Prader–Willi syndrome: From genetics to behaviour, with special focus on appetite treatments

doi:10.1016/j.neubiorev.2015.10.003

Neuroscience & Biobehavioral Reviews

Volume 59, December 2015, Pages 155-172

https://doi.org/10.1016/j.neubiorev.2015.10.003 Get rights and content

Highlights

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We discuss the different phases of the hyperphagia in Prader–Willi syndrome.
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We review the relationship between PWS behaviours and variation in the chromosome 15q11–q13 region.
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We table and discuss the efficacy of 20 pharmacological treatment trials for PWS.
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We report on the brain signalling and structural differences in PWS.
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We review the PWS aetiology addressing targets for research on appetite treatment.

Abstract

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder resulting from a deletion in the expression of the paternally derived alleles in the region of 15q11–q13. PWS has a prevalence rate of 1:10,000–1:30,000 and is characterized by marked endocrine abnormalities including growth hormone deficiency and raised ghrelin levels.

The hyperphagic phenotype in PWS is established over a number of phases and is exacerbated by impaired satiety, low energy expenditure and intellectual difficulties including obsessive–compulsive disorder and/or autistic behaviours. Clinical management in PWS typically includes familial/carer restriction and close supervision of food intake. If the supervision of food is left unmanaged, morbid obesity eventuates, central to the risk of cardiorespiratory disorder. None of the current appetite management/intervention strategies for PWS include pharmacological treatment, though recent research shows some promise.

We review the established aberrant genetics and the endocrine and neuronal attributes which may determine disturbed regulatory processes in PWS. Focusing on clinical trials for appetite behaviours in PWS, we define the effectiveness of pharmacological treatments with a view to initiating and focusing research towards possible targets for modulating appetite in PWS.

Introduction

Prader–Willi syndrome (PWS) results from a deletion in the expression of the paternally derived alleles in the region of 15q11–q13 (classified as the PWS region) and has a reported prevalence rate from 1:10,000 to 1:30,000 (Whittington and Holland, 2010, Whittington and Holland, 2011, Pignatti et al., 2013, Tuysuz et al., 2014, Smith et al., 2003).

PWS is characterized by endocrine abnormalities and complex physical, behavioural and intellectual difficulties. When the unremitting appetite and concentration on food in PWS is left unmanaged, future morbid obesity is predicted (Smith et al., 2003, Holson et al., 2006, Whittington and Holland, 2010). PWS has an evolving hyperphagia which is typically exacerbated by an impaired satiety (Holland, 2008, Cassidy et al., 2011) and obsessive compulsive disorder (OCD) and/or autistic spectrum disorder (ASD) (McCandless, 2011).

Phenotypical disruptions to appetite in PWS follow a specified trajectory. The phases eventuate in an unremitting hyperphagia coupled with a lack of satiety response (Holland et al., 2003, Benelam, 2009). Eventually these distinctive appetite phases and the accompanying appetite behaviours, necessitate preventative measures. Typically, practitioner guidance involves early dietary advice and treatment for the many medical conditions related to the physiology of PWS (Chen et al., 2007, Yearwood et al., 2011). Growth hormone is the most researched and clearly defined intervention within the PWS community. Unfortunately, growth hormone treatment (GHT) does not impact on appetite. Measures for appetite control include supervision of caloric intake and restriction, when within the proximity of food. Research into the timeline of the aetiology in PWS may determine some targets for treatment. The PWS-related transitions in hormone levels and the disrupted hypothalamic pathways of the brain demonstrate a genomic connection and are important factors in the appetite behaviours. Genes within the critical PWS region correlate to different phenotypic features of the full genetic syndrome which are documented by atypical microdeletions and animal model research.

Currently there are no on-going pharmacological treatments to regulate appetite in PWS, though recent research gives some hope to families in regards to future management of the hyperphagic behaviours. Historically studies on possible pharmacological interventions for appetite regulation in PWS have been limited with individualized and often non-effective outcomes. However, as research into treatments for obesity becomes mainstream, this rare condition may both benefit from and inform pharmacological treatment trials. We therefore focus on appetite treatments and the complexity of the condition with a view to establishing new pathways for modulating appetite in PWS and in favourably informing obesity research.

Electronic searches were conducted through EBSCO host research databases, Academic Search Premier, MEDLINE with full text, CINAHL with full text, PsycArticles, Health Source Nursing/Academic edition and PUBMED ranging from 1984 to 2015. Key words searched were: Prader–Willi syndrome, hyperphagia, obesity, hypothalamus, food seeking, satiation, appetite, appetite behaviours, medication, treatment, pharmaceuticals and intervention.

Section snippets

Prader–Willi syndrome: the evolving hyperphagia and behaviours

The appetite behaviour in PWS is life threatening. The literature describes families as the axis of support in food restricting routines. Over the trajectory of PWS, appetite issues are confounded by, among other things – late diagnosis, reduced daily caloric intake (Goldstone et al., 2008), anxiety, learning/cognition difficulties, mood related disorders, temper tantrums and aggressive behaviours (McCandless, 2011, Tunnicliffe et al., 2014).

In PWS there are four phenotypic phases that

Energy homeostasis in Prader–Willi syndrome

In general, energy homeostasis is linked to a complex regulation of caloric intake and energy expenditure, aligned to compensatory modulation within the system. The known PWS-related transitions in hormone levels are as follows. From 7 months to 5 years, there are significantly lowered fasting plasma levels of pancreatic polypeptide (PP), while leptin levels are significantly raised (Goldstone et al., 2012). There is conflicting opinion on the correlation between plasma ghrelin levels and the

The PWS critical region

Atypical expression in the area of chromosome 15, is confirmed through DNA methylation analysis, followed by cytogenetic testing, fluorescence in situ hybridization and microsatellite marker analysis to define the less common genotype classifications (Boyle et al., 2011, Rocha and Paiva, 2014). PWS is a contiguous gene syndrome with many simultaneously non-functioning genes on the paternal chromosome 15. These consist of MKRN3, MAGEL2, Necdin (NDN), NPAP1, SNURF-SNRPN and five small nucleolar

Pharmacological treatments in PWS

Treatment is imperative, demonstrated well by the international PWS association's slogan “still hungry for a cure” (PWSAUSA, 2015). Historically there have been only a limited number of studies on pharmacological treatment for typical PWS appetite behaviours. We will define the research and effectiveness of all the pharmacological treatments investigated in PWS including both past and recent trials from large and small cohorts. We also include single case studies and open label studies. We have

Discussion

This review has documented the individualized complexity of PWS and the existing literature on appetite treatments. Clearly, overeating is problematic for most with PWS. The perceived high appetite sensation and a delayed satiety make continual abstinence difficult to adhere to. There is significant research needed to determine a treatment capable of establishing independence for adults with PWS.

The literature suggests there is a complex interplay between established routines and management in

Conclusion

Prader–Willi syndrome is a complex life-threatening individualized genetic syndrome with minimal pharmacological interventions for the difficult appetite behaviours. Past treatment trials, in small cohorts, demonstrate minimal power and individualized effect with little or no appetite correction. We conclude that future research in regards to targets for treatment may need to be aligned to the phases of PWS. In researching pharmacological interventions, thorough observation during treatment

Conflict of interest

The authors declare there is no conflict of interest.

Acknowledgements

The authors are grateful to all those with PWS and their families, who have given of their time and support to help establish an understanding of this condition.

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