Retinal Degeneration

Purpose. To assess the frequency, the pattern of disease causing mutations, and phenotypic variations in patients with Leber congenital amaurosis (LCA) from Indonesia. Patients and methods. Twenty-one unrelated index cases with a clinical diagnosis of LCA were screened for mutations in the coding sequence of RetGC1, RPE65 and AIPL1 gene with single strand conformation polymorphism analysis followed by direct sequencing and restriction enzyme digestion. Results. Four novel disease causing mutations were identified: Three in the RPE65 gene (106del9bp, G32V and Y435C) in two of 21 index cases and one in the AIPL1 (K14E). Two of them were homozygous and one was compound-heterozygous. No disease causing mutation was identified in RetGC1. Conclusions. The four novel disease causing mutations identified in this study confirmed the diagnosis of LCA which has not been recognized before in Indonesia. The frequency of RPE65 mutations was 9.5%; and of AIPL1 mutations 4.8%. This was in general accordance with previous studies reported from other countries. Unlike in those studies, no disease causing RetGC1 mutations could be identified in our patients. Phenotypically, the RPE65 and AIPL1 mutations identified in this study caused nearly total blindness by the second decade of life, but had a different onset of symptoms. The patients with the RPE65 mutations retained some useful visual function until the end of the first decade, which progressed to total blindness during the second decade of life, whereas the (homozygous) AIPL1 mutation was associated with nearly total blindness from infancy on. Therefore, RPE65 mutations have to be considered to cause early onset severe retinal degeneration (EOSRD), and AIPL1 mutations a form of LCA.

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

Purpose: Exosomes derived from human mesenchymal stem cells (hMSCs) cultured under hypoxic conditions contain proteins and growth factors that promote angiogenesis. This study investigated the effect of intravitreal administration of these exosomes on retinal ischemia using a murine model. Methods: Oxygen-induced retinopathy (OIR) was induced by exposing one-week-old male C57BL/6J mice to 5 days of 75% hyperoxic conditioning, and returning to room air. After hyperoxic conditioning, the right eye of each mouse was injected intravitreally with 1 µl saline or exosomes derived from hMSCs and compared to control mice of the same age raised in room air without OIR injected intravitreally with saline. Two weeks post-injection, fluorescein angiography (FA) and phase-variance optical coherence tomography angiography (pvOCTA) were used to assess retinal perfusion. Retinal thickness was determined by OCT. The extent of retinal neovascularization was quantitated histologically by counting vascular nuclei on the retinal surface. Results: Among eyes with OIR, intravitreal exosome treatment partially preserved retinal vascular flow in vivo and reduced associated retinal thinning; retinal thickness on OCT was 111.1 ± 7.4µm with saline versus 132.1 ± 11.6µm with exosome, p < 0.001. Retinal neovascularization among OIR eyes was reduced with exosome treatment when compared to saline-treated eyes (7.75 ± 3.68 versus 2.68 ± 1.35 neovascular nuclei per section, p < 0.0001). No immunogenicity or ocular/systemic adverse effect was associated with intravitreal exosome treatment. Conclusions: Intravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration.

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.

Animal models of retinal degeneration are critical for understanding disease and testing potential therapies. Inducing degeneration commonly involves the administration of chemicals that kill photoreceptors by disrupting metabolic pathways, signaling pathways, or protein synthesis. While chemically induced degeneration has been demonstrated in a variety of animals (mice, rats, rabbits, felines, 13-lined ground squirrels (13-LGS), pigs, chicks), few studies have used noninvasive high-resolution retinal imaging to monitor the in vivo cellular effects. Here, we used longitudinal scanning light ophthalmoscopy (SLO), optical coherence tomography, and adaptive optics SLO imaging in the euthermic, cone-dominant 13-LGS (46 animals, 52 eyes) to examine retinal structure following intravitreal injections of chemicals, which were previously shown to induce photoreceptor degeneration, throughout the active season of 2019 and 2020. We found that iodoacetic acid induced severe pan-retinal damage in all but one eye, which received the lowest concentration. While sodium nitroprusside successfully induced degeneration of the outer retinal layers, the results were variable, and damage was also observed in 50% of contralateral control eyes. Adenosine triphosphate and tunicamycin induced outer retinal specific damage with varying results, while eyes injected with thapsigargin did not show signs of degeneration. Given the variability of damage we observed, follow-up studies examining the possible physiological origins of this variability are critical. These additional studies should further advance the utility of chemically induced photoreceptor degeneration models in the cone-dominant 13-LGS.

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Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1-/- mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe65Leu450Leu genetic variant -present in the mouse genetic background- which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function a...

ataract surgery improves vision and therefore quality of life. As critical as good vision is to maintaining independence, cataract extraction serves an equally valuable purpose: it increases the light available to retinal ganglion photoreceptors (RGPs). Bright, properly timed light exposure profoundly influences human health and psychology. Bright morning light enhances the early cortisol surge, facilitating the transition from sleep to daytime physiology. Bright daytime light improves mood, reduces depression and increases that evening's sleep quality. These processes are all guided by information on environmental light levels provided by RGPs. Cataract and age-related crystalline lens yellowing reduce retinal illuminance, especially in the short wavelength (violet and blue) end of the spectrum needed by RGPs. 1-5 Thus, it's no surprise that cataract surgery has many potential benefits beyond improving vision. Here's why.

