS) which results from the deletion of an imprinted locus on chromosome 15. We analysed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5’ snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance while genes that are upregulated are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data revealed the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provided a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature important for neuronal differentiation and development.
2021-04-07 | Snord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndrome
Abstract The smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA SNORD116 cluster; however, the function of SNORD116 remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of NHLH2, a gene previously implicated in both obesity and hypogonadism, was downregulated in PWS patients and differentiated stem cells. In silico RNA: RNA modeling identified several potential interaction domains between SNORD116 and NHLH2 mRNA. One of these interaction domains was highly conserved in most vertebrate NHLH2 mRNAs examined. A construct containing the Nhlh2 mRNA, including its 3’-UTR, linked to a c-myc tag was transfected into a hypothalamic neuron cell line in the presence and absence of exogenously-expressed Snord116. Nhlh2 mRNA expression was upregulated in the presence of Snord116 dependent on the length and type of 3’UTR used on the construct. Furthermore, use of actinomycin D to stop new transcription in N29/2 cells demonstrated that the upregulation occurred through increased stability of the Nhlh2 mRNA in the 45 minutes immediately following transcription. In silico modeling also revealed that a single nucleotide variant (SNV) in the NHLH2 mRNA could reduce the predicted interaction strength of the NHLH2:SNORD116 diad. Indeed, use of an Nhlh2 mRNA construct containing this SNV significantly reduces the ability of Snord116 to increase Nhlh2 mRNA levels. For the first time, these data identify a motif and mechanism for SNORD116-mediated regulation of NHLH2, clarifying the mechanism by which deletion of the SNORD116 snoRNAs locus leads to PWS phenotypes.
2020-06-14 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons
Abstract Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116 . Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116 . These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
other
2026-03-24 | Respiratory Syncytial Virus Infection Triggering a Pulmonary Hypertensive Crisis in a Boy With Prader-Willi Syndrome-Associated Sleep-Disordered Breathing.
Prader-Willi syndrome (PWS) is a multisystem genetic disorder frequently complicated by sleep-disordered breathing, including obstructive sleep apnea. Respiratory infections may precipitate acute decompensation in vulnerable patients with PWS. A four-year-old boy with genetically confirmed PWS receiving growth hormone therapy developed respiratory distress and cyanosis. He was found to be respiratory syncytial virus-positive and presented with acute respiratory acidosis and markedly elevated aminotransferases with coagulopathy. Echocardiography showed right-sided cardiac dilation consistent with pulmonary hypertension. He was managed with noninvasive ventilation, oxygen supplementation, and diuretics, followed by step-down to nasal continuous positive airway pressure. Liver enzymes normalized as his respiratory status improved. Polysomnography after stabilization showed obstructive sleep apnea with considerable nocturnal desaturation, and home continuous positive airway pressure was initiated. Respiratory syncytial virus (RSV) infection can trigger acute-on-chronic respiratory failure and cardiopulmonary decompensation in children with PWS and unrecognized severe nocturnal hypoxemia. Early screening and ongoing surveillance for sleep-disordered breathing, cardiopulmonary complications, and careful management during intercurrent infections are essential. RSV immunoprophylaxis, such as palivizumab, may warrant individualized consideration in high-risk young children with PWS who have impaired airway clearance or considerable respiratory comorbidity.
2026-03-24 | Epidemiology, Comorbidities, and Healthcare Costs of Prader-Willi Syndrome in South Korea Using the Korean National Health Insurance Service Database.
Prader-Willi syndrome (PWS) is a rare genetic disorder associated with substantial comorbidity and early mortality. However, the epidemiologic burden on Asian populations, particularly in South Korea, remains poorly understood. This study evaluates the nationwide incidence, prevalence, mortality, comorbidities, and healthcare costs of PWS in South Korea. We conducted a retrospective, population-based cohort study using the Korean National Health Insurance Database from 2005 to 2021. Among 2,553 individuals with PWS-related diagnostic codes, 458 patients were included in the study based on predefined criteria incorporating growth hormone therapy (GHT) or methylation-specific polymerase chain reaction testing. Epidemiologic trends, comorbidities, intensive care unit (ICU) admissions, and healthcare expenditures were analyzed. The overall birth incidence was 6.8 per 100,000 live births, with a significant increase evident after 2016. The median age at diagnosis was 1.0 years, and GHT was initiated at a median age of 2.0 years. The all-cause mortality rate was 3.5%, with pneumonia being the leading cause of death. ICU admission occurred in 25.5% of patients, often during infancy. Intellectual disability and/or developmental delay was present in 68.6% of patients, and type 2 diabetes mellitus in 15.1%. The mean cumulative healthcare cost per patient exceeded 86 million Korean won. Comorbidity prevalence and annual medical costs increased steadily over time. This is the first nationwide study to quantify the long-term epidemiological and economic burden of PWS in South Korea. Our findings underscore the need for early diagnosis, integrated care models, and policy support for this complex population.
2025-05-22 | Serum Lipoprotein(a) and High-Sensitivity C-reactive Protein Correlate With Somatic Parameters Including MLPA Subgroups in Children With Prader-Willi Syndrome.
