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Pediatric Endocrinology Reviews : PER Sep 2018The European Marketing Authorization for recombinant human growth hormone (rhGH) in children with Prader-Willi syndrome was the first indication for metabolic and body...
The European Marketing Authorization for recombinant human growth hormone (rhGH) in children with Prader-Willi syndrome was the first indication for metabolic and body composition effects in children. In the US it is indicated for short stature associated with PWS. Recombinant hGH is the first treatment for the PWS population and radically changed the care of these children by facilitating access to physicians who prescribe rhGH, mainly paediatric endocrinologists, and manage the organization of multidisciplinary care. Recombinant hGH treatment improved linear growth, body composition, and socialization not only in children but also in young adults. The pathophysiology of combined hormonal deficiencies including GH is starting to be unravelled. We now have to focus on co-morbidities that are not modified by rhGH treatment, such as feeding disorders and behaviour problems, to truly change the life of patients. The transition of care from adolescents to young adults also remains a challenge.
Topics: Body Composition; Child; Dwarfism; Human Growth Hormone; Humans; Prader-Willi Syndrome; Recombinant Proteins
PubMed: 30378786
DOI: 10.17458/per.vol16.2018.tdm.ghpraderwilli -
Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader-Willi Syndrome.Molecular Biology and Evolution Jan 2022The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader-Willi syndrome (PWS), yet its molecular function...
The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader-Willi syndrome (PWS), yet its molecular function remains poorly understood. Here, we combined phylogenetic and molecular analyses to identify candidate RNA targets. Based on the analysis of several eutherian orthologs, we found evidence of extensive birth-and-death and conversion events during SNORD116 gene history. However, the consequences for phylogenetic conservation were heterogeneous along the gene sequence. The standard snoRNA elements necessary for RNA stability and association with dedicated core proteins were the most conserved, in agreement with the hypothesis that SNORD116 generate genuine snoRNAs. In addition, one of the two antisense elements typically involved in RNA target recognition was largely dominated by a unique sequence present in at least one subset of gene paralogs in most species, likely the result of a selective effect. In agreement with a functional role, this ASE exhibited a hybridization capacity with putative mRNA targets that was strongly conserved in eutherians. Moreover, transient downregulation experiments in human cells showed that Snord116 controls the expression and splicing levels of these mRNAs. The functions of two of them, diacylglycerol kinase kappa and Neuroligin 3, extend the description of the molecular bases of PWS and reveal unexpected molecular links with the Fragile X syndrome and autism spectrum disorders.
Topics: Humans; Phylogeny; Prader-Willi Syndrome; RNA Stability; RNA, Messenger; RNA, Small Nucleolar
PubMed: 34893870
DOI: 10.1093/molbev/msab348 -
The Journal of ECT Mar 2021Given the limited therapeutic options for Prader-Willi syndrome (PWS), we conducted an open-label clinical trial to evaluate the effects of transcranial direct current...
BACKGROUND
Given the limited therapeutic options for Prader-Willi syndrome (PWS), we conducted an open-label clinical trial to evaluate the effects of transcranial direct current stimulation (tDCS) for hyperphagia, food craving, and aberrant behaviors on this population.
METHODS
Twelve subjects with PWS (11-35 years old) were included. The subjects underwent 10 daily 20-minute sessions of tDCS in 2 weeks. The anode was positioned over the left dorsolateral prefrontal cortex, and the cathode over the contralateral region.
RESULTS
We observed amelioration of hyperphagic and food craving symptoms (P < 0.05), as well as amelioration of behavioral symptoms measured with the Aberrant Behavior Checklist (P < 0.05).
DISCUSSION
To our knowledge, this is the first proof-of-concept trial to report the positive effects of increasing excitability of the left dorsolateral prefrontal cortex, using tDCS, for the behavioral, hyperphagia, and food craving symptoms in PWS, which is a low-cost, well-studied, safe alternative for brain stimulation.
Topics: Adolescent; Adult; Aged; Child; Female; Humans; Male; Middle Aged; Prader-Willi Syndrome; Transcranial Direct Current Stimulation
PubMed: 33009217
DOI: 10.1097/YCT.0000000000000722 -
Psychoneuroendocrinology Sep 2022Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13....
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity.
Topics: Adult; Child, Preschool; DNA Methylation; Humans; Hyperphagia; Leptin; Obesity; Prader-Willi Syndrome
PubMed: 35803048
DOI: 10.1016/j.psyneuen.2022.105857 -
American Journal of Medical Genetics.... Feb 2019Prader-Willi syndrome (PWS) is a multi-system disorder resulting from a lack of paternal gene expression in the 15q11.2-q13 region. Using databases compiled through...
