The Paradox of Prader Willi Syndrome: A genetic model of starvation

Abstract

Aims: To review the mechanisms that may explain the excessive eating behaviour observed in people with Prader Willi Syndrome (PWS) and the change in the ‘behavioural phenotype’ noted in infancy. Methods: The findings from different studies will be reviewed including those using direct observation and behavioural measures, those involving brain scanning technologies, and studies investigating the peripheral and hypothalamic feeding pathways. Results: Abnormalities of eating behaviour are universally found in people with PWS. The change from a failure to thrive in infancy to the later phenotype (characterized by excessive eating behaviour), occurs gradually from as early as one year of age. Underpinning the over‐eating behaviour is an abnormal satiety response to food intake with limited changes in feelings of hunger and fullness after normal or excessive food intake, and an absence of changes in patterns of brain activation, measured using PET and MRI scanning technologies, which are observed in people without PWS. Whilst abnormalities have been observed in the peripheral feeding pathway (increased levels of the appetite stimulating hormone ghrelin) at present the cause of the abnormal satiety response in PWS remains unclear. Discussion: In an hypothesis paper published in 2003 we proposed that these various observations, when taken together with the observed relative insufficiency of sex and growth hormones, could be explained by people with PWS responding as if in a state of chronic starvation. The difference for people with PWS was that they lived in a food rich, rather than a food poor environment. We hypothesized that this model of starvation could also explain the early phenotype and the intellectual disabilities observed.