LAUSR

Prader-Willi syndrome (PWS) is a complex, multisystem neurodevelopmental disorder that occurs with a frequency of approximately 1/10,000 to 1/30,000 . PWS results from the loss of expression of paternally derived genes by a variety of mechanisms, which include paternally inherited deletions (70– 75%), maternal uniparental disomy (20–30%), and imprinting defects (2–5%) [2,3]. DNA methylation analysis will correctly diagnose more than 99% of cases, and is the most sensitive genetic test available [1–4]. The genetic anomalies lead to a distinctive phenotype that includes central hypotonia, cognitive delay, developmental disabilities, behavioral problems, obesity, growth hormone deficiency, hypogonadism, and lifethreatening hyperphagia [1]. Infants with PWS have feeding difficulties, initially necessitating assisted feeding, often via gastrostomy tube or nasogastric tube. The feeding issues gradually improve and are followed by weight gain without a change in calories (18 months to 3 years of age) and subsequently, by an increased interest in food in early childhood (4–5 years of age) [5]. Hyperphagia and food-related behavior problems often evolve by 8–9 years of age, and are characterized by the lack of a normal satiety response, food preoccupations, and problematic food-seeking behaviors [5]. Although symptom severity varies, hyperphagia poses persistent, life-long risks to the health and safety of affected individuals. While strict environmental control and diet modifications may help reduce caloric intake and effectively manage weight for some individuals with PWS, the persistent drive for food prevents individuals with PWS from achieving a high quality of life or being well-integrated into their communities. Individuals with PWS have a characteristic eating pattern [6]. They exhibit a slower initiation of eating with a longer meal duration and no deceleration in the amount eaten over the entire mealtime [6]. They have an earlier return of hunger after completion of a meal, and will often start asking about the next meal while still eating. Left to their own devices, individuals with PWS will consume three times more food than obese control subjects [6,7]. They have a strong preference for higher-carbohydrate foods, and are more likely to consume inedible items (e.g. toothpaste, lotion) than obese controls [6,7]. This hyperphagia results in food-seeking behavior, often with hoarding or foraging for food, and stealing of food or money to buy food. In most individuals, gastric emptying is delayed, and vomiting is rare [8]. Thus, the drive to eat in individuals with PWS remains significantly elevated even in the face of delayed gastric emptying, which is unusual when compared to individuals with diet-induced obesity. Individuals with PWS have a very high risk for obesity, both due to the hyperphagia and eating behaviors, as well as from decreased total caloric requirement due to decreased muscle mass and lower resting energy expenditure. The obesity in PWS is primarily central (abdomen, buttocks, and thighs) in both sexes, and interestingly, there is less visceral fat in obese individuals with PWS than would be expected for the degree of obesity [9,10]. Although there are many common clinical features exhibited by people with PWS, the hyperphagia is the unifying symptom in this diagnosis [11], in addition to being the most life-limiting feature. The underlying molecular mechanisms that contribute to excessive weight gain and hyperphagia in PWS remain incompletely understood. Appetite and satiety issues are regulated by a complex interplay between gut hormones and hypothalamic neuropeptides. Most gut-related appetite-regulating hormones are normally expressed in PWS, with the notable exception being ghrelin, a growth hormone secretagogue that is high in fasting states and decreases with eating [12,13]. Highly elevated levels of ghrelin have been identified in individuals with PWS [12,13]. Ghrelin levels decrease after intake of a meal, as is normal, but still remain comparatively high [14]. However, it has been shown that circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding [15], so it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS. Thus, the underlying metabolic/hormonal cause of the hyperphagia remains unclear. Functional MRI studies have shown abnormally high activation of the reward pathways in the brain for food-related stimuli, as well as hyperfunction of the areas that drive eating behavior (e.g. amygdala) in individuals with PWS [16]. Functional MRI studies have also shown abnormal functional