A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome

Background: To describe a patient with a history of obesity, retinal dystrophy, type II diabetes, and mild cognitive impairment; found to harbour biallelic splice-site variants in VPS13B. // Materials & methods: A complete ophthalmic evaluation was performed at Moorfields Eye Hospital (London, United Kingdom), consisting of measurement of best-corrected visual acuity (BCVA), slit lamp and dilated fundus evaluation, colour, autofluorescence and near-infrared retinal imaging, spectral domain-optical coherence tomography, and electroretinogram (ERG). Whole-genome sequencing was performed as part of the UK’s 100,000 Genomes Project. // Results: A 26-year-old Pakistani man with normal appearance, stature, and head size presented with decreased BCVA and severely constricted visual fields to our Ophthalmic Genetics clinic. He had a history of obesity, type II diabetes, and mild cognitive impairment. His evaluation showed retina-wide, severe photoreceptor dysfunction in both eyes, with undetectable scotopic and photopic ERG waveforms. Genomic analysis identified a homozygous rare splice donor variant in the VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis). // Conclusions: Exon 31 skipping in VPS13B may lead to a hypomorphic change, with partial gene function and an incomplete, mild Cohen syndrome-like phenotype

Quantitative Analysis of Retinal Structure Using Spectral-Domain Optical Coherence Tomography in RPGR-Associated Retinopathy

PURPOSE: To quantify retinal structure and progression using spectral-domain optical coherence tomography (SDOCT) in patients with retinitis pigmentosa (RP) associated with retinitis pigmentosa GTPase regulator gene (RPGR) mutations. DESIGN: Retrospective observational case series. METHODS: Setting: Moorfields Eye Hospital, London, United Kingdom. Subjects: Both eyes of 32 patients. SDOCT follow-up period of >1 year (3.1 ± 1.4 years). Main Outcome Measures: Ellipsoid zone (EZ) width (EZW) and outer nuclear layer (ONL) and inner retinal layer (IRL) thickness measurements. Progression rates, interocular symmetry, and association with age and genotype were investigated. RESULTS: Significant differences were observed between baseline and final measurements of EZW and ONL thickness, but not for IRL thickness. Baseline and final EZWs were 2438 ± 1646 μm and 1901 ± 1423 μm for right eyes (P < .0001); 2420 ± 1758 μm and 1922 ± 1482 μm for left eyes (P < .0001). EZW constriction rates were 176.6 ± 130.1 μm/year and 173.1 ± 146.8 μm/year for right and left eyes. ONL thinning rates were 2.58 ± 2.85 μm/year and 2.52 ± 3.54 μm/year for right and left eyes. Interocular differences in EZW and ONL progression were not significant (P = .8609 and P = .6735, respectively). Strong correlations were found between EZW constriction rates of right and left eyes (rs = 0.627, P = .0002) and between EZW constriction and baseline EZW (rs = 0.714, P < .0001). There was moderate negative correlation between EZW constriction and age (rs = −0.532, P < .0001). Correlation between ONL thinning and age was not significant, as were differences between EZW and ONL progression rates with respect to genotype. CONCLUSIONS: This study provides SDOCT progression rates for RPGR-associated RP. There is overall interocular symmetry with implications for future treatment trials where 1 eye could serve as a control

Quantitative Analysis of Hyperautofluorescent Rings to Characterize the Natural History and Progression in Rpgr-associated Retinopathy

PURPOSE: Quantitative analysis of hyperautofluorescent rings and progression in subjects with retinitis pigmentosa associated with retinitis pigmentosa GTPase regulator (RPGR) gene mutations. METHODS: Prospective observational study of 46 subjects. Ring area, horizontal and vertical diameter measurements taken from outer and inner ring borders. Intraobserver repeatability, baseline measurements, progression rates, interocular symmetry, and association with age and genotype were investigated. RESULTS: Baseline ring area was 11.8 ± 13.4 mm and 11.4 ± 13.2 mm for right and left eyes, respectively, with very strong interocular correlation (r = 0.9398; P < 0.0001). Ring area constriction was 1.5 ± 2.0 mm/year and 1.3 ± 1.9 mm/year for right and left eyes, respectively, with very strong interocular correlation (r = 0.878, P < 0.0001). Baseline ring area and constriction rate correlated negatively with age (r = -0.767; P < 0.0001 and r = -0.644, P < 0.0001, respectively). Constriction rate correlated strongly with baseline area (r = 0.850, P < 0.0001). Age, but not genotype, exerted a significant effect on constriction rates (P < 0.0001), with greatest rates of progression seen in younger subjects. An exponential decline overall was found. CONCLUSION: This study provides disease-specific baseline values and progression rates together with a repeatability assessment of fundus autofluorescence metrics. Our findings can guide future treatment trials and contribute to the clinical care of patients with RPGR-associated retinitis pigmentosa

Standing Balance Stability and the Effects of Light Touch in Adults With Profound Loss of Vision-An Exploratory Study

