-
Handbook of Clinical Neurology 2021Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, arising from a loss of paternity expressed genetic material on the imprinted chromosome locus... (Review)
Review
Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, arising from a loss of paternity expressed genetic material on the imprinted chromosome locus 15q11-q13. Despite increasing clarity on the underlying genetic defects, the molecular basis of the condition remains poorly understood. Hypothalamic dysfunction is widely recognized as the basis of the core symptoms of PWS, which include a deficiency in growth hormone and reproductive hormones, circadian rhythm abnormalities, and a lack of satiety, leading to an extreme obesity, among others. Genome-wide gene expression analysis (transcriptomics) offers an unbiased interrogation of complex disease pathogenesis and a potential window into the dysregulated pathways involved in disease. In this chapter, we review the findings from recent work investigating the PWS hypothalamic transcriptome, discuss the significance of the findings in relation to the clinical presentation and molecular underpinnings of PWS, and highlight future research directions.
Topics: Genome; Humans; Hypothalamus; Obesity; Prader-Willi Syndrome; Transcriptome
PubMed: 34238471
DOI: 10.1016/B978-0-12-820683-6.00027-0 -
EBioMedicine Aug 2015Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic... (Clinical Trial)
Clinical Trial
UNLABELLED
Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation.
RESEARCH IN CONTEXT
Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader-Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.
Topics: Adolescent; Animals; Antigens, Bacterial; Child; Child, Preschool; Dietary Carbohydrates; Dysbiosis; Female; Gastrointestinal Microbiome; Humans; Male; Mice; Prader-Willi Syndrome
PubMed: 26425705
DOI: 10.1016/j.ebiom.2015.07.007 -
European Journal of Medical Genetics Feb 2023The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and...
The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and unmethylated in the paternally derived allele. Both unmethylated and methylated alleles are observed in normal individuals. Only the methylated allele is observed in patients with Prader-Willi syndrome, whereas only the unmethylated allele is observed in those with Angelman syndrome. Hence, detection of aberrant methylation at the differentially methylated region is fundamental to the molecular diagnosis of Prader-Willi syndrome and Angelman syndromes. Traditionally, bisulfite treatment and methylation-sensitive restriction enzyme treatment or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) have been used. We here developed a long-read sequencing assay that can distinguish methylated and unmethylated CpG sites at 15q11.2 by the difference in current intensity generated from nanopore reads. We successfully diagnosed 4 Prader-Willi syndrome patients and 3 Angelman syndrome patients by targeting differentially methylated regions. Concurrent copy number analysis, homozygosity analysis, and structural variant analysis also allowed us to precisely delineate the underlying pathogenic mechanisms, including gross deletion, uniparental heterodisomy, uniparental isodisomy, or imprinting defect. Furthermore, we showed allele-specific methylation in imprinting-related differentially methylated regions on chromosomes 6, 7, 11, 14, and 20 in a normal individual together with 4 Prader-Willi patients and 3 Angelman syndrome patients. Hence, presently reported method is likely to be applicable to the diagnosis of imprinting disorders other than Prader-Willi syndrome and Angelman syndrome as well.
Topics: Humans; Prader-Willi Syndrome; Angelman Syndrome; DNA Methylation; Nanopores; Uniparental Disomy; Chromosomes, Human, Pair 15; Genomic Imprinting
PubMed: 36587803
DOI: 10.1016/j.ejmg.2022.104690 -
Missouri Medicine 2024Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span.... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span. Beyond the primary care needs of all children and adults, the unique medical concerns and management needs of those with PWS are best served in a multidisciplinary academic center. Our PWS center has provided care for individuals with PWS and their families since 1981. Our growth hormone studies contributed to growth hormone supplementation becoming standard of care in this country. Here, in collaboration with the primary care provider, early childhood intervention programs, schools and local parent organizations, solid, patient-centered care for affected individuals and their families can be provided across the life-span. The purpose of this article is to provide a brief overview of PWS and the attendant medical and behavior management challenges attendant to the disorder.
