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Fragile X syndrome (FXS) is a monogenic disorder characterized by high rates of autism spectrum disorder (ASD) and anxiety. A longstanding "hyperarousal hypothesis" in FXS has argued that ANS dysfunction underpins many symptoms of FXS. However, the developmental onset and trajectory of ANS dysfunction, as well as the consequences of ANS dysfunction on later psychiatric symptoms, remain poorly understood in FXS. Insight into the emergence, trajectory, and consequences of ANS dysfunction across early development in FXS has critical implications for prevention, intervention, and optimal outcomes in both typical and atypical development. This longitudinal study investigated whether and when males with FXS evidence atypical ANS function from infancy through early childhood, and how trajectories of ANS function across infancy and early childhood predict ASD and anxiety symptom severity later in development. Participants included 73 males with FXS and 79 age-matched typically developing (TD) males. Baseline heart activity was recorded at multiple assessments between 3 and 83 months of age, resulting in 372 observations. General arousal and parasympathetic activity were indexed via interbeat interval (IBI) and respiratory sinus arrhythmia (RSA), respectively. ASD and anxiety symptoms were assessed at 36 months of age or later in a subgroup of participants (FXS = 28; TD = 25). Males with FXS exhibited atypical patterns of developmental change in ANS function across infancy and early childhood. As a result, ANS dysfunction became progressively more discrepant across time, with the FXS group exhibiting significantly shorter IBI and lower RSA by 29 and 24 months of age, respectively. Shorter IBI at 24 months and a flatter IBI slope across development predicted elevated anxiety symptoms, but not ASD symptoms, later in childhood in both FXS and TD males. Reduced RSA at 24 months predicted elevated ASD symptoms, but not anxiety symptoms, in both groups. Developmental change in RSA across early development did not predict later anxiety or ASD symptoms. This is the first longitudinal study to examine the "hyperarousal hypothesis" in infants and young children with FXS. Findings suggest that hyperarousal (i.e., shorter IBI, lower RSA) is evident in males with FXS by 24-29 months of age. Interestingly, unique aspects of early ANS function differentially relate to later ASD and anxiety symptoms. General arousal, indexed by shorter IBI that becomes progressively more discrepant from TD controls, predicts later anxiety symptoms. In contrast, parasympathetic-related factors, indexed by lower levels of RSA, predict ASD symptoms. These findings support the "hyperarousal hypothesis" in FXS, in that ANS dysfunction evident early in development predicts later-emerging symptoms of ASD and anxiety. This study also have important implications for the development of targeted treatments and interventions that could potentially mitigate the long-term effects of hyperarousal in FXS.

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Hogan, A., Hunt, E., Smith, K., Black, C., Bangert, K., Klusek, J., & Roberts, J. (2021). Trajectories of heart activity across infancy to early childhood differentially predict autism and anxiety symptoms in fragile X syndrome. Frontiers in Psychiatry, 12.

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