Purpose: We evaluated the postural stability of adults with inherited profound vision loss and examined the effects of touch on their balance control. Methods: A total of 11 severely-sight impaired patients (mean [SD] age, 51.6 [5.3] years) and 11 control subjects (mean age, 49.7 [5.3] years) participated. Postural stability was measured using a force-balance platform eyes open/closed on a firm/foam surface under 3 test conditions: no touch, light touch, and unrestricted touch (UT), where "touch" involved placing their index finger on a rigid table. Average magnitude of center of foot pressure displacement was calculated. A somatosensory ratio (SR) was used to evaluate the somatosensory contribution to balance. A repeated measures ANOVA was used to investigate the effects of touch on standing balance. Results: Patients had a significantly increased SR compared to control subjects (mean [SD] SR controls = 1.2 [0.2], patients = 1.9 [0.5]; P < 0.01). There was a significant effect of touch, vision, and surface on balance control ("touch" F = 68.1, P < 0.01; "vision" F = 20.1, P < 0.01; "surface" F = 200.8, P < 0.01). Light touch attenuated sway in patients and controls. The effects were greater in controls when their vision was removed, and greater in patients when their somatosensory system was disrupted. Light touch was as effective as UT in attenuating sway. Conclusions: The results of this exploratory study suggest that patients with severe sight impairment show an increased somatosensory contribution to balance control compared to their normally sighted counterparts. Light touch significantly reduces sway amplitude in severely sight impaired adults when standing on the foam surface, that is, when the somatosensory system is perturbed

Retinal detachment in retinitis pigmentosa

Objective: Retinitis pigmentosa-related retinal detachment (RPRD) is rare, and the full spectrum of retinal complications is not well defined. To describe the types of retinal detachment in patients with retinitis pigmentosa and the surgical outcomes of RPRD. Methods: This is a non-comparative, retrospective case series. An electronic database search was performed using Moorfields OpenEyes electronic health records. We identified 90 patients with RPRD between January 2000 and August 2017. Main outcome and measures are visual acuity (VA), surgical outcomes and classification of RPRD. Results: Of the 90 patients/detachments, 61 (67.8%) were rhegmatogenous retinal detachment (RRD), 19 (21.1%) were exudative, 3 (3.3%) were tractional retinal detachment (TRD) and 7 (7.8%) had combined. 37.5% (9/24) of patients with exudative retinal detachment were treated with either cryotherapy or laser, and one patient underwent vitrectomy for vitreous haemorrhage. 56/90 patients underwent surgical intervention. Nine patients presented late and were deemed inoperable (two exudative and seven RRD). Of the RRD patients with full operative record, the primary attachment rate was 76.2% (16/21) and final reattachment rate was 85.7% (18/21) over a mean 15.4-year follow-up period. Mean VA for RRD surgery improved from 6/190 (1.51 logMAR) to 6/120 (1.31 logMAR) (p=0.194). In the TRD group, the mean VA was 6/300 (1.66 logMAR) at baseline and improved after surgery to 6/48 (0.90 logMAR) (p=0.421). Conclusions: We demonstrated a final reattachment rate of 85.7% with a trend toward better vision following intervention for patients with RPRD. However, the final long-term vision may be poor due to the natural progression of retinitis pigmentosa-associated macular degeneration

Visual consequences of molecular changes in the guanylate cyclase activating protein

Purpose: In this study, we characterize and model changes in visual performance associated with a Tyr99Cys substitution in the guanylate cyclase activating protein (GCAP1) in four family members aged between 39 and 55 years. Guanylate cyclase and its activating protein are molecules in the visual transduction pathway that restore cyclic GMP (cGMP) following its light-activated hydrolysis. The mutation causes an excess of cGMP in the dark and results in progressive photoreceptor loss. Methods: L-cone temporal acuity was measured as a function of target irradiance; and L-cone temporal contrast-sensitivity was measured as a function of temporal frequency. Results: All four GCAP1-mutant family members show sensitivity or acuity losses relative to normal observers. The data for the youngest family member are consistent with an abnormal speeding up of the visual response relative to normals, but those for the older members show a progressive higher-frequency sensitivity loss consistent with a slowing down of their response. Conclusions: The speeding up of the visual response in the youngest observer is consistent with the Tyr99Cys-mutation resulting in the more rapid replacement of cGMP after light exposure, and thus in a reduction of temporal integration and relative improvement in high frequency sensitivity compared to normals. The high-frequency losses in the older observers are consistent with their vision being further limited by the interposition of some sluggish process. This might result from some residual or malfunctioning molecular process limiting transduction within damaged photoreceptors, or from an active or passive postreceptoral reorganization caused by the paucity of functioning photoreceptors

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies

Characterization of Retinal Function using Microperimetry-Derived Metrics in both Adults and Children with RPGR-Associated Retinopathy

PURPOSE: To investigate microperimetry testing of RPGR-associated retinopathy in a cohort of children and adults. STUDY DESIGN: Prospective observational case series. METHODS: The coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated for mesopic microperimetry. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), MS, total volume (VTOT), and central 3-degree field volume (V3) from volumetric and topographic analyses were acquired. RESULTS: Seventy-six RPGR subjects (53 adults, 23 children) were recruited. The mean follow-up period was 2.8 years. The ICC values for MS, VTOT and V3 were 0.982 dB (95% confidence intervals, CI 0.969 to 0.989), 0.970 dB-sr (95% CI -0.02658 to 0.03691) and 0.986 dB-sr (95% CI 0.978 to 0.991), respectively. The r values for interocular MS, VTOT and V3, were 0.97 (P<0.01), 0.97 (P<0.01) and 0.98 (P<0.01) respectively, indicating strong inter-ocular correlation. The interocular correlation of progression for MS, VTOT and V3 was 0.81 (P<0.01), 0.64 (P<0.01) and 0.81 (P<0.01), respectively. There was no statistically significant difference in the interocular progression rates for MS or VTOT. V3 did show a statistically significant difference. Most patients lost retinal sensitivity rapidly during their second and third decades of life. CONCLUSIONS: The high degree of reproducibility of results and the good interocular correlation lends this modality to accurately monitoring disease progression, as well as supporting validation of the use of MP in assessing the outcomes of gene therapy clinical treatment trials