The publication looked at CRISPR-Cas9 gene editing as one of the potential therapeutic strategies for LCA2 in pure bred dogs. The gRNA was designed in such a way that it would bind the canine RPE65 gene associated with LCA2. Also, an LV was designed to deliver the Cas9 nuclease and the gRNA into the target cells. The vector was further confirmed in immortalized canine retinal pigment epithelial (RPE) cells, therefore confirming modification to the target sequence. The research involved 8 pure bred dogs that had been diagnosed with LCA2 and who possesses the intended mutation. OCT and ERG were done at baseline and then at 4 weeks, 8 weeks and 12 weeks after the injection to analyse the changes in the retinal thickness and function. All the results highlighted long-standing and Statistically significant increases in retinal thickness in the treatment group compared to the control group at weeks 4, 8 and 12 after injection. The same is true with the treated group which exhibited marked increases in the a-wave and the b-wave in the electroretinogram (ERG), indicating better retinal function compared to the other group. These improvements were most apparent in the treated group, at the twelfth week after injection. The study shows that with the help of CRISPR-Cas9 gene editing, structural and functional changes occur in the canine retina in case of LCA2. In their study, the authors have provided strong grounds for considering this therapy beneficial in the hereditary retinal diseases in purebred dogs under the condition that further research will be conducted. More research endeavour is needed in order to evaluate the residual effects, mode of delivery, efficacy, and the issues of safety and ethicality of an innovation. Further research is therefore needed in order to assess the potential longer-term outcomes, implementation strategies, effectiveness and the issues of safety translation.

Cross-sectional study evaluating the relationship between: a) functional and structural measurements of neurodegeneration in initial stages of diabetic retinopathy (DR); and b) presence of neurodegeneration and early microvascular impairment. We analyzed baseline data of patients with type 2 diabetes (n=449) enrolled in the EUROCONDOR study (NCT01726075). Functional studies by multifocal ERG (mfERG) evaluated neurodysfunction and structural measurements using spectral domain optical-coherence tomography (SD-OCT) evaluated neurodegeneration. The mfERG P1 amplitude was more sensitive than the P1 implicit time (IT), and was lower in patients with ETDRS 20-35 than in patients with ETDRS &lt;20 (p=0.005). In 58% of cases, mfERG abnormalities were present in the absence of visible retinopathy. Correspondence between SD-OCT thinning and mfERG abnormalities was shown in 67% of the eyes with ETDRS &lt;20 and in 83% of the eyes with ETDRS 20-35. Notably, 32% of patients with ETDRS 20-35 prese...

Age-related macular degeneration (AMD) is the leading cause of blindness in people over age 55 in the U.S. and the developed world. This condition leads to the progressive impairment of central visual acuity. There are significant limitations in the understanding of disease progression in AMD as well as a lack of effective methods of treatment. Lately, there has been considerable enthusiasm for application of stem cell biology for both disease modeling and therapeutic application. Human embryonic stem cells and induced pluripotent stem cells (iPSCs) have been used in cell culture assays and in vivo animal models. Recently a clinical trial was approved by FDA to investigate the safety and efficacy of the human embryonic stem cell-derived retinal pigment epithelium (RPE) transplantation in sub-retinal space of patients with dry AMD These studies suggest that stem cell research may provide both insight regarding disease development and progression, as well as direction for therapeutic ...

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that courses with progressive degeneration of retinal tissue and loss of vision. Currently, RP is an unpreventable, incurable condition. We propose glycogen synthase kinase 3 (GSK-3) inhibitors as potential leads for retinal cell neuroprotection, since the retina is also a part of the central nervous system and GSK-3 inhibitors are potent neuroprotectant agents. Using a chemical genetic approach, diverse small molecules with different potency and binding mode to GSK-3 have been used to validate and confirm GSK-3 as a pharmacological target for RP. Moreover, this medicinal chemistry approach has provided new leads for the future disease-modifying treatment of RP.

The co-occurrence of ophthalmologic abnormality and intrinsic skeletal dysplasia is uncommon. We describe eight instances of a unique form of spondylometaphyseal dysplasia (SMD) associated with cone-rod dystrophy (although documentation is insufficient to be certain of that diagnosis in some). This is a new, syndromic form of SMD for which there is evidence for autosomal recessive transmission. Recognition of the specific bony features described here should precipitate comprehensive ophthalmologic assessment, since vision impairment becomes significantly disabling with age.

Multiple sclerosis is an inflammatory demyelinating disease characterized by progressive axonal loss affecting mainly the inner retinal layers. Optical coherence tomography (OCT) provides in-vivo quantification of the retinal layers and allows measuring progressive retinal changes. Our objective was to assess the longitudinal changes in the retina using spectral domain OCT (SDOCT) and to identify independent predictors affecting retinal thinning in MS patients. A prospective study in a tertiary care MS center was conducted to study the longitudinal retinal changes in MS patients. All subjects underwent baseline and follow up OCT assessment with segmentation analysis. Regression analysis was performed to assess clinical factors (age, sex, disease duration, history of optic neuritis before baseline, non-ocular clinical relapses) and MRI disease activity during the follow-up period. The study included 102 MS patients with a mean follow-up duration of 3.9 ± SD years. At the last follow-...

