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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 -
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 -
European Journal of Human Genetics :... Jan 2009Prader-Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor...
Prader-Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.
Topics: Adolescent; Adult; Child; Child Behavior Disorders; Child, Preschool; Chromosomes, Human, Pair 15; Developmental Disabilities; Female; Genetic Counseling; Human Growth Hormone; Humans; Hypogonadism; Infant; Male; Muscle Hypotonia; Obesity; Phenotype; Prader-Willi Syndrome; Psychotic Disorders; Young Adult
PubMed: 18781185
DOI: 10.1038/ejhg.2008.165 -
The Biochemical Journal Jun 2017Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated... (Review)
Review
Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated in the related neurodevelopmental syndromes, Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SHFYNG). MAGEL2 is highly expressed in the hypothalamus and plays an important role in a fundamental cellular process that recycles membrane proteins from endosomes through the retromer sorting pathway. MAGEL2 is part of a multi-subunit protein complex consisting of MAGEL2, the TRIM27 E3 ubiquitin ligase, and the USP7 deubiquitinating enzyme. The AGEL2-P7-RIM27 (or MUST) complex facilitates the retromer recycling pathway through ubiquitination and activation of the WASH actin nucleation promoting factor. This review provides an overview of the MAGE protein family of ubiquitin ligases regulators and details the molecular and cellular role of MAGEL2 in ubiquitination, actin regulation and endosomal sorting processes, as well as MAGEL2 implications in PWS and SHFYNG disorders. The physiological functions of MAGEL2, elucidated through the study of knockout mouse models, are also discussed.
Topics: Endosomes; Humans; Prader-Willi Syndrome; Protein Transport; Proteins; Ubiquitination
PubMed: 28626083
DOI: 10.1042/BCJ20160616 -
American Journal of Medical Genetics.... Oct 2022Prader-Willi Syndrome (PWS) is a multi-system genetic disorder characterized by hyperphagia and a range of medical complications. While register and cohort studies have...
Prader-Willi Syndrome (PWS) is a multi-system genetic disorder characterized by hyperphagia and a range of medical complications. While register and cohort studies have explored the natural course of the syndrome, there is little nationally-representative data. In this study the National Inpatient Sample, a de-identified all-payors database of acute care hospital discharges in the United States, was queried for patients discharged with a diagnosis of PWS in 2019. Hospitalizations involving PWS were compared to hospitalizations without a PWS diagnosis matched based on demographic and hospital factors. In total, 540 hospitalizations (95% CI: 513-567) included a diagnosis of PWS. Median age at time of admission was 22 years, with an interquartile range of 6.3-37.8 years. Respiratory conditions accounted for 110 (20.4%) of primary discharge diagnoses, with infectious conditions for 70 (13.0%) and digestive conditions for 65 (12.0%). Hospitalizations involving PWS were significantly more likely to involve respiratory failure (OR 5.49; 95% CI 3.86-7.80), septicemia (OR 2.80, 95% CI 1.97-3.96), or intestinal obstruction and ileus (OR 6.29; 95% CI 3.70-10.7) compared to matched hospitalizations without PWS. Obesity was diagnosed in 230 PWS hospitalizations (42.6%; OR 3.86, 95% CI 3.17-4.72 relative to non-PWS hospitalizations). These results point to an ongoing need for the improved diagnosis and treatment of PWS complications, and highlight the importance of specific billing codes for rare diseases to enhance the collection of real world evidence.
Topics: Adolescent; Adult; Child; Comorbidity; Demography; Humans; Inpatients; Obesity; Prader-Willi Syndrome; Young Adult
PubMed: 35838073
DOI: 10.1002/ajmg.a.62901 -
Journal of Pediatric Orthopedics. Part B Nov 2023Although scoliosis is commonly seen in patients with Prader-Willi syndrome, the patterns and extent of the deformity may change along their growth. Increased body weight...
Although scoliosis is commonly seen in patients with Prader-Willi syndrome, the patterns and extent of the deformity may change along their growth. Increased body weight is another issue in these patients, and its relationship with scoliosis is still controversial. The aim of this study was to evaluate scoliosis in patients with PWS, and its relationship with BMI. This was a retrospective cohort study in which a series of radiographic images and BMI from each patient were collected, and the data were rearranged following the age at which they were recorded. These patients were subsequently labeled as non-Scoliotic (<10°), Moderate (10° - 39°), and Severe (≥40°) according to their final Cobb angle, also as Normal (≤85%), Overweight (86%-95%), and Obese (≥95%) according to final BMI percentage. Thirty-four patients with age from 1 to 20 years old were recruited for this study, and the mean length of follow-up was 6.6 years. The prevalence of scoliosis was 71% (24 patients in Moderate, and 9 patients in Severe), and 65.6% were either overweight (11 patients) or obese (10 patients). The mean BMI percentage in non-scoliotic patients was 93.10 ± 13.84, which was significantly higher than that of the scoliotic groups ( P = 0.0180). When looking at the longitudinal change, the non-Scoliotic group had high BMI since childhood, and obese patients had less spine deformity also from early childhood. In this study, we found that the prevalence of scoliosis in Taiwanese population with PWS was 71% without gender preference. Not every patient had a high BMI, and obese patients seemed to have significantly less chance to develop scoliosis. Level III.
