Prader-Willi Research Articles

High flow nasal oxygenation and videolaryngoscopy - the two saviours in a case of Prader-Willi syndrome: A case report

High flow nasal oxygenation and videolaryngoscopy - the two saviours in a case of Prader-Willi syndrome: A case report

A case of congenital cytomegalovirus infection in a child with Prader–Willi syndrome

A possible manifestation of intrauterine infection with herpes viruses can be severe eye damage. Various visual disturbances with negative consequences have been described in Prader–Willi syndrome. The article describes bilateral chorioretinitis in a child with Prader–Willi syndrome, which developed against the background of congenital herpetic infection of CMV etiology.

Schaaf-Yang Syndrome Presenting with Prolonged Hyperthermia in a Child: A Case Report

Introduction: Schaaf-Yang syndrome (SYS) is a rare autosomal dominant disorder, first identified in 2013, resulting from mutations in the paternal allele of the MAGEL2 gene. Schaaf-Yang syndrome exhibits clinical features similar to those of Prader-Willi syndrome (PWS), including hypotonia, joint contractures, developmental delay, and intellectual disability. However, SYS is also characterized by unique manifestations, such as recurrent hyperthermia, feeding difficulties, respiratory distress, and seizures. This case report describes the first SYS case identified in Iran. Case Presentation: A one-year-old female, born to consanguineous parents, presented with recurrent episodes of hyperthermia, respiratory distress, and seizures since the neonatal period. Despite initial empirical treatment with broad-spectrum antibiotics for suspected infections, her symptoms persisted. Physical examination revealed hypotonia, camptodactyly, and hand contractures. Genetic testing confirmed SYS with a MAGEL2 gene mutation (c.1923dupC, p.V643Gfs*70) and probable pathogenic variants in ASPM and KIF7. The hyperthermia was attributed to hypothalamic dysfunction, a hallmark of SYS, rather than an infectious cause. The patient remains under follow-up without specific pharmacological intervention. Conclusions: This case emphasizes the importance of considering SYS in patients presenting with unexplained fever, seizures, and neurodevelopmental delays. Early genetic testing is crucial for diagnosing SYS and differentiating it from conditions such as PWS or infection-related disorders. Timely diagnosis can improve management strategies and help reduce the risk of lasting neurological impairments associated with this genetic disorder.

Fidarsi o non fidarsi del test prenatale non invasivo? Riflessioni a partire da un caso di falso negativo

Non-invasive prenatal testing (NIPT) is a screening for foetal chromosomal abnormalities that identifies at-risk pregnancies and is used to propose a possible invasive genetic confirmation testing in case of its positive results. For Down syndrome (trisomy 21), its accuracy is close to 100%, while for other investigated conditions, it presents various limitations. In a neonate who presented with severe hypotonia and syndromic features, the NIPT was negative for all the screened anomalies. However, among the various investigations performed for the diagnosis, there was an altered methylation of the chromosomal region 15q11.2, indicative of Prader-Willi syndrome (PWS), previously excluded by NIPT. The paper therefore questions the significance of the results of this investigation in front of a clinical suspicion and reviews the use of NIPT in clinical practice.

Use of Basket Trials to Solve Sleep Problems in Patients with Rare Diseases

The need for sleep is universal, and the ability to meet this need impacts the quality of life for patients, families, and caregivers. Although substantial progress has been made in treating rare diseases, many patients have unmet medical sleep needs, and current regulatory policy makes it prohibitively difficult to address those needs medically. This opinion reviews the rare disease experience with sleep disorders and explores potential solutions. First, we provide case profiles for the rare diseases Wilson’s Disease, Angelman Syndrome, and Prader–Willi Syndrome. These profiles highlight challenges in rare disease diagnosis and barriers to pinpointing disease pathophysiology, including biomarkers that intersect with sleep disorders. Second, we transition to a bird’s eye view of sleep disorders and rare diseases by reporting input from a stakeholder discussion with the U.S. Food and Drug Administration regarding abnormal sleep patterns in various rare diseases. Last, in response to the profound unmet medical needs of patients with rare diseases and sleep disorders, we propose adapting and using the clinical trial design known as a “basket trial”. In this case, a basket trial would include patients with different rare diseases but the same debilitating symptoms. This research approach has the potential to benefit many rare disease patients who are otherwise left with profound unmet medical needs.

