Materiały źródłowe

• #1 Prader-Willi Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK553161/

  Prader-Willi syndrome results from the absence of gene expression of the paternally inherited genes on the 15q11.2-q13 chromosome. Approximately 70% of cases result from errors in genomic imprinting due to a paternal deletion, while maternal uniparental disomy is responsible for about 25% of cases. Fewer cases stem from defects in the imprinting center, such as microdeletions or epimutations on chromosome 15.[1][2] […] Prader-Willi syndrome was the first genetic disorder identified to be caused by genomic imprinting, where the expression of the gene depends on the parental sex donating the affected gene. […] The progression leading to the hallmark hyperphagia and obesity in Prader-Willi syndrome can be described in 4 phases (see Table. Phases of Prader-Willi Syndrome). […] In Prader-Willi syndrome, central obesity is typical, leading to significant complications and increased morbidity and mortality.[5]

• #1 Prader-Willi Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK553161/

  The biological mechanism for this impaired satiety is unclear. In some studies, ghrelin levels are elevated in patients with Prader-Willi syndrome compared to weight and age-matched controls.[11][12] […] Hypogonadism is prevalent in patients with Prader-Willi syndrome. Almost all affected males experience cryptorchidism, often necessitating orchiopexy. […] Although the pathogenesis is unclear, insulin-like growth factor 1 (IGF-1) is deficient or subnormal in nearly all patients with Prader-Willi syndrome. […] The clinical manifestations of Prader-Willi syndrome vary across different age groups, constituting a range of features. Symptoms may manifest at birth and tend to become more apparent over time.

• #2 Prader-Willi Syndrome: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947954-overview

  Prader-Willi syndrome is the first human disorder to be attributed to genomic imprinting. In such conditions, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. […] Prader-Willi syndrome results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. […] Most cases of Prader-Willi syndrome that involve deletions, unbalanced translocations, and uniparental (maternal) disomy are sporadic. […] Approximately 70% of Prader-Willi syndrome cases arise from deletion of band 15q11-13 on chromosome 15. Maternal uniparental disomy caused by chromosomal nondisjunction accounts for 28% of Prader-Willi syndrome cases. […] Less than 1% of patients have mutations isolated to the imprinting center, which carries a risk of recurrence.

• #3 Prader-Willi syndrome | Genetics in Medicine

  https://www.nature.com/articles/gim0b013e31822bead0

  Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (13%). […] There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. […] PWS occurs as the result of absence of expression of paternal genes from chromosome 15q11.2-q13. A number of genes in this region are subject to genomic imprinting and are normally active only from the paternally contributed chromosome 15; those same alleles from the maternally contributed chromosome 15 are inactivated by epigenetic factors and are not expressed. The absence of expression of one or more of the paternally inherited genes must contribute to the phenotype of PWS. This lack of expression occurs by three primary mechanisms: (i) deletion of a 5-6 Mb region from the paternally contributed chromosome 15 (found in 65-75% of affected individuals); (ii) maternal uniparental disomy (UPD) 15 (found in 20-30%); and (iii) a defect in the genomic region that controls the imprinting process, a so-called imprinting defect (ID; 13%).

• #4 The Diagnosis and Genetic Mechanisms of Prader-Willi Syndrome: Findings From a Moroccan Population Study

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10202671/

  The cause of PWS is a genetic rearrangement, usually accidental, that leads to the absence or loss of function of genes located in the q11-q13 region of the paternal copy of chromosome 15. In PWS, maternal alleles are silent, and it is the lack of expression of paternal alleles that allows the disease to be expressed. This corresponds to the phenomenon of parental genomic imprinting, where the alleles of genes located in the 15q11-q13 region do not have the same functions on maternal and paternal chromosomes, but both are required for normal development. […] Three types of anomalies lead to the non-expression of these genes. The first type is a chromosomal microdeletion (65% of cases) or absence of the q11-q13 region on the paternal chromosome 15. Two types of deletions have recently been identified, type I and type II, with type I being the longer of the two. The second type of anomaly is maternal uniparental disomy (30% of cases) or absence of the paternal chromosome 15 (at least in the q11-q13 region) but with two copies of the maternal chromosome. The third type of anomaly is a mutation in the genetic imprinting center on the paternal chromosome 15, which renders the genes inactive (1%-5% of cases).