Prader-Willi syndrome (PWS) is 1 of the most common monochromosomal (15q11-13) causes of polygenic syndromic childhood obesity. We primarily compare and correlate serum lipoprotein(a) [Lp(a)], high-sensitivity C-reactive protein (hs-CRP), and baseline clinical characteristics of genetically confirmed children with PWS at their GH treatment-naïve stage to their control groups. Secondary objectives were to correlate serum Lp(a) and hs-CRP concentration to multiplex ligation-dependent probe amplification subgroups, body composition indices, sleep apnea parameters, and hepatic shear-stress by 2-dimensional shear wave elastography in children with PWS. A total of 32 genetically confirmed PWS children (age 5 to 18 years), 20 simple obesity children, and 20 healthy children as age-matched control groups were studied for the primary and secondary study objectives. Lp(a) was higher in the study group as compared to the control group (P < .0001), but we found no difference between the control groups (P = .9680).In addition, no correlation was detected in Lp(a) levels in the study population with respect to their body weight, body mass index, and waist circumference. hs-CRP levels were also higher in the study population compared to both control groups (P = .0962; P < .0001); in contrast, Lp(a) differed significantly between the control groups (P = .002). Lower fat-free mass index (FFMI) correlated with higher levels of serum Lp(a) (r = -0.5525; P = .001), whereas FFMI was not correlated with hs-CRP levels in PWS children (P = .657). Based on genomic subtypes, patients with PWS were divided into deletion and nondeletion genetic subgroups. We found significantly altered levels of Lp(a), hs-CRP, fat-free mass, and sleep apnea parameters, particularly in the deletion subgroup. Serum Lp(a) as well as hs-CRP stand out to be the core independent risk factors along with their strong correlation with the other study parameters, which necessitates the role of future targeted therapeutics in PWS, especially in deletion pathology. Thus, genetic subtyping during diagnostic confirmation endorses further prognostic elaboration.
2025-01-22 | Sex dimorphic associations of Prader-Willi imprinted gene expressions in umbilical cord with prenatal and postnatal growth in healthy infants.
The impact of Prader-Willi syndrome (PWS) domain gene expression on the growth of healthy children is not well understood. This study investigated associations between PWS domain gene expression in umbilical cord tissue and prenatal and postnatal growth, considering potential sex differences. Relative gene expression of paternally expressed MAGEL2, NDN, and SNURF-SNRPN, and the small nucleolar RNAs SNORD116 and SNORD115 were determined by real-time quantitative polymerase chain reaction in umbilical cord tissue from 122 healthy newborns (59 girls and 63 boys). Gene expression levels were correlated with auxological measures at birth, infancy, and childhood (ages 2, 4, and 6 years). MAGEL2, NDN, SNORD116, and SNORD115 expression in the umbilical cord was negatively associated with birth weight, length, and placental weight (P < 0.001). Postnatally, these genes were positively associated with weight and length at 3 months (P < 0.001) and weight gain from birth to ages 1, 2, and 4 years (P < 0.01). Negative associations at birth were stronger in girls (P < 0.001), while positive associations during infancy and childhood were stronger in boys (P < 0.001). MAGEL2, SNORD116, and SNORD115 expression predicted early-postnatal growth, explaining the higher growth rate in boys compared to girls and accounting for sex differences up to 1.5 kg in weight and 3 cm in height during infancy. Paternally expressed PWS domain gene expression in the umbilical cord was negatively associated with prenatal growth and positively with early-postnatal growth in healthy infants. This gene expression may predict early human postnatal growth and promote the well-known sex dimorphism in growth. These results can also help in understanding the etiology of PWS, which remains unclear.
2023-11-14 | Umbilical Cord Stem Cell Stem Cell Therapy For Rare Genetic Disease Prader-Willi Syndrome
This abstract summarises the studies on the use of umbilical cord stem cells to treat Prader-Willi syn- drome. Among the various stem cells found in the umbilical cord, hematopoietic and mesenchymal stem cells may create bioactive molecules that aid in tissue repair and regeneration, control immunological responses, and give birth to a variety of cell types. Because of this, they present a feasible option for treating the multidisciplinary character of PWS. Preclinical research on PWS animal models has shown promising outcomes, with umbilical cord stem cell transplantation improving metabolic disorders, hy- hypothalamic function, and general behavior. It has been investigated if immunological regulation, trophic support, and paracrine signaling are among the factors that promote stem cell therapeutic potential. Several clinical studies employing umbilical cord stem cells to treat PWS are now underway, and the findings should aid in assessing the advantages and disadvantages of using this approach on patients. The preliminary evidence is encouraging, since some trial participants improved in hyperphagia, mus- cular tone, and cognitive ability. Although the use of umbilical cord stem cells as a PWS treatment has shown some promise, further study is required to determine its long-term safety, optimal dose, and ongoing effectiveness. A variety of key elements, such as ethical issues, regulatory frameworks, and the availability of standardized stem cell products, will have a considerable impact on the future development of this treatment technique. SD is a disease known as a neurodevelopmental problem represented through problems with social communication, sensor sensitivity, and repetitive behaviors. Despite years of study, therapy options for autism spectrum disorder (ASD) remain relatively limited. As regenerative medicine has improved, stem cell treatment has been investigated as a novel therapeutic option for the underlying neurological disorders that underpin ASD. The development, possible methods, and potential uses of stem cell treatment for autistic children are discussed in this article.
small molecules
2026-09-17 | Sustained weight loss exceeding 100 kg with sequential incretin-based therapy in Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a neurogenetic disorder characterized by hyperphagia, severe obesity, and early-onset metabolic complications, in which durable weight loss is rarely achieved. We report a 29-year-old man with genetically confirmed maternal uniparental disomy PWS who presented with severe obesity (185 kg; body mass index [BMI] 59.7 kg/m2) and newly diagnosed type 2 diabetes (glycated hemoglobin [HbA1c], 8.3% [SI: 67 mmol/mol] [reference range, <5.7% (SI: <39 mmol/mol)]). He received sequential incretin-based therapy, initiated with retatrutide (1-12 mg weekly) within a clinical trial, followed by oral semaglutide and then dulaglutide after retatrutide became unavailable, together with a structured hypocaloric diet and supervised exercise. At 18 months, total weight loss reached 58.8% (-108.7 kg), with HbA1c of 4.9% (SI: 30 mmol/mol), consistent with diabetes remission after discontinuation of all glucose-lowering medications. Mild transient gastrointestinal symptoms occurred during dose escalation, with no serious adverse events. Follow-up bioimpedance showed a skeletal muscle mass of 38.5 kg after a 58.8% reduction in total body weight.
2026-09-08 | Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.
