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Frontiers in Endocrinology 2023Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique...
INTRODUCTION
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS.
METHODS
Circulating proteome profiling was conducted in 29 individuals with PWS (15 with steatosis, 14 without) using the Olink Target 96 metabolism and cardiometabolic panels. Correlation analysis was performed to identify the association between protein biomarkes and clinical variables, while the gene enrichment analysis was conducted to identify pathways linked to deregulated proteins. Receiver operating characteristic (ROC) curves assessed the discriminatory power of circulating protein while a logistic regression model evaluated the potential of a combination of protein biomarkers.
RESULTS
CDH2, CTSO, QDPR, CANT1, ALDH1A1, TYMP, ADGRE, KYAT1, MCFD, SEMA3F, THOP1, TXND5, SSC4D, FBP1, and CES1 exhibited a significant differential expression in liver steatosis, with a progressive increase from grade 1 to grade 3. FBP1, CES1, and QDPR showed predominant liver expression. The logistic regression model, -34.19 + 0.85 * QDPR*QDPR + 0.75 * CANT1*TYMP - 0.46 * THOP1*ALDH1A, achieved an AUC of 0.93 (95% CI: 0.63-0.99), with a sensitivity of 93% and specificity of 80% for detecting steatosis in individuals with PWS. These biomarkers showed strong correlations among themselves and were involved in an interconnected network of 62 nodes, related to seven metabolic pathways. They were also significantly associated with cholesterol, LDL, triglycerides, transaminases, HbA1c, FLI, APRI, and HOMA, and showed a negative correlation with HDL levels.
CONCLUSION
The biomarkers identified in this study offer the potential for improved patient stratification and personalized therapeutic protocols.
Topics: Humans; Prader-Willi Syndrome; Proteome; Obesity; Fatty Liver; Biomarkers; Membrane Proteins; Nerve Tissue Proteins
PubMed: 38034016
DOI: 10.3389/fendo.2023.1254778 -
International Journal of Molecular... Jul 2023Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...].
Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...].
Topics: Humans; Prader-Willi Syndrome; Genomic Imprinting; Drug Approval; Chromosomes; Chromosomes, Human, Pair 15
PubMed: 37511333
DOI: 10.3390/ijms241411574 -
Orphanet Journal of Rare Diseases Jun 2024Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in...
BACKGROUND
Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis.
RESULTS
We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles.
CONCLUSIONS
The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Genotype; Phenotype; Brazil; Child, Preschool; Child; Adolescent; Adult; Uniparental Disomy; Chromosomes, Human, Pair 15; Infant; Young Adult
PubMed: 38902749
DOI: 10.1186/s13023-024-03157-2 -
Surgery For Obesity and Related... Aug 2023Obesity is the leading cause of morbidity and mortality in patients with Prader-Willi Syndrome (PWS). Our objective was to compare changes in body mass index (BMI) after... (Meta-Analysis)
Meta-Analysis
Obesity is the leading cause of morbidity and mortality in patients with Prader-Willi Syndrome (PWS). Our objective was to compare changes in body mass index (BMI) after metabolic and bariatric surgery (MBS) for the treatment of obesity (BMI ≥35 kg/m) in PWS. A systematic review of MBS in PWS was performed using PubMed, Embase, and Cochrane Central, identifying 254 citations. Sixty-seven patients from 22 articles met criteria for inclusion in the meta-analysis. Patients were organized into 3 groups: laparoscopic sleeve gastrectomy (LSG), gastric bypass (GB), and biliopancreatic diversion (BPD). No mortality within 1 year was reported in any of the 3 groups after a primary MBS operation. All groups experienced a significant decrease in BMI at 1 year with a mean reduction in BMI of 14.7 kg/m (P < .001). The LSG groups (n = 26) showed significant change from baseline in years 1, 2, and 3 (P value at year 3 = .002) but did not show significance in years 5, 7, and 10. The GB group (n = 10) showed a significant reduction in BMI of 12.1 kg/m in the first 2 years (P = .001). The BPD group (n = 28) had a significant reduction in BMI through 7 years with an average reduction of 10.7 kg/m (P = .02) at year 7. Individuals with PWS who underwent MBS had significant BMI reduction sustained in the LSG, GB, and BPD groups for 3, 2, and 7 years, respectively. No deaths within 1 year of these primary MBS operations were reported in this study or any other publication.
