Search Results (133)

Background: Prader–Willi Syndrome (PWS) is a genetic neurodevelopmental disorder caused by an alteration of the paternal chromosome 15q11-q13. Youth with PWS present hyperphagia, increased fat/decreased muscle mass, hypotonia, and decreased metabolic rate with risk of obesity. Thermoregulation problems have been previously reported with hypothermia in adults or hyperthermia in children/infants with PWS. Methods: We retrospectively examined a cohort of 44 youths with PWS, 8–16 years old, presenting with a medical history of temperature dysregulation (TD), hypothermia or hyperthermia. Participants with (n = 10) and without (n = 34) a history of TD were compared for anthropometrics, body composition, medical history, and motor characteristics. Results: Youth with TD presented with hypothermia (n = 8), hyperthermia (n = 2), or both conditions (n = 2). Non-parametric statistics showed no significant differences in age, anthropometrics, body composition, or motor characteristics between the groups (p ≥ 0.064). Those with TD presented with a higher frequency of sleep apnea versus those without (50% vs. 18%; p = 0.038). Conclusions: The prevalence of TD in the cohort was one in five youth with PWS, suggesting that the problem is not isolated. The results do not suggest that anthropometrics, body composition, or motor characteristics explain differences in temperature excursions in youths with PWS. Possible physiological mechanisms and future research are discussed. Full article

Background/Objectives: Prader–Willi Syndrome (PWS) is a neurodevelopmental disease associated with multiple behavioral features, including a prevalence for psychosis. The genetic causes of PWS are well characterized and involve the silencing or deletion of the paternal copy of a region of chromosome 15q11–13. One gene within this region, Snord116, a non-coding RNA, has been determined to have a determinant role in the manifestation of PWS. However, it remains unclear as to how the deletion of this allele can affect activity in the brain and influence psychosis-like behaviors. Methods: In this study, we assessed the effects of the microdeletion of the paternal copy of Snord116 on regional neural activity in psychosis-associated brain regions and psychosis-like behaviors in mice. Results: The results suggest that Snord116 deletion causes increased c-Fos expression in the hippocampus and anterior cingulate cortex. Snord116 deletion also results in behavioral phenotypes consistent with psychosis, most notably in stressful paradigms, with deficits in sensorimotor gating and augmented contextual as well as cued fear conditioning. Conclusions: These results implicate the targets of Snord116 in the presentation of a psychosis-like state with regional specificity. Full article

Background: Currently, there is a lack of data regarding the reliability of different anthropometric, instrumental, and biochemical indexes in detecting metabolic syndrome (MetS) in pediatric patients with Prader–Willi syndrome (PWS). Therefore, this study aimed to compare the accuracy of different indices to identify the simplest and most accurate predictor of MetS in this at-risk population. Methods: We conducted a multicenter study involving 124 children and adolescents with PWS (61 males and 63 females), aged 13.6 ± 3.7 years. For each participant, we assessed all components of MetS, defined according to either the Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS (IDEFICS) study or the International Diabetes Federation (IDF) criteria, based on age. The following indexes were calculated: Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), tri-ponderal mass index, body mass fat index, fat mass index, fat-free mass index, body shape index, visceral adiposity index, waist-to-height ratio, cardiometabolic index, total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, and triglycerides/HDL-C (TG/HDL-C) ratio. Results: MetS was identified in 24 subjects (9 females and 15 males), representing 19.4% of the sample. When comparing the receiver operating characteristic (ROC) curves, the TG/HDL-C ratio and cardiometabolic index demonstrated significantly better performance than the other indices in detecting MetS, with no difference between the two. As a result, we focused on the TG/HDL-C ratio since it is the simplest measure, requiring no additional anthropometric data compared to the cardiometabolic index. Additionally, applying age- and gender-specific thresholds can further improve its accuracy. Conclusions: The TG/HDL-C ratio, which requires only two standard biochemical markers, provides the same accuracy as more complex indexes in detecting MetS in children and adolescents with PWS, making it the optimal predictor for MetS in this population. Full article