2026-09-06 | Young Boy’s Battle with Childhood Obesity: Unmasking A Rare Case of Prader-Willi-Syndrome
Prader-Willi syndrome (PWS) is one of the most prevalent causes of syndromic obesity. This genetic disorder begins with hypotonia and poor feeding in the neonatal period, later evolving into hyperphagia and rapid weight gain during early childhood, frequently leading to severe obesity in adolescence and adulthood. We report a case of a 14-year-old boy presenting with morbid obesity (BMI: 47.4) and related complications. Before admission, he was not properly evaluated for obesity. Along with obesity, the presence of hypogonadism, undescended testes since childhood, learning difficulties, poor academic performance, and behavioral abnormalities, including temper tantrums and emotional outbursts, raised a strong suspicion of Prader–Willi syndrome (PWS). We used the consensus criteria for the diagnosis of PWS clinically and focused on managing obesity with a dual GIP/GLP-1 receptor agonist; the patient achieved a remarkable weight loss of 25 kg over one year and marked reversal of obesity–related complications, significantly improving the patient’s overall health and quality of life. J MEDICINE 2026; 27(2): 151-154
2026-08-01 | EP1441 - ECE_1387 - Prader–willi syndrome—from diagnosis to substitution therapy
Abstract Prader–Willi syndrome is a rare genetic disorder involving chromosome 15, characterized by hypotonia, a characteristic facial appearance (reduced bifrontal diameter), convergent strabismus, and intellectual disability. In boys, it is usually accompanied by cryptorchidism and a hypoplastic scrotum. We present the case of a patient who initially consulted a urologist due to priapism, after which further endocrinological evaluation was recommended. Hormonal testing revealed elevated estradiol levels with low testosterone levels, while clinical examination showed obesity and cryptorchidism. Due to cryptorchidism, urological treatment was performed, followed by repeat endocrinological evaluation, after which testosterone replacement therapy was initiated. This led to a reduction in body weight, voice deepening, development of male-pattern body hair, and overall clinical improvement. Review of the patient’s medical documentation revealed that genetic testing had been performed at birth and the diagnosis of Prader–Willi syndrome had already been established; however, appropriate therapy had not been initiated at that time. This case highlights the importance of early detection and appropriate long-term follow-up by an endocrinologist, as this enables timely initiation of adequate substitution therapy as well as prompt urological surgical intervention when indicated.
2026-07-23 | Carbetocin Nasal Spray for the Treatment of Hyperphagia in Prader-Willi Syndrome: Results From the Randomized, Placebo-Controlled, Phase 3 Compass PWS Study.
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. The oxytocinergic system represents one of the key neural circuits that is dysfunctional in PWS, making it an attractive therapeutic target. The oxytocin analog carbetocin has a longer half-life and greater receptor selectivity than oxytocin and showed therapeutic potential in the phase 3 CARE-PWS study (ClinicalTrials.gov NCT03649477) based on nominally significant improvements in hyperphagia and anxiousness with the 3 times daily (TID) 3.2-mg dose of intranasal carbetocin over placebo. The phase 3 placebo-controlled COMPASS PWS study was conducted to confirm the potential benefit observed with carbetocin in the CARE-PWS study. In the 12-week COMPASS PWS study (ClinicalTrials.gov NCT06173531), 175 participants were randomized 1:1 to carbetocin 3.2 mg TID nasal spray (n = 85) and placebo (n = 90). The primary efficacy endpoint was the change from baseline at week 12 in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Secondary efficacy endpoints were the change in the Clinical Global Impression-Severity (CGI-S) score for PWS, and in the CGI-S for hyperphagia in PWS score from baseline at week 12, the CGI-Change for PWS score at week 12, and the percentage of participants with a treatment response (defined as improvement from baseline ≥8 points) based on the HQ-CT at week 12. Exploratory efficacy endpoints included the change from baseline at week 12 in scores for the PWS Anxiousness and Distress Behaviors Questionnaire. The least squares mean change (standard error) from baseline at week 12 in the HQ-CT was -4.8 (0.8) and -5.1 (0.8) in the carbetocin and placebo groups, respectively; the treatment difference of 0.3 (95% confidence interval: -1.8, 2.4; P = 0.79) was not statistically significant. There was no separation between carbetocin and placebo for any secondary or exploratory endpoint. The most frequently reported treatment-emergent adverse events in the carbetocin-treated participants were headache (n = 6 [7.2%]) and pyrexia (n = 5 [6.0%]). Carbetocin nasal spray did not demonstrate efficacy compared with placebo for hyperphagia in PWS in the 12-week COMPASS PWS study.
proteins
2026-09-06 | Case report: Tirzepatide-responsive refractory diabetes mellitus in an adult female with prader-willi syndrome.
Prader-Willi syndrome (PWS) is a complex genetic disorder that affects multiple systems and results from loss of expression of paternally inherited genes in the 15q11.2-q13 region. It is characterized by severe hypotonia and feeding difficulties during infancy, followed by hyperphagia in later childhood and adolescence, which, without strict control of excessive eating behaviors, ultimately leads to severe obesity associated with type 2 diabetes mellitus. We present the case of a woman who was diagnosed with PWS and diabetes mellitus in adulthood. She had a history of hypotonia, developmental delay, intellectual disability, hyperphagia, and morbid obesity since childhood, with gonadal dysplasia emerging during puberty. She presented with long-term poorly controlled blood glucose levels. Genetic testing revealed a heterozygous deletion in the 15q11.2-q13.1 region on chromosome 15, and DNA methylation analysis confirmed the diagnosis of PWS. The distinctiveness of this case lies in the patient's uncontrollable food-seeking behavior combined with PWS-related severe insulin resistance and β-cell dysfunction, which together resulted in refractory diabetes. Initial combination therapy using multiple glucose-lowering agents, including insulin, metformin, chiglitazar sodium, a glucagon-like peptide-1 receptor agonist, and a sodium-glucose cotransporter-2 inhibitor, demonstrated limited efficacy. Subsequent substitution of the glucagon-like peptide-1 receptor agonist with the dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide led to notable improvements in appetite suppression, body weight reduction, and glycemic control. This case underscores the importance of considering genetic syndromes in patients with diabetes presenting with early-onset severe obesity and developmental abnormalities and emphasizes the potential therapeutic value of novel antidiabetic agents such as tirzepatide for managing PWS-associated metabolic disturbances. These findings provide important insights into the diagnosis and treatment of diabetes complicated by PWS.
