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The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress.... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy.
OBJECTIVE
To evaluate safety and efficacy of intranasal carbetocin in PWS.
DESIGN
Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up.
SETTING
Twenty-four ambulatory clinics at academic medical centers.
PARTICIPANTS
A total of 130 participants with PWS aged 7 to 18 years.
INTERVENTIONS
Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose.
MAIN OUTCOME MEASURES
Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C).
RESULTS
Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing.
CONCLUSIONS
Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS.
CLINICAL TRIALS REGISTRATION NUMBER
NCT03649477.
Topics: Child; Humans; Prader-Willi Syndrome; Oxytocin; Pandemics; COVID-19; Hyperphagia; Anxiety
PubMed: 36633570
DOI: 10.1210/clinem/dgad015 -
Cell Stem Cell Sep 2021Human brain organoids represent remarkable platforms for recapitulating features of human brain development and diseases. Existing organoid models do not resolve fine...
Human brain organoids represent remarkable platforms for recapitulating features of human brain development and diseases. Existing organoid models do not resolve fine brain subregions, such as different nuclei in the hypothalamus. We report the generation of arcuate organoids (ARCOs) from human induced pluripotent stem cells (iPSCs) to model the development of the human hypothalamic arcuate nucleus. Single-cell RNA sequencing of ARCOs revealed significant molecular heterogeneity underlying different arcuate cell types, and machine learning-aided analysis based on the neonatal human hypothalamus single-nucleus transcriptome further showed a human arcuate nucleus molecular signature. We also explored ARCOs generated from Prader-Willi syndrome (PWS) patient iPSCs. These organoids exhibit aberrant differentiation and transcriptomic dysregulation similar to postnatal hypothalamus of PWS patients, indicative of cellular differentiation deficits and exacerbated inflammatory responses. Thus, patient iPSC-derived ARCOs represent a promising experimental model for investigating nucleus-specific features and disease-relevant mechanisms during early human arcuate development.
Topics: Cell Differentiation; Humans; Hypothalamus; Induced Pluripotent Stem Cells; Organoids; Prader-Willi Syndrome
PubMed: 33961804
DOI: 10.1016/j.stem.2021.04.006 -
The Journal of Clinical Endocrinology... Jun 2023Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled.
OBJECTIVE
The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones.
METHODS
In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo.
RESULTS
DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant).
CONCLUSION
DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.
Topics: Humans; Prader-Willi Syndrome; Diazoxide; COVID-19; Obesity; Hyperphagia
PubMed: 36639249
DOI: 10.1210/clinem/dgad014 -
Genes, Brain, and Behavior Jan 2022
Topics: Animals; Autistic Disorder; Developmental Disabilities; Humans
PubMed: 34891220
DOI: 10.1111/gbb.12789 -
Frontiers in Endocrinology 2023
Topics: Humans; Obesity; Prader-Willi Syndrome
PubMed: 38239989
DOI: 10.3389/fendo.2023.1349582 -
Current Neurology and Neuroscience... Mar 2023This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness... (Review)
Review
PURPOSE OF REVIEW
This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness (EDS).
RECENT FINDINGS
Hypothalamic dysfunction may underlie several aspects of the PWS phenotype. Central sleep apnea (CSA) can persist beyond infancy. Nocturnal hypoventilation is common and may occur without central or obstructive sleep apnea (OSA). Adenotonsillectomy, a mainstay of OSA treatment, may cause velopharyngeal insufficiency. Growth hormone (GH) is considered safe, but close surveillance for OSA remains important. Cardiac autonomic dysfunction occurs during slow wave sleep and may increase the risk of cardiovascular events. EDS and narcolepsy are also common. Modafinil and pitolisant are treatment options currently being studied. Sleep disorders are prevalent in individuals with PWS. Sleep-related breathing disorders present as CSA in infancy and later in life as OSA and hypoventilation. GH therapy has improved the clinical outcomes of patients with PWS, but close surveillance and treatment for OSA is recommended. EDS can persist even after sleep-related breathing disorders are treated, and some individuals may even develop narcolepsy. Early recognition and treatment of sleep-related disorders may prevent morbidity and result in improved survival of patients with PWS.
Topics: Humans; Prader-Willi Syndrome; Hypoventilation; Polysomnography; Sleep; Sleep Apnea, Obstructive; Disorders of Excessive Somnolence; Narcolepsy
PubMed: 36790642
DOI: 10.1007/s11910-023-01254-6 -
Frontiers in Genetics 2021Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically... (Review)
Review
Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically characterized by two nutritional stages. Stage 1 is hypotonia characterized by poor muscle tone that leads to poor feeding behavior causing failure to thrive in early neonatal life. Stage 2 is followed by the development of extreme hyperphagia, also known as insatiable eating and fixation on food that often leads to obesity in early childhood. Other major features of PWS include obsessive-compulsive and hoarding behaviors, intellectual disability, and sleep abnormalities. PWS is genetic disorder mapping to imprinted 15q11.2-q13.3 locus, specifically at the paternally expressed locus of small nucleolar RNAs and noncoding host gene transcripts. is processed into several noncoding components and is hypothesized to orchestrate diurnal changes in metabolism through epigenetics, according to functional studies. Here, we review the current status of epigenetic mechanisms in PWS, with an emphasis on an emerging role for in circadian and sleep phenotypes. We also summarize current ongoing therapeutic strategies, as well as potential implications for more common human metabolic and psychiatric disorders.
PubMed: 33659026
DOI: 10.3389/fgene.2021.624581 -
Archives of Endocrinology and Metabolism 2020Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic... (Review)
Review
Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic dysfunction that can lead to various endocrine changes such as: obesity, growth hormone deficiency, hypogonadism, hypothyroidism, adrenal insufficiency and low bone mineral density. In addition, individuals with PWS have increased risk of developing type 2 diabetes mellitus. This review summarizes and updates the current knowledge about the prevention, diagnosis and treatment of endocrine manifestations associated with Prader Willi syndrome, especially diagnosis of growth hormone deficiency, management and monitoring of adverse effects; diagnosis of central adrenal insufficiency and management in stressful situations; screening for central hypothyroidism; research and treatment of hypogonadism; prevention and treatment of disorders of glucose metabolism. Careful attention to the endocrine aspects of PWS contributes significantly to the health of these individuals. Arch Endocrinol Metab. 2020;64(3):223-34.
Topics: Diabetes Mellitus; Humans; Hypogonadism; Hypothyroidism; Obesity; Prader-Willi Syndrome
PubMed: 32555988
DOI: 10.20945/2359-3997000000248 -
Annals of Translational Medicine Dec 2023
PubMed: 38213817
DOI: 10.21037/atm-23-1718