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Orphanet Journal of Rare Diseases Feb 2023Prader-Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients' care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results.
MATERIALS AND METHODS
The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality.
RESULTS
A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019-2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment.
CONCLUSIONS
The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Male; Chromosomes, Human, Pair 15; Delayed Diagnosis; Italy; Prader-Willi Syndrome; Quality of Life; Registries
PubMed: 36793093
DOI: 10.1186/s13023-023-02633-5 -
Advances in Pediatrics Aug 2016
Review
Topics: Adrenal Insufficiency; Bariatric Surgery; Body Composition; Child; Child Behavior Disorders; Diabetes Mellitus, Type 2; Diet, Reducing; Dwarfism; Energy Metabolism; Ghrelin; Gonadal Steroid Hormones; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hyperphagia; Hypogonadism; Hypothyroidism; Mental Disorders; Obesity; Prader-Willi Syndrome; Sleep Wake Disorders
PubMed: 27426895
DOI: 10.1016/j.yapd.2016.04.005 -
Orphanet Journal of Rare Diseases Feb 2024Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal... (Review)
Review
BACKGROUND
Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca. 70%), a chromosome 15 maternal uniparental disomy (mUPD; ca. 25%), or an imprinting centre defect (IC; ca. 1-3%). At birth, individuals with PWS are severely hypotonic and fail to thrive. Hyperphagia and characteristic physical and neuropsychiatric phenotypes become apparent during childhood. The risk for the development of a co-morbid psychotic illness increases during the teenage years, specifically in those with PWS due to the presence of an mUPD. The primary aim of this literature review is to inform clinical practice. To achieve this, we have undertaken a systematic analysis of the clinical research literature on prevalence, presentation, course, characteristics, diagnosis and treatment of psychotic illness in people with PWS. The secondary aim is to identify clinical aspects of psychotic illness in PWS in need of further investigation.
METHODS AND FINDINGS
A systematic literature review on psychosis in PWS was conducted on the databases Web of Knowledge, PubMed and Scopus, using the terms "((Prader-Willi syndrome) OR (Prader Willi Syndrome)) AND ((psychosis) OR (psychotic illness))". All articles written in English and reporting original human research were reviewed. In all but three of the 16 cohort studies in which the genetic types were known, the authors reported higher rates of psychosis in people with PWS resulting from an mUPD, compared to those with the deletion subtype of PWS. When psychosis was present the presentation was psychosis similar regardless of genetic type and was usually characterised by an acute onset of hallucinations and delusions accompanied by confusion, anxiety and motor symptoms.
CONCLUSIONS
The onset of confusion, an affective cyclical pattern with the presence of abnormal mental beliefs and experiences, usually of rapid onset is suggestive of the development of psychotic illness. Phenomenologically, this psychosis in people with PWS is atypical in comparison to schizophrenia and bipolar disorder in the general population. The relationship to psychosis in the general population and the optimum treatments remain uncertain.
Topics: Adolescent; Infant, Newborn; Humans; Prader-Willi Syndrome; Psychotic Disorders; Comorbidity; Family; Anxiety; Chromosomes, Human, Pair 15
PubMed: 38360662
DOI: 10.1186/s13023-024-03026-y -
Expert Reviews in Molecular Medicine Jul 2005Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the... (Review)
Review
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that arises from lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11-q13 region. PWS is considered the most common syndromal cause of life-threatening obesity and is estimated at 1 in 10,000 to 20,000 individuals. A de novo paternally derived chromosome 15q11-q13 deletion is the cause of PWS in about 70% of cases, and maternal disomy 15 accounts for about 25% of cases. The remaining cases of PWS result either from genomic imprinting defects (microdeletions or epimutations) of the imprinting centre in the 15q11-q13 region or from chromosome 15 translocations. Here, we describe the clinical presentation of PWS, review the current understanding of causative cytogenetic and molecular genetic mechanisms, and discuss future directions for research.
Topics: Chromosome Aberrations; Chromosomes, Human, Pair 15; Feeding Behavior; Humans; Prader-Willi Syndrome; Uniparental Disomy
PubMed: 16038620
DOI: 10.1017/S1462399405009531 -
International Journal of Molecular... Jul 2023Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...].