• #5 Recommendations for the diagnosis and management of childhood Prader-Willi syndrome in China | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02302-z

  Prader-Willi syndrome (PWS) is a complex and multisystem neurobehavioral disease, which is caused by the lack of expression of paternally inherited imprinted genes on chromosome15q11.2-q13.1. […] The most common molecular mechanism of PWS is found in about 65%-75% of cases who show a de novo typical deletion on the paternal chromosome 15q11.2-q13.1 region, including two main subtypes. […] The second most common molecular mechanism of PWS is found in nearly 20%-30% of cases and associated with maternal uniparental disomy (mUPD) 15, in which both copies of chromosome 15 come from the mother. […] The third molecular mechanism of PWS is less common and is found in about 3% patients with PWS, termed imprinting defect (ID), including epimutation and the PWS imprinting center (PWS-IC) deletion.

• #6 Prader-Willi syndrome | Genetics in Medicine

  https://www.nature.com/articles/gim0b013e31822bead0

  The genomic and epigenetic changes causing PWS all lead to a loss of expression of the normally paternally expressed genes on chromosome 15q11.2-q13. Absence of the paternally inherited copy of these genes, or failure to express them, causes total absence of expression for those genes in the affected individual because the maternal contribution for these genes has been programmed by epigenetic factors to be silenced. […] A key region to explain much of the PWS phenotype has been narrowed to the SNORD116 snoRNA gene cluster by several unique deletion and translocation families.

• #7 Prader–Willi syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome

  Prader-Willi syndrome (PWS) is a rare genetic disorder caused by a loss of function of specific genes on chromosome 15. […] About 74% of cases occur when part of the father’s chromosome 15 is deleted. […] In another 25% of cases, the affected person has two copies of the maternal chromosome 15 from the mother and lacks the paternal copy. […] As parts of the chromosome from the mother are turned off through imprinting, they end up with no working copies of certain genes. […] PWS is related to an epigenetic phenomenon known as imprinting. […] Normally, a fetus inherits an imprinted maternal copy of PW genes and a functional paternal copy of PW genes. […] Due to imprinting, the maternally inherited copies of these genes are virtually silent, and the fetus therefore relies on the expression of the paternal copies of the genes.

• #7 Prader–Willi syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome

  In PWS, however, there is mutation/deletion of the paternal copies of PW genes, leaving the fetus with no functioning PW genes. […] The PW genes are the SNRPN and NDN genes, along with clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116 (HBII-85) and 48 copies of SNORD115 (HBII-52). […] Studies of human and mouse model systems have shown deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) to be the primary cause of PWS.

• #8 Prader–Willi syndrome | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2008165

  Most cases of PWS result from a deletion of 57Mb in 15q11.2q13. This region is highly complex and contains a number of imprinted and non-imprinted genes. […] The 15q11.2q13 region can be roughly divided into four distinct regions: (1) a proximal non-imprinted region between BP1 and BP2 containing four biparentally expressed genes; (2) a PWS paternal-only expressed region containing five protein coding genes, a cluster of five repetitious snoRNA genes and several antisense transcripts; (3) an AS region containing the preferentially maternally expressed genes UBE3A and ATP10A and (4) a distal non-imprinted region containing a cluster of three GABA receptor genes, the gene for oculocutaneous albinism type 2 and the HERC2 gene. The exact function of each of these genes in the PWS phenotype is still being elucidated. […] Although no single gene alteration has been found that explains all the features of PWS, several unique translocation and deletion patients have narrowed a key region to explain much of the PWS phenotype to the HBII-85 snoRNA gene.

• #9 Prader-Willi Syndrome: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947954-overview

  Several genes have been mapped to the 15q11.2-13 region, including the SNRPN gene, P gene (type II oculocutaneous albinism), UBE3A gene (encodes a ubiquitin-protein ligase involved in intracellular protein turnover), and necdin gene (codes for a nuclear protein expressed exclusively in the differentiated mouse brain). […] A report by Butler et al suggested that individuals with Prader-Willi syndrome have decreased mitochondrial function, with basal respiration, maximal respiratory capacity, and adenosine triphosphate (ATP)linked respiration in the study differing significantly between Prader-Willi syndrome patients and healthy controls. […] The role of ghrelin in the satiety defect found in Prader-Willi syndrome is a subject of active investigation. Cummings et al reported significantly elevated ghrelin levels (4.5-fold higher) in individuals with Prader-Willi syndrome.

