Background Objective physiological biomarkers that index underlying neural circuit dysfunction, such as electroretinography (ERG), are needed in Fragile X syndrome (FXS) research. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene and loss of fragile X messenger ribonucleoprotein (FMRP), leading to synaptic dysfunction and prominent sensory processing abnormalities. This study evaluated whether ERG waveform differences are detectable in FXS using a handheld RETeval® protocol while accounting for key technical and physiological determinants of signal variability. Methods ERG recordings were obtained during routine clinic visits using the RETeval® system in 24 males with genetically confirmed FXS [aged (mean ± SD) 28 ± 10 years; 19 full mutation, 5 mosaic] and 19 neurotypical male controls [aged (mean ± SD) 26 ± 2 years]. Outcomes included flash and flicker ERG parameters (a- and b-wave amplitudes and time-to-peak; flicker amplitude and time-to-peak). Feasibility was assessed using ERG waveform acquisition and success rates. Results Individuals with FXS demonstrated reduced flash b-wave amplitude (β = −6.84 µV; 95% CI [− 12.87 - −0.81]; p=.026) and prolonged time-to-peak for flash a-wave (β = 1.79 ms; 95% CI [0.32–3.26]; p=.017), flash b-wave (β = 1.10 ms; 95% CI [0.19–2.02]; p = .018), and flicker responses (β = 1.68 ms; 95% CI [0.49–2.88]; p=.006). Flash a-wave amplitude and flicker amplitude were not significantly different from controls. ERG feasibility was substantially reduced in FXS: participant-level flash acquisition and success were 67% and 46% in FXS versus 100% and 100% in controls, respectively (p=.0066 and p=.0001). Participant-level flicker acquisition and success were 46% and 38% in FXS versus 95% and 95% in controls (p=.0003 and p=.0001). No significant laterality effects were observed for waveform parameters or feasibility. Conclusions Handheld, light-adapted ERG detected reproducible abnormalities in retinal function in FXS, consistently in reduced flash b-wave amplitude and delayed response timings, supporting altered post-photoreceptor processing as a physiological feature of FXS. Low acquisition and success rates in a routine outpatient clinic workflow indicate feasibility constraints, supporting use of ERG as a context-dependent biomarker for mechanistic studies and interventional trials.

Electroretinography biomarkers indicate disrupted visual processing in Fragile X syndrome

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2026年3月27日

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Qianyi Pu,
Naomi Bennett,
Tejas C. Sekhar,
Mary T. Stanley,
Elizabeth Berry-Kravis

摘要

Background

Objective physiological biomarkers that index underlying neural circuit dysfunction, such as electroretinography (ERG), are needed in Fragile X syndrome (FXS) research. Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene and loss of fragile X messenger ribonucleoprotein (FMRP), leading to synaptic dysfunction and prominent sensory processing abnormalities. This study evaluated whether ERG waveform differences are detectable in FXS using a handheld RETeval^® protocol while accounting for key technical and physiological determinants of signal variability.

Methods

ERG recordings were obtained during routine clinic visits using the RETeval^® system in 24 males with genetically confirmed FXS [aged (mean ± SD) 28 ± 10 years; 19 full mutation, 5 mosaic] and 19 neurotypical male controls [aged (mean ± SD) 26 ± 2 years]. Outcomes included flash and flicker ERG parameters (a- and b-wave amplitudes and time-to-peak; flicker amplitude and time-to-peak). Feasibility was assessed using ERG waveform acquisition and success rates.

Results

Individuals with FXS demonstrated reduced flash b-wave amplitude (β = −6.84 µV; 95% CI [− 12.87 - −0.81]; p=.026) and prolonged time-to-peak for flash a-wave (β = 1.79 ms; 95% CI [0.32–3.26]; p=.017), flash b-wave (β = 1.10 ms; 95% CI [0.19–2.02]; p = .018), and flicker responses (β = 1.68 ms; 95% CI [0.49–2.88]; p=.006). Flash a-wave amplitude and flicker amplitude were not significantly different from controls. ERG feasibility was substantially reduced in FXS: participant-level flash acquisition and success were 67% and 46% in FXS versus 100% and 100% in controls, respectively (p=.0066 and p=.0001). Participant-level flicker acquisition and success were 46% and 38% in FXS versus 95% and 95% in controls (p=.0003 and p=.0001). No significant laterality effects were observed for waveform parameters or feasibility.

Conclusions

Handheld, light-adapted ERG detected reproducible abnormalities in retinal function in FXS, consistently in reduced flash b-wave amplitude and delayed response timings, supporting altered post-photoreceptor processing as a physiological feature of FXS. Low acquisition and success rates in a routine outpatient clinic workflow indicate feasibility constraints, supporting use of ERG as a context-dependent biomarker for mechanistic studies and interventional trials.