Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of ...photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.
Congenital stationary night blindness (CSNB) refers to a group of genetically and clinically heterogeneous retinal disorders. Seventeen different genes with more than 360 different mutations and more ...than 670 affected alleles have been associated with CSNB, including genes coding for proteins of the phototransduction cascade, those important for signal transmission from the photoreceptors to the bipolar cells or genes involved in retinoid recycling in the retinal pigment epithelium. This article describes the phenotypic characteristics of different forms of CSNB that are necessary for accurate diagnosis and to direct and improve genetic testing. An overview of classical and recent methods used to identify specific CSNB genotypes is provided and a meta-analysis of all previously published and novel data is performed to determine the prevalence of disease-causing mutations. Studies of the underlying molecular pathogenic mechanisms based on cell culture techniques and animal studies are outlined. The article highlights how the study of CSNB has increased understanding of the mechanisms of visual signalling in the retina, likely to prove important in developing future treatments for CSNB and other retinal disorders.
Dominant optic atrophy (DOA) is genetically heterogeneous and most commonly caused by mutations in OPA1. To distinguish between the classical OPA1-related and the recently identified SSBP1-related ...DOAs, the retina and fovea of 27 patients carrying the SSBP1 p.Arg38Gln variant were scrutinized using 20° × 20° macular cube and 30° and 55° field fundus autofluorescence photographs. Age of onset, visual acuity, retinal nerve fiber layer and macular thicknesses were recorded. Three SSBP1-patients were asymptomatic, 10 had isolated DOA, and 12 had a combined DOA plus foveopathy. The foveopathy, with a tiny defect of the ellipsoid and interdigitation lines, was similar in all patients, independent of age. There were no significant statistical differences in terms of visual acuity and SD-OCT measurements between patients with isolated DOA (mean visual acuity in decimals: 0.54 ± 0.41) and those with combined foveopathy (0.50 ± 0.23). Two patients over 50 years of age developed a progressive rod-cone dystrophy, leading to severe visual impairment. SSBP1-related DOA shares similarities with OPA1-related DOA with an incomplete penetrance and an early childhood visual impairment. Nevertheless, the presence of a congenital foveopathy with no impact on visual acuity is a major criterion to distinguish SSBP1 cases and orient the appropriate genetic analysis.
Masquerade syndromes represent a large set of ophthalmological entities that mimic inflammatory conditions. Any delay in their diagnosis may be correlated with systemic dissemination or worsening of ...the causal disease and, therefore, with poor prognosis. One of the disadvantages of the new potent treatments of uveitis is the delay that they can induce in the diagnosis of neoplastic intraocular infiltrations. Thorough and careful clinical examination of all patients referred for uveitis, especially when they are Caucasian, over 50 years of age, and with posterior segment involvement, is of paramount importance in this context. Ancillary investigations and often-invasive histo-pathologic evaluation of tissue specimens or ocular fluids are regularly required in these situations. The most common masquerade syndrome is primary vitreoretinal lymphoma (PVRL). New molecular diagnostic tools may be helpful in challenging cases lacking cytological confirmation. Therapeutic strategies targeting tumoral cells in the eye and also in the central nervous system can improve the life expectancy of affected patients. In this review, we discuss diagnostic strategies and current therapies in PVRL and provide an overview of other conditions that can mimic primary ocular inflammation, especially in the field of oncology and its new therapeutic armamentarium.
Since a substantial difference in the prevalence of genetic causes of rod-cone dystrophy (RCD) was found among different populations, we conducted a systematic review of the genetic findings ...associated with RCD in Arab countries. Of the 816 articles retrieved from PubMed, 31 studies conducted on 407 participants from 11 countries were reviewed. Next-generation sequencing (NGS) was the most commonly used technique (68%). Autosomal recessive pattern was the most common pattern of inheritance (97%) and half of the known genes associated with RCD (32/63) were identified. In the Kingdom of Saudi Arabia, in addition to RP1 (20%) and TULP1 (20%), gene defects in EYS (8%) and CRB1 (7%) were also prevalently mutated. In North Africa, the main gene defects were in MERTK (18%) and RLBP1 (18%). Considering all countries, RP1 and TULP1 remained the most prevalently mutated. Variants in TULP1, RP1, EYS, MERTK, and RLBP1 were the most prevalent, possibly because of founder effects. On the other hand, only ten Individuals were found to have dominant or X-linked RCD. This is the first time a catalog of RCD genetic variations has been established in subjects from the Arabi countries. Although the last decade has seen significant interest, expertise, and an increase in RCD scientific publication, much work needs to be conducted.