• #10 Prader-Willi syndrome — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/prader-willi-syndrome/

  Prader-Willi syndrome (PWS) is an imprinted condition caused by disruption of a number of paternally inherited genes, most notably SNRPN, in the Prader-Willi critical region (PWCR) at chromosome location 15q11.2-15q13. […] Most children with PWS have a deletion of the PWCR. […] 20%30% of cases are caused by maternal uniparental disomy (UPD), in which both alleles are maternally derived with no paternal contribution. […] In PWS, the genes in the PWCR have the maternal methylation pattern and are therefore switched off where they would be normally switched on. […] In rare cases, this methylation anomaly is due to a (potentially heritable) deletion in a downstream imprinting centre. […] Microarray will detect the majority of PWS cases, as deletions are the most common cause. […] Most deletions are one of two sizes. This is because the deletion is generated by misalignment of very similar genetic blocks (called low copy repeats) on either side of the deleted region.

• #11 Prader-Willi syndrome – wikidoc

  https://www.wikidoc.org/index.php/Prader-Willi_syndrome

  Prader-Willi syndrome (abbreviated PWS) is a genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome. […] PWS is caused by the deletion of the paternal copies of the imprinted SNRPN gene and necdin gene on chromosome 15 located in the region 15q11-13. […] This so-called PWS/AS region may be lost by one of several genetic mechanisms which, in the majority of instances occurs through chance mutation. […] Other less common mechanisms include; uniparental disomy, sporadic mutations, chromosome translocations, and gene deletions. […] Due to imprinting, the maternally inherited copies of these genes are virtually silent, only the paternal copies of the genes are expressed. […] PWS results from the loss of paternal copies of this region.

• #12 Prader-Willi Syndrome: The Disease that Opened up Epigenomic-Based Preemptive Medicine

  https://www.mdpi.com/2079-9721/4/1/15

  Prader-Willi syndrome (PWS) is a congenital neurodevelopmental disorder caused by loss of function of paternally expressed genes on chromosome 15 due to paternal deletion of 15q11–q13, maternal uniparental disomy for chromosome 15, or an imprinting mutation. […] The genetic etiology of PWS is a 15q11–q13 deletion on the paternal chromosome 15, maternal uniparental disomy (UPD) of chromosome 15 or an imprinting mutation (micro-deletion encompassing the imprinting center) on the paternal chromosome 15, which cause a loss of function of paternally expressed genes on 15q11–q13 including MKRN3, MAGEL2, NDN, SNURF-SNRPN, and SNORD116 snoRNA (HBII-85 C/D box small nucleolar RNA cluster). […] Recent studies demonstrated that small deletions of the paternal allele of the SNORD116 snoRNA and mutations on the paternal allele of MEGEL2 can cause PWS, suggesting that the phenotypic overlap between SNORD116 deletion cases and MAGEL2 mutation cases might be caused by changes in higher-order chromatin structure at the 15q11–q13 locus.

• #12 Prader-Willi Syndrome: The Disease that Opened up Epigenomic-Based Preemptive Medicine

  https://www.mdpi.com/2079-9721/4/1/15

  Furthermore, a recent study using induced pluripotent stem cells derived from the PWS patients revealed up-regulation of maternally expressed genes in the imprinted DLK1-DIO3 locus on chromosome 14 due to deficiency of the paternal allele of IPW, a long noncoding RNA at the 15q11–q13 locus that acts as a regulator of the DLK1-DIO3 region, and this indicates that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS critical region of 15q11–q13. […] PWS was one of the first human diseases that was caused by abnormal genomic imprinting. Genomic imprinting refers to a parental-of-origin specific gene expression based on epigenetic gene regulation that does not depend on DNA sequence but on DNA and histone chemical modifications. […] To date, a number of proteins and enzymes involved in epigenetic gene regulation have been identified, and some of these have been shown to be associated with congenital neurodevelopmental disorders.

• #13 Prader-Willi syndrome | MedLink Neurology

  https://www.medlink.com/articles/prader-willi-syndrome

  The third genetic mechanism for Prader-Willi syndrome is an imprinting center defect that is identified in the remaining 4% of patients. […] The individual roles of the inactivated paternally derived genes at the 15q11-q13 deletion site in the pathogenesis of Prader-Willi syndrome are far from clear. […] The SNORD116 cluster appears to be critically implicated in the pathogenesis of Prader-Willi syndrome; other genes may contribute to, but cannot fully account for, the Prader-Willi phenotype. […] Snord116-null mice recapitulate the main features of Prader-Willi syndrome including low birth weight, hyperphagia, obesity, and endocrine abnormalities. […] This work may provide new mechanistic insights into epigenetic influences on circadian rhythms and how alterations in regulation of circadian rhythm contribute to manifestations of Prader-Willi syndrome including sleep disorders, hyperphagia, and metabolic/endocrine dysfunction.