Purpose-Retinitis pigmentosa (RP), a group of inherited diseases characterized by the death of rod photoreceptors, followed by the death of cone photoreceptors, progressively leading to partial or complete blindness. Currently no specific treatment is available for RP patients. Sulforaphane (SFN) has been confirmed to be an effective antioxidant in the treatment of many diseases. In this study, we tested the therapeutic effects of SFN against photoreceptor degeneration in Pde6 rd10 (rd10) mice. Methods-rd10 mice and C57BL/6J wild-type (WT) mice were treated with SFN and saline, respectively, from P6 to P20. Electroretinography (ERG), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and western blot were tested, respectively, at P21 for the analysis of retinal function, retinal cell apoptosis or death and the protein express of GRP78/BiP (TUNEL) as a marker of endoplasmic reticulum stress. Results-Compared to the saline group, the SFN-treated group showed significantly higher ERG a-wave and b-wave amplitudes, less photoreceptor death, and downregulation of GRP78/BiP. Conclusions-Our data showed that SFN ameliorated the retinal degeneration of rd10 mice, which is possibly related to the downregulation of GRP78 expression.

PURPOSE. The association of single nucleotide polymorphisms of components of the complement alternative pathway with the risk of age-related macular degeneration (AMD) indicates that complement signaling plays an important role in retinal physiology. How genetic variation leads to retinal degeneration is unknown. It has been assumed that complement activation augments immune responses, which in turn initiate AMD pathogenesis. To better understand the relationship between complement and the outer retina, we examined mice lacking the main complement component C3 and the receptors for complement activation fragments C3a (C3aR) and/or C5a (C5aR). METHODS. Complement mutant mice were studied along with wild-type (WT) littermates from 6 weeks to 14 months of age. Strobe flash electroretinography (ERG) was used to examine outer retinal function and a dc-ERG technique was used to measure ERG components generated by the retinal pigment epithelium. Retinas were examined by histology, immunohistochemistry, and biochemistry. Mice lacking C3aR and/or C5aR developed early onset and progressive retinal degeneration, accompanied by cleaved caspase-3 upregulation. Genetic deletion of C3aR and/or C5aR led to cell-specific defects that matched the cellular localization of these receptors in the WT retina. Compared to WT, C3aR À/À and C3aR À/À C5aR À/À mice showed increased retinal dysfunction upon light exposure. C3aR À/À C5aR À/À mice immunized with 4hydroxynonenal-adducted protein developed severe retinal impairment unrelated to immune response. CONCLUSIONS. C3aR-and C5aR-mediated signaling was necessary to maintain normal retinal function and structure. These receptors may be important biomarkers for predicting retinal degeneration including AMD. (Invest

Background: Ranbp2 and its Ran-GTP-binding domains' roles in RPE survival/function, a multidisease target, are elusive. Results: RPE undergoes degeneration, disruptions of proteostasis of Ranbp2 partners, and blood-retinal barrier upon Ranbp2 ablation. Impairment of selective Ran-GTP-binding domains of Ranbp2 suffices to promote RPE degeneration. GTPase regulation by Ranbp2 is vital to RPE. Significance: Ranbp2-dependent targets/mechanisms with therapeutic potential in RPE degeneration are uncovered. Retinal pigment epithelium (RPE) degeneration underpins diseases triggered by disparate genetic lesions, noxious insults, or both. The pleiotropic Ranbp2 controls the expression of intrinsic and extrinsic pathological stressors impinging on cellular viability. However, the physiological targets and mechanisms controlled by Ranbp2 in tissue homeostasis, such as RPE, are ill defined. We show that mice, RPE-cre::Ranbp2 ؊/؊ , with selective Ranbp2 ablation in RPE develop pigmentary changes, syncytia, hypoplasia, age-dependent centrifugal and non-apoptotic degeneration of the RPE, and secondary leakage of choriocapillaris. These manifestations are accompanied by the development of F-actin clouds, metalloproteinase-11 activation, deregulation of expression or subcellular localization of critical RPE proteins, atrophic cell extrusions into the subretinal space, and compensatory proliferation of peripheral RPE. To gain mechanistic insights into what Ranbp2 activities are vital to the RPE, we performed genetic complementation analyses of transgenic lines of bacterial artificial chromosomes of Ranbp2 harboring loss of function of selective Ranbp2 domains expressed in a Ranbp2 ؊/؊ background. Among the transgenic lines produced, only Tg RBD2/3*-HA ::RPE-cre::Ranbp2 ؊/؊ -expressing mutations, which selectively impair binding of RBD2/3 (Ran-binding domains 2 and 3) of Ranbp2 to Ran-GTP, recapitulate RPE degeneration, as observed with RPE-cre::Ranbp2 ؊/؊ . By contrast, Tg RBD2/3*-HA expression rescues the degeneration of cone photoreceptors lacking Ranbp2. The RPE of RPE-cre::Ranbp2 ؊/؊ and Tg RBD2/3*-HA ::RPE-cre::Ranbp2 ؊/؊ share proteostatic deregulation of Ran GTPase, serotransferrin, and ␥-tubulin and suppression of light-evoked electrophysiological responses. These studies unravel selective roles of Ranbp2 and its RBD2 and RBD3 in RPE survival and functions. We posit that the control of Ran GTPase by Ranbp2 emerges as a novel therapeutic target in diseases promoting RPE degeneration.

