Visual phenotype in Williams-Beuren syndrome challenges magnocellular theories explaining human neurodevelopmental visual cortical disorders

Abstract

Williams-Beuren syndrome (WBS), a neurodevelopmental genetic disorder whose manifestations include visuospatial impairment, provides a unique model to link genetically determined loss of neural cell populations at different levels of the nervous system with neural circuits and visual behavior. Given that several of the genes deleted in WBS are also involved in eye development and the differentiation of retinal layers, we examined the retinal phenotype in WBS patients and its functional relation to global motion perception. We discovered a low-level visual phenotype characterized by decreased retinal thickness, abnormal optic disk concavity, and impaired visual responses in WBS patients compared with age-matched controls by using electrophysiology, confocal and coherence in vivo imaging with cellular resolution, and psychophysics. These mechanisms of impairment are related to the magnocellular pathway, which is involved in the detection of temporal changes in the visual scene. Low-level magnocellular performance did not predict high-level deficits in the integration of motion and 3D information at higher levels, thereby demonstrating independent mechanisms of dysfunction in WBS that will require remediation strategies different from those used in other visuospatial disorders. These findings challenge neurodevelopmental theories that explain cortical deficits based on low-level magnocellular impairment, such as regarding dyslexia.

Figures

Figure 1. Central retinal phenotype in a representative WBS subject.

(A) Optical biopsy using OCT of the central macular region of the retina reveals a normal layering of retinal structures in a WBS (WBS1) participant (color-coded log reflectivity map: red, high; black, low). An intact foveomacular depression is visible. However, quantitative morphometry revealed a decrease in RT. The bottom hyperreflective layer corresponds to the pigment epithelium and the top one to the ganglion cell RNFL. The hyporeflective region represents the photoreceptor layer. Top right inset represents a fundus photograph of the subject’s retina. Arrow in left inset shows axis of depicted OCT image. (B) Color-coded thickness map of the central 20 degrees of the same retina depicted in A (for details, see Methods). A generalized loss is visible (for statistical details, see text). Numbers indicate regional RT.

Figure 2. RT maps (in μm) of the central 20 degrees of the retina depicted in 3 control subjects and 3 WBS participants (WBS3, WBS7, and WBS8).

Figure 3. Analysis of RT and RNFL thickness across groups.

(A) Scheme of regions where RT and RNFL were analyzed. Numbers code different regions. (B) Overall thickness reduction in all 9 regions (see A for respective local labels) explored in the central 20 degrees of the WBS retina in comparison with age-matched control subjects, as illustrated by percentile plots. Box boundaries correspond to upper and lower twenty-fifth percentiles, outer bars to the tenth percentiles, and middle bars to the median. In spite of the preserved morphology of the foveomacular pit, we observed a significant thickness reduction in WBS subjects when compared with age-matched controls (P < 0.0001 for all 9 regions, Mann-Whitney U test). (C) The ganglion cell RNFL thickness in the central part of the retina was less dissimilar between groups, differences only being significant in outer and nasal sectors. RNFL, ganglion cell RNFL.

Figure 4. Optical biopsy (OCT) of the optic disc region of the retina depicting abnormal cupping and layering of retinal structures in 3 WBS participants (WBS1, WBS2, WBS3).

Arrows depict orthogonal axes of optical section. Although we observed that there is a bimodal pattern of deviation in our WBS group (see text), the cup region most often loses concavity, either by obliteration or partial covering by a thin membrane (subject WBS3).

Figure 5. Confocal scanning ophthalmoscopy confirms anatomical abnormalities suggested by OCT results, and multifocal electrophysiology shows functional impairment.

(A) The central deep segmented red region is often obliterated or reduced and displaced in WBS subjects as compared with normal subjects (N). The red area marks the cup. The rest of the disc area is divided into a sloping (blue) and stable (green) neuroretinal rim. Right-side images in each panel mark the optic nerve region in average confocal images. Loss of concavity is even more evident in these images. (WBS subjects: lower left, WBS3, right eye; lower right, WBS3, left eye; upper right, WBS1). (B) Abnormal deviation of the normal cup pattern by further deepening of that region in a WBS subject (WBS5), suggesting that the pattern of deviation is bimodal. The walls of the cup region are abnormally steep, as shown in the measurements in the HRT images (see top left, height profile) and confirmed by the OCT biopsy (top right; for comparison, see normal profile in Figure 4, bottom). Bottom row of images also suggest that the “neck” of the cup opening is abnormally large in this subject. (C) The P1 component of the multifocal first order kernel response was most significantly affected in WBS, as illustrated by percentile plots. Box boundaries correspond to upper and lower twenty-fifth percentiles, outer bars to the tenth percentiles, and middle bar to the median. The earlier N1 component is less significantly affected. R1–R5, rings of increasing eccentricity.

Figure 6. Objective functional evidence for retinal impairment in WBS.

Multifocal electrophysiological maps (average curves extracted by means of reverse correlation depicted for contiguous stimulus hexagons and respective color-coded amplitude maps) in a normal control subject (A) and the 2 retinas of a WBS subject (B, WBS6). The central peak is preserved, but many areas are clearly impaired, with a large heterogeneity within and across eyes in WBS. 3D Plots are normalized for area of stimulation. For each stimulus hexagon, the peak amplitude, defined as the difference between N1 and P1 (peak negative and positive deflections, marked as cyan and yellow in the high-resolution image version), was calculated. Hexagon with green outline represents the central fixation region.

Figure 7. Retinal measurements can predict low-level motion performance deficits but not high-level motion integration and dorsal stream function measurements.

Correlations with high-level ventral stream (face discrimination) performance are, as expected, also absent. Connecting lines depict significant correlations. Rho values next to lines depict correlation strength (they are in general negative because lower RTs correspond to less neurons in the outer retina, and lower performance implies higher thresholds). JLO, Benton’s Judgment of Line Orientation.