In vivo neuroimaging evidence of hypothalamic alteration in Prader–Willi syndrome

Abstract

Prader-Willi syndrome is a genetic neurodevelopmental disorder with an early phenotype characterised by neonatal hypotonia, failure to thrive, and immature genitalia. The onset of hyperphagia in childhood and developmental, physical and neuropsychiatric characteristics indicate atypical brain development and specifically hypothalamic dysfunction. Whether the latter is a consequence of disruption of hypothalamic pathways for genetic reasons or due to a failure of hypothalamic development remains uncertain. 20 participants with Prader-Willi syndrome, 40 age-matched controls and 42 obese participants underwent structural MRI scanning. The whole hypothalamus and its subnuclei were segmented from structural acquisitions. The Food Related Problem Questionnaire was used to provide information relating to eating behaviour. All hypothalamic nuclei were significantly smaller in the Prader-Willi group, compared to age and gender matched controls (p < 0.01) with the exception of the right anterior-inferior nucleus (p = 0.07). Lower whole hypothalamus volume was significantly associated with higher body mass index in Prader-Willi syndrome (p < 0.05). Increased preoccupation with food was associated with lower volumes of the bilateral posterior nuclei and left tubular superior nucleus. The whole hypothalamus and all constituent nuclei were also smaller in Prader-Willi syndrome compared to obese participants (p < 0.001). Connectivity profiles of the hypothalamus revealed that fractional anisotropy was associated with impaired satiety in Prader-Willi syndrome (p < 0.05). We establish that hypothalamic structure is significantly altered in Prader-Willi syndrome, demonstrating that hypothalamic dysfunction linked to eating behaviour is likely neurodevelopmental in nature and furthermore, distinctive compared to obesity in the general population.

Alteration of brain nuclei in obese children with and without Prader-Willi syndrome

“…However, limited by segmentation methods, most of the studies have not found significantly hypothalamic structural abnormality (Honea et al, 2012;Lukoshe et al, 2017). Recently, using the same Hypothalamic Subunits tool as in this manuscript, Brown et al (2022) reported PWS adults had smaller volumes of whole hypothalamus and its subunits except for right a-iHyp, than that in obese and control adults. Consistent with the results of PWS adults, atrophy of the bilateral hypothalamus in PWS children was found in our study, specifically contributed by the bilateral in fTub andposHyp, right supTub and left a-iHyp subregions.…”

Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype

“…In this model PWS might be considered to be a single gene disorder in which the phenotype arises as a consequence of abnormal brain development driven by the absence of expression of SNORD 116. A paper by [ 2 ] reported on recent neuroimaging findings showing significantly smaller hypothalamic nuclei in people with PWS compared to an aged-matched typically developing control group and also an obese group. The authors argue that the hypothalamus fails to develop in PWS and this would explain the varied phenotypic characteristics of hypothalamic origin.…”

“…We identify what we consider to be particular key questions that need to be addressed and suggest hypotheses as to how the absence of expression of this gene gives rise to the phenotype. We propose that this is either due to a direct effect on brain development, particularly affecting the hypothalamus [ 2 ] by impacting on foetal nutrition or by failing to modify the expression levels of a cascade of other (as yet unidentified) genes, which in turn affect brain development. The ultimate effect of the pattern of atypical brain development specific to PWS is to alter the response thresholds for particular networks in the brain thereby impairing the ability to maintain homeostasis, such as ensuring energy balance or responding to environmental change.…”

MRI Volumetric Analysis of the Hypothalamus and Limbic System across the Pediatric Age Span

“…In a cohort of 12 children with Prader–Willi syndrome, 18 obese children without Prader–Willi syndrome, and 18 healthy controls, Wu et al showed that children with Prader–Willi syndrome have a significantly smaller thalamus, globus pallidus, hippocampus, amygdala, nucleus accumbens, deep cerebellar nuclei, and hypothalamus [ 4 ]. Brown et al found similar differences with regard to the atrophy of hypothalamic nuclei, but they also showed that a lower whole hypothalamus volume was significantly associated with higher body mass index in Prader–Willi syndrome [ 5 ]. They described that an increased preoccupation with food was associated with lower volumes of the bilateral posterior nuclei and left tubular superior nucleus of the hypothalamus [ 5 ].…”

“…Brown et al found similar differences with regard to the atrophy of hypothalamic nuclei, but they also showed that a lower whole hypothalamus volume was significantly associated with higher body mass index in Prader–Willi syndrome [ 5 ]. They described that an increased preoccupation with food was associated with lower volumes of the bilateral posterior nuclei and left tubular superior nucleus of the hypothalamus [ 5 ].…”