Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main genetic subtypes are represented by paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defect. Clinical picture of PWS changes across life stages. The main clinical characteristics are represented by short stature, developmental delay, cognitive disability and behavioral diseases. Hypotonia and poor suck resulting in failure to thrive are typical of infancy. As the subjects with PWS age, clinical manifestations such as hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency due to hypothalamic dysfunction occur. Obesity and its complications are the most common causes of morbidity and mortality in PWS. Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. However, despite the advancement in the research field of the genetic basis of obesity in PWS, there are contradictory data on the management. Although it is mandatory to adopt obesity strategy prevention from infancy, there is promising evidence regarding the management of obesity in adulthood with current obesity drugs along with lifestyle interventions, although the data are limited. Therefore, the current manuscript provides a review of the current evidence on obesity and PWS, covering physiopathological aspects, obesity-related complications and conservative management.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC "Behavior Outcomes Working Group" sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive-compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

ContextThe hallmark condition of Prader-Willi syndrome, a rare, genetic neurobehavioral/metabolic disorder, is life-threatening hyperphagia.ObjectiveWe assessed the efficacy and safety of diazoxide choline extended-release (DCCR) tablets for the treatment of hyperphagia in adults and children four years of age and older with Prader-Willi syndrome.MethodsWe conducted a 16-week, randomized withdrawal study in children and adults with Prader-Willi syndrome and hyperphagia. Participants who previously completed randomized (13-week DCCR or placebo) and open-label (2.5-4.5 years DCCR) studies were randomized 1:1 to receive once-daily DCCR or placebo. The primary endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score change from baseline to 16 weeks. Secondary endpoints included Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I); exploratory endpoints included weight and body mass index (BMI) z-score.ResultsSeventy-seven participants were randomized (DCCR:38; placebo:39). Statistically significant increases in HQ-CT from baseline to week 16 were observed with placebo vs DCCR [least square (LS) mean (standard error) change 7.6 (1.09)] with placebo and 2.6 (1.12) with DCCR; P = .0022. CGI scores favored DCCR but were not significantly changed. Consistent with the hyperphagia response, the placebo cohort gained more weight and increased their BMI z-score more than the DCCR cohort [LS mean weight difference (95% confidence interval) -1.6 kg (-3.1, -0.1)]; LS mean z-score difference was -0.09 (-0.17, -0.01). Adverse events were similar with both treatments, with no serious adverse events in the DCCR arm.ConclusionContinued DCCR treatment was superior to placebo for hyperphagia. DCCR appears to offer meaningful therapeutic benefits for people with Prader-Willi syndrome.