2026-09-06 | Cognitive development in children with Prader-Willi syndrome receiving early growth hormone therapy.
Prader‒Willi syndrome (PWS) is a genetic disorder characterized by hypotonia, feeding difficulties in infancy, excessive eating in childhood, intellectual disability and short stature. Growth hormone therapy (GHT) improves body composition and decreases fat percentage in patients with PWS. However, the effect of GHT on cognitive function is not clear. The aim of this study was to evaluate the beneficial effects of GHT on cognition in younger patients with PWS. A retrospective analysis of patients with PWS who received GHT in four hospitals was conducted in Taiwan. Patient demographics, molecular diagnosis, age at GHT initiation, GHT dose, developmental quotient/full-scale intelligence quotient (DQ/FSIQ) scores, and verbal intelligence quotient/verbal comprehension index (VIQ/VCI) scores were analyzed. This retrospective study included a total of 61 patients. Seven patients who did not receive growth hormone treatment were assigned to the control group, while the remaining 54 patients composed the treatment group. After applying the exclusion criteria, 47 patients were ultimately included in the analysis. Twenty-nine patients were treated before 3 years of age, and eighteen patients were treated after 3 years of age. The DQ/FSIQ score was significantly greater in the younger age group (p < 0.05). Specifically, in the nondeletion type and female groups, younger patients presented significantly higher DQ/FSIQ scores (p < 0.05). Compared with the untreated group, the early GH treatment group had significantly higher VIQ/VCI scores (p < 0.05). According to linear regression, the age at GHT initiation was significantly negatively correlated with the DQ/FSIQ score (β1 = -1.264, R2 = 0.184, F = 4.16, p < 0.05) and the VIQ/VCI score (β(VIQ)1 = -1.981, R2 = 0.242, F = 4.09, p < 0.05). The initiation of GHT before 3 years of age and as early as possible had a significant effect on cognitive development after adjustments were made for sex and molecular type.
2026-08-27 | A Clinical Genetics-Driven Dual Diagnosis of Prader-Willi Syndrome Due to Mosaic Maternal UPD(15) and NOTCH3-Related CADASIL.
Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader-Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis. He presented with very mild neurodevelopmental impairment. Following the detection of proteinuria and microalbuminuria from age 22 years, focal segmental glomerulosclerosis was diagnosed upon renal biopsy. A family history of cerebrovascular events was recorded. Combined SNP-array and MS-MLPA analyses across tissues established a diagnosis of PWS due to mosaic UPD(15)mat. The mosaic fraction, estimated by SNP-array, was approximately 10% in peripheral blood and 40% in buccal cells; MS-MLPA detected abnormal methylation only in buccal cells, explaining the previous negative blood-based results. Exome sequencing identified the paternally inherited pathogenic NOTCH3 variant NM_000435.2:c.3016C>T, p.(Arg1006Cys). Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL, despite the absence of overt ischemic events in the proband. Collectively, these investigations established a dual molecular diagnosis of PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL. This report highlights the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases. With respect to PWS, it demonstrates that mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood. In addition, following the diagnosis of CADASIL, and based on the available evidence linking NOTCH3 to renal physiology and disease, we discuss whether NOTCH3-related renal microangiopathy may have contributed to the renal phenotype. However, given the patient's multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case.
2026-08-24 | Failure to thrive (FTT) in infants with Prader-Willi syndrome and long-term effects of GH-treatment on FTT.
Failure to thrive (FTT) with feeding difficulties and hypotonia are well-known features in infants with Prader-Willi syndrome (PWS). Limited studies reported the percentage of infants with FTT and it is unknown whether growth hormone (GH)-treatment affects body composition of infants with or without FTT differently. To evaluate the percentage of infants with PWS with FTT from birth to age 6 months and to investigate the 5-year GH effects on body composition in infants with or without FTT at GH-start. We defined FTT as weight-for-length <-2 SDS and evaluated the percentage of infants with FTT in a group of 54 infants from birth to age 6 months. In addition, we investigated in 166 children the 5-year GH effects on body composition, comparing children with and without FTT at GH-start. All infants were treated with 1.0 mg GH/m2/day (~0.035mg/kg/day). Body composition was determined by Dual energy X-ray Absorptiometry (DXA). From birth to age 6 months, 29% of infants had FTT at 1 month, 20% at 3 months, and 16% at 6 months. At GH-start, at a median age of 1.03 (IQR 0.45,1.89) year, 12% (20/166) had FTT (FTTGH-start). Infants with FTTGH-start had a lower lean body mass index (LBMI) compared to non-FTTGH-start, but a greater catch-up in LBMI in the first year of GH, resulting in a similar LBMI as the non-FTTGH-start after 5 years of GH-treatment. Children with FTTGH-start had lower FM% after 5 years of GH-treatment, but this difference disappeared after including covariates. Twenty-nine percent of infants had FTT at 1 month, 20% at 3 months, and 16% at 6 months. Twelve percent had FTT at the start of GH-treatment. Children with FTT at GH-start showed greatest LBM improvement during GH-treatment, resulting in a similar LBM after 5 years of GH-treatment as those without FTT at GH-start.
