Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

Abstract

Fragile X Syndrome (FXS) is characterised by features including anxiety and autistic-like behaviour, which led to early hypotheses that aberrant physiological arousal may underlie the behavioural phenotype. In line with this, several lines of evidence suggest that the HypothalamicPituitary-Adrenal (HPA) axis may be altered in the syndrome. This review collates evidence to determine the nature of HPA axis baseline activity and reactivity (as measured by glucocorticoid levels) differences in FXS, and its relationship to behaviour. Through a search electronic databases, 15 papers were identified which provided data on humans with FXS or the FMR1 knockout mouse model. The findings across studies are mixed, though trends in the findings can be seen, including elevations in cortisol levels, particularly in males. Preliminary findings also highlight associations between cortisol levels and key behaviours associated with the syndrome, such as gaze avoidance. Areas for future research are discussed. Many thanks to the editor and to the reviewers for taking the time to kindly re-review the manuscript and provide useful feedback. I have addressed the issues raised and made amendments, as detailed individually below, using tracked changes:As requested, I have re-structured the article to align to the review questions. I have, however, addressed gender differences according to each aspect of the cortisol release (baseline activity, magnitude/ duration of response, for humans and animals) following the discussion on that specific topic, and clearly marked this with sub-headings. However, I hope that I have now better highlighted the themes in gender differences observed, and have included a separate table on this issue, as requested.When referring to each study in the text, I have briefly stated how many individuals were involved and what the ages of the individuals. I have done this for the studies with human participants, as from drafting this for the animal studies (which are addressed often is less detail in the text) this became very cumbersome to read. However, the animal results are presented directly alongside the sample sizes in Table 1, which I hope will make this interpretation more simple.On p15 we mention the findings of Roberts et al (2009) in relation to the magnitude of cortisol responses. The authors of this study split their analyses according to two groups: those individuals with FXS who met the criteria for autism, and those who did not. The reviewer requested that this discussion be moved to the section on cortisol and behaviour. Given the paucity of studies discussing the magnitude of cortisol responses in this group, I have proposed that we leave this study here (as there is no option to present the results without referring to the grouping according to autism symptomatology) but to note that a further discussion on the topic is included later in the manuscript. Please do let me know if this is acceptable.The first paragraph on page 17 was noted to be out of place. I have now clarified the int...

Paternally expressed imprintedSnord116andPeg3regulate hypothalamic orexin neurons

“…GO analysis of all 833 DEGs in the mutant hypothalamus following SD suggested, instead, that loss of Snord116 leads to a homeostatic response that relies on several cellular growth processes of the hypothalamus ( Figure 3E). This result indicates that defects in sleep homeostasis in PWS can be derived from development processes of the hypothalamus, as has been described in other neurodevelopmental disorders [57][58][59].…”

Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder

“…The role of physiological hyperarousal as a biological vulnerability to stress resulting in elevations of anxiety aligns with Barlow’s diathesis-stress model (Barlow, 2002). Hyperarousal in FXS is a well-established phenomenon with consistent reports of elevated baseline heart activity (Hall, Lightbody, Huffman, Lazzeroni, & Reiss, 2009; Klusek, Roberts, & Losh, 2015, for a review; Roberts, Tonnsen, Robinson, & Shinkareva, 2012) and heightened salivary cortisol (Hardiman & Bratt, 2016, for a review; Hessl et al, 2002). …”

“…Specific stress conditions, including conversation, the approach of a stranger, and cognitive challenges have not been associated with stimulus-bound increases in autonomic arousal as measured by heart activity (Roberts, Boccia, Bailey, Hatton, & Skinner, 2001; Klusek, et al, 2013; Tonnsen et al, 2013). Likewise, a number of behaviors reflective of elevated stress, including crying and task avoidance, have not been associated with elevated cortisol (see Hardiman & Bratt, 2016 for review). However, elevated salivary cortisol has been linked to features of social anxiety, as indexed by gaze avoidance (Hall et al, 2009), physical avoidance (Roberts et al, 2009), and elevated parent ratings of social avoidance (Matherly et al, in press).…”

Feasibility of a Complex Setting for Assessing Sleep and Circadian Rhythmicity in a Fragile X Cohort

“…The role of the HPA-Axis in FXS in general as well as in the psychopathology of the syndrome (ADHD, ASD, depressive symptoms, challenging behavior etc.) has often been described (10)(11)(12)(13)(14). However, the association of the cortisol level and the manifestation of autistic behavior is discussed controversially in this context (11,13).…”

“…Different neuroendocrinologic parameters seem to be altered in FXS with respect to sleep and psychopathology. Interactions in symptomatology are controversially discussed (10)(11)(12)(13)(14)(15)(16). The role of melatonin in neuroprotection, cognitive, and learning disability has been discussed for FXS (17).…”