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Journal of Clinical Sleep Medicine :... Jun 2022Clinical experience and a growing body of evidence suggest that sleep disturbances are common in people with Prader-Willi syndrome (PWS). PWS is a rare neuroendocrine... (Review)
Review
UNLABELLED
Clinical experience and a growing body of evidence suggest that sleep disturbances are common in people with Prader-Willi syndrome (PWS). PWS is a rare neuroendocrine disorder characterized by early hypotonia and feeding difficulties; developmental delays; endocrinopathies; and behavioral concerns, especially rigidity, anxiety, and behavioral outbursts. PWS is also characterized by decreased resting energy expenditure and transition to hyperphagia and obesity. We propose that, for many people with PWS, clinical diagnosis and management of sleep disorders is an unmet need. We present current information to suggest disordered sleep is a significant burden for individuals with PWS and often overlooked. While central and obstructive sleep apnea are more widely recognized in PWS, other sleep disorders have increasingly gained recognition, including hypersomnia, narcolepsy-like phenotypes, and insomnia. Sleep disorders can impact behavior, cognition, and quality of life and health for individuals with PWS. Our goal is to bring sleep disorders to the forefront of therapeutic intervention for patients with PWS. This paper presents a review of the literature and recommendations for clinical practice based on published research and our clinical experience as sleep specialists, geneticists, psychiatrists, pediatricians, otolaryngologists, and pulmonologists with extensive experience with this patient population. We recommend that management of sleep be considered an integral part of successful medical management of PWS. Further research concerning sleep problems in PWS is urgently needed to develop best practices and work toward a consensus statement for medical management to meet the needs of people with PWS.
CITATION
Duis J, Pullen LC, Picone M, et al. Diagnosis and management of sleep disorders in Prader-Willi syndrome. . 2022;18(6):1687-1696.
Topics: Disorders of Excessive Somnolence; Humans; Narcolepsy; Prader-Willi Syndrome; Quality of Life; Sleep Wake Disorders
PubMed: 35172921
DOI: 10.5664/jcsm.9938 -
Open Biology Sep 2020Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in... (Review)
Review
Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from the may be the primary cause of PWS. Patients with small atypical deletions of the paternal cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.
Topics: Biomarkers; Chromosomes, Human, Pair 15; Disease Management; Disease Susceptibility; Epigenesis, Genetic; Gene Expression Regulation; Genetic Association Studies; Genetic Loci; Genomic Imprinting; Humans; Phenotype; Prader-Willi Syndrome; RNA, Untranslated
PubMed: 32961075
DOI: 10.1098/rsob.200195 -
Clinical Autonomic Research : Official... Jun 2023Prader-Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal... (Review)
Review
INTRODUCTION
Prader-Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal region, generally from a paternal deletion. Predominant features include infantile hypotonia, a poor suck with failure to thrive, craniofacial features, and developmental and behavioral problems including self-injury and childhood onset of obesity. In addition to severe obesity, patients with PWS present with other symptoms of autonomic nervous system dysfunction.
METHODS
We examined the features seen in Prader-Willi syndrome and searched the literature for evidence of autonomic nervous system involvement in this rare obesity-related disorder and illustrative findings possibly due to autonomic nervous system dysfunction. Additionally, we reviewed the literature in relation to childhood obesity syndromes and compared those syndromes to the syndromic obesity found in Prader-Willi syndrome.
RESULTS
We report autonomic nervous system-related symptoms associated with childhood obesity impacting features seen in Prader-Willi syndrome and possibly other obesity-related genetic syndromes. We compiled evidence of both an autonomic route for the obesity seen in PWS and other autonomic nervous system-related dysfunctions. These include decreased salvation, sleep disordered breathing, increased pain and thermal threshold instability, delayed gastric emptying, altered blood pressure readings, and pupillary constriction responses as evidence of autonomic nervous system involvement.
CONCLUSIONS
We summarized and illustrated findings of autonomic nervous system dysfunction in Prader-Willi syndrome and other obesity-related syndromes and genetic factors that may play a causative role in development.
