Abnormal rod- and cone-isolated flicker electroretinograms in carriers of X-linked retinoschisis

Abstract

Purpose: Identifying potential carriers of X-linked retinoschisis (XLRS) in some cases requires identifying mutations in the RS1 gene, as XLRS carriers generally do not exhibit clinically-apparent fundus abnormalities. This study evaluated rod- and cone-isolated electroretinograms (ERGs) as a possible means to identify such potential carriers.

Methods: Full-field ERGs were recorded from the right eye of 7 obligate carriers of XLRS (mean age, 63.7 years) and 10 normally-sighted subjects (mean age, 33.1 years) under two paradigms: 1) The standard ISCEV paradigm, consisting of scotopic single-flash, photopic single-flash, and 30-Hz flicker responses; 2) Rod-isolated (ERG_R), cone-isolated (ERG_C), and non-receptor-specific (ERG_R+C) flicker responses. ERGs were obtained using a 4-primary LED-based ganzfeld photostimulator and standard ERG recording techniques. The 4 primaries were modulated sinusoidally in phase to achieve non-receptor-specific activation (ERG_R+C) or in counter-phase to achieve ERG_R and ERG_C by means of triple silent substitution. After 30 minutes of dark adaptation, 8 and 15 Hz ERG_R, ERG_C, and ERG_R+C responses were obtained at a mean luminance level of 24 cd/m². Receiver operating characteristic (ROC) analysis was performed on the amplitude and phase of the fundamental response component derived by Fourier analysis.

Results: All ISCEV and 15-Hz flicker ERG responses were within the normal range for all carriers. The 8-Hz ERG_R, ERG_C, and ERG_R+C amplitudes were also generally within the normal range. In contrast, the carriers had clear ERG_R, ERG_C, and ERG_R+C timing abnormalities. That is, phase was advanced beyond the range of normal for the ERG_R (3 carriers), ERG_C (5 carriers), and ERG_R+C (4 carriers). Only one carrier had normal responses under all conditions. Using 8-Hz response phase as the sole metric to distinguish carriers from controls, ROC analysis found the area under the curve to be 90% (p = 0.006), 86% (p = 0.01), and 69% (p = 0.20), for the ERG_C, ERG_R+C, and ERG_R, respectively.

Conclusions: In 6 of 7 carriers of XLRS, abnormal flicker ERG timing was observed that was restricted to 8-Hz, which is the stimulus frequency at which abnormal rod-cone interactions were reported in a previous psychophysical study of XLRS carriers. The 8-Hz flicker ERG, particularly under conditions in which cone-pathway response is isolated, may be a useful marker for the carrier state of XLRS.