Reduced vagal tone in women with the FMR1 premutation is associated with FMR1 mRNA but not depression or anxiety

Abstract

BackgroundAutonomic dysfunction is implicated in a range of psychological conditions, including depression and anxiety. The fragile X mental retardation-1 (FMR1) premutation is a common genetic mutation that affects ~1:150 women and is associated with psychological vulnerability. This study examined cardiac indicators of autonomic function among women with the FMR1 premutation and control women as potential biomarkers for psychological risk that may be linked to FMR1.MethodsBaseline inter-beat interval and respiratory sinus arrhythmia (a measure of parasympathetic vagal tone) were measured in 35 women with the FMR1 premutation and 28 controls. The women completed anxiety and depression questionnaires. FMR1 genetic indices (i.e., CGG repeat, quantitative FMRP, FMR1 mRNA, activation ratio) were obtained for the premutation group.ResultsRespiratory sinus arrhythmia was reduced in the FMR1 premutation group relative to controls. While depression symptoms were associated with reduced respiratory sinus arrhythmia among control women, these variables were unrelated in the FMR1 premutation. Elevated FMR1 mRNA was associated with higher respiratory sinus arrhythmia.ConclusionsWomen with the FMR1 premutation demonstrated autonomic dysregulation characterized by reduced vagal tone. Unlike patterns observed in the general population and in study controls, vagal activity and depression symptoms were decoupled in women with the FMR1 premutation, suggesting independence between autonomic regulation and psychopathological symptoms that is atypical and potentially specific to the FMR1 premutation. The association between vagal tone and mRNA suggests that molecular variation associated with FMR1 plays a role in autonomic regulation.

Impaired eye contact in theFMR1premutation is not associated with social anxiety or the broad autism phenotype

“…Using a rating scale that has been shown to be sensitive to the BAP in family studies of autism spectrum disorder, we indexed BAP features in the FMR1 premutation and found no association with poor eye contact. In another study including an overlapping sample, Klusek et al (2017) also documented an unexpected decoupling between pragmatic language deficits (a primary feature of the BAP) and attention to eye gaze indexed via an experimental eye tracking paradigm. Taken together, these studies demonstrate that atypical use of eye gaze in the FMR1 premutation is not associated with the BAP, as suggested by evidence gathered across a combination of experimental, direct-observation, and informant- and self-report measures.…”

“…Participants included 38 women with the FMR1 premutation and 27 neurotypical control women who were participating in a larger study on communication profiles in the FMR1 premutation, which has been described previously (e.g., Klusek et al, 2017). Women with the FMR1 premutation were recruited through their children who were participating in larger developmental studies of fragile X syndrome or the FMR1 premutation, or from the local community by word of mouth.…”

“…However, this study focused on clinician impressions of eye contact during a medical examination and the blunt “present/absent” scale utilized may have been inadequate for capturing subtle differences. Other evidence of altered use of social gaze comes from a recent study by Klusek et al (2017), which found that women with the FMR1 premutation showed increased attention to averted gaze relative to controls during an experimental eye tracking paradigm. These studies underscore the need for focused investigation of eye contact in the FMR1 premutation.…”

Cardiovascular Problems in the Fragile X Premutation

“…Autonomic dysfunction is a common problem in the premutation carriers especially with FXTAS and it usually precedes diagnosis of FXTAS ( Jacquemont et al, 2003 , 2004 ; Pugliese et al, 2004 ; Leehey, 2009 ; Hagerman and Hagerman, 2013 ). In non-FXTAS carriers, a study found that the premutation females had reduced vagal tone which reflects impaired parasympathetic response ( Klusek et al, 2017 ). In terms of cardiovascular disorders, the clinical presentation of autonomic dysfunction includes episodic hypotension ( Pugliese et al, 2004 ; Greco et al, 2006 ; Gokden et al, 2009 ; Hagerman and Hagerman, 2013 ) and hypertension ( Jacquemont et al, 2003 ; Coffey et al, 2008 ; Chonchaiya et al, 2010 ; Hamlin et al, 2012 ).…”

Increased severity of fragile X spectrum disorders in the agricultural community of Ricaurte, Colombia

“…Children with the premutation usually have normal intellectual abilities but approximately 20% are diagnosed with developmental problems or autism spectrum disorder (ASD), which are part of the spectrum of fragile X disorders (FXSD) (Farzin et al, 2006; Lozano et al, 2014). Psychiatric problems such as anxiety, ADHD and/or depression are present in approximately 50% of children and adults with the premutation (Farzin et al, 2006; Bourgeois et al, 2011; Cordeiro et al, 2015; Klusek et al, 2017).…”