Long-term health outcomes in patients with Prader–Willi Syndrome: a nationwide cohort study in Denmark

Hedgeman, Elizabeth; Ulrichsen, Sinna Pilgaard; Carter, S; Kreher, Nerissa C.; Malobisky, K P; Braun, M M; Fryzek, Jon P.; Olsen, Morten

doi:10.1038/ijo.2017.139

Cited by 39 publications

(45 citation statements)

References 49 publications

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“…Intellectual disability, growth hormone deficiency, behavioral problems, including aggressive and threatening behaviors, and neuroendocrine abnormalities are also characteristic of PWS [88]. The death rate among PWS patients is markedly elevated [90]. According to a 2014 survey of parents and caregivers of PWS patients, reducing hunger and improving food-related behaviors were the most important unmet needs in PWS that could be addressed in the development of a new therapeutic [91].…”

Section: Experience With the Diazoxide Choline Controlled-release Tabmentioning

confidence: 99%

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity

Cowen

Bhatnagar

2020

Genes

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To evaluate the potential role of ATP-sensitive potassium (K ATP ) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the K ATP channel, the response to activating the K ATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of K ATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. K ATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by β-cells; and the synthesis and β-oxidation of fatty acids in adipocytes. K ATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a K ATP channel activator in Prader-Willi syndrome is consistent with the therapeutic responses observed in animal models. K ATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity.Genes 2020, 11, 450 2 of 16 pharmacological activators of the channel in obese hyperphagic animal models, and clinical studies of K ATP channel activators in obese hyperphagic syndromes. Search terms used included K ATP , SUR1, SUR2b, Kir6.1, Kir6.2, ABCC8, ABCC9, KCNJ8, KCNJ11, agonist, hypothalamus, motor neuron of vagus, adipocyte, β-cell, hyperphagia, appetite, neuropeptide, obesity, obese, animal model, leptin, insulin, α-MSH, insulin-resistance, and hyperinsulinemia. Terms were combined to generate searches which identified tissues in which the genes encoding the K ATP channel might be expressed that have a known role in appetite and obesity, hormones with known roles in appetite and the K ATP channel, and obese or hyperphagic obese animal models in which a K ATP channel agonist might have been evaluated. Prior to conducting the searches, the authors already possessed extensive knowledge of the K ATP channel and its role in the regulation of appetite, having studied the channel for more than 15 years. The searches were conducted to supplement that understanding, rather than as the sole source of information summarized in this publication.Genes 2020, 11, 450 3 of 16 NPY injected into the brain either in the ventricles or in different hypothalamic nuclei induces a robust feeding response, even in sated animals [11]. NPY achieves this effect by reducing the latency to eat, delaying satiety and thereby augmenting meal size and meal duration [11]. NPY also causes treated animals to be more motivated to obtain food [11]. Specifically activating neurons pharmacologically with AgRP induces a robust hyperphagic response in rodents with a distinct temporal dynamic from that of NPY [7], NP...

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Section: Experience With the Diazoxide Choline Controlled-release Tabmentioning

confidence: 99%

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity

Cowen

Bhatnagar

2020

Genes

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“…Without strictly supervised caloric restriction and regular exercise, appetite disturbances and physical difficulties predispose the majority of children to child‐onset obesity. The Danish National Patient Registry database reported that individuals with PWS ( n = 155) were 10 times more likely to be obese and 9 times more likely to be diagnosed with type 2 diabetes mellitus than the matched general population ( n = 15 500) . The development of obesity and impaired glucose metabolism are linked to various aspects of hypothalamic pituitary axis dysfunction.…”

Section: Resultsmentioning

confidence: 99%

“…Abnormalities in hormones influencing appetite regulation and satiety signalling, such as ghrelin or peptide YY, may contribute to the hyperphagia in PWS . Obesity contributes to the increased risk of obstructive sleep apnoea, cardiovascular disease, reduced bone mineral density and fracture and scoliosis observed in patients with PWS …”

Section: Resultsmentioning

confidence: 99%

Requirements for improving health and well‐being of children with Prader‐Willi syndrome and their families