• #14

  https://link.springer.com/article/10.1007/s40618-021-01574-9

  Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. […] Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. […] The proposed mechanisms include disruption in limbic-hypothalamic pathways of satiety control resulting in hyperphagia, alterations in hormones regulating food intake, reduced energy expenditure. […] Despite the exact mechanisms remain to be fully elucidated, the development of obesity is mainly related to dysfunction in the hypothalamic satiety centre and its hormonal regulatory circuitry, affecting food intake and energy expenditure.

• #14

  https://link.springer.com/article/10.1007/s40618-021-01574-9

  Disruption in the hypothalamic pathways of satiety control results in persistent and insatiable appetite, hyperphagia and hunger-related eating behaviours. […] Alterations in several brain areas (hypothalamus, amygdala, hippocampus, orbitofrontal and medial prefrontal cortex) play a crucial role in the abnormal food intake regulation in PWS. […] These brain functional studies clearly indicate that disruption of hypothalamic control of satiety, dysfunction in the associated reward circuitry regions and impairment in inhibitory control areas jointly contribute to extreme hyperphagia and obesity in PWS. […] Several orexigenic and anorexigenic hormones are deemed to be involved in the development and maintenance of obesity in PWS, through appetite dysregulation. […] Ghrelin, a potent orexigenic hormone, is secreted by the stomach during fasting and starvation and its circulating levels are suppressed by food intake.

• #14

  https://link.springer.com/article/10.1007/s40618-021-01574-9

  Most studies reported persistently increased ghrelin levels in subjects with PWS at any age compared with BMI-, age- and sex-matched control children. […] It has been hypothesized that the increase in circulating ghrelin levels occurs early in infancy, in response to difficulties to thrive and poor feeding. […] Persistent hyper-ghrelinemia promotes hyperphagia and obesity later in childhood. […] However, several groups have shown that pharmacological reduction of ghrelin to normal levels in PWS, using either short or long-acting somatostatin analogue (SSA), did not improve feeding behaviour and did not reduce the appetite of children and adults with PWS nor affect the weight. […] Multiple endocrine abnormalities due to hypothalamic dysfunction are quite common in subjects with PWS and may represent factors contributing to abnormal body weight and composition.

• #14

  https://link.springer.com/article/10.1007/s40618-021-01574-9

  Growth hormone deficiency (GHD) is associated with decreased lean mass, increased fat mass (mainly truncal fat with increased waist/hip ratio), poor muscle tone and strength, decreased movements and reduced energy expenditure and exercise tolerance. […] The excessive fat mass in subjects with PWS is typically distributed to the trunk and to the proximal extremity of the limbs, with a lower trunk-to-appendicular fat mass ratio and prevalent subcutaneous and less visceral fat accumulation. […] According to the reduction in visceral adiposity, preserved insulin sensitivity and lower metabolic consequences are observed in subjects with PWS in comparison to BMI-matched obese controls.

• #15 apem :: Annals of Pediatric Endocrinology & Metabolism

  https://e-apem.org/m/journal/view.php?number=907

  Prader-Willi syndrome (PWS) is a rare complex genetic disorder that results from a lack of expression of the paternally inherited chromosome 15q11-q13. […] Hypothalamic dysfunction in PWS can lead to several endocrine disorders, including short stature with growth hormone deficiency, hypothyroidism, central adrenal insufficiency, and hypogonadism. […] Understanding the pathophysiology of hyperphagia and obesity in PWS is very important for the care of patients with PWS. […] Hypothalamic dysfunction might affect appetite control, energy expenditure, and orexigenic/anorexigenic hormone regulation, leading to hyperphagia and obesity in PWS. […] These findings suggest that dysfunction in the subcortical reward circuitry and the cortical inhibitory regions associated with appetite and behavioral control in the hypothalamus is involved in development and progression of hyperphagia and obesity in PWS.

• #15 apem :: Annals of Pediatric Endocrinology & Metabolism

  https://e-apem.org/m/journal/view.php?number=907

  In PWS, high serum level of total ghrelin (especially AG) was persistent even after food intake, which can cause a delay in the sense of fullness and lead to hyperphagia and obesity. […] The roles of ghrelin and oxytocin in appetite regulation and obesity in PWS remain unclear. […] Hyperphagia and obesity in PWS are thought to be caused by complex mechanisms of hypothalamic dysfunction, hormonal circuits involved in appetite or satiety control, changes in body composition, and decreased REE.