A number of retinal degenerative diseases may be amenable to treatment with continuous intraocular delivery of therapeutic agents that cannot be delivered effectively to the retina via systemic or topical administration. Among these disorders are lysosomal storage diseases resulting from deficiencies in soluble lysosomal enzymes. Most cells, including those of the retina, are able to take up these enzymes and incorporate them in active form into their lysosomes. In theory, therefore, continuous intraocular administration of a normal form of a soluble lysosomal enzyme should be able to cure the molecular defect in the retinas of subjects lacking this enzyme. Experiments were conducted to determine whether genetically modified bone marrow-derived stem cells implanted into the vitreous could be used as vehicles for continuous delivery of such enzymes to the retina. Bone marrow-derived mesenchymal stem cells (MSCs) from normal mice were implanted into the vitreous of mice undergoing retinal degeneration as a result of a mutation in the PPT1 gene. The implanted cells appeared to survive indefinitely in the vitreous without proliferating or invading the retina. This indicates that intravitreal implantation of MSCs is likely a safe means of long-term delivery of proteins synthesized by the implanted cells. Experiments have been initiated to test the efficacy of using genetically modified autologous MSCs to inhibit retinal degeneration in a canine model of neuronal ceroid lipofuscinosis.

A number of retinal degenerative diseases may be amenable to treatment with continuous intraocular delivery of therapeutic agents that cannot be delivered effectively to the retina via systemic or topical administration. Among these disorders are lysosomal storage diseases resulting from deficiencies in soluble lysosomal enzymes. Most cells, including those of the retina, are able to take up these enzymes and incorporate them in active form into their lysosomes. In theory, therefore, continuous intraocular administration of a normal form of a soluble lysosomal enzyme should be able to cure the molecular defect in the retinas of subjects lacking this enzyme. Experiments were conducted to determine whether genetically modified bone marrow-derived stem cells implanted into the vitreous could be used as vehicles for continuous delivery of such enzymes to the retina. Bone marrow-derived mesenchymal stem cells (MSCs) from normal mice were implanted into the vitreous of mice undergoing retinal degeneration as a result of a mutation in the PPT1 gene. The implanted cells appeared to survive indefinitely in the vitreous without proliferating or invading the retina. This indicates that intravitreal implantation of MSCs is likely a safe means of long-term delivery of proteins synthesized by the implanted cells. Experiments have been initiated to test the efficacy of using genetically modified autologous MSCs to inhibit retinal degeneration in a canine model of neuronal ceroid lipofuscinosis.

Embryonic stem (ES) cells differentiate into all cell types of the body during development, including those of the central nervous system (CNS). After transplantation, stem cells have the potential to replace host cells lost due to injury or disease or to supply host tissues with therapeutic factors and thus provide a functional benefit. In the current study, we assessed whether mouse neuralized ES cells can incorporate into retinal tissue and prevent retinal degeneration in mnd mice. These mice have an inherited lysosomal storage disease characterized by retinal and CNS degeneration. Sixteen weeks after intravitreal transplantation into adult mice, donor cells had incorporated into most layers of the retina, where they resembled retinal neurons in terms of morphology, location in the retina, and expression of cell type–specific marker proteins. Presence of these donor cells was correlated with a reduction in the sizes and numbers of lysosomal storage bodies in host retinal cells. T...

Aim-To evaluate the ciliary body and peripheral retina in degenerative retinoschisis associated with pars plana cysts using ultrasound biomicroscopy (UBM). Methods-18 eyes of 12 patients with degenerative retinoschisis associated with pars plana cysts were selected through binocular indirect ophthalmoscopy and Goldmann three mirror lens examination, both with scleral depression. These patients were studied in detail with UBM. Results-Study of the ciliary body with UBM showed pars plana cysts of diVerent size and uneven shape. In cross sections the morphology of pars plana cysts in detail and the close relation of the cysts with the oral region and the peripheral retina, where areas of cystoid degeneration and retinoschisis were present, were observed. In transverse sections three main morphological aspects of pars plana cysts could be diVerentiated ("isolated," "confluent," and "clustered" cysts). Furthermore, ultrabiomicroscopy allowed diVerential diagnosis between retinoschisis and associated retinal detachment in six eyes. Conclusions-The study of peripheral degenerative retinoschisis and pars plana cysts is possible in vivo by means of UBM, showing the detailed morphology of the lesions (not otherwise evident through ophthalmoscopic examination) and the close relation between pars plana cysts, cystoid degeneration, and peripheral retinoschisis.