Topics: Humans; Bariatric Surgery; Biliopancreatic Diversion; Gastric Bypass; Obesity; Prader-Willi Syndrome; Body Mass Index
PubMed: 36872159
DOI: 10.1016/j.soard.2023.01.017 -
Orphanet Journal of Rare Diseases Jul 2023Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence suggests that inflammation is implicated in the pathogenesis. Here we investigated CVD related immune markers to shed light on pathogenetic mechanisms.
METHODS
We performed a cross-sectional study with 22 participants with PWS and 22 healthy controls (HC), and compared levels of 21 inflammatory markers that reflect activity in different aspects of CVD related immune pathways and analyzed their association with clinical CVD risk factors.
RESULTS
Serum levels of matrix metalloproteinase 9 (MMP-9) was (median (range)) 121 (182) ng/ml in PWS versus 44 (51) ng/ml in HC, p = 1 × 10), myeloperoxidase (MPO) was 183 (696) ng/ml versus 65 (180) ng/ml, p = 1 × 10) and macrophage inhibitory factor (MIF) was 46 (150) ng/ml versus 121 (163) ng/ml (p = 1 × 10), after adjusting for age and sex. Also other markers tended to be elevated (OPG, sIL2RA, CHI3L1, VEGF) but not significantly after Bonferroni correction (p > 0.002). As expected PWS had higher body mass index, waist circumference, leptin, C-reactive protein, glycosylated hemoglobin (HbA1c), VAI and cholesterol, but MMP-9, MPO and MIF remained significantly different in PWS after adjustment for these clinical CVD risk factors.
CONCLUSION
PWS had elevated levels of MMP-9 and MPO and of reduced levels of MIF, which were not secondary to comorbid CVD risk factors. This immune profile suggests enhanced monocyte/neutrophil activation, impaired macrophage inhibition with enhanced extracellular matrix remodeling. These findings warrant further studies targeting these immune pathways in PWS.
Topics: Humans; Peroxidase; Prader-Willi Syndrome; Matrix Metalloproteinase 9; Cross-Sectional Studies; Macrophages; Cardiovascular Diseases
PubMed: 37430349
DOI: 10.1186/s13023-023-02730-5 -
The Journal of Clinical Endocrinology... Apr 2024Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing...
Children with skeletal dysplasias have not been consistently managed by pediatric endocrinologists despite the recognized expertise of these practitioners in managing genetic growth disorders. Growth-altering treatments have broadened the role of the pediatric endocrinologist to manage and sometimes become primary coordinators for genetic disorders such as Turner syndrome and Prader-Willi syndrome. We illustrate how recent advances in understanding the pathophysiology of skeletal disorders and the development of targeted treatments provide an opportunity for pediatric endocrinologists to further expand their role in managing certain skeletal dysplasias, including achondroplasia.
Topics: Child; Humans; Endocrinologists; Osteochondrodysplasias; Achondroplasia; Prader-Willi Syndrome
PubMed: 38078681
DOI: 10.1210/clinem/dgad726 -
Pediatrics and Neonatology Jun 2024
PubMed: 38902162
DOI: 10.1016/j.pedneo.2024.06.002 -
Obesity Science & Practice Aug 2023Prader-Willi syndrome (PWS) is the most frequently diagnosed genetic cause of early childhood obesity. Individuals with PWS typically progress through 7 different...
OBJECTIVE
Prader-Willi syndrome (PWS) is the most frequently diagnosed genetic cause of early childhood obesity. Individuals with PWS typically progress through 7 different nutritional phases during their lifetime. The main objective of this study was to assess potential factors, particularly insulin, that may be responsible for the weight gains in sub-phase 2a and their role in the subsequent increase in fat mass and obesity in sub-phase 2b and insatiable appetite in phase 3.
METHODS
Fasting plasma insulin levels were measured in children with PWS between the ages of 0-12 years and in age-matched non-PWS participants with early-onset major (clinically severe) obesity (EMO) and in healthy-weight sibling controls (SC).