• #16 Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

  https://e-emj.org/journal/view.php?number=86

  Prader-Willi syndrome (PWS), which is considered the most common genetic form of obesity, results from the absence of imprinted genes in the paternally derived PWS critical region located on chromosome 15q11.213. […] Although the underlying mechanism of hyperphagia is not completely understood, hypothalamic and endocrine dysregulation is believed to be responsible for the lack of satiety and abnormal food-seeking behaviors that lead to severe obesity. […] The PWS phenotype is currently believed to result from the complex dysregulation of hypothalamic control. […] Structural brain alterations, including a scarcity of oxytocin neurons in the hypothalamus and reduced fractional anisotropy in neuron fibers, have been linked to uncontrollable hyperphagia and a lack of satiety. […] The mechanism underlying abnormal hyperphagia in PWS is not fully understood. However, several studies have demonstrated alterations in anorexigenic and orexigenic hormones in patients with PWS relative to obese individuals.

• #16 Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

  https://e-emj.org/journal/view.php?number=86

  Elevated serum leptin, an anorexigenic hormone, has been reported. […] Patients with PWS have lower circulating levels of brain-derived neurotrophic factor than individuals with simple obesity. […] Low levels of this hormone have also been observed in patients with PWS, suggesting a potential causal relationship with PWS-associated hyperphagia. […] A well-known endocrine characteristic of PWS is relative hypoinsulinemia and low insulin resistance, despite severe obesity. […] Among the orexigenic hormones, an elevated level of ghrelin has been observed in children and adults with PWS. […] The obesity phenotype in PWS is distinguishable from other common forms of obesity. […] The management of PWS necessitates a multidisciplinary team approach that includes a neonatologist, medical geneticist, pediatric endocrinologist, dietitian, orthopedist, and rehabilitation therapist. […] Although no medications have consistently demonstrated effectiveness in managing obesity in PWS to date, ongoing research efforts are essential for the development of potential pharmacological therapies.

• #17 Obesity management in Prader-Willi syndrome: current perspective | DMSO

  https://www.dovepress.com/obesity-management-in-prader-willi-syndrome-current-perspectives-peer-reviewed-fulltext-article-DMSO

  Prader-Willi syndrome (PWS) is a complex multisystem disorder due to the absent expression of the paternally active genes in the PWS critical region on chromosome 15 (15q11.2-q13). […] The mechanisms underlying hyperphagia in PWS are not completely known, and to date no drugs have proven their efficacy in controlling appetite. […] A complex hypothalamic dysregulation is currently thought to be responsible for the PWS phenotype. […] Altered brain structures have been documented in PWS that may underlie the excessive hyperphagia and the constant hunger, including low number of oxytocin neurones in the hypothalamus and reduced fractional anisotropy of white matter fibers. […] More recently, it has been shown that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.

• #17 Obesity management in Prader-Willi syndrome: current perspective | DMSO

  https://www.dovepress.com/obesity-management-in-prader-willi-syndrome-current-perspectives-peer-reviewed-fulltext-article-DMSO

  These results, combined with imaging studies showing both an increased functional response of the hypothalamus to food stimuli, the involvement of the amygdala, and the reduced coupling of the ventral striatum with limbic structures for basic internal homeostasis, suggest a crucial role of several brain areas in the abnormal regulation of food intake in PWS. […] Several clinical studies have been carried out to evaluate the appetite regulatory systems in PWS patients, in order to understand the role of endogenous appetite suppressants and stimulants underlying the hyperphagic attitude. […] However, the basis for the abnormal eating behavior observed in PWS has not yet been understood. […] High ghrelin levels have been described in PWS at all ages, both before the development of obesity and after the appearance of hyperphagia in older children and in adults.

• #17 Obesity management in Prader-Willi syndrome: current perspective | DMSO

  https://www.dovepress.com/obesity-management-in-prader-willi-syndrome-current-perspectives-peer-reviewed-fulltext-article-DMSO

  The mechanisms underlying ghrelin dysregulation in this syndrome are currently unknown. […] It is of note that circulating ghrelin is present in both acylated and unacylated forms. […] The unacylated form has been shown to inhibit food intake, while acylated ghrelin exerts an orexigenic effect. […] However, the suppression of ghrelin achieved with acute or chronic administration of somatostatin in PWS is not associated to a positive effect on food intake and body weight reduction, indicating that the role of ghrelin in hyperphagia of these patients remains to be clarified.