Exploring Sleep-Related Breathing Disorders in Pediatric Obesity and Prader-Willi Syndrome

ObjectiveTo analyze the differences of clinical and diagnostic features of sleep related breathing disorders (SRBDs) between children with PWS and obese children, considering obesity as a unifying risk factor for sleep apnea. Study designThis retrospective cohort study included ≥2 years of age children who had obesity and genetically confirmed Prader-Willi syndrome (PWS) or were non-PWS obese children. Out of 267 children, 58 children met inclusion criteria. Clinical data and records of standard overnight polysomnography (PSG) were collected and compared between groups during the study. ResultsObstructive sleep apnea (OSA) was identified in 97.2% non-PWS obese children and 72.7% PWS children (p=0.072). Central sleep apnea (CSA) events were more commonly found in children with PWS (p=0.035, OR 4.35, CI 95% 1.05-18.03) as well as sleep-related hypoventilation (p=0.016, OR 4.66, CI 95% 1.26-17.34). Sleep efficiency was higher in PWS patients (p=0.038). Sleep fragmentation was significantly associated with higher AHI only in non-PWS obese children (p=0.027). In the PWS group patients, a moderate correlation was found between BMI and age (p=0.025, r=0.559, CI 95% 0.087-0.826) as well as AHI and age (p=0.003, r=0.686, CI 95% 0.232-0.895). ConclusionsNon-PWS obese children, similar to those with PWS, exhibit a high risk of SRBDs. Although CSA and sleep-related hypoventilation may occur more frequently in patients with PWS, OSA remains the predominant disorder. Both patient groups are advised to undergo PSG due to the significant risk of SRBDs, particularly during adolescence.

Setmelanotide: A Melanocortin-4 Receptor Agonist for the Treatment of Severe Obesity Due to Hypothalamic Dysfunction.

Obesity is a silent global pandemic. It is a condition associated with multiple risk factors and adverse outcomes that arise from the intertwined relationship between environmental factors and genetics. The genetic factors that cause phenotypic expression are variable. Monogenic obesity is a severe early-onset and rarer form of obesity, which presents with co-morbidities such as abnormal feeding behaviour. Monogenic obesity causes impaired weight regulation in the hypothalamus due to defects in the leptin-melanocortin signalling pathway. The emergence of a new therapeutic treatment, the melanocortin-4 receptor agonist setmelanotide (originally RM-493), has represented a breakthrough in the management of monogenic obesity and has raised hope in managing complex obesity. This review provides an overview of the setmelanotide trials that have taken place, as well as its mechanism of action, side effects and weight loss outcomes that led to its approval in the treatment of pro-opiomelanocortin (POMC) deficiency and proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency. It also explores setmelanotide's role in other genetic forms of obesity, such as hypothalamic obesity, Prader-Willi syndrome, Alström syndrome and other rare genetic conditions that are being investigated. This review aims to help to understand the pathophysiology of genetic obesity and aid in future treatment options for people with severe, complex genetic obesity.

Inpatient hospitalisations for patients with Prader-Willi syndrome: a 2019-2021 National Inpatient Sample analysis.

Prader-Willi syndrome (PWS) is a genetic disorder characterised by hyperphagia, intellectual disability and increased propensity to a range of medical disorders. To better characterise the clinical presentation of PWS across the lifespan, this study reports on the demographics and clinical diagnosis of individuals with PWS hospitalised in the United States. The National Inpatient Sample, an all-payor administrative claims database of hospitalisations in the United States, was queried for patients with a coded diagnosis of PWS from October 2019 through December 2021. Hospitalisations for patients with PWS were matched to five non-PWS hospitalisations based on age, sex, year and hospital characteristics. There were 4400 (95% CI: 3,885 to 4,915) PWS hospitalisations, with a median age of 24. Compared to controls, PWS hospitalisations had longer hospital stays (median 5 vs. 3days) and higher in-hospital mortality (2.2% vs. 1.3%). Infectious (19.0%) and respiratory (16.2%) diagnoses were most common for PWS patients. Codes for overweight or obesity were present in 38.1% of PWS hospitalisations, with Hispanic ethnicity was associated with a higher odds of overweight/obesity in PWS patients (aOR 1.73; 95% CI: 1.11-2.71). PWS hospitalisations are characterised by higher healthcare utilisation and complexity compared to matched controls. The high prevalence of obesity and significant rates of infectious and respiratory conditions highlight specific health challenges for PWS patients. Validation of the Q87.11 administrative claims code is an essential step for ongoing health services research in this condition.

