The paradox of Prader-Willi syndrome: a genetic model of starvation

doi:10.1016/S0140-6736(03)14370-X

The Lancet

Volume 362, Issue 9388, 20 September 2003, Pages 989-991

https://doi.org/10.1016/S0140-6736(03)14370-X Get rights and content

Summary

The neurodevelopmental disorder, Prader-Willi syndrome, is generally regarded as a genetic model of obesity. Although the values of some hypothalamic neuropeptides are as expected in obesity, and should result in satiety, we propose that abnormal hypothalamic pathways mean that these are ineffective. We postulate that the body incorrectly interprets the absence of satiation as starvation, and therefore, paradoxically, this syndrome should be redefined as one of starvation that manifests as obesity in a food-rich environment. Also, this syndrome is generally believed to be a contiguous gene disorder, which results from the absence of expression of the paternally derived alleles of maternally imprinted genes on chromosome 15 (15q11–13). We argue, however, that the whole phenotype can be explained by one mechanism and, by implication, the failure of expression of the paternal allele of a single maternally imprinted gene that controls energy balance. We suggest clinical and laboratory approaches to test our hypotheses.

Section snippets

Phenotype

Prader-Willi syndrome is thought to result from the absence of expression of the paternally derived alleles of maternally imprinted genes in a critical region of about 121 kb of the SNRPN locus at 15q11–13.¹ The syndrome is mainly characterised by two distinct phenotypes. In the first, fetal movement is restricted, and evidence of fetal growth retardation and severe hypotonia is noted at birth. The infant fails to thrive and tube feeding is necessary. The second phenotype is seen from about age

Pathophysiology

The mechanisms underpinning the physical phenotype include growth hormone deficiency and central hypogonadism. Thyroid and adrenal function are normal.⁴ Growth hormone replacement in childhood is recommended and not only improves adult height, but also size of hands and feet, facial dysmorphism, and muscle bulk.⁵ Growth hormone and gonadotropin deficiencies might also, together with other abnormalities, partly account for the disproportionate fat versus lean body mass in people with

Hypothesis

We propose that this syndrome should be redefined as one of starvation that manifests as obesity in a food-rich environment, and that the whole phenotype can be explained by a single mechanism. We put forward two main arguments in support of our hypothesis of starvation. Neither contains all the research evidence, and some evidence is contradictory, but together they provide strong support for this idea. The first is related to the body's ability to balance energy intake and energy expenditure

Fetal starvation

Other features of the phenotype that also need to be clarified are neonatal hypotonia, failure to thrive, and arrested brain development. We believe that the starvation model could also apply to the early phenotype. We propose that absence of expression of the imprinted gene for Prader-Willi syndrome in the placenta could disrupt nutrition to the fetus, resulting in fetal starvation and abnormal brain development. Another factor might be the detrimental effects of low concentrations of growth

Testing the hypothesis

Although people with this disorder are not starved, their behaviour and much of the associated physiology is as if they are in a state of starvation. This hypothesis led us to the idea that the mechanisms giving rise to the phenotype could result from a single abnormality in energy balance, and by implication, the absence of expression of a single gene. Other phenotypic characteristics, such as the high pain threshold and skin picking, might also originate from associated dysfunction of the

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Cited by (82)

