Pre-Pulse Inhibition: Its Expanded Use in Differentiation of Autism Caused by Fragile X Syndrome Versus Idiopathic Autism

Background: Pre-pulse inhibition (PPI) of the eyeblink startle reflex in response to auditory stimuli has been shown to be reliably indicative of sensorimotor gating deficits in fragile X syndrome (FXS).  In addition, PPI deficit rescue has been linked to the pharmacological use of mGluR5 antagonists.  As such, PPI has become an important quantitative outcome measure for FXS targeted treatment studies.  Prior literature suggests that idiopathic autism and autism caused by FXS share a common pathophysiological etiology, though few studies have directly compared these two groups.  Some individuals with idiopathic autism have demonstrated sensorimotor gating deficits similar to those seen in FXS, which could be quantitatively measured through the PPI protocol and perhaps explained through the theory of shared neurobiology. 

Objectives: To compare the PPI profiles in individuals with idiopathic autism with those of the individuals with autism caused by FXS in order to further characterize their neurobiology, which may important implications for future pharmacological interventions (particularly the use of mGluR5 antagonists) in autism. 

Methods: PPI was compared in age- and IQ-matched groups with FXS and autism (FXS+A), FXS without autism (FXS-A), idiopathic autism confirmed negative for fragile X (IA) and controls.  In addition, a Repetitive Behavior Scale, a Short Sensory Profile and cognitive measures were collected from each subject.

Results: The FXS-A group had lower PPI compared to controls (p < 0.001), as did the FXS+A group (p < 0.05).  The FXS-A group had lower PPI than the IA group (p < 0.05).  The PPI difference between the FXS+A group and the IA group approached statistical significance, with the FXS+A group having lower PPI than the IA group.  There were no other significant differences in PPI among other comparison groups, including the comparison between the two FX groups and the comparison between the IA group and the controls.  PPI did not significantly correlate with any of the behavioral measures administered.  Conclusions: The significant difference between the FXS-A and the IA groups and the trend towards significance between the IA and FXS+A groups suggest that the presence of FXS may be the driving force behind a sensorimotor gating deficit in these comparisons.  As such, the underlying physiological mechanism of sensorimotor gating may not be common between individuals with FXS (with or without autism) and individuals with IA, so PPI may be a valuable tool for distinguishing autism that is due to FX from other etiologies.   However, the IA sample size is small, and given the heterogeneous nature of IA, greater numbers are needed to validate these conclusions.   Nonetheless, these results, when combined with recent findings linking PPI to the mGluR5 theory and neurobiology of FXS, support the potential of PPI to be an important outcome measure in testing the efficacy of targeted treatments for FX and other neurobiologically-related populations.