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Genes Sep 2019Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support...
Advances in technologies offer new opportunities to collect and integrate data from a broad range of sources to advance the understanding of rare diseases and support the development of new treatments. Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental disorder, which has a variable and incompletely understood natural history. PWS is characterized by early failure to thrive, followed by the onset of excessive appetite (hyperphagia). Additional characteristics include multiple endocrine abnormalities, hypotonia, hypogonadism, sleep disturbances, a challenging neurobehavioral phenotype, and cognitive disability. The Foundation for Prader-Willi Research's Global PWS Registry is one of more than twenty-five registries developed to date through the National Organization of Rare Disorders (NORD) IAMRARE Registry Program. The Registry consists of surveys covering general medical history, system-specific clinical complications, diet, medication and supplement use, as well as behavior, mental health, and social information. Information is primarily parent/caregiver entered. The platform is flexible and allows addition of new surveys, including updatable and longitudinal surveys. Launched in 2015, the PWS Registry has enrolled 1696 participants from 37 countries, with 23,550 surveys completed. This resource can improve the understanding of PWS natural history and support medical product development for PWS.
Topics: Global Health; Humans; Prader-Willi Syndrome; Registries
PubMed: 31540108
DOI: 10.3390/genes10090713 -
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 -
Journal of Endocrinological... Nov 2022Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on...
CONTEXT
Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS.
OBJECTIVE
This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI).
METHODS
We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years.
RESULTS
MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 ± 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007).
CONCLUSIONS
The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.
Topics: Child; Cross-Sectional Studies; Estradiol; Follicle Stimulating Hormone; Glycated Hemoglobin; Humans; Pilot Projects; Prader-Willi Syndrome; Testosterone; Ubiquitin-Protein Ligases
PubMed: 35854182
DOI: 10.1007/s40618-022-01860-0 -
Frontiers in Endocrinology 2022Noonan, Turner, and Prader-Willi syndromes are classical genetic disorders that are marked by short stature. Each disorder has been recognized for several decades and is... (Review)
Review
Noonan, Turner, and Prader-Willi syndromes are classical genetic disorders that are marked by short stature. Each disorder has been recognized for several decades and is backed by extensive published literature describing its features, genetic origins, and optimal treatment strategies. These disorders are accompanied by a multitude of comorbidities, including cardiovascular issues, endocrinopathies, and infertility. Diagnostic delays, syndrome-associated comorbidities, and inefficient communication among the members of a patient's health care team can affect a patient's well-being from birth through adulthood. Insufficient information is available to help patients and their multidisciplinary team of providers transition from pediatric to adult health care systems. The aim of this review is to summarize the clinical features and genetics associated with each syndrome, describe best practices for diagnosis and treatment, and emphasize the importance of multidisciplinary teams and appropriate care plans for the pediatric to adult health care transition.
Topics: Adult; Child; Humans; Transition to Adult Care; Prader-Willi Syndrome
PubMed: 36339399
DOI: 10.3389/fendo.2022.1011960 -
Neurotherapeutics : the Journal of the... Apr 2024Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.
Topics: Humans; Prader-Willi Syndrome; Vagus Nerve Stimulation; Transcranial Magnetic Stimulation; Deep Brain Stimulation; Transcranial Direct Current Stimulation
PubMed: 38430811
DOI: 10.1016/j.neurot.2024.e00339 -
Genes Nov 2019Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone...
Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy ( < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy.
Topics: Age Factors; Child; Child, Preschool; Chromosomes, Human, Pair 15; Comorbidity; Early Diagnosis; Female; Genomic Imprinting; Hormone Replacement Therapy; Human Growth Hormone; Humans; Infant; Male; Obesity; Prader-Willi Syndrome; Rare Diseases
PubMed: 31698873
DOI: 10.3390/genes10110898 -
Epidemiology and Health 2022Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This...
OBJECTIVES
Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This study aimed to develop and validate the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome (PYHAP) as a tool targeting children and adolescents.
METHODS
After an extensive literature review and qualitative interviews, the final version of the PYHAP with 14 questions in 3 domains (verbal [5], behavior [4], and social [5]) was developed and tested at Samsung Medical Center in Seoul, Korea from July 2018 to September 2019. Exploratory factor analysis and confirmatory factor analysis (CFA) were performed to confirm construct validity. The correlations between the PYHAP and the Korean Children's Eating Behavior Questionnaire (K-CEBQ) were calculated to evaluate convergent and discriminant validity. Criterion validity and the validity of the response categories were also tested.
RESULTS
Cronbach's alpha coefficient of the PYHAP was 0.91. The fit indices for CFA were good (comparative fit index, 0.87; standardized root mean squared residual, 0.08). The domains of the PYHAP were closely correlated with the relevant domains of the K-CEBQ. The accuracy of the PYHAP score for predicting uncontrolled hyperphagia was good (area under the curve, 0.75; 95% confidence interval, 0.65 to 0.85).