2026-08-01 | P260 - ECE_1902 - Effect of growth hormone treatment on muscle strength in adults with Prader-Willi syndrome (PWS)
Abstract Introduction Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hypothalamic dysfunction, intellectual disability, hypotonia and hyperphagia. Individuals with PWS display features of growth hormone (GH) deficiency, including short stature, increased fat mass, and low muscle mass and strength. Reduced muscle mass results in a low basal metabolic rate (BMR). Combined with hyperphagia, this often results in severe obesity. As obesity is the primary contributor to increased morbidity and mortality in adults with PWS, addressing it is essential for long-term health in this population. GH treatment improves body composition and muscle strength in children with PWS. Smaller studies suggest similar improvements in body composition in adults. However, the effect of GH treatment on muscle strength in adults with PWS has not yet been demonstrated. We have studied the effect of GH treatment on muscle strength in a Dutch population of GH-naïve adults with PWS. Methods At the Dutch Center of Reference for PWS, 24 GH-naïve patients with PWS were included in this open-label prospective cohort study. We measured muscle strength before the start of GH treatment (0.6 mg once daily) and after 3, 6 and 12 months of therapy. Muscle strength was quantified using a handgrip dynamometer for hand and forearm strength, as well as the 30-second sit-to-stand test and the 5× sit-to-stand test for leg muscle strength. In addition, subjective improvements in muscle and side-effects were assessed. All tests were validated for adult individuals with an intellectual disability. Results Ten females and fourteen males were included (17 deletion and 7 mUPD, age range 22-63 years, BMI range 23-38 kg/m2). Overall, patients, parents and caregivers reported notable improvements in muscle strength. Most remarkable subjective changes were increased walking speed and increased ability to get out of chairs, walk without help or climb the stairs. They also reported a decrease in fatigue and daytime sleepiness. Objective improvements were significant increases in muscle strength as measured by the handgrip dynamometer (P = .042), the 30-second sit-to-stand test (P = .002), and the 5× sit-to-stand test (P = .032). Conclusions GH treatment significantly improves muscle strength in adults with PWS. As improved muscle strength improves exercise tolerance, it enables a healthier lifestyle needed to reduce obesity and cardiovascular complications in this vulnerable population.
gene therapies
2026-09-29 | Modeling the Prader-Willi Syndrome Associated Growth Phases in Snord116 KO Mice
Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by distinctive developmental transition from neonatal hypotonia and poor feeding to pro-gressive weight gain and, later, hyperphagia and obesity. The paternally expressed SNORD116 cluster is critical for postnatal growth, but how its deficiency shapes this progression remains unclear. Here, we analyzed day-over-day growth rates in 351 mice carrying Snord116 deletion or altered Snord116 dosage, including wild-type littermates, across both sexes and two genetic backgrounds. Snord116 expression increased markedly during early brain development. Snord116-deficient mice exhibited a distinct three-stage growth trajectory: impaired growth until approximately P16, normalization between P17 and P21, followed by transient accelerated weight gain until approximately P30. Alt-hough growth rates subsequently normalized, the accumulated deficit was not fully compensated, and adult Snord116KO mice remained smaller than wild-type controls. These developmental transitions broadly parallel early nutritional phases of human PWS, although mice did not progress to persistent obesity-associated growth. Reactivation of the maternal Snord116 cluster partially rescued the growth phenotype, whereas activation of both parental alleles produced a modest growth advantage, most evident in males. These findings identify early postnatal development as a critical window of Snord116-dependent growth regulation and provide a framework for investigating mechanisms underlying PWS progression.
2026-09-22 | Targeted Epigenetic Reactivation strategies as new treatments for Prader-Willi Syndrome: Achievements and Challenges.
Prader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder caused by the loss of expression of paternal genes in the 15q11-q13 locus. The same genes on the maternal allele are present but are epigenetically silenced. This genetic alteration causes a spectrum of symptoms associated with hypothalamic dysfunction. Research is increasingly focused on setting strategies aiming to reactivate the maternal locus and restore the expression of that critical gene cluster. Early therapeutic efforts explored broad-spectrum epigenetic drugs, such as DNA- and histone-methyltransferase inhibitors. While these compounds demonstrated some efficacy in preclinical models, their lack of genomic specificity limits their clinical viability. To overcome this barrier, high-precision epigenome editing tools, most notably dCas9-based systems, have emerged as highly promising strategies capable of inducing site-specific demethylation and stable reactivation of the silenced maternal allele. However, translating these targeted strategies into clinical practice requires overcoming major therapeutic hurdles. This review discusses these key translational challenges, focusing on the imperative to optimize delivery vectors for widespread central nervous system distribution, the necessity of advanced human-derived neuronal models to validate functional recovery, and the critical need to prevent iatrogenic Angelman Syndrome caused by UBE3A imprinting. Finally, we explore future therapeutic horizons, highlighting how newly identified epigenetic regulators and non-coding RNAs could serve as alternative targets to unlock the maternal PWS locus.
2026-07-01 | 10031 Prader willi syndrome(PWS) genetics: connecting the dots to attempt to explain variation in phenotype
Why did you do this work?
PWS is the first disorder attributed to genomic imprinting and caused by absent expression of paternally active genes on chromosomal region 15q11.2q13. Genomic imprinting is a complex concept, where one set of genes (paternally or maternally derived) are silenced and the other is expressed in normal individuals. This work endeavours: To discuss various genes affected in PWS and demonstrate association with individual disorders and syndromes through genetic similarities. To associate phenotypic variation in PWS patients to different genes being affected.
What did you do?
I assimilated information from electronic patient records, patient files and analysed well-researched publications regarding PWS and disorders with similar gene involvement. Two patients with PWS were followed up for more than fifteen years. They have very different medical problems and needs. While the affected boy has done well academically and has mild scoliosis, he has obesity, delayed puberty and some mental health struggles. He has been cooperative with his family to control hyperphagia. The girl with PWS does not have hyperphagia or obesity, but moderate scoliosis requiring spinal braces and learning difficulties in need of support. Such profound variation of phenotype may be related to environmental factors but also due to PWS gene variation among patients.
What did you find?
About 20 genes, all located in the PWS critical region, are defective in PWS.
What does it mean?
Many genes affected in PWS are discovered as causative factors in unrelated disorders. This may also contribute to PWS patients having different clinical presentations and symptom intensity varies among patients. Further research in this prospect may lead towards identifying gene modulation therapies which may help ameliorate major manifestations of PWS.