Prader-Willi syndrome (PWS) is a neuroendocrine genetic disorder resulting from the loss of paternally expressed imprinted genes in chromosome 15q11-q13 [...].
Topics: Humans; Prader-Willi Syndrome; Genomic Imprinting; Drug Approval; Chromosomes; Chromosomes, Human, Pair 15
PubMed: 37511333
DOI: 10.3390/ijms241411574 -
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 -
Metabolism: Clinical and Experimental Nov 2022Prader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11-13....
OBJECTIVE
Prader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11-13. Early-onset life-thriving obesity and hyperphagia represent the clinical hallmarks of PWS. The noncoding RNA gene SNORD116 within the minimal PWS genetic lesion plays a critical role in the pathogenesis of the syndrome. Despite advancements in understanding the genetic basis for PWS, the pathophysiology of obesity development in PWS remains largely uncharacterized. Here, we aimed to investigate the signatures of adipose tissue development and expansion pathways and associated adipose biology in PWS children without obesity-onset at an early stage, mainly from the perspective of the adipogenesis process, and further elucidate the underlying molecular mechanisms.
METHODS
We collected inguinal (subcutaneous) white adipose tissues (ingWATs) from phase 1 PWS and healthy children with normal weight aged from 6 M to 2 Y. Adipose morphology and histological characteristics were assessed. Primary adipose stromal vascular fractions (SVFs) were isolated, cultured in vitro, and used to determine the capacity and function of white and beige adipogenic differentiation. High-throughput RNA-sequencing (RNA-seq) was performed in adipose-derived mesenchymal stem cells (AdMSCs) to analyze transcriptome signatures in PWS subjects. Transient repression of SNORD116 was conducted to evaluate its functional relevance in adipogenesis. The changes in alternative pre-mRNA splicing were investigated in PWS and SNORD116 deficient cells.
RESULTS
In phase 1 PWS children, impaired white adipose tissue (WAT) development and unusual fat expansion occurred long before obesity onset, which was characterized by the massive enlargement of adipocytes accompanied by increased apoptosis. White and beige adipogenesis programs were impaired and differentiated adipocyte functions were disturbed in PWS-derived SVFs, despite increased proliferation capacity, which were consistent with the results of RNA-seq analysis of PWS AdMSCs. We also experimentally validated disrupted beige adipogenesis in adipocytes with transient SNORD116 downregulation. The transcript and protein levels of PPARγ, the adipogenesis master regulator, were significantly lower in PWS than in control AdMSCs as well as in SNORD116 deficient AdMSCs/adipocytes than in scramble (Scr) cells, resulting in the inhibited adipogenic program. Additionally, through RNA-seq, we observed aberrant transcriptome-wide alterations in alternative RNA splicing patterns in PWS cells mediated by SNORD116 loss and specifically identified a changed PRDM16 gene splicing profile in vitro.
CONCLUSIONS
Imbalance in the WAT expansion pathway and developmental disruption are primary defects in PWS displaying aberrant adipocyte hypertrophy and impaired adipogenesis process, in which SNORD116 deficiency plays a part. Our findings suggest that dysregulated adiposity specificity existing at an early phase is a potential pathological mechanism exacerbating hyperphagic obesity onset in PWS. This mechanistic evidence on adipose biology in young PWS patients expands knowledge regarding the pathogenesis of PWS obesity and may aid in developing a new therapeutic strategy targeting disturbed adipogenesis and driving AT plasticity to combat abnormal adiposity and associated metabolic disorders for PWS patients.