Topics: Humans; Child, Preschool; Infant; Child; Adolescent; Young Adult; Adult; Prader-Willi Syndrome; Scoliosis; Body Mass Index; Retrospective Studies; Overweight; Obesity
PubMed: 36445375
DOI: 10.1097/BPB.0000000000001031 -
Orphanet Journal of Rare Diseases Jun 2022Prader-Willi syndrome (PWS) is a complex and multisystem neurobehavioral disease, which is caused by the lack of expression of paternally inherited imprinted genes on... (Review)
Review
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 clinical manifestations of PWS vary with age. It is characterized by severe hypotonia with poor suck and feeding difficulties in the early infancy, followed by overeating in late infancy or early childhood and progressive development of morbid obesity unless the diet is externally controlled. Compared to Western PWS patients, Chinese patients have a higher ratio of deletion type. Although some rare disease networks, including PWS Cooperation Group of Rare Diseases Branch of Chinese Pediatric Society, Zhejiang Expert Group for PWS, were established recently, misdiagnosis, missed diagnosis and inappropriate intervention were usually noted in China. Therefore, there is an urgent need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy. Our purpose is to evaluate the current literature and evidences on diagnosis and management of PWS in order to provide evidence-based guidelines for this disease, specially from China.
Topics: Child; Child, Preschool; China; Early Diagnosis; Humans; Muscle Hypotonia; Prader-Willi Syndrome; Quality of Life
PubMed: 35698200
DOI: 10.1186/s13023-022-02302-z -
Value in Health : the Journal of the... Feb 2023To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common...
OBJECTIVES
To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families.
METHODS
The PWS Anxiousness and Distress Behaviors Questionnaire (PADQ) was developed with extensive input from clinical experts, as well as caregivers of individuals with PWS, who participated in iterative sets of qualitative interviews. The psychometric properties of the PADQ were subsequently demonstrated in a cross-sectional evaluation using data from the Global PWS Registry provided by > 400 caregivers and confirmed using data from a phase 3 clinical trial of an oxytocin analogue (intranasal carbetocin, LV-101).
RESULTS
Qualitative interview participants consistently endorsed the content of the PADQ and were confident they could accurately respond to each item based on their observations of their child's behavior. Analysis of cross-sectional data supported the computation of a total PADQ score, as well as the reliability and validity of the measure. The results of analyses using longitudinal clinical trial data confirmed these properties and provided evidence for the responsiveness of the PADQ, further supporting its appropriateness for the evaluation of new treatments targeting anxiousness and distress in PWS.
CONCLUSIONS
The current body of evidence supports the conclusion that the PADQ measures observable behaviors that are meaningful to patients and their families and provides a valid and reliable method to assess beneficial treatment effects for some of the most challenging behaviors associated with PWS.
Topics: Child; Humans; Prader-Willi Syndrome; Psychometrics; Reproducibility of Results; Cross-Sectional Studies; Anxiety; Surveys and Questionnaires
PubMed: 36202701
DOI: 10.1016/j.jval.2022.08.004 -
Journal of Medical Genetics Nov 1997Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile... (Review)
Review
Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial appearance, obesity, hypogonadism, and short stature. Obesity and the behavioural problems are the major causes of morbidity and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted region of proximal 15q and results from absence of the normally active paternal genes in this region. Such absence results from paternal interstitial deletion, maternal uniparental disomy, or a mutation or other abnormality in the imprinting process. Diagnostic identification of all causes has become available in recent years, permitting early detection and institution of appropriate management. This testing has permitted recent identification of some phenotypic differences among affected subjects of different race and between those with deletions and uniparental disomy as a cause.
Topics: Humans; Prader-Willi Syndrome
PubMed: 9391886
DOI: 10.1136/jmg.34.11.917 -
American Journal of Medical Genetics.... Feb 2018We describe the National Institutes of Health rare disease consortium for Prader-Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis,... (Review)
Review
We describe the National Institutes of Health rare disease consortium for Prader-Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11-q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early-onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11-q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype-phenotype correlations, and clinical outcomes in PWS.
Topics: Age of Onset; Clinical Studies as Topic; History, 21st Century; Humans; Mortality; National Institutes of Health (U.S.); Obesity, Morbid; Outcome Assessment, Health Care; Prader-Willi Syndrome; Rare Diseases; United States
PubMed: 29271568
DOI: 10.1002/ajmg.a.38582