Mackay

McCallum

Ambler

et al. 2019

J Paediatrics Child Health

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Prader‐Willi syndrome (PWS) is a rare genetic condition with multi‐system involvement. The literature was reviewed to describe neurodevelopment and the behavioural phenotype, endocrine and metabolic disorders and respiratory and sleep functioning. Implications for child and family quality of life were explored. Challenging behaviours contribute to poorer well‐being and quality of life for both the child and caregiver. Recent evidence indicates healthy outcomes of weight and height can be achieved with growth hormone therapy and dietary restriction and should be the current target for all individuals with PWS. Gaps in the literature included therapies to manage challenging behaviours, as well as understanding the effects of growth hormone on respiratory and sleep function. New knowledge regarding the transition of children and families from schooling and paediatric health services to employment, accommodation and adult health services is also needed. Developing a national population‐based registry could address these knowledge gaps and inform advocacy for support services that improve the well‐being of individuals with PWS and their families.

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“…Genes 2020, 11, 67 2 of 11 between obesity and early death in adults with PWS [4]. Comorbidities that are commonly associated with obesity in PWS include respiratory problems (pulmonary embolism, respiratory failure, and pulmonary hypertension) and deep venous thrombosis [5][6][7][8][9].…”

Section: Have Suggested An Important Associationmentioning

confidence: 99%

“…An increased risk of venous thromboembolisms (VTEs) was recently reported in PWS patients by using Prader-Willi syndrome Association (USA) syndrome-specific database of deaths between 1973 and 2015 [5,9]. Seven percent of all deaths in the reported PWS survey commonly found in adulthood were attributable to pulmonary embolism, which represented only a quarter of the most common causes of death that were related to respiratory failure [5,6].…”

Section: Have Suggested An Important Associationmentioning

confidence: 99%

Age Distribution, Comorbidities and Risk Factors for Thrombosis in Prader–Willi Syndrome

Butler

Oyetunji

Manzardo

2020

Genes

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Prader–Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2–q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or blood clots and venous thromboembolism (VTE) are uncommon but reported in PWS. Two phases of analyses were conducted in our study: unadjusted and adjusted frequency with odds ratios and a regression analysis of risk factors. Individuals with PWS or non-PWS controls with exogenous obesity were identified by specific International Classification of Diseases (ICD)-9 diagnostic codes reported on more than one occasion to confirm the diagnosis of PWS or exogenous obesity in available national health claims insurance datasets. The overall average age or average age per age interval (0–17 year, 18–64 year, and 65 year+) and gender distribution in each population were similar in 3136 patients with PWS and 3945 non-PWS controls for comparison purposes, with exogenous obesity identified from two insurance health claims dataset sources (i.e., commercial and Medicare advantage or Medicaid). For example, 65.1% of the 3136 patients with PWS were less than 18 years old (subadults), 33.2% were 18–64 years old (adults), and 1.7% were 65 years or older. After adjusting for comorbidities that were identified with diagnostic codes, we found that commercially insured PWS individuals across all age cohorts were 2.55 times more likely to experience pulmonary embolism (PE) or deep vein thrombosis (DVT) than for obese controls (p-value: 0.013; confidence interval (CI): 1.22–5.32). Medicaid-insured individuals across all age cohorts with PWS were 0.85 times more likely to experience PE or DVT than obese controls (p-value: 0.60; CI: 0.46–1.56), with no indicated age difference. Age and gender were statistically significant predictors of VTEs, and they were independent of insurance coverage. There was an increase in occurrence of thrombotic events across all age cohorts within the PWS patient population when compared with their obese counterparts, regardless of insurance type.

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Long-term health outcomes in patients with Prader–Willi Syndrome: a nationwide cohort study in Denmark

Abstract: Multiple cardiovascular and behavioral illnesses are more likely to occur among patients with PWS than within the general population. These increased risks may provide an impetus for enhanced disease prevention, screening, diagnosis and treatment.

Cited by 39 publications

References 49 publications

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity

The Potential Role of Activating the ATP-Sensitive Potassium Channel in the Treatment of Hyperphagic Obesity

Requirements for improving health and well‐being of children with Prader‐Willi syndrome and their families

Age Distribution, Comorbidities and Risk Factors for Thrombosis in Prader–Willi Syndrome

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