Topics: Prader-Willi Syndrome; Humans; Child; Human Growth Hormone
PubMed: 38854617
DOI: No ID Found -
Handbook of Clinical Neurology 2019At times psychotropic drug use is required to address behavioral and other interfering symptoms that accompany neurobehavioral disorders. We review such prescribing... (Review)
Review
At times psychotropic drug use is required to address behavioral and other interfering symptoms that accompany neurobehavioral disorders. We review such prescribing practice in autism spectrum disorder, fragile X syndrome, and Prader-Willi syndrome.
Topics: Antidepressive Agents; Antipsychotic Agents; Autism Spectrum Disorder; Fragile X Syndrome; Humans; Intellectual Disability; Mental Disorders; Prader-Willi Syndrome; Psychopharmacology
PubMed: 31727225
DOI: 10.1016/B978-0-444-64012-3.00023-X -
The Journal of Clinical Endocrinology... Nov 2023Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its... (Review)
Review
CONTEXT
Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health.
OBJECTIVE
To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening.
METHODS
We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy, and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies.
RESULTS
Seven adults (age range, 18-55 years) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma, and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies.
CONCLUSION
Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present, such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged.
Topics: Adolescent; Adult; Child; Humans; Middle Aged; Young Adult; Adenocarcinoma; Fathers; Hyperphagia; Prader-Willi Syndrome; Retrospective Studies
PubMed: 37267430
DOI: 10.1210/clinem/dgad312 -
Andes Pediatrica : Revista Chilena de... Jun 2021Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However,...
INTRODUCTION
Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However, undernutrition secondary to severe hypotonia and feeding difficulties is the predominant initial feature.
OBJECTIVE
to reprodu ce and communicate the nutritional phases on a series of Chilean cases with PWS.
PATIENTS AND METHOD
Cross-sectional study in which clinical records of PWS individuals under nutritional con trol at the Clínica Santa María in Santiago, Chile between 2017 and 2018 were analyzed. The anthro pometric references of the World Health Organization were used to carry out the nutritional as sessment. The classification into nutritional phases was according to the Miller criteria.
RESULTS
24 patients from infants to adults were included. All children aged under 9 months were in phase I and had malnutrition or were eutrophic; those between 9 and 25 months were classified in phase 2a; pa tients between 2.1 and 4.5 years were distributed between phases 1 and 2 and 66% were eutrophic; those between 4.5 to 8 years, 80% were in phase 2a and 2b and obesity begins to appear, and patients over 8 years of age, 75% were in phase 3 and all are overweight or obese. There was an association bet ween nutritional phase and age but not between it and nutritional status.
CONCLUSIONS
In our series, the nutritional phases described according to age were reproduced according to those internationally described. There was no association between nutritional status and age.
Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Cross-Sectional Studies; Disease Progression; Female; Humans; Hyperphagia; Infant; Infant, Newborn; Male; Malnutrition; Pediatric Obesity; Prader-Willi Syndrome; Young Adult
PubMed: 34479241
DOI: 10.32641/andespediatr.v92i3.2400 -
Journal of Neuroendocrinology Jul 2021Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the... (Review)
Review
Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have abnormal neurocircuitry engaged in the hedonic and physiological control of feeding behavior. This is translated into diminished production of hypothalamic effector peptides which are responsible for the coordination of energy homeostasis and satiety. So far, studies with animal models for PWS and with human post-mortem hypothalamic specimens demonstrated changes particularly in the infundibular and the paraventricular nuclei of the hypothalamus, both in orexigenic and anorexigenic neural populations. Moreover, many PWS patients have a severe endocrine dysfunction, e.g. central hypogonadism and/or growth hormone deficiency, which may contribute to the development of increased fat mass, especially if left untreated. Additionally, the role of non-neuronal cells, such as astrocytes and microglia in the hypothalamic dysregulation in PWS is yet to be determined. Notably, microglial activation is persistently present in non-genetic obesity. To what extent microglia, and other glial cells, are affected in PWS is poorly understood. The elucidation of the hypothalamic dysfunction in PWS could prove to be a key feature of rational therapeutic management in this syndrome. This review aims to examine the evidence for hypothalamic dysfunction, both at the neuropeptidergic and circuitry levels, and its correlation with the pathophysiology of PWS.