References
Eddiry S, Diene G, Molinas C, Salles J, Auriol FC, Gennero I, Bieth E, Skryabin BV, Rozhdestvensky TS, Burnett LC, Leibel RL, Tauber M, Salles JP. SNORD116 and growth hormone therapy impact IGFBP7 in Prader-Willi syndrome. Genetics in Medicine: Official Journal of the American College of Medical Genetics 2021;23(9):1664–1672. https://doi.org/10.1038/s41436-021-01185-y Spritz RA, Bailin T, Nicholls RD, Lee ST, Park SK, Mascari MJ, Butler MG. Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. American Journal of Medical Genetics 1997;71(1):57–62. https://doi.org/10.1002/(sici)1096-8628(19970711)71:1<57::aid-ajmg11>3.0.co;2-u
2026-05-15 | 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 × 1010 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 × 1010 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.
2026-05-14 | SMCHD1 is a novel target for gene-activation therapy to treat Prader-Willi Syndrome
ABSTRACT Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by lack of gene expression from the active paternal allele at an imprinted gene cluster on chromosome 15. Current treatments have limited efficacy as they target individual symptoms rather than the underlying cause of disease. All patients preserve a normal, yet epigenetically-silenced, copy of the PWS cluster genes; activation of this imprinted copy to restore necessary gene expression is an appealing option for tackling the root of the disorder. Here we have addressed the potential to activate these silent maternal genes by targeting the epigenetic regulator Structural Maintenance of Chromosomes Hinge domain containing 1 (SMCHD1). First, we expanded the role of SMCHD1 in repressing the PWS cluster from mice to humans, a critical step if SMCHD1 is to be a drug target. Second, we discovered that SMCHD1 represses the entire PWS locus in neural lineages, extending its previously known role at only half of the PWS genes. We show that deleting Smchd1 after early development in vivo is effective at causing PWS gene-activation in disease-relevant mouse tissues including hypothalamus, and that this has beneficial effects on phenotypes observed in a PWS mouse model. Despite SMCHD1 having a role in gene silencing elsewhere in the genome, our data suggest that targeting SMCHD1 after early development is remarkably safe. Taken together, these data propose SMCHD1 as a novel target for gene-activation therapy for PWS.
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2022-08-25 | Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity.
Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of the Magel2 gene disrupts POMC neuronal circuits and functions. Here, we report that loss of the Magel2 gene exclusively in ARC POMC neurons innervating the medial amygdala (MeA) causes a reduction in body weight in both male and female mice fed with a high-fat diet. This anti-obesity effect is associated with an increased locomotor activity. There are no significant differences in glucose and insulin tolerance in mice without the Magel2 gene in ARC POMC neurons innervating the MeA. Plasma estrogen levels are higher in female mutant mice than in controls. Blockade of the G protein–coupled estrogen receptor (GPER), but not estrogen receptor-α (ER-α), reduces locomotor activity in female mutant mice. Hence, our study provides evidence that knockdown of the Magel2 gene in ARC POMC neurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.
2021-10-11 | Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia.
Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition, and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternally imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implications for potential therapeutic interventions.
2021-05-11 | Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells
ABSTRACT Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders such as Prader-Willi syndrome (PWS) which results from the deletion of an imprinted locus on chromosome 15. We analysed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5’ snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance while genes that are upregulated are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data revealed the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provided a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature important for neuronal differentiation and development.
2021-04-07 | Snord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndrome
Abstract The smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA SNORD116 cluster; however, the function of SNORD116 remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of NHLH2, a gene previously implicated in both obesity and hypogonadism, was downregulated in PWS patients and differentiated stem cells. In silico RNA: RNA modeling identified several potential interaction domains between SNORD116 and NHLH2 mRNA. One of these interaction domains was highly conserved in most vertebrate NHLH2 mRNAs examined. A construct containing the Nhlh2 mRNA, including its 3’-UTR, linked to a c-myc tag was transfected into a hypothalamic neuron cell line in the presence and absence of exogenously-expressed Snord116. Nhlh2 mRNA expression was upregulated in the presence of Snord116 dependent on the length and type of 3’UTR used on the construct. Furthermore, use of actinomycin D to stop new transcription in N29/2 cells demonstrated that the upregulation occurred through increased stability of the Nhlh2 mRNA in the 45 minutes immediately following transcription. In silico modeling also revealed that a single nucleotide variant (SNV) in the NHLH2 mRNA could reduce the predicted interaction strength of the NHLH2:SNORD116 diad. Indeed, use of an Nhlh2 mRNA construct containing this SNV significantly reduces the ability of Snord116 to increase Nhlh2 mRNA levels. For the first time, these data identify a motif and mechanism for SNORD116-mediated regulation of NHLH2, clarifying the mechanism by which deletion of the SNORD116 snoRNAs locus leads to PWS phenotypes.
2020-06-14 | Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons
Abstract Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger protein capable of recruiting epigenetic machinery to deposit the H3K9me3 repressive histone modification, can activate expression from the normally silent maternal allele of SNORD116 in neurons derived from PWS iPSCs. However, ZNF274 has many other targets in the genome in addition to SNORD116 . Depleting ZNF274 will surely affect the expression of other important genes and disrupt other pathways. Here we used CRISPR/Cas9 to delete ZNF274 binding sites at the SNORD116 locus to determine whether activation of the maternal copy of SNORD116 could be achieved without altering ZNF274 protein levels. We obtained similar activation of gene expression from the normally silenced maternal allele in neurons derived from PWS iPSCs, compared to ZNF274 knockout, demonstrating that ZNF274 is directly involved in the repression of SNORD116 . These results suggest that interfering with ZNF274 binding at the maternal SNORD116 locus is a potential therapeutic strategy for PWS.
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2026-03-24 | Respiratory Syncytial Virus Infection Triggering a Pulmonary Hypertensive Crisis in a Boy With Prader-Willi Syndrome-Associated Sleep-Disordered Breathing.