Thirty-eight patients from 37 families with retinitis pigmentosa (RP) underwent macular 6 × 6-mm swept-source optical coherence tomography angiography (SS-OCTA) and 30° near-infrared fundus ...autofluorescence (NIR-FAF) acquisitions in one eye. Superficial vascular complex (SVC), deep capillary complex (DCC) and choriocapillaris (CC) angiograms were registered with NIR-FAF acquisitions to comparatively assess subjects with and without central area of preserved NIR-FAF (APA). On the subset of patients showing an APA, the vessel densities for SVC and DCC and flow deficits for CC were assessed in three directions (superior, inferior and temporal) from the fovea and compared to healthy 1:1 age-matched controls. Nine patients with no APA had evidence of severe central OCTA alterations at all levels, especially in the DCC. In the other 29 subjects presenting APA, all OCTA parameters were similar to healthy eyes within the APA, where the retina preserves its structural integrity. Outside the APA, both the DCC and CC were significantly reduced in all directions. These alterations are probably related to the outer retinal atrophy outside the APA. Comparing OCTA to other imaging modalities is helpful to determine the potential interest of OCTA findings as an outcome measure for disease status and progression.
Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease.
To describe the yearly progression rate of atrophic lesions in the retrospective Progression ...of Stargardt Disease study.
A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye.
Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable.
Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence.
A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean SD age, 29.9 14.7 years; mean SD age of onset of symptoms, 21.9 13.3 years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean SD age, 33.0 15.1 years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion.
In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.
To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed ...in the interphotoreceptor matrix.
Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study.
The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included.
Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically.
Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized.
IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases.
IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.
Abstract Purpose To determine the relationship between visual function and quality of life, education, mental health and employment among young adults with Retinitis Pigmentosa (RP). Design ...Cross-sectional study. Methods Inclusion of 148 patients (mean age 38.2 +/- 7.1 yrs) diagnosed with RP, living in France. Quality of life was assessed using the National Eye Institute Visual Function Questionnaire (VFQ-25), mental state with the Hospital and Anxiety and Depression Scale (HADS) and employment with a specifically designed questionnaire. Results Limited visual impairment was noted in 22.3%, low vision in 29.7% and legal blindness in 48.0%. There was a correlation between quality of life scores and residual visual field (P < .0001). Mental health scores were suggestive of anxiety in 36.5 % and depression in 15.5%. The rates did not increase with disability level (P = .738, P = .134). The percentage of subjects with higher education did not significantly decrease with disability level (P = .113). The employment rate did not significantly decrease with disability level (P = .276). It was lower in subjects reporting depression (P = .0414). Self-rated impact of RP on employment increased with disability level (P =.02642). Conclusions Our results differ from previous results showing lower education rates and employment rates in young adults with RP. Further research is warranted focusing on the impact of mental health, education, workplace conditions and employment aids on employment rate vs. age and education matched normally sighted controls to guide visual disability strategies in RP.
Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). Using a cCSNB mouse model lacking Lrit3 (nob6), we recently have shown that LRIT3 has a role in the correct ...localization of TRPM1 (transient receptor potential melastatin 1) to the dendritic tips of ON-bipolar cells (BCs), contacting both rod and cone photoreceptors. Furthermore, postsynaptic clustering of other mGluR6 cascade components is selectively eliminated at the dendritic tips of cone ON-BCs. The purpose of this study was to further define the role of LRIT3 in structural and functional organization of cone synapses.
Exhaustive electroretinogram analysis was performed in a patient with LRIT3 mutations. Multielectrode array recordings were performed at the level of retinal ganglion cells in nob6 mice. Targeting of GluR1 and GluR5 at the dendritic tips of OFF-BCs in nob6 retinas was assessed by immunostaining and confocal microscopy. The ultrastructure of photoreceptor synapses was evaluated by electron microscopy in nob6 mice.
The patient with LRIT3 mutations had a selective ON-BC dysfunction with relatively preserved OFF-BC responses. In nob6 mice, complete lack of ON-pathway function with robust, yet altered signaling processing in OFF-pathways was detected. Consistent with these observations, molecules essential for the OFF-BC signaling were normally targeted to the synapse. Finally, synaptic contacts made by ON-BC but not OFF-BC neurons with the cone pedicles were disorganized without ultrastructural alterations in cone terminals, horizontal cell processes, or synaptic ribbons.
These results suggest that LRIT3 is likely involved in coordination of the transsynaptic communication between cones and ON-BCs during synapse formation and function.
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