Purpose-To compare the temporal and spatial expression patterns of amyloid precursor protein (APP), amyloid-β deposits, inflammatory chemokines, and apoptosis in the retina of a mouse model of Alzheimer disease (AD). Methods-Retinas of transgenic mice harboring a mutant presenilin (PS1) and a mutant APP gene were processed for TUNEL and immunohistochemistry with antibodies against APP, amyloid-β, monocyte chemotactic protein (MCP)-1, and F4/80. Comparisons were made between age groups and between transgenic and wild-type congeners. Results-The neuroretina demonstrated age-dependent increases in APP in the ganglion cells (RGCs) and in neurons of the inner nuclear layer (INL). Amyloid-β demonstrated significant agedependent deposition in the nerve fiber layer (NFL). TUNEL-positive RGC increased in an agedependent fashion and in transgenic compared with wild-type congeners. Concomitant overexpression of MCP-1 and intense immunoreactivity for F4/80 suggested that RGCs upregulate MCP-1 in response to amyloid-β. Activated microglia proliferated in response to MCP-1. In the outer retina, retinal pigment epithelium (RPE) demonstrated moderate age-dependent APP immunoreactivity, but nearby drusenlike deposits were not present. Amyloid-β was observed in the choriocapillaris of the older animals. Conclusions-Amyloid-β deposits accumulate with age in the retina of a transgenic mouse model of AD. The amyloid-β loads are accompanied by increased immunoreactivity for MCP-1, F4/80, and TUNEL-positive profiles in the RGC layer. The results suggest that amyloid-β causes neurodegeneration in the retina of the doubly mutant transgenic mouse model of AD. Alzheimer disease (AD) is the most common form of dementia among older people and is the seventh leading cause of death in the United States. Although the disease principally affects the central nervous system (CNS) and memory, cognition, and behavior, complaints of visual disturbances are not uncommon in AD. Recent studies have demonstrated that problems with vision in AD may arise not only from cortical abnormalities, but also from retinal abnormalities. Several studies have demonstrated abnormalities in the optic nerve

Rod outer segment membrane guanylate cyclase1 (ROS-GC1) is the original member of the membrane guanylate cyclase subfamily whose distinctive feature is that it transduces diverse intracellularly generated Ca 2+ signals in the sensory neurons. In the vertebrate retinal neurons, ROS-GC1 is pivotal for the operations of phototransduction and, most likely, of the synaptic activity. The phototransduction-and the synapse-linked domains are separate, and they are located in the intracellular region of ROS-GC1. These domains sense Ca 2+ signals via Ca 2+ -binding proteins. These proteins are ROS-GC activating proteins, GCAPs. GCAPs control ROS-GC1 activity through two opposing regulatory modes. In one mode, at nanomolar concentrations of Ca 2+ , the GCAPs activate the cyclase and as the Ca 2+ concentrations rise, the cyclase is progressively inhibited. This mode operates in phototransduction via two GCAPs: 1 and 2. The second mode occurs at micromolar concentrations of Ca 2+ via S100β. Here, the rise of Ca 2+ concentrations progressively stimulates the enzyme. This mode is linked with the retinal synaptic activity. In both modes, the final step in Ca 2+ signal transduction involves ROS-GC dimerization, which causes the cyclase activation. The identity of the dimerization domain is not known. A heterozygous, triple mutation -E786D, R787C, T788M-in ROS-GC1 has been connected with autosomal cone-rod dystrophy in a British family. The present study shows the biochemical consequences of this mutation on the phototransduction-and the synapse-linked components of the cyclase. (1) It severely damages the intrinsic cyclase activity. (2) It significantly raises the GCAP1-and GCAP2-dependent maximal velocity of the cyclase, but this compensation, however, is not sufficient to override the basal cyclase activity. (3) It converts the cyclase into a form that only marginally responds to S100β. The mutant produces insufficient amounts of the cyclic GMP needed to drive the machinery of phototransduction and of the retinal synapse at an optimum level. The underlying cause of the breakdown of both types of machinery is that, in contrast to the native ROS-GC1, the mutant cyclase is unable to change from its monomeric to the dimeric form, the form required for the functional integrity of the enzyme. The study defines the CORD in molecular terms, at a most basic level identifies a region that is critical in its dimer formation, and, thus, discloses a single unifying mechanistic theme underlying the complex pathology of the disease. Phototransduction is a biochemical process by which the vertebrate rods and cones generate electrical signals in response to captured photons (reviewed in refs 1 and 2). This process occurs in the rod (or cone) outer segments (ROS). 1 The photon induces a decline in the level of cyclic GMP and closure of the cyclic GMP-gated cation channels. This results in a drop of intracellular Ca 2+ from ∼500 nM in darkadapted photoreceptor cell to below 100 nM after illumina-tion. This drop activates ROS guanylate cyclase (ROS-GC). Increased synthesis of cyclic GMP, concomitant with the inactivation of the phototransduction cascade, leads to the reopening of the cyclic GMP-gated channels and restoration of the dark current of the photoreceptors. Thus, two pivotal molecules, Ca 2+ and cyclic GMP, are interlocked in a reciprocal feedback loop.

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH•by H 2 gas we have previously demonstrated, we hypothesized that ingestion of H 2 water may delay the progression of photoreceptor death in rd6 mice. H 2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H 2 mice than controls, as well as higher counts of opsin red/greenpositive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H 2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H 2 mice. Our results show that drinking water high in H 2 (1.2-1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H 2 for the treatment of RP. Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders characterized by diffuse progressive dysfunction of predominantly rod photoreceptors, with subsequent degeneration of cone photoreceptors and the retinal pigment epithelium (RPE) 1 . Visual impairment usually manifests as night blindness and progressive visual field loss. The prevalence of RP is 1:3000-1:5000 2,3 , and approximately 1.4 million people worldwide are affected by RP. Currently, no treatment options are available for patients with RP, and disease progression to blindness is unavoidable. Over 100 different gene mutations have been identified as factors that influence the development and progression of RP 4 . Although genetic mutations trigger RP, disease progression is affected by microenvironmental changes associated with retinal degeneration such as oxidative stress , and inflammation . Oxidative stress causes various neurological disorders of the retina 9 . Oxidative damage leads to cone cell death, and antioxidants reduce oxidative damage and promote cone survival and function 10 . Compared to people without RP, those with RP have increased carbonyl content and a decreased ratio of reduced to oxidized glutathione 10 . Oxidative stress is derived from reactive oxygen species (ROS), such as hydroxyl radicals (OH•), superoxide anion radicals (O 2 -• ), hydrogen peroxide (H 2 O 2 ), and nitric oxide. We reported that molecular