The paradox of Prader-Willi syndrome revisited: Making sense of the phenotype
2022, eBioMedicine
Prader-Willi syndrome arises as a consequence of absent paternal copies of maternally imprinted genes at 15q11-13. Such gender-of-origin imprinted genes are expressed in the brain and also in mammalian placenta where paternally expressed imprinted genes drive foetal nutritional demand. We hypothesise that the PWS phenotype is the result of the genotype impacting two pathways: first, directly on brain development and secondly, on placental nutritional pathways that results in its down-regulation and relative foetal starvation. The early PWS phenotype establishes the basis for the later characteristic phenotype. Hyperphagia. and other phenotypic characteristics arise as a consequence of impaired hypothalamic development. Hypothalamic feeding pathways become set in a state indicative of starvation, with a high satiety threshold and a dysfunctional neurophysiological state due to incorrect representations of reward needs, based on inputs that indicate a false requirement for food. Our hypotheses, if confirmed, would lead to novel and effective interventions.
Transcriptomics of the Prader–Willi syndrome hypothalamus
2021, Handbook of Clinical Neurology
Citation Excerpt :
Considered altogether, the PWS hypothalamic transcriptome overlapped with a conserved signature of the neural response to fasting or food deprivation. This finding speaks to the previously presented hypothesis for PWS as a disease of chronic starvation (Holland et al., 2003). In order to establish similarities between the PWS transcriptomic data and other published transcriptomic signatures, the differentially expressed genes were compared to curated pathways from the Molecular Signatures Database (Subramanian et al., 2005; Liberzon et al., 2015).
Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder, arising from a loss of paternity expressed genetic material on the imprinted chromosome locus 15q11-q13. Despite increasing clarity on the underlying genetic defects, the molecular basis of the condition remains poorly understood.
Hypothalamic dysfunction is widely recognized as the basis of the core symptoms of PWS, which include a deficiency in growth hormone and reproductive hormones, circadian rhythm abnormalities, and a lack of satiety, leading to an extreme obesity, among others.
Genome-wide gene expression analysis (transcriptomics) offers an unbiased interrogation of complex disease pathogenesis and a potential window into the dysregulated pathways involved in disease. In this chapter, we review the findings from recent work investigating the PWS hypothalamic transcriptome, discuss the significance of the findings in relation to the clinical presentation and molecular underpinnings of PWS, and highlight future research directions.
Show me what happens next: Preliminary efficacy of a remote play-based intervention for children with Prader-Willi syndrome
2021, Research in Developmental Disabilities
Prader-Willi Syndrome (PWS) is characterized by decreased social and emotional functioning. Due to the low base-rate of children with PWS, developing behavioral interventions for individuals with PWS is faced with the challenge of enrolling enough local participants for adequate study of behavioral intervention efficacy. However, these types of studies are greatly needed in PWS and telehealth methodology may be useful in addressing this challenge. This article is a follow-up to a previous feasibility study (Dimitropoulos et al., 2017) and reports on the preliminary efficacy of a telehealth intervention delivered to 15 children, ages 6–12, with PWS. Overall, children demonstrated significantly improved cognitive and affective processes in pretend play and general cognitive flexibility following the 6-week remote intervention. These findings are limited by the lack of control group and small sample size which should be considered when interpreting results. Overall, these preliminary findings point to the potential role pretend play can serve as a means of enacting cognitive and behavioral change via telehealth.
Behaviour and cognition in the imprinted gene disorder, Prader-Willi Syndrome (PWS)
2019, Current Opinion in Behavioral Sciences
A review of psychiatric conceptions of mental and behavioural disorders in Prader-Willi syndrome
2018, Neuroscience and Biobehavioral Reviews
We present a review of psychiatric associations with comorbid mental and behavioural disorders affecting people with Prader-Willi syndrome (PWS). This literature review suggests that some assumptions about psychiatric associations of PWS behaviours are unjustified (eg skin picking as OCD) and that genetic aetiology should be considered when making associations between PWS mental and behavioural disorders and psychiatric disorders in the general populationThe literature review also demonstrates the limitations of the studies in terms of small numbers, non-representativeness, and lack of replication.
Epigenetics and obesity
2017, Neuropsychiatric Disorders and Epigenetics
Obesity is a significant public health concern and a central component of metabolic syndrome. An important scientific and clinical aspect of obesity is the considerable evidence for its developmental origins in the periconceptual and perinatal environment, indicating that the susceptibility to obesity can be mediated by environmental inputs that stably alter metabolic outcomes. These observations reflect the function of an active epigenetic mechanism that can biochemically program gene expression through DNA and histone modification, a hypothesis supported by studies in animal models and human cohorts showing strong correlations between early developmental exposures, chromatin modifications, and obesity. Consistent with the central role of the hypothalamus in regulating energy balance, many of the epigenetic effects of obesogenic exposures are targeted to the orexigenic and anorexigenic functions of the hypothalamic feeding center, and their ability to properly regulate feeding behavior, energy expenditure, and metabolic flux in peripheral tissues.

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HypothesisThe paradox of Prader-Willi syndrome: a genetic model of starvation

Summary

Section snippets

Phenotype

Pathophysiology

Hypothesis

Fetal starvation

Testing the hypothesis

Am J Hum Genet

Lancet

Am J Clin Nutr

Biochem Biophys Res Commun

Placenta

Brain Res

Behavioural phenotypes associated with specific genetic disorders: Evidence from a population-based study of people with Prader-Willi syndrome

Psychol Med

Hypogonadism and endocrine metabolic disorders in Prader-Willi syndrome

Acta Paediatr Suppl

Measurement of excessive appetite and metabolic changes in Prader-Willi syndrome

Int J Obes Relat Metab Disord

Hypothesis
The paradox of Prader-Willi syndrome: a genetic model of starvation