Psychological conditions of caregivers of adult subjects with Prader-Willi syndrome

BackgroundPrader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder. Individuals with PWS face a range of cognitive, behavioral, and emotional challenges that require comprehensive and lifelong care, posing significant demands on their caregivers. The study is not only aimed to assess the psychological conditions of caregivers of adult subjects with PWS focusing on psychological distress and coping, but also to shed light on a crucial yet often overlooked aspect of healthcare. This study aims to compare the psychological well-being of individuals with PWS and their caregivers, providing valuable insights that can potentially improve the quality of care for these individuals. The sample recruited at the Division of Auxology, IRCCS Istituto Auxologico Italiano, was composed of 30 adult subjects with PWS (11 men and 19 women; mean age ± SD: 36.4 ± 10.31 years; mean Body Mass Index (BMI): 35.7 ± 8.92: kg/m2) and their caregivers (10 men and 20 women). To assess the psychological condition of caregivers, the Italian-validated versions of the Depression Anxiety and Stress Scale (DASS-21) and the Coping Orientation to the Problems Experiences (COPE) were used, while to assess the psychological well-being of individuals with PWS and their caregivers, the Italian validated version of the Psychological General Well-Being Index (PGWBI) was used.ResultsDepression (p < 0.001), Stress (p = 0.050), and Total score (p = 0.009) of DASS 21 were higher in the caregivers of subjects with PWS than in the general population. PGWBI scores of caregivers were significantly lower than in individuals with PWS in Positive Well-being (p < 0.001), General Health (p = 0.006), Vitality (p = 0.004), and the total score (p = 0.006). The depression subscale of PGWBI was higher in caregivers than in subjects with PWS. Correlations between the subscales of COPE and the total score of PGWBI in caregivers revealed that the Avoidance subscale of COPE had a negative significant correlation with the total score of PGWBI (p = 0.003).ConclusionsOur results highlighted several critical insights into the profound emotional and psychological challenges faced by the caregivers of individuals with PWS.

Effects of long-term transcutaneous auricular vagus nerve stimulation on circadian vagal activity in people with Prader-Willi Syndrome: A case-series

BackgroundPrader-Willi Syndrome (PWS) is a genetic neurodevelopmental disorder marked by disruptions in circadian rhythms and autonomic nervous system (ANS) activity, hyperphagia, and episodes of emotional outbursts. Previous trials suggest that both invasive and non-invasive vagus nerve stimulation (VNS) can reduce emotional outbursts in PWS, potentially through its effects on vagal activity. AimThis case series investigated the effects of transcutaneous auricular VNS (taVNS) on cardiac markers of circadian vagal activity, specifically heart rate variability (HRV) and heart rate (HR), and their potential links to improvements in emotional outbursts. MethodsFive individuals with PWS (mean age: 26.9 years; 3 males, 2 females) received four hours of daily taVNS for 12 months, followed by one month of two-hour daily sessions. Outcome measures included daily recording of emotional outbursts and every three months 24-h HRV and HR recordings. Mixed cosinor models were applied to analyze changes in circadian rhythms of HRV and HR. A linear mixed model was used to assess the predictive value of cardiac vagal activity on emotional outbursts. ResultsCircadian amplitudes of HRV and HR were significantly higher at the end of the treatment compared to baseline (all p’s < .01). There was a significant increase in the rhythm-adjusted mean of HRV (p < .01), while the rhythm-adjusted HR mean significantly decreased, both indicating increased cardiac vagal activity. Higher rhythm-adjusted mean HRV predicted a lower number of emotional outbursts. ConclusionThe results suggest that taVNS may be effective by targeting ANS activity in individuals with PWS, contributing to improvements in behavioral regulation.

Potential of GLP-1 Analogs in Managing Hyperphagia and Obesity in Prader-Willi Syndrome: A Review of Efficacy and Safety

Introduction: Prader-Willi Syndrome (PWS) is a genetic disorder marked by hyperphagia, obesity, developmental delays, and behavioral challenges. Traditional treatments like dietary control and growth hormone therapy often fail to effectively manage these symptoms. Recently, glucagon-like peptide-1 (GLP-1) analogs have shown potential in treating PWS. This review assesses the efficacy, safety and mechanisms of GLP-1 analogs in PWS treatment. They improve glycemic control, cardiovascular health, and appetite regulation, contributing to better weight management and overall health in PWS patients. These analogs enhance insulin secretion, inhibit glucagon release, and slow gastric emptying, helping to reduce postprandial glucose spikes and caloric intake. Results: Several small-scale studies and case reports have shown mixed results regarding the effectiveness of GLP-1 analogs in reducing BMI and hyperphagia in PWS patients. Although the studies demonstrated varied outcomes in terms of BMI reduction, all of them reported improvement in satiety or appetite levels.Conclusions: Overall, GLP-1 analogs hold promise for addressing hyperphagia, obesity, and glycemic control in PWS patients, improving their overall health and quality of life. Continued research and long-term studies are essential to establish these benefits and optimize treatment strategies.