• #18 SciELO Brazil – Prader-Willi syndrome: endocrine manifestations and management Prader-Willi syndrome: endocrine manifestations and management

  https://www.scielo.br/j/aem/a/NLFDQWgPhcvtkRBzdwt7FLB/

  The main endocrine abnormalities of PWS, detailed in the following paragraphs, are: growth hormone deficiency; gonadotrophins deficiency and/or gonadal disorders; obesity; metabolic syndrome; early pubarche and precocious puberty; central hypothyroidism; central adrenal insufficiency; type 2 diabetes mellitus and low bone mineral density. […] Growth hormone deficiency (GHD) is present in 40%-100% of patients. […] The beneficial effects of rhGH on PWS substantially improved the phenotype of these individuals; including: decreased fat mass, increased muscle mass, increased growth rate (up to 16 cm increase in final height), normalization of cranial diameter, improvement of bone mineral density, dyslipidemia, development, quality of life, and physical performance. […] The etiology of hypogonadism in PWS is quite heterogeneous and can be caused by defect in the hypothalamic-pituitary axis, failure of the gonad response or the combination of the two forms.

• #18 SciELO Brazil – Prader-Willi syndrome: endocrine manifestations and management Prader-Willi syndrome: endocrine manifestations and management

  https://www.scielo.br/j/aem/a/NLFDQWgPhcvtkRBzdwt7FLB/

  Several mechanisms have been proposed to explain the etiology of obesity in PWS, which include discontinuation of the satiety control hypothalamic pathways, changes in hormones that regulate food intake, and reduced basal metabolic rate. […] In PWS, hypothalamic dysfunction may lead to central hypothyroidism. […] Children and adults with PWS have increased risk of adrenal insufficiency (AI) due to generalized hypothalamic dysfunction probably due to inappropriate secretion of corticotrophin releasing hormone by the hypothalamus. […] Type 2 diabetes mellitus (T2DM) is common in adults with PWS reaching up to 25% of patients and rarely develops during childhood. […] Historically, an increase in the frequency of osteoporosis and fractures in individuals with PWS has been reported.

• #19 Updates on Obesity in Prader-Willi Syndrome: From Genetics to Management

  https://www.e-emj.org/journal/view.php?number=86

  Depletion of SNORD116 has been demonstrated to cause an imbalance in the neuromodulatory systems of the hypothalamus, leading to abnormal food intake behavior and sleep problems in a mouse model that mimics the clinical manifestations of PWS. […] These findings suggest that structural or functional dysregulation of the hypothalamus plays a critical role in the hyperphagia and obesity associated with PWS.

• #20 Prader-Willi syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/prader-willi-syndrome/

  Prader-Willi syndrome is caused by the loss of function of genes in a particular region of chromosome 15. […] Most cases of Prader-Willi syndrome (about 70 percent) occur when a segment of the paternal chromosome 15 is deleted in each cell. […] It appears likely that the characteristic features of Prader-Willi syndrome result from the loss of function of several genes on chromosome 15. Among these are genes that provide instructions for making molecules called small nucleolar RNAs (snoRNAs). […] Studies suggest that the loss of a particular group of snoRNA genes, known as the SNORD116 cluster, may play a major role in causing the signs and symptoms of Prader-Willi syndrome. […] In some people with Prader-Willi syndrome, the loss of a gene called OCA2 is associated with unusually fair skin and light-colored hair. […] Researchers are studying other genes on chromosome 15 that may also be related to the major signs and symptoms of this condition.

• #21 The role of ancient gene variants in Prader-Willi syndrome pathophysiology

  https://www.fondazionetelethon.it/en/what-we-do/research/projects-funded/the-role-of-ancient-gene-variants-in-prader-willi-syndrome-pathophysiology/

  Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by genetic defects within a locus on chromosome 15(15q11-q13), in which the loss of expression of paternally inherited genes causes severe symptoms; for example, neurodevelopmental delays, hyperphagia, and obesity, as well as various disturbances in the rhythms of sleep and wakefulness. […] Recently we have identified an appealing evolutionary mechanism involved in the nuclear pore functions, which promises to reveal an understanding of how the cellular mechanisms related to the obesity in PWS are regulated. […] In particular, our preliminary data suggest a cross-link between the lipid homeostasis of PWS patients and their circadian alteration. […] 3D modelling of ancient variants of a PWS gene, namely NPAP1, predicted that the structure of its protein is a determinant for altered dynamics in lipid accumulation and circadian homeostasis. […] The results of our investigation will lead to a better comprehension of why PWS patients, which are lean in infancy due to feeding difficulties, later develop obesity and sleep-wake disturbances.

