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Background: Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl−/−, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model. Methods: Rd16;Nrl−/− mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7–48) were compared with those of the model. Results: CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl−/− model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl−/− mice, UV- and M-cone ERGs of rd16;Nrl−/− were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age. Conclusions: The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl−/− murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35–40 and re-study after one month by assaying interocular difference in the UV-cone ERG. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine the natural history of the photoreceptor disease in a large group of pediatric patients with RHD12-associated Leber congenital amaurosis (RDH12-LCA), to estimate the changes expected over the duration of a clinical trial, and to define the relationship between the photoreceptor loss and visual dysfunction., Methods: Forty-six patients representing 36 families were included. The great majority of patients were under the age of 18 years. Patients underwent complete ophthalmic examinations and imaging with various modalities including adaptive optics scanning laser ophthalmoscopy. Visual function was assessed with static and kinetic perimetry, and full-field stimulus test (FST) under dark- and light-adapted conditions., Results: Patients had a severe and early onset retinal degeneration (EORD). Visual acuity losses showed a progression rate of 0.04 logMAR per year. A small foveal island could be retained but showed degeneration over time. Foveal cone sensitivity losses were predictable by the loss of photoreceptors. Peripapillary retina could be retained with no significant progression detectable. Peripapillary rod sensitivity was substantially less than expected from photoreceptor structure pointing to a large improvement potential. FST sensitivities were reliably recordable in pediatric patients and showed a small but significant improvement with age. Locally and globally, loss of rod sensitivity tended to be larger than loss of cone sensitivity., Conclusions: Foveal cones of RDH12-LCA should be targeted with treatments aimed to slow progression, whereas peripapillary rod photoreceptors should be targeted with treatments aimed to improve night vision. Pediatric FST testing may be complicated by age-related maturation of decision making regarding threshold criteria.

A first-in-human clinical trial of gene therapy in Leber congenital amaurosis due to mutations in the GUCY2D gene is underway, and early results are summarized. A recombinant adeno-associated virus serotype 5 (rAAV5) vector carrying the human GUCY2D gene was delivered by subretinal injection to one eye in three adult patients with severe visual loss, nystagmus, but preserved retinal structure. Safety and efficacy parameters were monitored for 9 months post-operatively. No systemic toxicity was detected; there were no serious adverse events, and ocular adverse events resolved. P1 and P2 showed statistically significant rod photoreceptor vision improvement by full-field stimulus testing in the treated eye. P1 also showed improvement in pupillary responses. Visual acuity remained stable from baseline in P1 and P2. P3, however, showed a gain of 0.3 logMAR in the treated eye, indicating greater cone-photoreceptor function. The results show safety and both rod- and cone-mediated efficacy of this therapy., Competing Interests: S.E.B. and S.L.B. are scientific founders of and equity holders in Atsena Therapeutics, Inc. and are patent holders on the use of AAV-GUCY2D for the treatment of LCA1. B.L.C., V.D., and C.R.O. participated in trial design and implementation., (© 2021 The Authors.)