8486 Age at diagnosis in Prader Willi Syndrome (PWS)

Abstract Disclosure: R. Sritharan: None. J. Lodge: None. S. Tadros: None. L. Menzies: None. E.F. Gevers: None. PWS is a complex neurodevelopmental disorder characterised by neonatal hypotonia,failure to thrive, hypothalamic and endocrine dysfunction, behavioural and learning difficulties and hyperphagia. It is caused by absence of expression of paternally imprinted genes on chromosome 15q11-q13. PWS is confirmed by genetic methylation analysis of this region. Most patients with PWS are referred for genetic investigations in the first months of life due to severe hypotonia and/or failure to thrive. However, it is known that some patients are still only diagnosed in adulthood, with resulting missed opportunities for prompt early treatments for PWS, such as growth hormone therapy. Little information is available on age of diagnosis of PWS, and whether opportunities to request genetic investigation are missed in childhood. We therefore aimed to study age at diagnosis of PWS in the UK. To do so, we assessed data as reported to the UK patient association PWSA-UK from 1968-2023, and additionally audited PWS genetic testing by the North Thames Genomics Laboratory Hub from 2019-22. Of 1145 people registered at PWSA as having PWS, 945 had an age of diagnosis recorded. Of these, 254 (28%) were diagnosed over 1 year of age. From March 2021 to Sept 2023, 13 were diagnosed over 1 year of age with a mean age at diagnosis of 9.27 yr (95% CI 4.15 to 14.4) and with 8 patients below 5 years of age. We assessed PWS diagnoses made in blocks of 4 years from 1968, and the number of PWS diagnoses in people over age 1 year in those time blocks. The number of diagnoses in people over 1 year of age appeared to decrease since 1996 to 7 but from 2015 this has been fluctuating. North Thames Genomics Laboratory Hub provides testing for around 10 million people in and around London. Over a 3-year period between 2019-2022, there were 59 requests for PWS testing. 28 of these were positive (a 47% diagnostic yield). 20/28 (71%) of patients were diagnosed under 1 month of age, 7% were diagnosed at 1-24 months of age, 3.5% at 2-5 yrs and 18% at &amp;gt;5 yrs of age (one at age 9, two at age 18, one at age 29 and one at 33 yrs of age). Most tests were performed in children under1 month of age (91% yield), followed by those over 5 yrs of age (30% yield). For 10 individuals, microarray was requested, however methylation studies would have been more appropriate. All patients diagnosed over 5 years of age had hypotonia and were described as hyperphagic and having intellectual disability, and 75% were obese. Patients diagnosed after age 8were described as having neonatal hypotonia and may have been eligible for genetic testing soon after birth. These data suggest that a considerable percentage of patients are diagnosed with PWS after the first year of life in the UK. Further root analysis, interventions, and education is required to reduce age at diagnosis in patients with PWS to allow for optimal management starting in the first few months of life. Presentation: 6/1/2024

7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome

Abstract Disclosure: E.F. Gevers: Advisory Board Member; Self; Pfizer, Inc., Soleno. Research Investigator; Self; Soleno Therapeutics, Inc.. Speaker; Self; Pfizer, Inc., Novo Nordisk, Soleno Therapeutics, Inc. J.L. Miller: Research Investigator; Self; Soleno Therapeutics, Inc. N.A. Bridges: Research Investigator; Self; Soleno Therapeutics, Inc. E.I. Felner: Research Investigator; Self; Soleno Therapeutics, Inc. P. Salehi: Research Investigator; Self; Soleno Therapeutics, Inc. D. Stevenson: Research Investigator; Self; Soleno Therapeutics, Inc. J. Yanovski: Research Investigator; Self; Soleno Therapeutics, Inc. L. Bird: Research Investigator; Self; Soleno Therapeutics, Inc. V. Kimonis: Research Investigator; Self; Soleno Therapeutics, Inc. A.H. Shoemaker: Research Investigator; Self; Soleno Therapeutics, Inc. K.S. Obrynba: Research Investigator; Self; Soleno Therapeutics, Inc. M. Lah: Research Investigator; Self; Soleno Therapeutics, Inc. E. Littlejohn: Research Investigator; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. K. Yen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. S. Ballal: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. P. Hirano: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. M. Huang: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. A. Bhatnagar: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc.. Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition. Presentation: 6/2/2024