Facial palsy can be defined as a kind of paralysis affecting facial muscles. It is termed Bell's palsy if it is unilateral. It may occur due to trauma to the facial nerve, infections as herpes zoster, neoplastic lesions, or unknown cause. It may be also associated with metabolic and systemic diseases as hypertension, toxicity, amyloidosis, alcoholism, auto-immune diseases and diabetes mellitus. Mesenchymal stem cells (MSCs) are multipotent adult stromal cells that have many benefits as an evolving treatment modality. Bone marrow stem cells (BMSCs) divide progressively in culture, and differentiate into neurons exclusively with use of a simple protocol. Most ongoing preclinical and clinical cell treatment modalities composed of local or systemic transplantation of stem or progenitor cells. In addition, they depend on the migration and retention of transplanted cells at insult areas. Nevertheless, one of the main obstacles against this modality is how to detect the fate and exact location of these cells inside the body, and how to maintain the cells at this specific site. Magnetic targeting systems, which depends on cells labelled by magnetic carriers, have been assessed as a more efficient technique for stem cell delivery to target sites. These systems depend on loading stem cells with magnetic nanoparticles and attracting them to the exact intended area within the body by placing an external magnetic field. Superparamagnetic iron oxide nanoparticles (SPIONs) have been introduced int the last few years as a rising applicant of nanoparticles in a vast variety of medical fields as magnetic separation, drug delivery, magnetic resonance imaging (MRI) and magnetic hyperthermia. In addition, applications of SPIONs, as a site-specific drug carrier, diagnostic agent and stem cell delivery agent, receive most attention of researchers in that field. In this review, up-to-date information about Magnetic targeting of degenerated facial nerve by BMSCs labelled with SPIONs may suggest its capacity of better regeneration than injection of BMSCs alone.

Background: To appraise the role of volumetric modulated arc (RapidArc, RA) in the treatment of anal canal carcinoma (ACC). Methods: A retrospective analysis has been conducted on 36 patients treated with RA since 2009 comparing outcome against a group of 28 patients treated with conformal therapy (CRT). RA treatments were prescribed with SIB technique with 59.4 Gy to the primary tumor and nodes and 49.5 Gy to the elective nodes. CRT was sequentially delivered with 45 Gy to the pelvic target and a boost of 14.4 Gy to the primary tumor. Results: Median age of patients was 65 yrs for RA (59 yrs for CRT); 90% had Stage II-III (93% in the CRT group). No statistically significant differences were observed concerning survival or control. 5 yrs disease specific survival was 85.7% and 81.2%, loco-regional control was of 78.1% and 82.1% for RA and CRT respectively. RA treatments lead to lower incidence of higher grade of toxicity events (all retrospectively retrieved from charts as worse events). Grade 2-3 toxicity, compared to CRT, reduced from 89% to 68% for GI, from 39% to 33% for GU and from 82% to 75% for the skin. Late toxicity was as follows: 5/36 (14%) and 3/36 (8%) patients had G1 or G2 GI toxicity in the RA group (1/28 (4%) and 4/28 (14%) in the CRT group). GU late toxicity was observed only in 4/28 (14%) patients of the CRT group: 3/28 (11%) had G2 and 1/28 (4%) had G1. Conclusions: RA treatments of ACC patients proved to be equally effective than CRT but it was associated to a reduction of toxicity.

The interactions between steroid gonadal hormones and the retina (a part of the visual system and the central nervous system (CNS)) have received limited attention and beneficial effects of these hormones in retinal diseases is controversial. Retinitis pigmentosa (RP) is the most common cause of retinal hereditary blindness and to date no treatment is available. However, results regarding the effects of progesterone on the progression of RP are promising. With the idea of demonstrating if the progesterone retinal protection in RP is related to its possible anti-inflammatory properties, we have administered orally progesterone to rd10 mice, an animal model of RP. We observed that progesterone decreased photoreceptors cell death, reactive gliosis and the increase in microglial cells caused by RP. We also examined the expression of neuronal and inducible nitric oxide synthase (nNOS and iNOS), the enzyme responsible for NO production. The results demonstrated a decrease in nNOS expression only in control mice treated with progesterone. Inflammation has been related with an increase in lipid peroxidation. Noticeably progesterone administration was able to diminish retinal malondialdehyde (MDA, a lipid peroxidation product) concentrations in rd10 mice. Altogether, we can conclude that progesterone could be a good therapeutic option not only in RP but also for other retinal diseases that have been associated with inflammation and lipid peroxidation.