Inherited retinal diseases (IRDs) were first classified clinically by history, ophthalmoscopic appearance, type of visual field defects, and electroretinography (ERG). ERGs isolating the two major photoreceptor types (rods and cones) showed some IRDs with greater cone than rod retinal dysfunction; others were the opposite. Within the cone-rod diseases, there can be phenotypic variability, which can be attributed to genetic heterogeneity and the variety of visual function mechanisms that are disrupted. Most cause symptoms from childhood or adolescence, although others can manifest later in life. Among the causative genes for cone-rod dystrophy (CORD) are those encoding molecules in phototransduction cascade activation and recovery processes, photoreceptor outer segment structure, the visual cycle and photoreceptor development. We review 11 genes known to cause cone-rod disease in the context of their roles in normal visual function and retinal structure. Knowledge of the pathobiology of these genetic diseases is beginning to pave paths to therapy., Competing Interests: Declaration of Competing Interest The authors declare no competing interests or conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mutations in photoreceptor cilium genes CEP290 and NPHP5 cause a form of Leber congenital amaurosis (LCA) which typically lacks rods but retains central cones. The current study evaluated the transient pupillary light reflex (TPLR) as an objective outcome measure to assess efficacy of ongoing and future therapies. Eleven eyes of six patients selected for retained cone function were tested with TPLR using full-field stimuli in the dark-adapted state. Stimuli were red or blue with 1 s duration and spanned a 6-log unit dynamic range. TPLR response amplitude was quantified at fixed times of 0.9 and 2 s after stimulus onset and TPLR latency was defined as the time to reach 0.3 mm constriction. Full-field stimulus testing (FST) and static perimetry were used to correlate subjective perception with objective TPLR parameters. TPLR and FST thresholds with both red and blue stimuli were abnormally elevated in patients to near -1.25 log phot-cd·m -2 consistent with the lack of rods. TPLR latencies were delayed on average but showed some differences among patients. Remnant extrafoveal vision was correlated with faster TPLR latencies. Our results support the use of a short TPLR protocol with full-field red stimuli of 0.7 log phot-cd·m -2 or brighter as an objective and convenient outcome measure of cone function in CEP290- and NPHP5-LCA. The latency parameter of the TPLR would be expected to show a detectable change when an intervention modifies cone sensitivity in the extrafoveal region., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To use supervised machine learning to predict visual function from retinal structure in retinitis pigmentosa (RP) and apply these estimates to CEP290- and NPHP5-associated Leber congenital amaurosis (LCA) to determine the potential for functional improvement., Methods: Patients with RP (n = 20) and LCA due to CEP290 (n = 12) or NPHP5 (n = 6) mutations were studied. A patient with CEP290 mutations but mild retinal degeneration was included. RP patients had cone-mediated macular function. A machine learning technique was used to associate perimetric sensitivities to local structure in RP patients. Models trained on RP data were applied to predict visual function in LCA., Results: The RP and LCA patients had comparable retinal structure. RP patients had peak sensitivity at the fovea surrounded by decreasing sensitivity. Machine learning could successfully predict perimetry results from segmented or unsegmented optical coherence tomography (OCT) input. Application of machine learning predictions to LCA within the residual macular island of photoreceptor structure showed differences between predicted and measured sensitivities defining treatment potential. In patients with retained vision, the treatment potential was 4.6 ± 2.9 dB at the fovea but 16.4 ± 4.4 dB at the parafovea. In patients with limited or no vision, the treatment potential was 17.6 ± 9.4 dB., Conclusions: Cone vision improvement potential in LCA due to CEP290 or NPHP5 mutations is predictable from retinal structure using a machine learning approach. This should allow individual prediction of the maximal efficacy in clinical trials and guide decisions about dosing. Similar strategies can be used in other retinal degenerations to estimate the extent and location of treatment potential.

Purpose: To determine the progression rate and the variability of rod and cone sensitivities in patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in ORF15-RPGR., Methods: ORF15-RPGR-XLRP patients (n = 15) were studied prospectively over 2 years with static perimetry sampling the visual field under dark-adapted and light-adapted conditions on a 12° square grid covering 168° width and 84° height. Natural history of rod and cone sensitivity loss and test-retest variability were estimated. Data were analyzed pointwise as well as averaged across small regions of neighboring loci of approximately 80 mm2 (900 deg2) in size representing the likely extent of localized gene therapy injections., Results: Retinal loci with mild to moderate loss of sensitivity tended to be in the mid- to far-peripheral retina in most patients. When averaged across small regions, dark-adapted rod vision progressed at an average of 2 dB per year with a coefficient of repeatability (CR) of 6.3 dB, and light-adapted cone vision with white stimulus progressed at an average of 0.9 dB per year with a CR of 3.8 dB. For an average patient enrolled in an early-phase clinical trial, significant (α = 0.05) progression would be predicted to occur with 80% power in 4.5 years for rod vision and 6.1 years for cone vision. Localization of regions in the temporal hemifield and grouping of results from multiple patients would permit trial designs of shorter duration., Conclusions: Measurement of rod sensitivity under dark-adapted conditions averaged across a small region showed the greatest potential for detectability of progression in the shortest period.

Purpose: To determine the progression of cone vision loss in patients with recessive disease from NR2E3 gene mutations., Methods: Patients with NR2E3 mutations (n = 37) were studied as a retrospective observational case series clinically and with chromatic static perimetry. Patients were investigated cross-sectionally, and a subset was followed longitudinally., Results: Patients showed a range of visual acuities; there was no clear relationship to age. With kinetic perimetry (V4e target), a full field could be retained over many years. Other patients showed progression from a full field, with or without pericentral scotomas, to a small central island. Three patterns of S-cone function were defined, based on percentage of hypersensitive S-cone loci in the field. From occupying most of the visual field, hyperfunctioning S-cone loci could diminish in percent, remaining largely in the periphery. Normal S-cone functioning then dominates, followed by the appearance of an annular region of abnormal S-cone loci approximately 10° to 40° from the fovea. Overall, S-cone sensitivity declined 2.6 times faster than L/M-cone sensitivity., Conclusions: Murine proof-of-concept studies suggest that clinical trials of patients with NR2E3 mutations may be forthcoming. Patterns of S-cone hyperfunction across the field would serve as a means to categorize patients as entry criteria or cohort selection in clinical trials. S-cone perimetry can be measured in the clinic and would be the logical efficacy monitor for therapeutic strategies. Given further understanding of the natural history of the disease, targeting the annular region of S-cone dysfunction for a focal therapy or for monitoring in a retina-wide intervention warrants consideration.