Topics: Adipogenesis; Adipose Tissue, White; Child; Humans; Hyperphagia; Obesity; PPAR gamma; Prader-Willi Syndrome; RNA Precursors; RNA, Small Nucleolar; Tissue Expansion
PubMed: 36007622
DOI: 10.1016/j.metabol.2022.155295 -
Neuroscience and Biobehavioral Reviews Nov 2022Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder. Global hypothalamic dysfunction is a core feature of PWS and has been implicated as a driver of... (Review)
Review
Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder. Global hypothalamic dysfunction is a core feature of PWS and has been implicated as a driver of many of PWS's phenotypic characteristics (e.g., hyperphagia-induced obesity, hypogonadism, short stature). Although the two neuropeptides (i.e., oxytocin [OXT] and arginine vasopressin [AVP]) most implicated in mammalian prosocial functioning are of hypothalamic origin, and social functioning is markedly impaired in PWS, there has been little consideration of how dysregulation of these neuropeptide signaling pathways may contribute to PWS's social behavior impairments. The present article addresses this gap in knowledge by providing a comprehensive review of the preclinical and clinical PWS literature-spanning endogenous neuropeptide measurement to exogenous neuropeptide administration studies-to better understand the roles of OXT and AVP signaling in this population. The preponderance of evidence indicates that OXT and AVP signaling are indeed dysregulated in PWS, and that these neuropeptide pathways may provide promising targets for therapeutic intervention in a patient population that currently lacks a pharmacological strategy for its debilitating social behavior symptoms.
Topics: Animals; Humans; Prader-Willi Syndrome; Oxytocin; Arginine Vasopressin; Hyperphagia; Social Behavior; Mammals
PubMed: 36113782
DOI: 10.1016/j.neubiorev.2022.104870 -
Orphanet Journal of Rare Diseases May 2022In recent years, more studies have observed that patients with Prader-Willi syndrome have lower insulin levels and lower insulin resistance than body mass index-matched... (Review)
Review
BACKGROUND
In recent years, more studies have observed that patients with Prader-Willi syndrome have lower insulin levels and lower insulin resistance than body mass index-matched controls, which may suggest protected glucose metabolism.
METHOD
The PubMed and Web of Science online databases were searched to identify relevant studies published in the English language using the terms "Prader-Willi syndrome" with "glucose", "insulin", "diabetes mellitus", "fat", "adipo*", "ghrelin", "oxytocin", "irisin" or "autonomic nervous system".
RESULTS
The prevalence of impaired glucose intolerance, type 2 diabetes mellitus and some other obesity-associated complications in patients with Prader-Willi syndrome tends to be lower when compared to that in general obesity, which is consistent with the hypothetically protected glucose metabolism. Factors including adipose tissue, adiponectin, ghrelin, oxytocin, irisin, growth hormone and the autonomic nervous system possibly modulate insulin sensitivity in patients with Prader-Willi syndrome.
CONCLUSION
Although lower insulin levels, lower IR and protected glucose metabolism are widely reported in PWS patients, the causes are still mysterious. Based on existing knowledge, we cannot determine which factor is of utmost importance and what are the underlying mechanisms, and further research is in urgent need.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Obesity; Prader-Willi Syndrome
PubMed: 35525976
DOI: 10.1186/s13023-022-02344-3 -
Biochemical and Biophysical Research... Aug 2024Prader-Willi syndrome (PWS) is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13. This syndrome also includes...
Prader-Willi syndrome (PWS) is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13. This syndrome also includes endocrine dysfunction, leading to short stature, hypogonadism, and obscure hyperphagia. Although recent progress has been made toward understanding the genetic basis for PWS, the molecular mechanisms underlying its pathology in obesity remain unclear. In this study, we examined the adipocytic characteristics of two PWS-induced pluripotent stem cell (iPSC) lines: those with the 15q11-q13 gene deletion (iPWS cells) and those with 15q11-q13 abnormal methylation (M-iPWS cells). The transcript levels of the lipid-binding protein aP2 were decreased in iPWS and M-iPWS adipocytes. Flow-cytometry analysis showed that PWS adipocytes accumulated more lipid droplets than did normal individual adipocytes. Furthermore, glucose uptake upon insulin stimulation was attenuated compared to that in normal adipocytes. Overall, our results suggest a significantly increased lipid content and defective in glucose metabolism in PWS adipocytes.
Topics: Prader-Willi Syndrome; Adipocytes; Humans; Induced Pluripotent Stem Cells; Glucose; Chromosomes, Human, Pair 15; Fatty Acid-Binding Proteins; Cell Line; DNA Methylation; Gene Deletion; Lipid Metabolism; Insulin
PubMed: 38776833
DOI: 10.1016/j.bbrc.2024.150124