Topics: Humans; Child; Prader-Willi Syndrome; Pediatric Obesity
PubMed: 36515769
DOI: 10.1007/s10286-022-00909-7 -
Bioscience Reports Jun 2022Prader-Willi Syndrome (PWS) is a rare complex genetic disease that is associated with pathological disorders that include endocrine disruption, developmental,... (Review)
Review
Prader-Willi Syndrome (PWS) is a rare complex genetic disease that is associated with pathological disorders that include endocrine disruption, developmental, neurological, and physical problems as well as intellectual, and behavioral dysfunction. In early stage, PWS is characterized by respiratory distress, hypotonia, and poor sucking ability, causing feeding concern and poor weight gain. Additional features of the disease evolve over time. These include hyperphagia, obesity, developmental, cognitive delay, skin picking, high pain threshold, short stature, growth hormone deficiency, hypogonadism, strabismus, scoliosis, joint laxity, or hip dysplasia. The disease is associated with a shortened life expectancy. There is no cure for PWS, although interventions are available for symptoms management. PWS is caused by genetic defects in chromosome 15q11.2-q13, and categorized into three groups, namely Paternal deletion, Maternal uniparental disomy, and Imprinting defect. PWS is confirmed through genetic testing and DNA-methylation analysis. Studies revealed that at least two key proteins namely MAGEL-2 and NECDIN along with two proteases PCSK1 and PCSK2 are linked to PWS. Herein, we summarize our current understanding and knowledge about the role of these proteins and enzymes in various biological processes associated with PWS. The review also describes how loss and/or impairment of functional activity of these macromolecules can lead to hormonal disbalance by promoting degradation of secretory granules and via inhibition of proteolytic maturation of precursor-proteins. The present review will draw attention of researchers, scientists, and academicians engaged in PWS study and will help to identify potential targets and molecular pathways for PWS intervention and treatment.
Topics: Endopeptidases; Genetic Testing; Humans; Obesity; Peptide Hydrolases; Prader-Willi Syndrome
PubMed: 35621394
DOI: 10.1042/BSR20220610 -
Reviews in Endocrine & Metabolic... Jun 2019Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities,... (Review)
Review
Prader-Willi syndrome (PWS) is a genetic disorder characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. It is caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13. This genetic disorder has an estimated prevalence that ranges between 1/10,000-1/30,000. Hypothalamic dysfunction is a common finding in PWS and it has been implicated in several manifestations of this syndrome such as hyperphagia, temperature instability, high pain threshold, sleep disordered breathing, and multiple endocrine abnormalities. These include growth hormone deficiency, central adrenal insufficiency, hypogonadism, hypothyroidism, and obesity often complicated by type 2 diabetes. The aim of this manuscript is to overview the current literature on metabolic and endocrine complications of PWS, focusing on human studies and providing insights on the physio pathological mechanisms. A careful management of metabolic and endocrine complications can contribute to improve quality of life, prevent complications, and prolong life expectancy of PW patients.
Topics: Diabetes Mellitus, Type 2; Humans; Hyperphagia; Prader-Willi Syndrome; Quality of Life
PubMed: 31065942
DOI: 10.1007/s11154-019-09502-2 -
Frontiers in Endocrinology 2022The generalized dysfunction of the hypothalamic-pituitary axis in patients with Prader-Willi syndrome (PWS) is the most likely cause of hypogonadism, inadequate growth... (Review)
Review
The generalized dysfunction of the hypothalamic-pituitary axis in patients with Prader-Willi syndrome (PWS) is the most likely cause of hypogonadism, inadequate growth hormone secretion, excessive appetite and associated obesity, impaired body temperature regulation, and hypothyroidism. The syndrome is also related to an increased risk of central adrenal insufficiency, although its prevalence remains unknown. The results of the studies in which different methods of pharmacological stimulation were used do not provide conclusive outcomes. As a result, there are no clear guidelines with regard to diagnosis, prevention, or long-term care when adrenal insufficiency is suspected in patients with PWS. Currently, most patients with PWS are treated with recombinant human growth hormone (rhGH). It has been confirmed that rhGH therapy has a positive effect on growth, body composition, body mass index (BMI), and potentially on psychomotor development in children with PWS. Additionally, rhGH may reduce the conversion of cortisone to cortisol through inhibition of 11β-hydroxysteroid dehydrogenase type 1. However, its influence on basal adrenal function and adrenal stress response remains unexplained in children with PWS. This paper reviews the literature related to the hypothalamic-pituitary-adrenal axis dysfunction in the PWS patient population with a focus on children.
Topics: Child; Humans; Prader-Willi Syndrome; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Hydrocortisone; Human Growth Hormone; Adrenal Insufficiency
PubMed: 36465638
DOI: 10.3389/fendo.2022.1021704 -
Current Obesity Reports Dec 2022Prader-Willi syndrome (PWS) is a rare and complex genetic disorder with multiple effects on the metabolic, endocrine, and neurological systems, as well as behavioral and... (Review)
Review
PURPOSE OF REVIEW
Prader-Willi syndrome (PWS) is a rare and complex genetic disorder with multiple effects on the metabolic, endocrine, and neurological systems, as well as behavioral and intellectual difficulties. Despite advances in understanding the genetic basis of obesity in PWS, there are conflicting data on its management. Therefore, the present manuscript aims to provide an update on the nutritional treatment and pharmacological approach in adult patients with PWS.