Purpose: The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy., Methods: Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy., Results: All patients were able to fixate on a 1° diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas., Conclusions: The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.)., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To investigate visual function and outer and inner retinal structure in the rare form of retinal degeneration (RD) caused by TULP1 (tubby-like protein 1) mutations., Methods: Retinal degeneration patients with TULP1 mutations (n = 5; age range, 5-36 years) were studied by kinetic and chromatic static perimetry, en face autofluorescence imaging, and spectral-domain optical coherence tomography (OCT) scans. Outer and inner retinal laminar thickness were measured and mapped across the central retina. Comparisons were made with results from patients with RD associated with four ciliopathy genotypes (MAK, RPGR, BBS1, and USH2A)., Results: The TULP1-RD patients were severely affected already in the first decade of life and there was rapidly progressive visual loss. No evidence of rod function was present at any age. Small central islands showed melanized retinal pigment epithelium by autofluorescence imaging and well-preserved photoreceptor laminar thickness by OCT imaging. There was extracentral loss of laminar architecture and increased inner retinal thickening. Structure-function relationships in residual foveal cone islands were made in TULP1-RD patients and in other retinopathies considered ciliopathies. Patients with TULP1-RD, unlike the others, had greater dysfunction for the degree of foveal structural preservation., Conclusions: Retinal degeneration with TULP1 mutations leads to a small central island of residual foveal cones at early ages. These cones are less sensitive than expected from the residual structure. The human phenotype is consistent with experimental evidence in the Tulp1 knockout mouse model that visual dysfunction could be complicated by abnormal processes proximal to cone outer segments., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To investigate the human disease due to CRB1 mutations and compare results with the Crb1-mutant rd8 mouse., Methods: Twenty-two patients with CRB1 mutations were studied. Function was assessed with perimetry and electroretinography (ERG) and retinal structure with optical coherence tomography (OCT). Cortical structure and function were quantified with magnetic resonance imaging (MRI). Rd8 mice underwent ERG, OCT, and retinal histopathology., Results: Visual acuities ranged from 20/25 to light perception. Rod ERGs were not detectable; small cone signals were recordable. By perimetry, small central visual islands were separated by midperipheral scotomas from far temporal peripheral islands. The central islands were cone mediated, whereas the peripheral islands retained some rod function. With OCT, there were small foveal islands of thinned outer nuclear layer (ONL) surrounded by thick delaminated retina with intraretinal hyperreflective lesions. MRI showed structurally normal optic nerves and only subtle changes to occipital lobe white and gray matter. Functional MRI indicated that whole-brain responses from patients were of reduced amplitude and spatial extent compared with those of normal controls. Rd8 mice had essentially normal ERGs; OCT and histopathology showed patchy retinal disorganization with pseudorosettes more pronounced in ventral than in dorsal retina. Photoreceptor degeneration was associated with dysplastic regions., Conclusions: CRB1 mutations lead to early-onset severe loss of vision with thickened, disorganized, nonseeing retina. Impaired peripheral vision can persist in late disease stages. Rd8 mice also have a disorganized retina, but there is sufficient photoreceptor integrity to produce largely normal retinal function. Differences between human and mouse diseases will complicate proof-of-concept studies intended to advance treatment initiatives.

Purpose: To determine the human retinal phenotype caused by mutations in the gene encoding AIPL1 (Aryl hydrocarbon receptor-interacting protein-like 1) now that there are proof-of-concept results for gene therapy success in Aipl1-deficient mice., Methods: Leber congenital amaurosis (LCA) patients (n = 10) and one patient with a later-onset retinal degeneration (RD) and AIPL1 mutations were studied by ocular examination, retinal imaging, perimetry, full-field sensitivity testing, and pupillometry., Results: The LCA patients had severe visual acuity loss early in life, nondetectable electroretinograms (ERGs), and little or no detectable visual fields. Hallmarks of retinal degeneration were present in a wide region, including the macula and midperiphery; there was some apparent peripheral retinal sparing. Cross-sectional imaging showed foveal cone photoreceptor loss with a ring of minimally preserved paracentral photoreceptor nuclear layer. Features of retinal remodeling were present eccentric to the region of detectable photoreceptors. Full-field sensitivity was reduced by at least 2 log units, and chromatic stimuli, by psychophysics and pupillometry, revealed retained but impaired rod function. The RD patient, examined serially over two decades (ages, 45-67 years), retained an ERG in the fifth decade of life with abnormal rod and cone signals; and there was progressive loss of central and peripheral function., Conclusions: AIPL1-LCA, unlike some other forms of LCA with equally severe visual disturbance, shows profound loss of foveal as well as extrafoveal photoreceptors. The more unusual late-onset and slower form of AIPL1 disease may be better suited to gene augmentation therapy and is worthy of detection and further study.