Background and Clinical Significance: Prader–Willi syndrome (PWS) is a rare genetic disease caused by imprinted gene dysfunction, typically involving deletion of the chromosome 15q11.2-q13 region, balanced translocation, or related gene mutations in this region. PWS presents with complex and varied clinical manifestations. Abnormalities can be observed from the fetal stage and change with age, resulting in growth, developmental, and metabolic issues throughout different life stages. Case Presentation: We report the prenatal characteristics observed from the second to third trimester of pregnancy in a neonate with PWS. Prenatal ultrasound findings included a single umbilical artery, poor abdominal circumference growth from 26 weeks, normal head circumference and femur length growth, increased amniotic fluid volume after 30 weeks, undescended fetal testicles in the third trimester, small kidneys, and reduced fetal movement. The male infant was born at 38 weeks of gestation with a birth weight of 2580 g. He had a weak cry; severe hypotonia; small eyelid clefts; bilateral cryptorchidism; low responsiveness to medical procedures such as blood drawing; and poor sucking, necessitating tube feeding. Blood methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) showed paternal deletion PWS. Notably, this case revealed two previously unreported prenatal features in PWS: a single umbilical artery and small kidneys. Conclusions: Through literature review and our case presentation, we suggest that a combination of specific sonographic features, including these newly identified markers, may aid clinicians in the early diagnosis of PWS. Full article

Background: Uniparental disomy (UPD) refers to the condition in which both chromosomes (or part of chromosome) of a pair are inherited from the same parent. There are two types of UPD: uniparental isodisomy (both chromosomes inherited from one parent are identical copies) and uniparental heterodisomy (two different chromosomes are inherited from one parent). UPD presents two primary developmental risks: recessive trait inheritance or an imprinting disorder. These risks may coexist, leading to an ultra-rare comorbidity. Managing the comorbidities associated with rare diseases presents unique clinical challenges. Results: The existence of such phenomena is evidenced by our case report of a boy who was ultimately diagnosed with two rare diseases: Prader–Willi syndrome (PWS), due to the maternal uniparental disomy of chromosome 15 (UPD), and autosomal recessive Lodder–Merla type 1 syndrome, linked to a novel pathogenic variant in the G protein subunit β 5 (GNB5) gene, as detailed in this paper. Conclusions: An unusual or severe phenotype in a patient diagnosed with PWS should invariably prompt the consideration of a comorbid genetic disease attributable to genes located in the PWS critical region of chromosome 15q, or elsewhere on chromosome 15. In cases of epileptic encephalopathy with cardiac arrhythmia, prompt consultation with a cardiologist and comprehensive genetic testing are essential to reduce the risks associated with untreated arrhythmia and ensure the provision of appropriate and safe anti-epileptic therapy. The presented case provides further support for the hypothesis that uniparental disomy may serve as an underlying cause of Lodder–Merla syndrome. This underscores the significance of comprehensive genetic testing, encompassing parental testing and familial cascade testing (in selected cases where there is consanguinity, or the likelihood of close common ancestral background between partners) to establish the recurrence risk. Full article

Background/Objectives: This study compared metabolic syndrome (MetS) features in patients with Prader-Willi syndrome (PWS) to those in age-, BMI-, and gender-matched subjects with essential obesity (EOB). Methods: Thirty-two PWS patients (23 females, 9 males; median age 31.6 years; BMI 42.0 kg/m²) underwent several assessments, including anthropometric measurements, body composition via bio-impedance analysis, basal metabolic rate (BMR) using indirect calorimetry, and blood sampling. Results: Their data were compared to a matched EOB group (23 females, 9 males; median age 31.4 years; BMI 43.5 kg/m²). The study groups (PWS and EOB) were subsequently divided into two subgroups based on the International Diabetes Federation criteria for the definition of MetS. Results showed that individuals with PWS had significantly lower (p < 0.001) body weight (BW, −20.9%), height (−8.9%), fat-free mass (FFM, −23.5%), and fat mass (FM, −19.2%) in absolute terms compared to EOB subjects. However, the relative percentages of FFM and FM were similar. Absolute BMR was 25.5% (p < 0.001) lower in the PWS group; however, this difference disappeared when adjusted for FFM or body weight (BW). Metabolic outcomes were broadly similar between the groups, except for higher fasting glucose (+7.3%) and HbA1c levels (+7.9%), and lower fasting insulin (−29.0%) in PWS patients. Conclusions: Moreover, PWS subjects exhibited higher total cholesterol (+9.6%) and HDL-cholesterol (+19.8%), suggesting a more favourable lipid profile and no extra risk beyond severe obesity. Full article