Idiopathic demyelinating optic neuritis (ON) most commonly presents as acute unilateral vision loss and eye pain and is frequently associated with multiple sclerosis. Although emphasis is often placed on the good recovery of high-contrast visual acuity, persistent deficits are frequently observed in other aspects of vision, including contrast sensitivity, visual field testing, color vision, motion perception, and vision-related quality of life. Persistent and profound structural and functional changes are often revealed by imaging and electrophysiologic techniques, including optical coherence tomography, visual-evoked potentials, and nonconventional MRI. These abnormalities can impair patients&#39; abilities to perform daily activities (e.g., driving, working) so they have important implications for patients&#39; quality of life. In this article, we review the sequelae from ON, including clinical, structural, and functional changes and their interrelationships. The unmet needs in ea...

IMPORTANCE A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). OBJECTIVE To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected

This report presents four generations of hereditary atypical (pericentric) retinitis pigmentosa in an Itsekiri family of Warri, Delta state of Nigeria. The patients presented with nyctalopia, waxy disc pallor, arteriolar attenuation, pigment deposits around the optic nerve and visual field loss. The cases were typically mild with satisfactory vision beyond the fifth decade of life. The mode of inheritance was most probably autosomal dominant. Keywords : retinitis pigmentosa, hereditary, atypical Resume L\&#39;objet de ce rapport est de presenter quatre generations de pigmentolyse retinite (pericentrique) atypique hereditaire chez une famille d\&#39;Itsekiri de Warri, Etat de Delta au Nigeria. Les patients se sont presentes atteints de la nyctalopie, waxy disc pallor, attenuation arteriolaire, depot du pigment autour de la nerve optique et la perte du champ visuel. Les cas etaient typiquement benins avec la vision satiffaisante au dela de la cinquieme decennie de la vie. La methode d...

The COL9A3 gene encodes one of the three alpha chains of Type IX collagen, with heterozygous variants reported to cause multiple epiphyseal dysplasia, and suggested as contributory in some cases of sensorineural hearing loss. Patients with homozygous variants have midface hypoplasia, myopia, sensorineural hearing loss, epiphyseal changes and carry a diagnosis of Stickler syndrome. Variants in COL9A3 have not previously been reported to cause vitreoretinal degeneration and/or retinal detachments. This report describes two families with autosomal dominant inheritance and predominant features of peripheral vitreoretinal lattice degeneration and retinal detachment. Genomic sequencing revealed a heterozygous splice variant in

Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially treatable photoreceptors across the human retinas and the rate of degeneration are not known. Here, we have defined structural and functional features of the disease in 70 individuals with ORF15 mutations. We also correlated the features observed in patients with those of three Rpgr-mutant (Rpgr-ko, Rd9, and Rpgr-cko) mice. In patients, there was pronounced macular disease. Across the retina, rod and cone dysfunction showed a range of patterns and a spectrum of severity between individuals, but a high symmetry was observed between eyes of each individual. Genotype was not related to disease expression. In the Rpgr-ko mice, there were intraretinal differences in rhodopsin and cone opsin trafficking. In Rd9 and Rpgr-cko mice, retinal degeneration showed interocular symmetry. Longitudinal results in patients revealed localized rod and cone dysfunction with progression rates of 0.8 to 1.3 log per decade in sensitivity loss. Relatively retained rod and cone photoreceptors in mid-and far-peripheral temporal-inferior and nasal-inferior visual field regions should be good targets for future localized gene therapies in patients. † J.C. and A.V.C. contributed equally to this study.

Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially treatable photoreceptors across the human retinas and the rate of degeneration are not known. Here, we have defined structural and functional features of the disease in 70 individuals with ORF15 mutations. We also correlated the features observed in patients with those of three Rpgr-mutant (Rpgr-ko, Rd9, and Rpgr-cko) mice. In patients, there was pronounced macular disease. Across the retina, rod and cone dysfunction showed a range of patterns and a spectrum of severity between individuals, but a high symmetry was observed between eyes of each individual. Genotype was not related to disease expression. In the Rpgr-ko mice, there were intraretinal differences in rhodopsin and cone opsin trafficking. In Rd9 and Rpgr-cko mice, retinal degeneration showed interocular symmetry. Longitudinal results in patients revealed localized rod and cone dysfunction with progression rates of 0.8 to 1.3 log per decade in sensitivity loss. Relatively retained rod and cone photoreceptors in mid-and far-peripheral temporal-inferior and nasal-inferior visual field regions should be good targets for future localized gene therapies in patients. † J.C. and A.V.C. contributed equally to this study.

Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports ofin vivoinactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APN-null mice. These findings establish that AP...

Background: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. Methods: Research- grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rats, a rodent model for retinitis pigmentosa (RP); An IND-enabling study with CNS10-NPC was perform in the same rodent model; Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in large animal model-Yucatan minipig. Results: Both research grade hNPC and clinical-grade hNPC (termed CNS10-NPC) can survive and provide functional and morphological protection in a dose-dependent fa...