8650 Co-Localization Pattern of Snhg14 Long Noncoding RNA and Nhlh2 mRNA in Hypothalamus Coincides with Obesity and Endocrine Impairment Phenotypes in Prader-Willi Syndrome

Abstract Disclosure: S. Ariyanfar: None. C.K. Thompson: None. S. Tobet: None. D.J. Good: None. Prader–Willi syndrome (PWS) is a multisystemic neurodevelopmental disorder, characterized by biphasic symptoms, including diminished weight gain during development, along with neonatal hypotonia and failure to thrive, with later onset hyperphagia, severe weight gain, and morbid obesity. PWS arises from the deletion or inactivation of paternally inherited genes, with the smallest region encompassing a group of 30 small nucleolar RNAs ‘snoRNAs’ known as the SNORD116@ locus. SNORD116@ snoRNAs are cleaved from a larger long non-coding gene, SNHG14. Whole-body deletion of Nhlh2 in mice results in PWS-like phenotypes, such as later onset weight gain, and delayed puberty. We previously have shown that overexpression of Snord116-3 in a mouse hypothalamic cell line improves the stability of Nhlh2 mRNA, likely through a motif in the 3’ untranslated region of the Nhlh2 mRNA. This motif can be disrupted by the presence of a single nucleotide polymorphism, confirming the mechanism of action. Nevertheless, to date, no published studies are showing the in vivo co-localization between Nhlh2 and Snord116 (or its host gene, Snhg14), and the question of where and when Snord116 snoRNAs interact with target mRNA Nhlh2 remains unanswered. To fill this gap, we mapped simultaneous expression of Snhg14 and Nhlh2 throughout the adult mouse brain, using quantitative RNA multi-plex in situ hybridization “RNAScope”. In our initial analysis, we focused on Pomc neurons of the hypothalamus as targeted deletion of Nhlh2 in these neurons results in obesity levels similar to that of the whole body deletion of Nhlh2, a present phenotype in PWS. Our data for the first time showed the co-expression of Nhlh2 and Snhg14 in Pomc neurons of Arcuate nucleus. In the analysis of 54 Pomc neurons, 72% and 39% were positive for Nhlh2 and Snhg14 expression respectively, with 39% of detected signals co-expressed in the same cell (correlation coefficient 0.78, P &amp;lt; 0.0001). Interestingly, in neurons that only expressed Nhlh2 (33) there were nearly evenly distributed signals in the cytoplasm (9 cells) and nucleus (10 cells). When both Nhlh2 and Snhg14 messages were coexpressed, 17 of the 21 cells expressed Nhlh2 in the nucleus only (P &amp;lt; 0.0003, P&amp;lt; 0.0007 for the Likelihood ratio test and Chi-square test, respectively). Thus, based on the high magnification cell analysis, acquired 3D images, and probe location, we can conclude that the Snhg14 host transcript and Nhlh2 interact spatially. This new in vivo data supports the previously shown regulatory role for Snord 116 snoRNAs towards Nhlh2 mRNA stability and suggests that regulation may involve nuclear sequestration of Nhlh2. We are currently extending our studies to examine expression in the brains from patients with PWS and determine if energy balance signals affect co-localization patterns within the hypothalamus. Presentation: 6/3/2024

Comprehensive molecular and clinical findings in 29 patients with multi-locus imprinting disturbance

