Enhanced S-cone function with preserved rod function: a new clinical phenotype

Abstract

Purpose: To describe the clinical findings and genetic analysis in two brothers having a novel retinal disease characterized by an enhanced S-cone phenotype with normal rod function.

Methods: Both patients underwent complete ophthalmologic examinations, including fundus photography, electroretinography (ERG), fluorescein angiography and optical coherence tomography (OCT). Mutation analysis of the following candidate genes was performed: nuclear receptor subfamily 2 group E member 3 (NR2E3), neural retina leucine zipper (NRL), nuclear receptor subfamily 1 group D member 1 (NR1D1), and thyroid hormone receptor beta (THRB).

Results: Spectral photopic ERG responses demonstrated enhanced S-cone function in both patients. Their scotopic b-wave ERG amplitude responses, however, were within normal limits. Their scotopic a-wave amplitude responses were within the lower limit of normal. The a- and b-wave latencies were normal for one sibling and on the upper limit of normal for the other. Peripheral retinal findings were normal. OCT showed flattening of the macular curvature and thinning of the photoreceptor layer. Mutation analysis of NR2E3, NRL, NR1D1, and THRB genes was negative.

Conclusions: We describe what appears to be a previously unidentified familial retinal phenotype with enhanced S-cone function and well preserved rod system function in contrast to the severely reduced rod function seen in the enhanced S-cone syndrome (ESCS). Genetic analysis of candidate genes did not reveal the cause of disease. We postulate that the disease might be caused by mutation of another, as yet unidentified gene, which encodes a protein that functions as a negative inhibitor of rod and S-cone development.

Figure 1

A: Fundus photography of patient 1 (P1) demonstrating bilateral cystoid-like macular lesions. There are no pigmentary changes. B: Optical coherence tomography (OCT) scans through the macular region of P1 (upper part) and P2 (lower part). There is loss of foveal contour (asterisks) and thinning of the hyporeflective layer representing the photoreceptors in the macular region (white arrows). P1 and P2 scans are off-center, but foveas can be seen. C: Reference areas within an OCT through the macular region of a normal patient. GCL, Ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; NFL, nerve fiber layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.

Figure 2

Electroretinograms from patient 1 (P1) and patient 2 (P2) compared to a normal subject. A: Photopic responses. No responses to red stimuli can be detected, whereas white stimuli show responses that are mostly within normal limits. Amplitudes of the response to blue stimuli are markedly higher than in normal subjects. Photopic 30-Hz flicker ERG responses are absent. Isolated rod b-wave amplitudes and maximal responses are generally within the normal limits (see B). B: Plots of scotopic response intensities from both patients. ERG intensities are shown as logarithmic values of stimulus intensity. P1 and P2 are represented in red and blue lines, respectively (one line for each eye). Black and Vertical lines represent the normal average and range from 100 normal eyes, respectively. As this parameter does not follow a normal (Gaussian) distribution but is skewed [15,16], to obtain the normal range the values were first converted to their log₁₀ values, which normalizes the distribution. Mean values±2.5 standard deviations (SD) were then calculated and the values were converted back to their antilog values. The a-wave amplitudes (left) are generally within the lower normal limit (except for P1 at the lowest ERG intensity, where it is lower than normal). The b-wave amplitudes (right) are within normal limits at all light intensities tested. C: Latency plots of the scotopic responses from both patients. For normal values, the normal range was calculated as the mean±2.5 SD. The a-wave latencies (left) are within normal limits (except for P1 at the lowest ERG intensity, where it is longer than normal). The b-wave latencies (right) are within the normal limits at all intensities, other than in P1 at 2.44 cd-s/m² (log=0.39).