Prader-Willi syndrome (PWS) is a multi-system disorder resulting from a lack of paternal gene expression in the 15q11.2-q13 region. Using databases compiled through response questionnaires completed by families known to the Prader-Willi Syndrome Association (USA), this study tested the hypothesis that PWS genetic subtype, BMI, age of diagnosis, clinical symptoms, and growth hormone treatment differ among deceased and living individuals with PWS. Categorical and continuous variables were compared using chi-square and two-group t tests, respectively. Deceased individuals had higher rates of clinical features, including increased weight concerns, heart problems, sleep apnea, other respiratory complications, diabetes, osteoporosis, high pain tolerance, and severe skin picking, when compared to living individuals. Meanwhile, living individuals had higher rates of growth hormone use and early puberty. Obesity and subsequent consequences are the primary contributors to increased mortality in PWS. Additional emphasis on areas to decrease mortality is needed.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Mass Index; Child; Child, Preschool; Chromosomes, Human, Pair 15; Female; Growth Hormone; Heart Failure; Humans; Infant; Infant, Newborn; Longitudinal Studies; Male; Middle Aged; Obesity; Paternal Inheritance; Prader-Willi Syndrome; Young Adult
PubMed: 30569567
DOI: 10.1002/ajmg.a.60688 -
Journal of Neurodevelopmental Disorders Nov 2023The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman...
OBJECTIVE
The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]).
METHODS
Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences.
RESULTS
The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications.
CONCLUSION
Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.
Topics: Humans; Child; Infant; Prader-Willi Syndrome; Chromosome Disorders; Chromosomes; Angelman Syndrome; Trisomy
PubMed: 37936142
DOI: 10.1186/s11689-023-09504-x -
Clinical Oral Investigations Mar 2019To assess the significance of changes in the saliva in the etiology of gingivitis and tooth wear in children and adolescents with Prader-Willi syndrome (PWS).
OBJECTIVE
To assess the significance of changes in the saliva in the etiology of gingivitis and tooth wear in children and adolescents with Prader-Willi syndrome (PWS).
MATERIALS AND METHODS
The study included 80 (2.8-18 years old; 39 girls and 41 boys): 40 in PWS group (mean age 8.0 ± 4.24 years) and 40 in control group (mean age 7.9 ± 4.12 years). General condition, oral para-functional habits, tooth wear (modified TWI), oral hygiene and gingival status (Plaque Index (PLI) and Gingival Index (GI)), localization of gingivitis, and salivary characteristics were assessed. The chi-square test, the Mann-Whitney U test, Spearman's rank correlation, and odds ratio based on logistic regression in a statistical analysis were applied.
RESULTS
Chances of gingivitis were increased by low PLI (odds ratio (OR) = 32.53), low resting salivary flow (OR = 3.96), increased viscosity of saliva (OR = 3.54), and mouth breathing (OR = 8.17). For gingivitis in anterior regions, low PLI (OR = 107.67), low resting (OR = 5.73) and stimulated (OR = 1.86) salivary flow, increased viscosity of saliva (OR = 5.87), mouth breathing (OR = 10.00), and low stimulated salivary flow (OR = 3.18) were observed. Tooth wear rates were increased by teeth grinding (OR = 16.20), mouth breathing (OR = 4.33), increased viscosity of saliva (OR = 11.67) and low resting (OR = 6.07), and stimulated (OR = 4.22) salivary flow.
CONCLUSIONS
In PWS, reduced salivary secretion, increased viscosity, of saliva and mouth breathing increase the risk of plaque-induced gingivitis and tooth wear.
CLINICAL RELEVANCE
The prevention and treatment of tooth wear and gingivitis in PWS patients is necessary not only to treat bruxism and mouth breathing but also to limit the influence of negative changes of saliva.
