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Endocrine Connections Jun 2024Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000.... (Review)
Review
Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.
PubMed: 38838713
DOI: 10.1530/EC-24-0091 -
IScience Jun 2024Prader-Willi syndrome (PWS) is a genetic disorder characterized by behavioral disturbances, hyperphagia, and intellectual disability. Several surveys indicate that PWS...
Prader-Willi syndrome (PWS) is a genetic disorder characterized by behavioral disturbances, hyperphagia, and intellectual disability. Several surveys indicate that PWS is also associated with cardiac abnormalities, possibly contributing to a high incidence of sudden death. However, the pathological mechanisms underlying cardiac dysfunction in PWS remain unclear. In this study, we found that deficiency in necdin, an intronless gene within PWS region, led to heart systolic and diastolic dysfunction in mice. Through yeast two-hybrid screening, we identified an interaction between necdin and non-muscle myosin regulatory light chain 12a/b (MYL12 A/B). We further showed that necdin stabilized MYL12 A/B via SGT1-heat shock protein 90 (HSP90) chaperone machinery. The zebrafish lacking the MYL12 A/B analog, MYL12.1, exhibited impaired heart function, while cardiac-specific overexpression of MYL12A normalized the heart dysfunction in necdin-deficient mice. Our findings revealed necdin dysfunction as a contributing factor to cardiomyopathy in PWS patients and emphasized the importance of HSP90 chaperone machinery and non-muscle myosin in heart fitness.
PubMed: 38832028
DOI: 10.1016/j.isci.2024.109974 -
Fertility and Sterility May 2024To assess whether the use of assisted reproductive technology for conception is associated with imprinting disorders in children and the impact of parental factors...
OBJECTIVE
To assess whether the use of assisted reproductive technology for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility.
DESIGN
A nationwide register-based cohort study.
SUBJECTS
All liveborn singletons in Sweden (N = 2 084 127) between 1997-2017 with follow-up to December 31, 2018.
EXPOSURE
The use of specific methods implemented in the assisted reproductive technology MAIN OUTCOME MEASURES: The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Prader-Willi/Silver-Russell syndrome, Beckwith-Wiedemann syndrome, and central precocious puberty. The Cox model combined with inverse probability treatment weights were used to estimate weighted hazard ratio (wHR) with 95% confidence interval (CI), accounting for multiple confounders.
RESULTS
A total of 1044 children were diagnosed with the disorders of interest, and 52 of them were conceived with assisted reproductive technology. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived with ART compared to all other children (HR 1.84, 95% CI: 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR 1.50, 95% CI: 0.97-2.32), but remained also in the weighted comparison restricted to children of couples with known infertility (wHR 1.52, 95% CI: 1.05-2.21). For the specific diagnoses of Prader-Willi/Silver-Russell syndrome and Beckwith-Wiedemann syndrome, compared to children of couples with known infertility, children conceived with assisted reproductive technology showed a small excess risk, which could not be distinguished from the null (wHR 1.56 [95% CI: 0.93-2.62] and 1.80 [95% CI: 0.99-3.28], respectively). Further subgroup analysis showed that the combined use of intra-cytoplasmic sperm injection and cryopreserved embryos was associated with higher risk of both Prader-Willi/Silver-Russell syndrome (wHR 4.60, 95% CI: 1.72-12.28) and Beckwith-Wiedemann syndrome (wHR 6.69, 95% CI: 2.09-21.45). The number of central precocious puberty cases in children conceived with assisted reproductive technology was too small (N=3) to make any meaningful inference.
CONCLUSION
The combined use of intra-cytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of Prader-Willi/Silver-Russell syndrome and Beckwith-Wiedemann syndrome in children, independent of parental factors related to infertlity.
PubMed: 38825304
DOI: 10.1016/j.fertnstert.2024.05.168 -
Frontiers in Endocrinology 2024Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB).... (Comparative Study)
Comparative Study
INTRODUCTION
Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB.
METHODS
A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m).
RESULTS
Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB.
CONCLUSIONS
PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Adult; Metabolomics; Case-Control Studies; Retrospective Studies; Obesity, Morbid; Metabolome; Young Adult; Body Mass Index; Body Composition; Chromatography, Liquid; Tandem Mass Spectrometry
PubMed: 38812813
DOI: 10.3389/fendo.2024.1386265 -
Gait & Posture Jul 2024Prader-Willi syndrome (PWS) is characterized by a complex clinical condition, whose typical features lead to impaired motor and functional skills. To date, limited data...
BACKGROUND
Prader-Willi syndrome (PWS) is characterized by a complex clinical condition, whose typical features lead to impaired motor and functional skills. To date, limited data is available as regards symmetry of gait in PWS.
RESEARCH QUESTION
The aim of this study was to characterize lower-limb asymmetry during gait in a group of Prader-Willi Syndrome (PWS) individuals by using the synchronized cyclograms and to compare it with those of two different control groups, a normal-weight group and an obese group.