• #22 The role of ancient gene variants in Prader-Willi syndrome pathophysiology

  https://www.telethon.it/en/what-we-do/research/projects-funded/the-role-of-ancient-gene-variants-in-prader-willi-syndrome-pathophysiology

  Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by genetic defects within a locus on chromosome 15(15q11-q13), in which the loss of expression of paternally inherited genes causes severe symptoms; for example, neurodevelopmental delays, hyperphagia, and obesity, as well as various disturbances in the rhythms of sleep and wakefulness. […] Recently we have identified an appealing evolutionary mechanism involved in the nuclear pore functions, which promises to reveal an understanding of how the cellular mechanisms related to the obesity in PWS are regulated. […] 3D modelling of ancient variants of a PWS gene, namely NPAP1, predicted that the structure of its protein is a determinant for altered dynamics in lipid accumulation and circadian homeostasis. […] The results of our investigation will lead to a better comprehension of why PWS patients, which are lean in infancy due to feeding difficulties, later develop obesity and sleep-wake disturbances.

• #23 The Pivotal Role of Oxytocin’s Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder

  https://www.mdpi.com/1422-0067/25/4/2066

  Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. […] Recent data indicate the involvement of the hormone neurotransmitter oxytocin (Oxt) in the etiology of PWS. […] An abnormality in the Oxt system is often reported, especially in PWS children. […] Oxt regulates energy metabolism. […] The hypothesis that hyperphagia may be caused by impairment in the anorexic Oxt circuitry arose at the time of these studies, although the quantification of Oxt expression in these mice has not been established.

• #23 The Pivotal Role of Oxytocin’s Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder

  https://www.mdpi.com/1422-0067/25/4/2066

  The dysfunctional Oxt system in PWS and SYS individuals may go beyond the Oxt/Oxtr expression level and affect the overall Oxt neuron activity by the imbalance of synaptic excitation/inhibition, as seen in Oxt-neurons in which MAGEL2 has been inactivated. […] Oxt is a master gene in the regulation of thermogenesis. […] This phenotype of PWS individuals showing less Oxtr in the brain and high circulating Oxt is a mirror image of the cold-stressed mice in our model of a thermogenic challenge. […] The negative feedback between the brain and the peripheral organs that trigger a higher expression of Oxtr in the brain and of Sol and low circulating Oxt was called in our laboratory “the Oxytonic effect.” […] The evidence that Oxt is a master gene that regulates thermogenesis may be related to the sensory deficits seen in ASD individuals.

• #24

  https://www.jci.org/articles/view/91307

  Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. […] Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. […] Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency. […] While these compelling results support a critical role for PC1 deficiency in PWS, more work needs to be done to fully understand how and to what extent loss of this prohormone processing enzyme underlies disease manifestations in PWS patients. […] The current work by Burnett et al. highlights the strengths of a combined approach using human and mouse models to study a complex neuroendocrine disorder and adds to a growing literature using iPSCs to investigate the molecular etiology of PWS.

• #24

  https://www.jci.org/articles/view/91307

  PC1 deficiency represents an intriguing potential mechanism that links many of the diverse phenotypes observed in PWS. […] Burnett et al. state Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency. While this work has opened up an important new investigative window on possible mechanisms of the neuroendocrine features of PWS, it is perhaps premature to conclude that PC1 deficiency is the sole explanation for these.

• #25 Gene Silencing Mechanism Linked to PWS Focus of Early StudyEnvelope icon

  https://praderwillinews.com/news/gene-silencing-mechanism-linked-to-pws-focus-of-early-study/

  The maternal SMCHD1 protein ensures genomic imprinting and the effective silencing of particular genes by protecting them from “gene-activating” proteins in the fertilized egg cell (or oocyte), according to a study in mice. […] Since SMCHD1’s gene silencing effects are known to contribute to Prader-Willi syndrome (PWS), these findings may help to identify new targets and therapeutic approaches for PWS, its researchers said. […] PWS is most commonly caused by genetic alterations that lead to the loss of function of paternal genes located on chromosome 15, which control metabolism, appetite, growth, intellectual function, and social behavior. […] Due to genomic imprinting and silencing of this region — known as the PWS locus — in the maternally inherited-chromosome 15, defects in the paternal gene copies cannot be compensated by healthy ones inherited from the mother.

