Abnormal cone structure in foveal schisis cavities in X-linked retinoschisis from mutations in exon 6 of the RS1 gene

Abstract

Purpose: To evaluate macular cone structure in patients with X-linked retinoschisis (XLRS) caused by mutations in exon 6 of the RS1 gene.

Methods: High-resolution macular images were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography (SD-OCT) in two patients with XLRS and 27 age-similar healthy subjects. Retinal structure was correlated with best-corrected visual acuity, kinetic and static perimetry, fundus-guided microperimetry, full-field electroretinography (ERG), and multifocal ERG. The six coding exons and the flanking intronic regions of the RS1 gene were sequenced in each patient.

Results: Two unrelated males, ages 14 and 29, with visual acuity ranging from 20/32 to 20/63, had macular schisis with small relative central scotomas in each eye. The mixed scotopic ERG b-wave was reduced more than the a-wave. SD-OCT showed schisis cavities in the outer and inner nuclear and plexiform layers. Cone spacing was increased within the largest foveal schisis cavities but was normal elsewhere. In each patient, a mutation in exon 6 of the RS1 gene was identified and was predicted to change the amino acid sequence in the discoidin domain of the retinoschisin protein.

Conclusions: AOSLO images of two patients with molecularly characterized XLRS revealed increased cone spacing and abnormal packing in the macula of each patient, but cone coverage and function were near normal outside the central foveal schisis cavities. Although cone density is reduced, the preservation of wave-guiding cones at the fovea and eccentric macular regions has prognostic and therapeutic implications for XLRS patients with foveal schisis. (Clinical Trials.gov number, NCT00254605.).

Figures

Figure 1.

Color (top), AF (middle), and SD-OCT images (bottom) of the right (left column) and left (right column) eyes of XLRS patient 1 (A) and patient 2 (B). Locations of the AOSLO images (Figures 2–4) are indicated by the thin, black outlines. SD-OCT locations are shown by the horizontal white lines. Vitreous veils created dark shadows visible in AF images of the right eye of patient 1 and the left eye of patient 2 and precluded acquisition of AOSLO images in the right eye of patient 1.

Figure 2.

(A) AOSLO image of the left eye of patient 1. (B) Fundus-guided microperimetry scores superimposed on AOSLO image. (C) Cone spacing z-scores superimposed on AOSLO image. Sensitivities are reduced by 1 to 2 log units, and cone spacing is increased by 2.3 to 5.7 SD from normal. The white circle with a black outline indicates the preferred locus for fixation, which coincides with the anatomic fovea. Scale bar, 1° (∼300 μm).

Figure 3.

(A) AOSLO image of the right eye of patient 2. (B) Fundus-guided microperimetry scores superimposed on AOSLO image. (C) Cone spacing z-scores superimposed on AOSLO image. Sensitivities and cone spacing are near normal temporal-to-large central foveal schisis cavities seen on SD-OCT. The white circle indicates the anatomic fovea, and the black circle indicates the PRL. Scale bar, 1° (∼300 μm).

Figure 4.

(A) AOSLO image of the left eye of patient 2. (B) Fundus-guided microperimetry scores superimposed on AOSLO image. (C) Cone spacing z-scores superimposed on AOSLO image. Sensitivities and cone spacing are near normal nasal-to-large central foveal schisis cavities seen on SD-OCT. The white circle indicates the anatomic fovea, and the black circle indicates the PRL. Scale bar, 1° (∼300 μm).

Figure 5.

Cone spacing in the maculae of three eyes with XLRS. In patient 1, walls of small schisis cavities precluded measurement of cone spacing beyond 2° eccentricity. Cone spacing was increased within the central 2° but was normal at greater eccentricities imaged in patient 2.