Introduction The aim of this study was to report the incidence and management of acute endophthalmitis after intravitreal injection of Avastin (bevacizumab), and visual acuity outcomes of three eyes of three patients who developed acute endophthalmitis following intravitreal injection of Avastin. Methods This clinical retrospective, non-comparative study included 3022 intravitreal injections of 1.25 mg bevacizumab consecutively performed for 1822 eyes with exudative age-related macular degeneration and other retinal diseases. Of 3022 injections, 1200 were reinjections. After clinical appearance of post-injection endophthalmitis, immediate intervention was performed, including injection of intravitreal antibiotics and early pars plana vitrectomy. Results Three eyes of three patients with acute postoperative endophthalmitis were identified in the first week following intravitreal injections of 1.25 mg bevacizumab. Among of these patients, two cases were culture-positive and one case was culture-negative. Compared with presenting visual acuities, all of three patients improved at the end of follow-up time. The overall incidence rate of post-injection culture-proven endophthalmitis was 0.066%. Discussion Acute culture-proven endophthalmitis is still a potential complication of intravitreal bevacizumab injection (approximately 0.066%) despite using maximal sterile techniques. Acute post-injection endophthalmitis following intravitreal bevacizumab occurs rapidly and can result in severe loss of vision. Prompt recognition and treatment are key in maximizing outcomes in patients who developed endophthalmitis after intravitreal injection of bevacizumab.

Background: Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/ hypoplasia, retinal degeneration and mental retardation. In Senior-Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS. Methods: Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis. Results: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

Usher syndrome type 2A (USH2A) is a genetic disorder characterized by retinal degeneration and hearing loss. To better understand the pathogenesis and progression of this syndrome, animal models such as USH2A knockout (USH2AKO) rabbits have been developed. In this study, we employed multimodal imaging techniques, including photoacoustic microscopy (PAM), optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine green angiography (ICGA) imaging to evaluate the retinal changes in the USH2AKO rabbit model. Twelve New Zealand White rabbits including USH2AKO and wild type (WT) were used for the experiments. Multimodal imaging was implemented at different time points over a period of 12 months to visualize the progression of retinal changes in USH2AKO rabbits. The results demonstrate that ellipsoid zone (EZ) disruption and degeneration, key features of Usher syndrome, began at the age of 4 months old and persisted up to 12 months. The EZ degeneration areas were clearly observed on the FAF and OCT images. The FAF images revealed retinal pigment epithelium (RPE) degeneration, confirming the presence of the disease phenotype in the USH2AKO rabbits. In addition, PAM images provided high-resolution and high image contrast of the optic nerve and the retinal microvasculature, including retinal vessels, choroidal vessels, and capillaries in threedimensions. The quantification of EZ fluorescent intensity using FAF and EZ thickness using OCT provided comprehensive quantitative data on the progression of degenerative changes over time. This multimodal imaging approach allowed for a comprehensive and non-invasive assessment of retinal structure, microvasculature, and degenerative changes in the USH2AKO rabbit model. The combination of PAM, OCT, and fluorescent imaging facilitated longitudinal monitoring of disease progression and provided valuable insights into the pathophysiology of USH2A syndrome. These findings contribute to the understanding of USH2A syndrome and may have implications for the development of diagnostic and therapeutic strategies for affected individuals. The multimodal imaging techniques employed in this study offer a promising platform for preclinical evaluation of potential treatments and may pave the way for future clinical applications in patients with Usher syndrome. Usher syndrome (USH) is an autosomal recessive genetic disorder characterized by sensorineural hearing loss (SNHL), type-dependent vestibular impairment, and retinitis pigmentosa (RP), an inherited degenerative eye disease that progressively causes severe vision loss 1 . In RP, the photoreceptor cells deteriorate and lose function over time, resulting in night blindness and peripheral vision loss before progressing to permanent, late central

Senior-Loken syndrome is a rare hereditary disease that combines a disorder resembling familial juvenile nephronophthisis with retinitis pigmentosa. Retinitis pigmentosa is even less frequently associated with exudative retinopathy. The patient, a IS-year-old boy, had hereditary renal-retinal dystrophy combined with an exudative vasculopathy of the Coats' type. The patient is on thrice-weekly hemodialysis after two kidney transplants failed. One eye became painful and blind and was eventually enucleated. SENIOR-LoKEN SYNDROME is an entity that combines a renal disease, familial juvenile nephronophthisis, with tapetoretinal degeneration. This hereditary renal-retinal dystrophy, transmitted as an autosomal recessive trait, is relatively rare. Still more infrequent is the association between retinitis pigmentosa and exudative retinopathy. We studied a case of hereditary renal-retinal dystrophy combined with an exudative retinopathy characteristic of Coats' disease.

Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was optcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene 10CUS.

To report a case of central ellipsoid loss with supernormal rod electroretinogram and KCNV2 gene mutation. Retrospective case report. Thirty-eight-year-old man. We report a patient with longstanding vision loss and photophobia who illustrated central atrophy of the inner segment ellipsoid zone band on spectral domain optical coherence tomography. Fundus autofluorescence displayed mild perifoveal mottled autofluorescence. Electroretinography demonstrated a diminished rod-isolated response with delayed timing but a normal dark-adapted maximal response to bright flashes. Cone-mediated responses under light-adapted conditions were abnormal with evidence of selective loss of the b wave and a normal a wave consistent with cone dystrophy with supernormal rod electroretinogram. Genetic testing demonstrated a frameshift mutation in the KCNV2 gene. Cone dystrophy with supernormal rod electroretinogram is believed to be a monogenic disease due to KCNV2 gene mutations that affect a transmembran...