Purpose: To define the phenotype of the retinal degeneration associated with mutations in the CERKL gene., Methods: Six patients (ages, 26-54 years) from three unrelated families with CERKL mutations were studied clinically and by electroretinography, kinetic, and chromatic static perimetry, autofluorescence (AF) imaging, and optical coherence tomography (OCT)., Results: Three siblings were homozygotes for p.R257X mutation; two siblings were compound heterozygotes for p.R257X and a novel p.C362X mutation; and one patient had only p.R257X mutation identified to date. There was a spectrum of severity: from mild visual acuity loss to light perception; from full kinetic fields with relative central scotomas to remnant peripheral islands; from reduced ERGs (some with negative waveforms) to nondetectable signals. Maculopathy showed residual foveal islands or extensive central rod and cone scotomas. With AF imaging, there was evidence of hyperautofluorescence at earlier and hypoautofluorescence at later disease stages. Peripheral function was generally less affected than central function. With OCT there were small foveal islands of outer nuclear layer (ONL) in those with preserved acuity. Eccentric to an annular region with no discernible ONL, there could be ONL in the midperiphery. At early disease stages, ganglion cell layer thickness was less affected than ONL. Later disease stages were accompanied by inner nuclear layer and nerve fiber layer abnormalities., Conclusions: CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. The clinical presentation is that of an autosomal recessive cone-rod dystrophy. Photoreceptor loss appears at all stages of disease and inner laminopathy complicates the phenotype at later stages.

Human gene therapy with rAAV2-vector was performed for the RPE65 form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, the procedure was deemed safe and there was evidence of visual gain in the short term. At 12 months after treatment, our young adult subjects remained healthy and without vector-related serious adverse events. Results of immunological assays to identify reaction to AAV serotype 2 capsid were unchanged from baseline measurements. Results of clinical eye examinations of study and control eyes, including visual acuities and central retinal structure by in vivo microscopy, were not different from those at the 3-month time point. The remarkable improvements in visual sensitivity we reported by 3 months were unchanged at 12 months. The retinal extent and magnitude of rod and cone components of the visual sensitivity between 3 and 12 months were also the same. The safety and efficacy of human retinal gene transfer with rAAV2-RPE65 vector extends to at least 1 year posttreatment.

Purpose: To determine the retinal phenotype of Usher syndrome type III (USH3A) caused by clarin-1 (CLRN1) gene mutations in a non-Finnish population., Methods: Patients with USH3A (n = 13; age range, 24-69) representing 11 different families were studied and the results compared with those from patients with USH2A (n = 24; age range, 17-66). The patients were evaluated by ocular examination, kinetic and static perimetry, near-infrared autofluorescence, and optical coherence tomography (OCT)., Results: Ten of 11 families had Ashkenazi Jewish origins and the N48K CLRN1 mutation. Rod function was lost in the peripheral field in the first two decades of life, but central rod function could be retained for another decade. Peripheral cone function was detectable into the third decade of life. Central cone function had a slower decline that extended for decades. Photoreceptor layer loss and features of retinal remodeling were present in retinal regions with severe visual dysfunction, even at the youngest ages tested. Central retinal structure could be normal in younger patients but structural integrity was lost in older patients. RPE disease generally paralleled photoreceptor degeneration. Comparisons between USH3A and USH2A suggested a common rod and cone phenotype but a more accelerated time course of rod loss in USH3A., Conclusions: USH3A and USH2A share patterns of rod and cone dysfunction and retinal structural abnormalities. Peripheral function measurements showed USH3A to be more rapidly progressive than USH2A.

