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Handbook of Clinical Neurology 2021Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, hypotonia, learning disability, as well as a range of psychiatric conditions.... (Review)
Review
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, hypotonia, learning disability, as well as a range of psychiatric conditions. The conservation of the PWS genetic interval on chromosome 15q11-q13 in human, and a cluster of genes on mouse chromosome 7, has facilitated the use of mice as animal models for PWS. Some models faithfully mimic the loss of all gene expression from the paternally inherited PWS genetic interval, whereas others target smaller regions or individual genes. Collectively, these models have provided insight into the mechanisms, many of which lead to alterations in hypothalamic function, underlying the core symptoms of PWS, including growth retardation, hyperphagia and metabolism, reproductive maturation and endophenotypes of relevance to behavioral and psychiatric problems. Here we review and summarize these studies.
Topics: Animals; Humans; Mice; Models, Animal; Prader-Willi Syndrome
PubMed: 34238473
DOI: 10.1016/B978-0-12-820683-6.00029-4 -
Neuroscience and Biobehavioral Reviews Feb 2023Neurotrophins (NTs) as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play multiple roles in different settings including neuronal development,... (Review)
Review
Neurotrophins (NTs) as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play multiple roles in different settings including neuronal development, function and survival in both the peripheral and the central nervous systems from early stages. This report aims to provide a summary and subsequent review of evidences on the role of NTs in rare and non-common pediatric human diseases associated with changes in neurodevelopment. A variety of diseases has been analyzed and many have been linked to NTs neurobiological effects, including chronic granulomatous disease, hereditary sensory and autonomic neuropathy, Duchenne muscular dystrophy, Bardet-Biedl syndrome, Angelman syndrome, fragile X syndrome, trisomy 16, Williams-Beuren syndrome, Prader-Willi syndrome, WAGR syndrome, fetal alcohol spectrum disorders, Down syndrome and Klinefelter Syndrome. NTs alterations have been associated with numerous pathologic manifestations including cognitive defects, behavioral abnormalities, epilepsy, obesity, tumorigenesis as well as muscle-skeletal, immunity, bowel, pain sensibility and cilia diseases. In this report, we discuss that further studies are needed to clear a possible therapeutic role of NTs in these still often uncurable diseases.
Topics: Child; Humans; Brain-Derived Neurotrophic Factor; Nerve Growth Factor; Obesity; Prader-Willi Syndrome; Syndrome
PubMed: 36563920
DOI: 10.1016/j.neubiorev.2022.105015 -
American Journal of Medical Genetics.... May 2022Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well...
Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly, seizures, sleep apnea, and narcolepsy with or without cataplexy. This study used data in the Global PWS Registry (N = 893) to explore the onset and severity over time of the neuropsychiatric features reported in individuals with PWS and explored its associations with sleep disorders, seizures, and psychiatric symptoms. Results demonstrate that seizures are more common in the deletion subtype and that narcolepsy and cataplexy are more common in individuals who have sleep-related seizures. Finally, this work shows that anxiety and compulsive behaviors are persistent features of PWS that may arise early in childhood, and that anxiety is associated with higher frequency of other comorbid psychiatric diagnoses. In conclusion, this study is one of the largest to date characterizing sleep disorders and neuropsychiatric characteristics of individuals with PWS and reports on the novel association between sleep disorders and seizures. This study is also one of the first to offer details on the nature of the progression of these features in individuals with PWS.
Topics: Anxiety Disorders; Cataplexy; Child; Humans; Narcolepsy; Prader-Willi Syndrome; Seizures
PubMed: 35098642
DOI: 10.1002/ajmg.a.62662 -
Endocrinologia, Diabetes Y Nutricion Nov 2019Prader-Willi syndrome is a genetic disorder caused by chromosomal changes in segment 15q11-q13 including cognitive, mental, and behavioral symptoms, as well as a... (Review)
Review
Prader-Willi syndrome is a genetic disorder caused by chromosomal changes in segment 15q11-q13 including cognitive, mental, and behavioral symptoms, as well as a specific physical phenotype. Both the most common psychopathological changes (intellectual disability, obsessions, impulsivity, autism spectrum disorders, self-injuries) and the main psychiatric comorbidities (affective disorders, psychosis, obsessive-compulsive disorder, autism spectrum disorder) are characterized by a great heterogeneity, which warrants the need for better identification of their frequency and clinical signs. In addition to its effects on body compositionand hypotony, growth hormone has been shown to be useful for regulating patient behavior, and psychoactive drugs are also an option. Other alternatives have shown promising results in experimental trials. Adequate understanding of the psychopathology associated to Prader-Willi syndrome would allow for improving clinical approach, symptom identification, detection of comorbidities, and administration of more effective treatments, leading to better clinical outcomes.
Topics: Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder; Child; Cognition Disorders; Comorbidity; Emotional Regulation; Food Addiction; Humans; Intellectual Disability; Mood Disorders; Obsessive-Compulsive Disorder; Phenotype; Prader-Willi Syndrome; Self-Injurious Behavior; Sleep Wake Disorders
PubMed: 31006652
DOI: 10.1016/j.endinu.2019.03.004 -
Current Gene Therapy 2020Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease characterized by cognitive impairments, developmental delay, hyperphagia, obesity, and sleep... (Review)
Review
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. The purpose of this review is to summarize the main advances in the molecular study of PWS and discuss current and future perspectives on the development of CRISPR/Cas9- mediated epigenome editing in the epigenetic therapy of PWS. Twelve studies on the molecular mechanism or epigenetic therapy of PWS were included in the review. 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.
Topics: CRISPR-Cas Systems; Chromosomes, Human, Pair 15; Epigenesis, Genetic; Epigenome; Genetic Therapy; Genomic Imprinting; Humans; Maternal Inheritance; Paternal Inheritance; Prader-Willi Syndrome
PubMed: 32329685
DOI: 10.2174/1566523220666200424085336 -
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 -
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 -
International Journal of Molecular... Jan 2023A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS)....
A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS). Of these 154 PWS individuals, 87 (56.5%) showed the typical 15q11-q13 deletion subtypes, 62 (40.3%) showed non-deletion maternal disomy 15 and five individuals (3.2%) had separate unexpected microarray findings. For example, one PWS male had Klinefelter syndrome with segmental isodisomy identified in both chromosomes 15 and X. Thirty-five (40.2%) of 87 individuals showed typical larger 15q11-q13 Type I deletion and 52 individuals (59.8%) showed typical smaller Type II deletion. Twenty-four (38.7%) of 62 PWS individuals showed microarray patterns indicating either maternal heterodisomy 15 subclass or a rare non-deletion (epimutation) imprinting center defect. Segmental isodisomy 15 was seen in 34 PWS subjects (54.8%) with 15q26.3, 15q14 and 15q26.1 bands most commonly involved and total isodisomy 15 seen in four individuals (6.5%). In summary, we report on PWS participants consecutively enrolled internationally in a single clinical trial with high-resolution chromosome microarray analysis to determine and describe an unbiased estimate of the frequencies and types of genetic defects and address potential at-risk genetic disorders in those with maternal disomy 15 subclasses in the largest PWS cohort studied to date.
Topics: Humans; Male; Prader-Willi Syndrome; Microarray Analysis; Family; Chromosomes; Chromosomes, Human, Pair 15
PubMed: 36674736
DOI: 10.3390/ijms24021220 -
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