Detailed phenotype and long-term follow-up of RAB28-associated cone-rod dystrophy.

PURPOSE: To gain an insight into the pathophysiology of RAB28-associated inherited retinal degeneration through detailed phenotyping and long-term longitudinal follow-up. METHODS: The patient underwent complete ophthalmic examinations. Visual function was assessed with microperimetry, full-field electroretinography (ffERG), imaging with optical coherence tomography (OCT), short-wave (SW), and near-infrared (NIR) fundus autofluorescence (FAF). RESULTS: A healthy Haitian woman with homozygous pathogenic variants (c.68C > T; p.Ser23Phe) in RAB28 presented at 16 years of age with a four-year history of blurred vision. Visual acuities were 20/125 in each eye, which remained relatively stable since. At age 27, cone ffERGs were non-detectable and borderline for rod-mediated responses. Kinetic fields were full to a V-4e target, undetectable to a small I-4e stimulus. Microperimetry showed an absolute central scotoma surrounded by a pericentral relative scotoma. SD-OCT showed an undetectable or barely detectable foveal and parafoveal photoreceptor outer nuclear layer (ONL), photoreceptor outer segment (POS), and retinal pigment epithelium (RPE) signals and loss of the SW- and NIR-FAF signals. This atrophic region was separated from a normally laminated retina by a narrow transition zone (TZ) of hyper SW- and NIR-FAF that co-localized with preserved ONL but abnormally thinned POS and RPE. There was minimal centrifugal (<100 µm) expansion over a six-year period. CONCLUSION: The cone-rod dystrophy phenotype documented herein supports a critical role of RAB28 for cone function and POS maintenance. Severe central photoreceptor and RPE loss with a predilection for POS loss in TZs suggests possible disruptions of complex mechanisms that maintain central cone photoreceptor and RPE homeostasis.

Optimization and Validation of a Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations.

Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs). Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ). Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects). Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly. Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

Fleck-like lesions in CEP290-associated leber congenital amaurosis: a case series.

PURPOSE: To provide a detailed ophthalmic phenotype of a small cohort of patients with Leber Congenital Amaurosis (LCA) caused by mutations in CEP290 (CEP290-LCA) with a focus on elucidating the origin of yellow-white lesions observed in 30% of patients with this condition. METHODS: This is a retrospective review of records of five patients with CEP290-LCA. Patients had comprehensive ophthalmic evaluations. Visual function was assessed with full-field electroretinograms (ffERGs) and full-field sensitivity testing (FST). Multimodal imaging was performed with spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) with short- (SW) and near-infrared (NIR) excitation wavelengths. RESULTS: All patients showed relative structural preservation of the foveal and near midperipheral retina separated by a pericentral area of photoreceptor loss. Yellow-white, fleck-like lesions in an annular distribution around the near midperiphery co-localized with hyperreflective lesions on SD-OCT. The lesions located between the inner segment ellipsoid signal and the apical retinal pigment epithelium (RPE). The inner retina was normal. Longitudinal observations in one of the patients indicates the abnormalities may represent an intermediate stage in the degenerative process between the near normal appearing retina previously documented in young CEP290-LCA patients and the pigmentary retinopathy observed along the same region in older individuals. CONCLUSIONS: We speculate that fleck-like lesions in CEP290-LCA correspond to malformed, rudimentary or degenerated, including shed, photoreceptor outer segments. The topography and possible origin of the abnormalities may inform the planning of evolving genetic therapies for this disease.