Prader-Willi syndrome (PWS) is a rare genetic disorder. The main characteristics are muscular hypotonia, failure to thrive and feeding problems in infancy, which switch to hyperphagia in early childhood and continue into adulthood. Due to hyperphagia, the risk of developing morbid obesity is high without treatment. PWS is considered a hypothalamic disease, and within the hypothalamus the arcuate nucleus (AC) is of central importance for controlling metabolism, hunger, and satiety. The AC has been studied in several animal models as well as in humans, including PWS. The function of AC is regulated by several neuropeptides and proteins produced within the central nervous system such as oxytocin, orexin, tachykinins as well as the hypothalamic hormones, regulating the adeno-hypophyseal hormones, also acting as neurotransmitters. Additionally, there are many peripheral hormones among which insulin, leptin, adiponectin, ghrelin, and glucagon-like peptide (GLP-1) are the most important. High levels of adiponectin and ghrelin have consistently been reported in PWS, but dysregulation and deviating levels of many other factors and hormones have also been demonstrated in both individuals with PWS and in animal models. In this review, we focus on the role of AC and peptides and proteins produced within the central nervous system in the regulation of hunger and satiety in PWS. Full article

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder mapping to the imprinted 15q11-13 locus, specifically at the paternally expressed snord116 region, which has been implicated in controlling epigenetic mechanisms. Some aspects of the PWS-related clinical phenotype, such as the high mortality rate in adulthood, might be attributed to accelerated epigenetic ageing. Objectives: The aim of the present case–control study was to evaluate epigenetic age, age acceleration, vascular age (VA), and vascular ageing in adults with PWS (n = 24; F/M = 11/13; age = 36.8 [26.6; 45.3] years; body mass index, BMI = 36.8 [33.9; 44.8] kg/m²), compared with a sex- and age-matched group of subjects with essential obesity (EOB) (n = 36; F/M = 19/17; age = 43.4 [30.6; 49.5] years; BMI = 44.8 [41.2; 51.7] kg/m²). Results: In subjects with PWS, there was a younger epigenetic age and a lower age acceleration than in subjects with EOB. No differences were found between VA and vascular ageing in the two groups. Epigenetic age was associated with chronological age and VA within each group. For each group, no relevant associations of epigenetic age or age acceleration with demographic, biochemical, and clinical parameters were found. When considering individuals with PWS, there were no associations of epigenetic age with growth hormone (GH) deficiency, duration of hormone replacement therapy, and plasma levels of insulin-like growth factor 1 (IGF-1). Conclusions: The hypothesis of accelerated epigenetic ageing in PWS should be rejected. Additionally, considering the existence of a SNORD116-dependent epigenetic dysregulation in PWS, the results of the present study might be misleading, since an epigenetics-based approach was used to measure ageing. Full article

Background: Prader–Willi Syndrome (PWS) is a rare, genetic, multi-systemic disorder. Its main characteristics are muscular hypotonia, behavioral problems, intellectual disability, endocrine deficiencies, hyperphagia, and a high risk of morbid obesity and related comorbidities. This study aimed to investigate the rate of comorbidity, prescription of endocrine medications, and mortality in individuals with PWS compared to the general population. Methods: The association between PWS and outcomes were investigated in a matched cohort study of individuals born in the period of 1930–2018 with data from Swedish national health and welfare registers. Each individual was matched with 50 non-PWS comparisons. The associations between PWS, outcomes and prescribed endocrine medications were estimated through Cox proportional hazard models, presented as Hazard Ratios (HR) with 95% Confidence Intervals (CIs). Results: Among 360 individuals (53% men) with PWS, 16% had diabetes mellitus, 6% heart failure, 4% vein thrombosis, 2% atrial fibrillation, 2% coronary heart disease, and 1% pulmonary embolism. Individuals with PWS had an increased rate of heart failure (HR: 23.85; 95% CI: 14.09–40.38), diabetes mellitus (HR: 17.49; 95% CI: 12.87–23.74), vein thrombosis (HR: 10.44; 95% CI: 5.69–19.13), pulmonary embolism (HR: 5.77; 95% CI: 2.27–14.67), atrial fibrillation (HR: 5.19; 95% CI: 2.48–10.86), and coronary heart disease (HR: 3.46; 95% CI: 1.50–7.97) compared to non-PWS individuals. Somatotropin was prescribed in 63%, antidiabetics in 18%, and thyroid hormones in 16% of the PWS individuals (<1%, 2%, and 3%, respectively, in non-PWS individuals). The rate of mortality was fifteen times higher in PWS than in non-PWS, with a mean age at death of 42 years. Conclusions: The rates of diabetes mellitus and cardiovascular comorbidities were higher in individuals with PWS. As expected, the prescription of somatotropin was high, but the endocrine prescription pattern also reflected the high prevalence of diabetes mellitus and thyroid illness. Although the mean age at death was older than previously reported, a higher awareness and intensified efforts to avoid obesity, as well as the prevention and early treatment of cardiovascular and endocrine comorbidity, are crucial aims in the care of people with PWS. Full article