CONCLUSIONS
The PYHAP was confirmed to be a reliable and valid tool to evaluate hyperphagia in children and adolescents with PWS via caregivers' assessments. It is recommended to use the PYHAP to communicate with parents or caregivers about patients' hyperphagia or to monitor and manage extreme behaviors in children with PWS.
Topics: Adolescent; Caregivers; Child; Feeding Behavior; Humans; Hyperphagia; Prader-Willi Syndrome; Surveys and Questionnaires
PubMed: 35038830
DOI: 10.4178/epih.e2022014 -
Italian Journal of Pediatrics Jul 2022Prader-Willi syndrome (PWS) is a complex disorder caused by impaired paternally expressed genes on chromosome 15q11-q13. Variable findings have been reported about the...
BACKGROUND
Prader-Willi syndrome (PWS) is a complex disorder caused by impaired paternally expressed genes on chromosome 15q11-q13. Variable findings have been reported about the phenotypic differences among PWS genetic subtypes.
METHODS
A total of 110 PWS patients were diagnosed from 8,572 pediatric patients included from July 2013 to December 2021 by MLPA and MS-MLPA assays. Atypical deletions were defined by genomic CNV-sequencing. Maternal uniparental disomy (UPD) was subgrouped by microsatellite genotyping. Clinical data were collected for phenotype-genotype associations. Twenty-one patients received growth hormone (GH) treatment, and the anthropometric and laboratory parameters were evaluated and compared.
RESULTS
Genetically, the 110 patients with PWS included 29 type I deletion, 56 type II deletion, 6 atypical deletion, 11 heterodisomy UPD, and 8 isodisomy UPD. The UPD group had significantly higher maternal age (31.4 ± 3.4 vs 27.8 ± 3.8 years), more anxiety (64.29% vs 26.09%) and autistic traits (57.14% vs 26.09%), and less hypopigmentation (42.11% vs 68.24%) and skin picking (42.86% vs 71.01%) than the deletion group. The type I deletion group was diagnosed at earlier age (3.7 ± 3.3 vs 6.2 ± 3.2 years) and more common in speech delay (95.45% vs 63.83%) than the type II. The isodisomy UPD group showed a higher tendency of anxiety (83.33% vs 50%) than the heterodisomy. GH treatment for 1 year significantly improved the SDS of height (- 0.43 ± 0.68 vs - 1.32 ± 1.19) and IGF-I (- 0.45 ± 0.48 vs - 1.97 ± 1.12). No significant changes were found in thyroid function or glucose/lipid metabolism.
CONCLUSION
We explored the physical, psychological and behavioral phenotype-genotype associations as well as the GH treatment effect on PWS from a large cohort of Chinese pediatric patients. Our data might promote pediatricians' recognition and early diagnosis of PWS.
Topics: Humans; Body Height; Maternal Age; Phenotype; Prader-Willi Syndrome; Uniparental Disomy; Female; Adult; Child
PubMed: 35870983
DOI: 10.1186/s13052-022-01319-1 -
Journal of Intellectual Disability... Feb 2020Prader-Willi syndrome (PWS) is a neurogenetic syndrome with an associated behavioural phenotype and a high incidence of behaviours of concern and psychiatric...
BACKGROUND
Prader-Willi syndrome (PWS) is a neurogenetic syndrome with an associated behavioural phenotype and a high incidence of behaviours of concern and psychiatric co-morbidity. These associated behaviours and co-morbidities are not well addressed by existing interventions, and they impact significantly on affected individuals and their caregivers.
METHODS
We undertook a national survey of the needs of individuals with PWS and their families in Ireland. In this paper, we report on the parent/caregiver-reported mental health, behavioural and access to services.
RESULTS
Over 50% of individuals with PWS in this survey had at least one reported psychiatric diagnosis, the most common diagnosis was anxiety. The most commonly reported behaviours in children were skin picking, repetitive questioning, difficulty transitioning and non-compliance. The same four behaviours were reported by caregivers as being the most commonly occurring in adolescents and adults in addition to food-seeking behaviours. Increased needs for mental health services were also reported by caregivers. Individuals with PWS had an average wait of 22 months for an appointment with a psychologist and 4 months for an appointment with a psychiatrist.
CONCLUSION
This study highlighted high levels of psychiatric co-morbidities and behavioural concerns in individuals with PWS in Ireland. The findings of this study suggest that there is an urgent need to provide specialist psychiatric and behavioural interventions to manage complex mental health and behavioural needs to better support individuals with PWS and reduce caregiver burden.
Topics: Adolescent; Adult; Behavioral Symptoms; Caregivers; Child; Child, Preschool; Female; Health Services Accessibility; Humans; Infant; Ireland; Male; Mental Disorders; Mental Health Services; Middle Aged; Prader-Willi Syndrome; Young Adult
PubMed: 31849130
DOI: 10.1111/jir.12707 -
The Journal of Clinical Endocrinology... Aug 2023
Topics: Humans; Prader-Willi Syndrome; Hyperphagia; Oxytocin; Anxiety
PubMed: 36896885
DOI: 10.1210/clinem/dgad131