• #25 Gene Silencing Mechanism Linked to PWS Focus of Early StudyEnvelope icon

  https://praderwillinews.com/news/gene-silencing-mechanism-linked-to-pws-focus-of-early-study/

  PWS also may be caused by inheriting two chromosome 15s from the mother, both of which are shut down in the PWS locus, or by an imprinting defect that turns off the parental PWS locus. […] As such, reactivating these silenced genes may be a way of treating the disease. […] Previous studies showed that SMCHD1 — a protein involved in epigenetics and gene silencing — turns off PWS-related genes and that SMCHD1’s loss restores gene activity. […] Further analyses suggested that SMCHD1 ensures that specific epigenetic marks in histones effectively result in gene silencing by “preventing the action of … epigenetic activators via an insulating [protective] mechanism.” […] Marnie Blewitt, PhD, the study’s senior author, said that “studying SMCHD1 in early embryos has uncovered new gene targets that this protein silences,” and that “this could explain how changes in SMCHD1 activity contribute to diseases.”

• #26 Potential Drug Appears to Ease Effects of Prader-Willi Syndrome | Duke Health

  https://corporate.dukehealth.org/news/potential-drug-appears-ease-effects-prader-willi-syndrome

  DURHAM, N.C. Duke Health researchers have identified a drug-like small molecule that, in animal experiments, appears to be an effective treatment for a genetic disorder called Prader-Willi syndrome. […] In most cases of Prader-Willi syndrome, the responsible gene in the region of chromosome 15 from the father is missing and the mothers copy is silent. Jiang and colleagues focused their work on finding a way to activate the silent gene from the mothers chromosome to recover the necessary gene function that would ordinarily be performed by the fathers gene. […] A class of small molecule that are known as G9a inhibitors were successful, both in the mouse model of Prader-Willi syndrome and in human cells from patients with the disorder. G9a is an enzyme that is important for gene regulation. […] Our findings suggest that G9a inhibitors may play a role in regulating the silencing of parental chromosomes on certain genes that require an imprinting process for normal function, Jiang said. This could provide a new insight for the molecular mechanism of genomic imprinting.

• #27 Game-changer drug is the first to tackle overeating in Prader-Willi syndrome | Drug Discovery News

  https://www.drugdiscoverynews.com/game-changer-drug-is-the-first-to-tackle-overeating-in-prader-willi-syndrome-16355

  PWS is caused by the deletion or alteration of genes on chromosome 15 in a region called the Prader-Willi critical region (PWCR). […] Maith explained that the exact mechanism that causes hyperphagia in PWS is unknown, although it is likely related to abnormalities in hypothalamic development and function. Vykat XR is a formulation of a crystalline salt, diazoxide choline, which blocks potassium channels in the hypothalamus and suppresses appetite-stimulating hormones.

• #28 What is Prader-Willi Syndrome

  https://www.fpwr.org/what-is-prader-willi-syndrome

  PWS results from an abnormality of chromosome 15, and definitive diagnosis is now based on genetic testing. […] Although hypothalamic dysfunction is believed to lead to the symptoms of PWS, it is not yet clear how the genetic abnormality causes hypothalamic dysfunction. […] The PWS region of chromosome 15 is one of the most complex regions of the human genome. Although there have been significant advances in understanding and characterizing the genetic changes associated with PWS, the exact mechanism by which lack of functional genetic material in this region leads to the symptoms associated with PWS is not understood. Scientists are actively studying the normal role of the genetic sequences in the PWS region and how their loss affects the hypothalamus and other systems in the body.

• #29 What is Prader-Willi Syndrome

  https://www.fpwr.ca/about-prader-willi-syndrome

  Prader-Willi syndrome is caused by a lack of active genetic material in a particular region of chromosome 15 (15q11-q13). […] The mechanism by which the lack of functional genetic material on chromosome 15 leads to the symptoms associated with PWS is not understood. Scientists are actively studying the normal role of the genetic sequences in the PWS region, and how their loss affects the hypothalamus and other systems in the body.

• #30 Prader-Willi Syndrome: Molecular Mechanism and Epigenetic Therapy | Bentham Science Publishers

  https://www.benthamdirect.com/content/journals/cgt/10.2174/1566523220666200424085336

  Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease characterized by cognitive impairments, developmental delay, hyperphagia, obesity, and sleep abnormalities. It is caused by a lack of expression of the paternally active genes in the PWS imprinting center on chromosome 15 (15q11.2-q13). […] Owing to the imprinted gene regulation, the same genes in the maternal chromosome, 15q11-q13, are intact in structure but repressed at the transcriptional level because of the epigenetic mechanism. The specific molecular defect underlying PWS provides an opportunity to explore epigenetic therapy to reactivate the expression of repressed PWS genes inherited from the maternal chromosome. […] Although our understanding of the molecular basis of PWS has changed fundamentally, there has been a little progress in the epigenetic therapy of PWS that targets its underlying genetic defects.

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