METHODS
A total of 18 PWS, 30 normal weight (NW) and 28 obese individuals (OG) matched for age, sex and height were assessed via 3D gait analysis. Gait spatio-temporal parameters were computed together with angle-angle diagrams, characterized in terms of their geometric features (i.e. area, orientation, and trend symmetry index).
RESULTS
Individuals with PWS exhibit reduced speed, stride length and cadence and increased duration of both stance and double support phase than the other groups. OG was characterized by the same pattern when compared to NW. With respect to inter-limb symmetry, individuals with PWS exhibited significantly larger cyclogram areas at hip joint with respect to the other two groups (203.32 degrees vs. 130.73 degrees vs. 111.59 degrees) and significantly higher orientation angle (4.17° vs. 2.11° vs. 1.22°) and Trend Symmetry (3.72 vs. 2.02 vs. 1.21) with respect to the other two groups at knee joint; no differences were found at ankle joint. Both individuals with PWS and those of OG exhibited reduced ROM at knee and ankle joints with respect with normal weight, but no statistically significant differences were observed between PWS and OG.
SIGNIFICANCE
The obtained results may provide novel and useful insights to understand better the impairments in motor control associated with this pathological state, supporting clinics in the identification of the best rehabilitation program for this rare pathological state, aimed to improve stability and motor control.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Adult; Gait; Young Adult; Adolescent; Case-Control Studies; Gait Analysis; Obesity; Biomechanical Phenomena; Lower Extremity; Hip Joint; Knee Joint; Child; Ankle Joint
PubMed: 38805861
DOI: 10.1016/j.gaitpost.2024.05.026 -
Children (Basel, Switzerland) May 2024This narrative review study investigates the correlations between obesity, allergies, and sleep-disordered breathing in pediatric populations. Searches for pertinent... (Review)
Review
This narrative review study investigates the correlations between obesity, allergies, and sleep-disordered breathing in pediatric populations. Searches for pertinent articles were conducted on the Medline PubMed Advanced Search Builder, Scopus, and Web of Science databases from unlimited to April 2024. Sleep-disordered breathing causes repeated upper airway obstructions, leading to apneas and restless sleep. Childhood obesity, which affects around 20% of children, is often associated with sleep-disordered breathing and allergies such as asthma and allergic rhinitis. It is distinguished between diet-induced obesity (resulting from excess of diet and physical inactivity) and genetic obesity (such as is seen in Down syndrome and Prader-Willi syndrome). In children with diet-induced obesity, chronic inflammation linked to weight can worsen allergies and increase the risk and severity of asthma and rhinitis. Furthermore, the nasal congestion typical of rhinitis can contribute to upper respiratory tract obstruction and obstructive sleep apnea. A vicious circle is created between asthma and sleep-disordered breathing: uncontrolled asthma and sleep-disordered breathing can worsen each other. In children with genetic obesity, despite alterations in the immune system, fewer allergies are observed compared to the broader population. The causes of this reduced allergenicity are unclear but probably involve genetic, immunological, and environmental factors. Additional research is necessary to elucidate the underlying mechanisms. The present narrative review study emphasizes the importance of jointly evaluating and managing allergies, obesity, and obstructive sleep apnea in children considering their close interconnection.
PubMed: 38790590
DOI: 10.3390/children11050595 -
Genes May 2024Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of...
Establishing a Standardized DNA Extraction Method Using NaCl from Oral Mucosa Cells for Its Application in Imprinting Diseases Such as Prader-Willi and Angelman Syndromes: A Preliminary Investigation.
BACKGROUND
Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like newborns, who possess limited blood volumes and are often too fragile for invasive procedures. Oral swab samples emerge as an excellent source of DNA, effectively overcoming obstacles associated with rare diseases.
METHODS
In our study, we specifically addressed the determination of the quality and quantity of DNA extracted from oral swab samples using NaCl procedures.
RESULTS
We compared these results with extractions performed using a commercial kit. Subsequently, the obtained material underwent MS-HRM analysis for loci associated with imprinting diseases such as Prader-Willi and Angelman syndromes.
CONCLUSIONS
Our study emphasizes the significance of oral swab samples as a reliable source for obtaining DNA for MS-HRM analysis. NaCl extraction stands out as a practical and cost-effective method for genetic studies, contributing to a molecular diagnosis that proves particularly beneficial for patients facing delays in characterization, ultimately influencing their treatment.
Topics: Humans; Mouth Mucosa; Angelman Syndrome; Prader-Willi Syndrome; DNA; Genomic Imprinting; Sodium Chloride; Infant, Newborn; Male; Imprinting Disorders
PubMed: 38790270
DOI: 10.3390/genes15050641 -
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 -
Frontiers in Endocrinology 2024Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.
Topics: Prader-Willi Syndrome; Humans; Genetic Association Studies; Endocrine System Diseases; Phenotype
PubMed: 38737552
DOI: 10.3389/fendo.2024.1382583 -
BMJ Paediatrics Open May 2024
PubMed: 38719566
DOI: 10.1136/bmjpo-2019-000630corr1