RECENT FINDINGS
The management of obesity in patients with PWS is challenging and requires the cooperation of an experienced multidisciplinary team, including the nutritionist. An adequate clinical evaluation including nutritional and biochemical parameters should be performed to tailor the best therapeutic strategy. Both lifestyle and pharmacological interventions may represent useful strategies to prevent the high rate of morbidity and mortality related to PWS. The use of bariatric surgery is still controversial. Although it is imperative to adopt an obesity prevention strategy in childhood, there is promising evidence for the treatment of obesity in adulthood with current obesity medications in conjunction with lifestyle interventions.
Topics: Humans; Adult; Prader-Willi Syndrome
PubMed: 36063285
DOI: 10.1007/s13679-022-00478-w -
Current Pediatric Reviews 2016Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with... (Review)
Review
BACKGROUND
Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction.
OBJECTIVE
Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report.
METHODS AND RESULTS
An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner.
CONCLUSIONS
Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed.
Topics: Child; Child, Preschool; Cognition Disorders; Developmental Disabilities; Gene Expression Profiling; Genetic Counseling; Hormone Replacement Therapy; Humans; Hyperphagia; Obesity; Phenotype; Practice Guidelines as Topic; Prader-Willi Syndrome; Prognosis
PubMed: 26592417
DOI: 10.2174/1573396312666151123115250 -
Sleep Medicine Reviews Jun 2021Prader-Willi Syndrome (PWS) is a complex genetic disorder with multiple cognitive, behavioral and endocrine dysfunctions. Sleep alterations and sleep disorders such as... (Meta-Analysis)
Meta-Analysis Review
Prader-Willi Syndrome (PWS) is a complex genetic disorder with multiple cognitive, behavioral and endocrine dysfunctions. Sleep alterations and sleep disorders such as Sleep-disordered breathing and Central disorders of hypersomnolence are frequently recognized (either isolated or in comorbidity). The aim of the review is to highlight the pathophysiology and the clinical features of sleep disorders in PWS, providing the basis for early diagnosis and management. We reviewed the genetic features of the syndrome and the possible relationship with sleep alterations in animal models, and we described sleep phenotypes, diagnostic tools and therapeutic approaches in humans. Moreover, we performed a meta-analysis of cerebrospinal fluid orexin levels in patients with PWS; significantly lower levels of orexin were detected in PWS with respect to control subjects (although significantly higher than the ones of narcoleptic patients). Sleep disorders in humans with PWS are multifaceted and are often the result of different mechanisms. Since hypothalamic dysfunction seems to partially influence metabolic, respiratory and sleep/wake characteristics of this syndrome, additional studies are required in this framework.
Topics: Animals; Disorders of Excessive Somnolence; Humans; Models, Animal; Prader-Willi Syndrome; Sleep Apnea Syndromes; Sleep Wake Disorders
PubMed: 33567377
DOI: 10.1016/j.smrv.2021.101432 -
Expert Review of Endocrinology &... Mar 2021: Prader-Willi syndrome (PWS) is the most well-known condition of genetic obesity. Over the past 20 years, advances have been achieved in the diagnosis and treatment of... (Review)
Review
: Prader-Willi syndrome (PWS) is the most well-known condition of genetic obesity. Over the past 20 years, advances have been achieved in the diagnosis and treatment of PWS with a significant improvement in prognosis.: This review focuses on the benefits of multidisciplinary approach in children and adolescents with PWS. In particular, the neonatologist and geneticist play a key role in early diagnosis and the clinical follow-up of the PWS patient must be guaranteed by a team including pediatric endocrinologist, psychologist, nutritionist/dietician, neurologist/neuropsychiatrist, sleep specialist, ears, nose and throat specialist (ENT), lung specialist, dentist, orthopedist and ophthalmologist and, eventually, gastroenterologist. We searched PubMed and critically summarized what has been reported in the last 10 years on PWS.: The multidisciplinary care in association with an early diagnosis and GH treatment postpones overweight development and decreases prevalence of obesity in individuals with PWS. Further prognostic improvements are expected through the selection of teams particularly experienced in the management of individuals with PWS and the discovery of new drugs.
Topics: Adolescent; Child; Early Diagnosis; Humans; Obesity; Prader-Willi Syndrome; Prognosis
PubMed: 33724138
DOI: 10.1080/17446651.2021.1898375