Prader-Willi syndrome (PWS) is a multisystem genetic disorder frequently complicated by sleep-disordered breathing, including obstructive sleep apnea. Respiratory infections may precipitate acute decompensation in vulnerable patients with PWS. A four-year-old boy with genetically confirmed PWS receiving growth hormone therapy developed respiratory distress and cyanosis. He was found to be respiratory syncytial virus-positive and presented with acute respiratory acidosis and markedly elevated aminotransferases with coagulopathy. Echocardiography showed right-sided cardiac dilation consistent with pulmonary hypertension. He was managed with noninvasive ventilation, oxygen supplementation, and diuretics, followed by step-down to nasal continuous positive airway pressure. Liver enzymes normalized as his respiratory status improved. Polysomnography after stabilization showed obstructive sleep apnea with considerable nocturnal desaturation, and home continuous positive airway pressure was initiated. Respiratory syncytial virus (RSV) infection can trigger acute-on-chronic respiratory failure and cardiopulmonary decompensation in children with PWS and unrecognized severe nocturnal hypoxemia. Early screening and ongoing surveillance for sleep-disordered breathing, cardiopulmonary complications, and careful management during intercurrent infections are essential. RSV immunoprophylaxis, such as palivizumab, may warrant individualized consideration in high-risk young children with PWS who have impaired airway clearance or considerable respiratory comorbidity.
2026-03-24 | Epidemiology, Comorbidities, and Healthcare Costs of Prader-Willi Syndrome in South Korea Using the Korean National Health Insurance Service Database.
Prader-Willi syndrome (PWS) is a rare genetic disorder associated with substantial comorbidity and early mortality. However, the epidemiologic burden on Asian populations, particularly in South Korea, remains poorly understood. This study evaluates the nationwide incidence, prevalence, mortality, comorbidities, and healthcare costs of PWS in South Korea. We conducted a retrospective, population-based cohort study using the Korean National Health Insurance Database from 2005 to 2021. Among 2,553 individuals with PWS-related diagnostic codes, 458 patients were included in the study based on predefined criteria incorporating growth hormone therapy (GHT) or methylation-specific polymerase chain reaction testing. Epidemiologic trends, comorbidities, intensive care unit (ICU) admissions, and healthcare expenditures were analyzed. The overall birth incidence was 6.8 per 100,000 live births, with a significant increase evident after 2016. The median age at diagnosis was 1.0 years, and GHT was initiated at a median age of 2.0 years. The all-cause mortality rate was 3.5%, with pneumonia being the leading cause of death. ICU admission occurred in 25.5% of patients, often during infancy. Intellectual disability and/or developmental delay was present in 68.6% of patients, and type 2 diabetes mellitus in 15.1%. The mean cumulative healthcare cost per patient exceeded 86 million Korean won. Comorbidity prevalence and annual medical costs increased steadily over time. This is the first nationwide study to quantify the long-term epidemiological and economic burden of PWS in South Korea. Our findings underscore the need for early diagnosis, integrated care models, and policy support for this complex population.
2025-05-22 | Serum Lipoprotein(a) and High-Sensitivity C-reactive Protein Correlate With Somatic Parameters Including MLPA Subgroups in Children With Prader-Willi Syndrome.
Prader-Willi syndrome (PWS) is 1 of the most common monochromosomal (15q11-13) causes of polygenic syndromic childhood obesity. We primarily compare and correlate serum lipoprotein(a) [Lp(a)], high-sensitivity C-reactive protein (hs-CRP), and baseline clinical characteristics of genetically confirmed children with PWS at their GH treatment-naïve stage to their control groups. Secondary objectives were to correlate serum Lp(a) and hs-CRP concentration to multiplex ligation-dependent probe amplification subgroups, body composition indices, sleep apnea parameters, and hepatic shear-stress by 2-dimensional shear wave elastography in children with PWS. A total of 32 genetically confirmed PWS children (age 5 to 18 years), 20 simple obesity children, and 20 healthy children as age-matched control groups were studied for the primary and secondary study objectives. Lp(a) was higher in the study group as compared to the control group (P < .0001), but we found no difference between the control groups (P = .9680).In addition, no correlation was detected in Lp(a) levels in the study population with respect to their body weight, body mass index, and waist circumference. hs-CRP levels were also higher in the study population compared to both control groups (P = .0962; P < .0001); in contrast, Lp(a) differed significantly between the control groups (P = .002). Lower fat-free mass index (FFMI) correlated with higher levels of serum Lp(a) (r = -0.5525; P = .001), whereas FFMI was not correlated with hs-CRP levels in PWS children (P = .657). Based on genomic subtypes, patients with PWS were divided into deletion and nondeletion genetic subgroups. We found significantly altered levels of Lp(a), hs-CRP, fat-free mass, and sleep apnea parameters, particularly in the deletion subgroup. Serum Lp(a) as well as hs-CRP stand out to be the core independent risk factors along with their strong correlation with the other study parameters, which necessitates the role of future targeted therapeutics in PWS, especially in deletion pathology. Thus, genetic subtyping during diagnostic confirmation endorses further prognostic elaboration.
2025-01-22 | Sex dimorphic associations of Prader-Willi imprinted gene expressions in umbilical cord with prenatal and postnatal growth in healthy infants.
The impact of Prader-Willi syndrome (PWS) domain gene expression on the growth of healthy children is not well understood. This study investigated associations between PWS domain gene expression in umbilical cord tissue and prenatal and postnatal growth, considering potential sex differences. Relative gene expression of paternally expressed MAGEL2, NDN, and SNURF-SNRPN, and the small nucleolar RNAs SNORD116 and SNORD115 were determined by real-time quantitative polymerase chain reaction in umbilical cord tissue from 122 healthy newborns (59 girls and 63 boys). Gene expression levels were correlated with auxological measures at birth, infancy, and childhood (ages 2, 4, and 6 years). MAGEL2, NDN, SNORD116, and SNORD115 expression in the umbilical cord was negatively associated with birth weight, length, and placental weight (P < 0.001). Postnatally, these genes were positively associated with weight and length at 3 months (P < 0.001) and weight gain from birth to ages 1, 2, and 4 years (P < 0.01). Negative associations at birth were stronger in girls (P < 0.001), while positive associations during infancy and childhood were stronger in boys (P < 0.001). MAGEL2, SNORD116, and SNORD115 expression predicted early-postnatal growth, explaining the higher growth rate in boys compared to girls and accounting for sex differences up to 1.5 kg in weight and 3 cm in height during infancy. Paternally expressed PWS domain gene expression in the umbilical cord was negatively associated with prenatal growth and positively with early-postnatal growth in healthy infants. This gene expression may predict early human postnatal growth and promote the well-known sex dimorphism in growth. These results can also help in understanding the etiology of PWS, which remains unclear.