BackgroundMulti-locus imprinting disturbance (MLID) with methylation defects in various differentially methylated regions (DMRs) has recently been identified in approximately 150 cases with imprinting disorders (IDs), and deleterious variants have been found in genes related to methylation maintenance of DMRs, such as those encoding proteins constructing the subcortical maternal complex (SCMC), in a small fraction of patients and/or their mothers. However, integrated methylation analysis for DMRs and sequence analysis for MLID-causative genes in MLID cases and their mothers have been performed only in a single study focusing on Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) phenotypes.ResultsOf 783 patients with various IDs we have identified to date, we examined a total of 386 patients with confirmed epimutation and 71 patients with epimutation or uniparental disomy. Consequently, we identified MLID in 29 patients with epimutation confirmed by methylation analysis for multiple ID-associated DMRs using pyrosequencing and/or methylation-specific multiple ligation-dependent probe amplification. MLID was detected in approximately 12% of patients with BWS phenotype and approximately 5% of patients with SRS phenotype, but not in patients with Kagami-Ogata syndrome, Prader-Willi syndrome, or Angelman syndrome phenotypes. We next conducted array-based methylation analysis for 78 DMRs and whole-exome sequencing in the 29 patients, revealing hypomethylation-dominant aberrant methylation patterns in various DMRs of all the patients, eight probably deleterious variants in genes for SCMC in the mothers of patients, and one homozygous deleterious variant in ZNF445 in one patient. These variants did not show gene-specific methylation disturbance patterns. Clinically, neurodevelopmental delay and/or intellectual developmental disorder (ND/IDD) was observed in about half of the MLID patients, with no association with the identified methylation disturbance patterns and genetic variants. Notably, seven patients with BWS phenotype were conceived by assisted reproductive technology (ART).ConclusionsThe frequency of MLID was 7.5% (29/386) in IDs caused by confirmed epimutation. Furthermore, we revealed diverse patterns of hypomethylation-dominant methylation defects, nine deleterious variants, ND/IDD complications in about half of the MLID patients, and a high frequency of MLID in ART-conceived patients.

The influence of genotype makeup on the effectiveness of growth hormone therapy in children with Prader-Willi syndrome

BackgroundPrader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS.MethodsA review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment.ResultsChildren with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05).ConclusionsrhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.

Listening to Patients: Incidence and Distribution of Sleep Disorders in Prader-Willi Syndrome

Listening to Patients: Incidence and Distribution of Sleep Disorders in Prader-Willi Syndrome

Long-Term Follow-up of an Infant with Prader-Willi Syndrome.

Long-Term Follow-up of an Infant with Prader-Willi Syndrome.

Neuropeptide therapeutics to repress lateral septum neurons that disable sociability in an autism mouse model.

Confronting oxytocin and vasopressin deficits in autism spectrum disorders and rare syndromes brought promises and disappointments for the treatment of social disabilities. We searched downstream of oxytocin and vasopressin for targets alleviating social deficits in a mouse model of Prader-Willi syndrome and Schaaf-Yang syndrome, both associated with high prevalence of autism. We found a population of neurons in the lateral septum-activated on termination of social contacts-which oxytocin and vasopressin inhibit as per degree of peer affiliation. These are somatostatin neurons expressing oxytocin receptors coupled to GABA-B signaling, which are inhibited via GABA-A channels by vasopressin-excited GABA neurons. Loss of oxytocin or vasopressin signaling recapitulated the disease phenotype. By contrast, deactivation of somatostatin neurons or receptor signaling alleviated social deficits of disease models by increasing the duration of contacts with mates and strangers. These findings provide new insights into the treatment framework of social disabilities in neuropsychiatric disorders.

Characterization of Circulating Protein Profiles in Individuals with Prader–Willi Syndrome and Individuals with Non-Syndromic Obesity

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder characterized by distinctive physical, cognitive, and behavioral manifestations, coupled with profound alterations in appetite regulation, leading to severe obesity and metabolic dysregulation. These clinical features arise from disruptions in neurodevelopment and neuroendocrine regulation, yet the molecular intricacies of PWS remain incompletely understood. Methods: This study aimed to comprehensively profile circulating neuromodulatory factors in the serum of 53 subjects with PWS and 34 patients with non-syndromic obesity, utilizing a proximity extension assay with the Olink Target 96 neuro-exploratory and neurology panels. The ANOVA p-values were adjusted for multiple testing using the Benjamani–Hochberg method. Protein–protein interaction networks were generated in STRING V.12. Corrplots were calculated with R4.2.2 by using the Hmisc, Performance Analytics, and Corrplot packages Results: Our investigation explored the potential genetic underpinnings of the circulating protein signature observed in PWS, revealing intricate connections between genes in the PWS critical region and the identified circulating proteins associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment involving, CD38, KYNU, NPM1, NMNAT1, WFIKKN1, and GDF-8/MSTN. The downregulation of CD38 in individuals with PWS (p &lt; 0.01) indicates dysregulation of oxytocin release, implicating pathways associated with NAD metabolism in which KYNU and NMNAT1 are involved and significantly downregulated in PWS (p &lt; 0.01 and p &lt; 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p &lt; 0.05) were also observed. Conclusions: This study highlights potential circulating protein biomarkers associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment in PWS individuals with potential clinical implications.