Background/Objectives: Prader–Willi syndrome (PWS) is a rare, genetically determined neurodevelopmental disorder. Individuals with PWS face numerous challenges that significantly impact their psychological well-being and quality of life, ultimately limiting their personal and social functioning. This study aimed to evaluate the quality of life and psychological well-being in a sample of Italian adult patients with PWS compared to an age-matched control group of normal-weight Italian individuals. Methods: Thirty patients 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 thirty Italian adult individuals from the general population (5 men and 25 women; mean age ± SD: 32.1 ± 6.86 years; mean Body Mass Index (BMI: 21.8 ± 2.90 kg/m²) were studied. Quality of life and well-being were assessed using the Italian versions of the 36-item Health Survey Short Form and the Psychological General Well-Being Index. Results: Normal-weight subjects scored significantly higher than PWS patients on the physical health (p < 0.001) and social functioning (p = 0.047) subscales of the SF-36. Conversely, PWS patients scored higher on the vitality subscale (p < 0.001). Similarly, the vitality subscale of the PGWBI was significantly higher in PWS patients than in controls (p = 0.010), whereas the Self-Control subscale of the PGWBI was higher in controls compared to PWS patients, albeit not statistically significant (p = 0.057). Discussion: Patients with PWS exhibited impairments in various aspects of quality of life and psychological well-being, including physical, behavioral, and social domains. However, the higher vitality scores observed in PWS patients suggest a preserved dimension of their psychological well-being. Conclusions: These findings enhance the understanding of the psychological condition of patients with PWS and provide valuable insights for improving multidisciplinary psychological treatment approaches for these individuals. Full article

Background/objectives: Euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is a mammalian histone methyltransferase that catalyzes the dimethylation of histone 3 lysine 9 (H3K9). On human chromosome 15, the parental-specific expression of Prader–Willi Syndrome (PWS)-related genes, such as SNRPN and SNORD116, are regulated through the genetic imprinting of the PWS imprinting center (PWS-IC). On the paternal allele, PWS genes are expressed whereas the epigenetic maternal silencing of PWS genes is controlled by the EHMT2-mediated methylation of H3K9 in PWS-IC. Here, we measured the effects of RNA interference of EHMT2 on the maternal expression of genes deficient in PWS in mouse model and patient iPSC-derived cells. Methods: We used small interfering RNA (siRNA) oligonucleotides and lentiviral short harpin RNA (shRNA) to reduce Ehtm2/EHMT2 expression in mouse Snord116 deletion primary neurons, PWS patient-derived induced pluripotent stem cell (iPSC) line and PWS iPSC-derived neurons. We then measured the expression of transcript or protein (if relevant) of PWS genes normally silenced on the maternal allele. Results: With an approximate reduction of 90% in EHMT2 mRNA and more than 80% of the EHMT2 protein, we demonstrated close to a 2-fold increase in the expression of maternal transcripts for SNRPN and SNORD116 in PWS iPSCs treated with siEHMT2 compared to PWS iPSC siControl. A similar increase in SNORD116 and SNRPN RNA expression was observed in PWS iPSC-derived neurons treated with shEHMT2. Conclusions: RNAi reduction in EHMT2 activates maternally silenced PWS genes. Further studies are needed to determine whether the increase is therapeutically relevant. This study confirms the role of EHMT2 in the epigenetic regulation of PWS genes. Full article

