HypothesisThe paradox of Prader-Willi syndrome: a genetic model of starvation
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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Transcriptomics of the Prader–Willi syndrome hypothalamus
2021, Handbook of Clinical NeurologyCitation 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).
Show me what happens next: Preliminary efficacy of a remote play-based intervention for children with Prader-Willi syndrome
2021, Research in Developmental DisabilitiesBehaviour and cognition in the imprinted gene disorder, Prader-Willi Syndrome (PWS)
2019, Current Opinion in Behavioral SciencesA review of psychiatric conceptions of mental and behavioural disorders in Prader-Willi syndrome
2018, Neuroscience and Biobehavioral ReviewsEpigenetics and obesity
2017, Neuropsychiatric Disorders and Epigenetics