Autonomic Function in Fragile X Syndrome: A Systematic Review

Fragile X syndrome (FXS) is a monogenic X-linked cause of intellectual disability and autism. Individuals with FXS often have high levels of anxiety and sometimes display challenging behaviours. Autonomic dysfunction has been suggested to be one physiological mechanism that may contribute to these. Therefore, the objective of this review is to systematically examine existing evidence on autonomic function in FXS.

An electronic literature search was conducted on OVID platforms (Medline, Embase and PsycINFO) and Web of Knowledge databases for references published before 22 April 2025, which physiologically measured autonomic function in FXS. A preregistered search strategy was designed to gather literature on the autonomic nervous system in FXS.

A total of 1426 articles were identified, and 28 studies met the inclusion criteria. Samples comprised individuals across the lifespan (ages < 1-71 years), with most studies utilising a case control design to examine indices of autonomic function; 75% of studies found a between-group difference in autonomic function metrics. Of these studies, hyperarousal in the FXS group was present in 86% (N = 18) of studies. Although some studies reported associations of autonomic function with clinical characteristics, findings varied considerably between studies. There was some evidence of potential differences between genders, although more research in female populations is required. Of the 28 included studies, 64% (N = 18) further examined links between autonomic function and clinical characteristics associated with FXS, demonstrating links between relevant clinical symptoms, that is, autistic traits and hyperarousal, as well as potential gender differences in autonomic function.

The findings demonstrate evidence for autonomic hyperarousal as a clinical phenotype in FXS across the lifespan. Future work is required to define whether overactivation of the sympathetic nervous system, as indicated by hyperarousal in FXS, can be linked to clinical symptoms. Variations in sample demographics as well as in methodological approaches to measuring autonomic function both hinder accurate comparison of the results from included studies.