RESULTS
Participants with PWS in nutritional phases 1a and 1b had plasma insulin levels comparable to SC. However, the transition from phase 1b up to phase 3 in the PWS group was accompanied by significant increases in insulin, coinciding in weight gains, obesity, and hyperphagia. Only individuals with PWS in phase 3 had comparable insulin levels to the EMO group who were higher than the SC group at any age.
CONCLUSIONS
Elevated insulin signaling is a probable trigger for weight gain and onset of hyperphagia in children with Prader-Willi syndrome. Regulating insulin levels early in childhood before the onset of the early weight gain may be key in modulating the onset and severity of obesity and hyperphagia in individuals with PWS, as well as in other young children with non-PWS early-onset obesity. Preventing or reversing elevated insulin levels in PWS with pharmacological agents and/or through diet restrictions such as a combined low carbohydrate, low glycemic-load diet may be a viable therapeutic strategy in combating obesity in children with PWS and others with early childhood obesity.
PubMed: 37546289
DOI: 10.1002/osp4.663 -
Journal of the Formosan Medical... May 2024This review summarizes the current evidence in systematic reviews, meta-analysis and randomized controlled trials regarding adenotonsillectomy outcomes in pediatric... (Review)
Review
This review summarizes the current evidence in systematic reviews, meta-analysis and randomized controlled trials regarding adenotonsillectomy outcomes in pediatric obstructive sleep apnea (OSA). Adenotonsillectomy is effective in treating OSA in children without co-morbidities, despite postoperative residual OSA remained in roughly half of these children. For children with comorbidities such as Down syndrome, Prader-Willi syndrome, sickle cell disease, or cerebral palsy, adenotonsillectomy is less effective and associated with more postoperative complications than that in children without comorbidities. For other OSA-related outcomes, evidence from meta-analyses and randomized controlled trials confirm adenotonsillectomy results in improvement of subjective OSA-related outcomes (e.g. symptoms, behaviors, and quality of life), but the results in objective OSA-related outcomes (e.g. cardiometabolic parameters or neurocognitive functions) are inconsistent. Future studies should focus on randomized controlled trials comparing objective OSA-related outcomes and the long-term effects of adenotonsillectomy in children with OSA.
Topics: Humans; Tonsillectomy; Sleep Apnea, Obstructive; Adenoidectomy; Child; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome; Postoperative Complications
PubMed: 37718211
DOI: 10.1016/j.jfma.2023.09.004 -
Frontiers in Endocrinology 2023Spinal kinematics/motion are reported to be altered in adolescents and adults with essential obesity, while no information is available in patients with Prader-Willi...
INTRODUCTION
Spinal kinematics/motion are reported to be altered in adolescents and adults with essential obesity, while no information is available in patients with Prader-Willi syndrome so far. The aim of this study was to examine cross-sectionally the characteristics of spinal postures and mobility in 34 patients with PWS, in 35 age- and sex-matched adults with essential obesity, and in 37 normal-weight individuals.
METHODS
Spinal posture and mobility were assessed using a radiation-free back scan, the Idiag M360 (Idiag, Fehraltorf, Switzerland). Differences in spinal posture and mobility between the three groups were determined using a two-way analysis of variance.
RESULTS
Adults with Prader-Willi syndrome had greater thoracic kyphosis [difference between groups (Δ) = 9.6, 95% CI 3.3 to 15.6, p = 0.001], less lumbar lordosis (Δ = -6.5, 95% CI -12.7 to -0.3, p = 0.03) as well as smaller lumbar and hip mobility than those with normal weight.
DISCUSSION
Although the characteristics of the spine in patients with Prader-Will syndrome appear to be similar to that found in subjects with essential obesity, Prader-Willi syndrome was found to influence lumbar movements more than thoracic mobility. These results provide relevant information about the characteristics of the spine in adults with Prader-Willi syndrome to be taken into careful consideration in the management of spinal conditions. These findings also highlight the importance of considering the musculoskeletal assessment of spinal postures and approaches targeting spinal and hip flexibility in adults with Prader-Willi syndrome.
Topics: Adolescent; Humans; Adult; Prader-Willi Syndrome; Obesity; Posture; Switzerland
PubMed: 37800136
DOI: 10.3389/fendo.2023.1235030