Purpose: To determine the underlying retinal micropathology in subclasses of autosomal dominant retinitis pigmentosa (ADRP) caused by rhodopsin (RHO) mutations., Methods: Patients with RHO-ADRP (n = 17, ages 6-73 years), representing class A (R135W and P347L) and class B (P23H, T58R, and G106R) functional phenotypes, were studied with optical coherence tomography (OCT), and colocalized visual thresholds were determined by dark- and light-adapted chromatic perimetry. Autofluorescence imaging was performed with near-infrared light. Retinal histology in hT17M-rhodopsin mice was compared with the human results., Results: Class A patients had only cone-mediated vision. The outer nuclear layer (ONL) thinned with eccentricity and was not detectable within 3 to 4 mm of the fovea. Scotomatous extracentral retina showed loss of ONL, thickening of the inner retina, and demelanization of RPE. Class B patients had superior-inferior asymmetry in function and structure. The superior retina could have normal rod and cone vision, normal lamination (including ONL) and autofluorescence of the RPE melanin; laminopathy was found in the scotomas. With Fourier-domain-OCT, there was apparent inner nuclear layer (INL) thickening in regions with ONL thinning. Retinal regions without ONL had a thick hyporeflective layer that was continuous with the INL from neighboring regions with normal lamination. Transgenic mice had many of the laminar abnormalities found in patients., Conclusions: Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. The results in human class B and the transgenic mice support the following disease sequence: ONL diminution with INL thickening; amalgamation of residual ONL with the thickened INL; and progressive retinal remodeling with eventual thinning.

Purpose: Dramatic restoration of retinal function has followed subretinal viral-mediated gene therapy in RPE65-deficient animal models of human Leber congenital amaurosis (LCA) caused by RPE65 mutations. Progress in early-phase clinical trials of RPE65-LCA prompted us to begin development of an in vivo bioassay of clinical grade vector stability for later-phase trials., Methods: Naturally-occurring Rpe65-mutant rd12 mice (2-4 mo of age) were studied with full-field electroretinograms (ERGs). Flash stimuli (range, -4.1 to 3.6 log scot-cd x s x m(-2)) were used to evoke ERGs in anesthetized, dark-adapted mice. B-wave amplitudes were measured conventionally and luminance-response functions were fit. Leading edges of photoresponses were analyzed with a model of rod phototransduction activation. A unilateral subretinal injection of AAV2-CB(SB)-hRPE65 vector was delivered and therapeutic efficacy of 4 doses spanning a 2 log unit range was studied with ERGs performed about 6 weeks after injection. Uninjected rd12 eyes and wild-type (wt) mice served as controls., Results: Rd12 mice showed substantially smaller amplitudes and lower sensitivities than wt mice for all measured ERG b-wave and photoresponse parameters. For the dose-response study, there was no difference between 0.01X-dosed mice and untreated mutants. Improved receptoral and post-receptoral function was evident for 0.1X, 0.3X, 1X doses: b-wave semi-saturation constants decreased, b-wave amplitudes increased with dose; photoresponses showed faster kinetics and higher maximum amplitudes. ERG b-wave amplitude to a selected stimulus light intensity could provide evidence of biologic activity of the vector; interocular differences in b-wave amplitude comparing treated versus untreated eyes in the same animal also revealed vector efficacy., Conclusions: We have taken the first steps toward developing an ERG assay of biologic activity of human grade vector for future clinical trials of RPE65-LCA. Faithful murine models of treatable human disease tested with specific ERG protocols may emerge as valuable in vivo bioassays for future human clinical trials of therapy in many retinal degenerative diseases.

Purpose: Human blindness caused by mutation of visual cycle genes has been discussed as potentially treatable by retinoid replacement either through gene transfer or pharmacological bypass. Mutations in the RDH12 gene disrupt the visual cycle in vitro, but little is known of the in vivo effects of mutant RDH12, other than the association with severe early-onset autosomal recessive retinal disease. The relationship of retinal organization and visual function in patients with RDH12 mutations was determined and comparisons made with the disease from mutations in another visual cycle gene, RPE65., Methods: Young patients with RDH12 mutations were studied with optical coherence tomography (OCT) and colocalized measures of vision with dark-adapted absolute thresholds. Results were compared to those in patients with RPE65 mutations., Results: Retinal architecture of patients with RDH12 mutations was appreciably distorted, precluding identification of the normal laminae. Some RDH12-mutant retinas were remarkably thick and others were thin, but all had the same dysplastic pattern. A comparison with the structural and functional consequences in patients with mutations in RPE65 indicated that the pathogenesis of retinal degeneration in RDH12 mutations was distinctly different., Conclusions: The results demand critical consideration of the human disease mechanism and the therapeutic approach in patients with mutations in the putative visual cycle gene RDH12.

Purpose: To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome., Methods: Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT)., Results: The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change., Conclusions: USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.