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 < 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 < 0.01 and p < 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p < 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. Full article

Despite therapy with growth hormone (GH) in children with Prader–Willi syndrome (PWS), low bone mineral density and various orthopedic deformities have been observed often. Therefore, this study aimed to analyze bone markers, with an emphasis on vitamin K-dependent proteins (VKDPs), in normal-weight children with PWS undergoing GH therapy and a low-energy dietary intervention. Twenty-four children with PWS and 30 healthy children of the same age were included. Serum concentrations of bone alkaline phosphatase (BALP), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), periostin, osteopontin, osteoprotegerin (OPG), sclerostin, C-terminal telopeptide of type I collagen (CTX-I), and insulin-like growth factor-I (IGF-I) were determined using immunoenzymatic methods. OC levels and the OC/CTX-I ratios were lower in children with PWS than in healthy children (p = 0.011, p = 0.006, respectively). Glu-OC concentrations were lower (p = 0.002), but Gla-OC and periostin concentrations were higher in patients with PWS compared with the controls (p = 0.005, p < 0.001, respectively). The relationships between IGF-I and OC (p = 0.013), Gla-OC (p = 0.042), and the OC/CTX-I ratio (p = 0.017) were significant after adjusting for age in children with PWS. Bone turnover disorders in children with PWS may result from impaired bone formation due to the lower concentrations of OC and the OC/CTX-I ratio. The altered profile of OC forms with elevated periostin concentrations may indicate more intensive carboxylation processes of VKDPs in these patients. The detailed relationships between the GH/IGF-I axis and bone metabolism markers, particularly VKDPs, in children with PWS requires further research. Full article

Prader–Willi Syndrome (PWS) is a rare genetic disorder typically characterized by decreased social interaction, hyperphagia, poor behavioral control and temper tantrums, together with a high risk of morbid obesity unless food intake is controlled. The genetic defects that cause PWS include paternal 15q deletion (estimated in 60% of cases), chromosome 15 maternal uniparental disomy (UPD) (estimated in 35% of cases) and imprinting defects and translocations. Several studies indicate an oxytocin deficiency in PWS. Oxytocin is a hypothalamic nonapeptide with receptors located in the brain and in various other tissues in the body. It acts as a neuropeptide in several brain areas of great importance for behavioral and metabolic effects, as well as a neurohypophyseal hormone released into the circulation. Oxytocin in both rats and humans has strong and long-lasting behavioral and metabolic effects. Thus, an oxytocin deficiency might be involved in several of the behavioral and metabolic symptoms characterizing PWS. Treatment with oxytocin has, in some studies, shown improvement in psycho-social behavior and hyperphagia in individuals with PWS. This review focus on the behavioral and metabolic effects of oxytocin, the symptoms of a potential oxytocin deficiency in PWS and the effects of oxytocin treatment. Full article

Purpose: An investigation for the co-occurrence of two unrelated genetic disorders of muscular dystrophy and Prader-Willi syndrome (PWS) (OMIM#176270) using joint whole genome sequencing (WGS). Methods: Trio WGS joint analysis was performed to investigate the genetic etiology in a proband with PWS, prolonged muscular hypotonia associated hyperCKemia, and early-onset obesity. The parents were unaffected. Results: Results showed maternal isodisomy uniparental disomy (UPD) in chromosome 15, expanding from 15q11.2 to 15q22.2, including PWS regions at 15q11.2–15q13. Maternal heterodisomy was detected from 15q22.2 to 15q26.3. A pathogenic variant, NM_000070.3(CAPN3):c.550del (p.Thr184fs), was identified at 15q15.1 in a heterozygous state in the mother that was homozygous in the proband due to maternal isodisomy. Conclusion: This is the first study of the concurrent molecular etiology of PWS and calpainopathy (OMIM#253600) in the same patient. This report highlights the utility of joint analysis and the need for the assessment of autosomal recessive disease in regions of isodisomy in patients with complex and unexplained phenotypes. Full article