2023-11-14 | Umbilical Cord Stem Cell Stem Cell Therapy For Rare Genetic Disease Prader-Willi Syndrome
This abstract summarises the studies on the use of umbilical cord stem cells to treat Prader-Willi syn- drome. Among the various stem cells found in the umbilical cord, hematopoietic and mesenchymal stem cells may create bioactive molecules that aid in tissue repair and regeneration, control immunological responses, and give birth to a variety of cell types. Because of this, they present a feasible option for treating the multidisciplinary character of PWS. Preclinical research on PWS animal models has shown promising outcomes, with umbilical cord stem cell transplantation improving metabolic disorders, hy- hypothalamic function, and general behavior. It has been investigated if immunological regulation, trophic support, and paracrine signaling are among the factors that promote stem cell therapeutic potential. Several clinical studies employing umbilical cord stem cells to treat PWS are now underway, and the findings should aid in assessing the advantages and disadvantages of using this approach on patients. The preliminary evidence is encouraging, since some trial participants improved in hyperphagia, mus- cular tone, and cognitive ability. Although the use of umbilical cord stem cells as a PWS treatment has shown some promise, further study is required to determine its long-term safety, optimal dose, and ongoing effectiveness. A variety of key elements, such as ethical issues, regulatory frameworks, and the availability of standardized stem cell products, will have a considerable impact on the future development of this treatment technique. SD is a disease known as a neurodevelopmental problem represented through problems with social communication, sensor sensitivity, and repetitive behaviors. Despite years of study, therapy options for autism spectrum disorder (ASD) remain relatively limited. As regenerative medicine has improved, stem cell treatment has been investigated as a novel therapeutic option for the underlying neurological disorders that underpin ASD. The development, possible methods, and potential uses of stem cell treatment for autistic children are discussed in this article.
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Drug Discovery Landscape
32 orphan drug designations for Prader-Willi syndrome, including 2 approved therapies.
32 orphan drug designations for Prader-Willi syndrome, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Cannabidiol acid methyl ester | small molecules | EMA | — | Scendea (NL) B.V. |
celastrol | small molecules | FDA | — | ERX Pharmaceuticals, Inc. |
pitolisant | small molecules | FDA | Harmony Biosciences, LLC | |
5-BROMO-N-(PROP-2-YN-1-YL)-2-(1H-1,2,4-TRIAZOL-1-YL) PYRIMIDINE-4,6-DIAMINE | small molecules | FDA | Palobiofarma S.L. | |
5-bromo-N-(prop-2-yn-1-yl)-2-(1H-1,2,4-triazol-1-yl)pyrimidine-4,6-diamine | small molecules | EMA | Palo Biofarma S.L. | |
Denatonium acetate monohydrate | small molecules | FDA | Aardvark Therapeutics, Inc. | |
avasimibe | small molecules | FDA | — | EFIL BioScience Inc. |
Cannabidiol acid methyl ester (CBDA-ME) | small molecules | FDA | — | EPM Group Inc. |
Oxytocin | peptides | FDA | Tonix Pharmaceuticals, Inc. | |
Synthetic analogue of cyclic Glycine-Proline | small molecules | FDA | Neuren Pharmaceuticals, Ltd. | |
Tesofensine plus metoprolol in a fixed-dose combination | small molecules | FDA | Saniona S/A | |
(R)-3-(1-(2,3-dichloro-4-(pyrazin-2-yl)phenyl)-2,2,2-trifluoroethyl)-1-methyl-1-(1-methylpiperidin-4-yl)urea fumarate | small molecules | EMA | — | Helsinn Birex Pharmaceuticals Limited |
cannabidiol | small molecules | FDA | Benuvia Operations LLC | |
Diazoxide choline | small molecules | EMA | Soleno Therapeutics Europe Limited | |
Synthetic cyclic 8 amino acid analogue of human unacylated ghrelin | small molecules | EMA | Millendo Therapeutics SAS | |
synthetic cyclic 8 amino acid analog of human unacylated ghrelin | small molecules | FDA | Millendo Therapeutics, Inc. | |
oxytocin | peptides | FDA | Eric Hollander, MD | |
Oleoylethanolamide | small molecules | FDA | — | NutriForward, LLC |
D-tagatose | small molecules | FDA | — | Biospherics.net LLC |
Setmelanotide | peptides | EMA | Rhythm Pharmaceuticals Netherlands B.V. | |
setmelanotide | peptides | FDA | Rhythm Metabolics, Inc. | |
oxytocin | peptides | FDA | OT4B | |
Oxytocin | peptides | EMA | OT4B | |
Beloranib | small molecules | EMA | FGK Representative Service GmbH | |
diazoxide choline [Vykat XR] | small molecules | FDA | Approved | Soleno Therapeutics, Inc. |
carbetocin (nasal spray) | small molecules | FDA | Acadia Pharmaceuticals Inc. | |
beloranib | small molecules | FDA | Zafgen, Inc. | |
diazoxide | small molecules | FDA | Sedogen, LLC | |
Carbetocin [FE992097] | small molecules | EMA | Voisin Consulting Life Sciences | |
Betahistine dihydrochloride | small molecules | FDA | Altamira Therapeutics Inc. | |
Somatropin [rDNA] [Genotropin] | proteins | FDA | Approved | Pharmacia & Upjohn |
Etiocholanedione | small molecules | FDA | — | SuperGen, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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