Topics: Animals; Humans; Hyperphagia; Hypogonadism; Hypothalamic Hormones; Hypothalamus; Nerve Net; Neuropeptides; Obesity; Prader-Willi Syndrome
PubMed: 34156126
DOI: 10.1111/jne.12994 -
Current Opinion in Endocrinology,... Feb 2020Prader Willi syndrome is characterized not only by hyperphagia frequently resulting in obesity, but also by endocrine dysfunction across a variety of axes. This article... (Review)
Review
PURPOSE OF REVIEW
Prader Willi syndrome is characterized not only by hyperphagia frequently resulting in obesity, but also by endocrine dysfunction across a variety of axes. This article reviews the most recent literature regarding possible causes of hyperphagia and the nature of endocrinopathies seen in Prader Willi syndrome, as well as current research into possible therapies.
RECENT FINDINGS
Investigation into neurologic, metabolic and hormonal drivers of hyperphagia and obesity has revealed new insights and clarified underlying pathophysiology. Additional studies continue to elucidate the hormonal deficiencies seen in the syndrome, allowing for improvements in clinical care.
SUMMARY
The underlying causes of the hyperphagia and progressive obesity frequently seen in Prader Willi Syndrome are largely unknown and likely multifactorial. Understanding the hormonal and metabolic drivers at work in PWS, as well as the nature of other hormonal dysfunction seen in the syndrome is necessary to guide current management and future research directions.
Topics: Drugs, Investigational; Endocrine System; Humans; Hyperphagia; Obesity; Prader-Willi Syndrome; Therapies, Investigational
PubMed: 31815782
DOI: 10.1097/MED.0000000000000517 -
Clinical Anatomy (New York, N.Y.) Jul 2016Prader-Willi Syndrome (PWS) is estimated to affect 400,000 people worldwide. First described clinically in 1956, PWS is now known to be a result of a genetic mutation,... (Review)
Review
Prader-Willi Syndrome (PWS) is estimated to affect 400,000 people worldwide. First described clinically in 1956, PWS is now known to be a result of a genetic mutation, involving Chromosome 15. The phenotypical appearance of individuals with the syndrome follows a similar developmental course. During infancy, universal hypotonia accompanied by feeding problems, hypogonadism, and dolichocephaly are evident. Characteristic facial features such as narrow bifrontal diameter, almond-shaped eyes, and small mouth (with downturned corners and thin upper lip) may also be evident at this stage. In early childhood, the craniofacial features become more obvious and a global developmental delay is observed. Simultaneously, individuals develop hyperphagia that leads to excessive or rapid weight gain, which, if untreated, exists throughout their lifespan and may predispose them to numerous, serious health issues. The standard tool for differential diagnosis of PWS is genetic screening; however, clinicians also need to be aware of the characteristic features of this disorder, including differences between the genetic subtypes. As the clinical manifestations of the syndrome vary between individuals and become evident at different developmental time points, early assessment is hindered. This article focuses on the clinical and anatomical manifestations of the syndrome and highlights the areas of discrepancy and limitations within the existing literature. Clin. Anat. 29:590-605, 2016. © 2016 Wiley Periodicals, Inc.
Topics: Dentition; Facies; Humans; Hypopigmentation; Musculoskeletal Abnormalities; Phenotype; Prader-Willi Syndrome; Vision, Ocular
PubMed: 26749552
DOI: 10.1002/ca.22686