Topics: Adolescent; Bruxism; Case-Control Studies; Child; Child, Preschool; Dental Plaque; Female; Gingivitis; Humans; Male; Mouth Breathing; Prader-Willi Syndrome; Saliva; Salivation; Tooth Attrition
PubMed: 30006686
DOI: 10.1007/s00784-018-2559-y -
American Journal of Medical Genetics.... Dec 2015Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion... (Meta-Analysis)
Meta-Analysis Review
Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in some respects overlaps with autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by restricted or repetitive behaviors (RRBs) and social-communication impairment. The goal of this review was to (i) review published literature investigating core ASD symptoms in PWS and (ii) provide a prevalence estimate of ASD in PWS. Two independent reviewers searched Medline, CINAHL, PsychINFO, Embase, and Web of Science to find studies that answered the research questions. Individuals with PWS demonstrate significant levels of RRBs and social-communication impairment, in some reports reaching similar levels to those of non-PWS ASD comparison groups. Individuals with UPD had more social-communication impairment than those with DEL. Of 786 PWS participants, 210 (26.7%) were reported as meeting criteria for ASD, either based on clinical diagnosis or by exceeding clinical cut-points on relevant ASD symptom measures. In studies that distinguished genetic subtypes, rates of ASD were higher in individuals with PWS with UPD (67 of 190; 35.3%) than those with DEL (47 of 254; 18.5%). Published data on the association of PWS and ASD to date are limited to sample means of 8 years of age and older. Further research is needed to identify early markers of ASD in PWS children, to support earlier diagnosis and intervention for this important comorbidity.
Topics: Autism Spectrum Disorder; Humans; Prader-Willi Syndrome; Sequence Deletion; Social Communication Disorder; Uniparental Disomy
PubMed: 26331980
DOI: 10.1002/ajmg.a.37286 -
Journal of Clinical Research in... Aug 2021To investigate clinical characteristics and response to growth hormone (GH) treatment in patients with Prader-Willi syndrome (PWS) in Turkey.
OBJECTIVE
To investigate clinical characteristics and response to growth hormone (GH) treatment in patients with Prader-Willi syndrome (PWS) in Turkey.
METHODS
The data of 52 PWS patients from ten centers was retrospectively analyzed. A nation-wide, web-based data system was used for data collection. Demographic, clinical, genetic, and laboratory data and follow-up information of the patients were evaluated.
RESULTS
The median age of patients at presentation was 1.5 years, and 50% were females. Genetic analysis showed microdeletion in 69.2%, uniparental disomy in 11.5%, imprinting defect in 1.9% and methylation abnormality in 17.3%. Hypotonia (55.7%), feeding difficulties (36.5%) and obesity (30.7%) were the most common complaints. Cryptorchidism and micropenis were present in 69.2% and 15.3% of males, respectively. At presentation, 25% had short stature, 44.2% were obese, 9.6% were overweight and 17.3% were underweight. Median age of obese patients was significantly higher than underweight patients. Central hypothyroidism and adrenal insufficiency were present in 30.7% and 4.7%, respectively. Hypogonadism was present in 75% at normal age of puberty. GH treatment was started in 40% at a mean age of 4.7±2.7 years. After two years of GH treatment, a significant increase in height SDS was observed. However, body mass index (BMI) standard deviation (SDS) remained unchanged.
CONCLUSION
The most frequent complaints were hypotonia and feeding difficulty at first presentation. Obesity was the initial finding in 44.2%. GH treatment was started in less than half of the patients. While GH treatment significantly increased height SDS, BMI SDS remained unchanged, possibly due to the relatively older age at GH start.
Topics: Adolescent; Adolescent Development; Age Factors; Body Height; Body Mass Index; Child; Child Development; Child, Preschool; Female; Genetic Predisposition to Disease; Human Growth Hormone; Humans; Infant; Infant, Newborn; Male; Phenotype; Prader-Willi Syndrome; Retrospective Studies; Treatment Outcome; Turkey
PubMed: 33565750
DOI: 10.4274/jcrpe.galenos.2021.2020.0228 -
Current Diabetes Reports Feb 2020This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common... (Review)
Review
PURPOSE OF REVIEW
This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common syndromic cause of obesity, and serves as a guide for future research and current best practice.
RECENT FINDINGS
Diabetes occurs in 10-25% of PWS patients, usually in adulthood. Severe obesity is a significant risk factor for developing of T2DM in PWS. Paradoxically, despite severe obesity, a relative hypoinsulinemia, without the expected insulin resistance, is frequently observed in PWS. The majority of PWS subjects with T2DM are asymptomatic and diabetes-related complications are infrequent. Long-term growth hormone therapy does not adversely influence glucose homeostasis in all ages, if weight gain does not occur. Early intervention to prevent obesity and the regular monitoring of glucose levels are recommended in PWS subjects. However, further studies are required to better understand the physiopathological mechanisms of T2DM in these patients.
Topics: Blood Glucose; Carbohydrate Metabolism; Comorbidity; Diabetes Mellitus, Type 2; Glucose; Glucose Metabolism Disorders; Growth Hormone; Hormones; Humans; Hyperphagia; Insulin; Obesity; Prader-Willi Syndrome
PubMed: 32030506
DOI: 10.1007/s11892-020-1284-5