Inherited multifocal RPE-diseases: mechanisms for local dysfunction in global retinoid cycle gene defects

AbstractAlterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In “flecked retina diseases” heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance

Early Visual Symptom Patterns in Inherited Retinal Dystrophies

The present retrospective study compared initial visual symptom patterns in inherited retinal dystrophies (IRD) on the basis of records of 544 patients diagnosed with a wide variety of IRD at the Tuebingen University Eye Hospital from 2005 to 2008. Age at first onset of symptoms was noted, and the following clinical data were analyzed: visual acuity (VA), night vision disturbances, photophobia, onset of visual field defects, best corrected VA, and types of visual field defects. Median age at visual symptom onset was defined with 25th and 75th percentiles and compared in 15 IRD types. The main trends in VA changes in retinitis pigmentosa and cone-rod dystrophies were identified. This study was the first to combine disease history and clinical data analysis in such a wide variety of IRD. It showed that patterns of initial symptoms in IRD can provide extra clues for early differential diagnosis and inclusion of IRD patients in clinical trials

Visual acuity changes in cone and cone-rod dystrophies

PURPOSE: The purpose of the study was to evaluate longitudinal visual acuity (VA) changes in cone (CD) and cone-rod dystrophies (CRD) in order to develop recommendations for follow-up strategies and to define an optimal time for potential therapeutic intervention. METHODS: Patients with clinically defined CD and CRD, who had at least three clinical examinations within a follow-up period of a minimum of 2 years, were included in the study. The observation period was divided into segments: between 1-2 visits and 2-3 visits in intervals of 2 years, and between 3-4 visits in 3-year intervals. Disease history was collected during the baseline examination. Median age of onset, age at first examination, and period between disease onset and 1st visit (latency) were estimated. Medians with 25th and 75th quantile of VA decrease in logMAR for each segment of observation were calculated. The median percentage of VA decrease was also calculated. RESULTS: Initial results of the Tuebingen longitudinal study of VA changes in CRD and CD are presented as medians with 25th and 75th quintiles. Twenty-nine patients (14 men and 15 women) were studied. Nineteen of them had CRD and 10 CD. Median age at the baseline visit was 18 (11, 31) years for CRD and 26 (8, 41.5) years for CD. Median age of disease onset was 9 (8, 25) years for CRD and 7.5 (5, 15) years for CD. The median latency was 6.5 (3; 8.25) years in CD and 4 (2, 10) years in CRD patients. VA in CD and CRD patients was significantly different only during the first visit (p < 0.03). VA decrease was highest in the period between 2-3 visits with a median VA decrease of 36%, for CDR and between 3-4 visits for CD with a median VA decrease of 80%. In the CRD group the rate of VA decline was fairly even over the four visits, whereas in the CD group the decline appeared to progressively increase towards the end of the follow-up. CONCLUSION: CRD patients were younger than those with CD at a baseline visit and had a longer period of follow-up. A statistically significant difference in VA in CRD and CD was observed at the first ophthalmological examination only. VA decrease was most prominent in the second decade of life in CRD and in third decade in CD patients. CRD was characterized by a more progressive VA decrease than CD. CRD had a high decline of VA over the second and the third examination, whereas VA decline in CD progressed towards the end of follow-up period (fourth examination). These results should be considered when advising and following up such patients on a long-term basis

Characterizing Retinal Ganglion Cell Responses to Electrical Stimulation Using Generalized Linear Models

The ability to preferentially stimulate different retinal pathways is an important area of research for improving visual prosthetics. Recent work has shown that different classes of retinal ganglion cells (RGCs) have distinct linear electrical input filters for low-amplitude white noise stimulation. The aim of this study is to provide a statistical framework for characterizing how RGCs respond to white-noise electrical stimulation. We used a nested family of Generalized Linear Models (GLMs) to partition neural responses into different components-progressively adding covariates to the GLM which captured non-stationarity in neural activity, a linear dependence on the stimulus, and any remaining non-linear interactions. We found that each of these components resulted in increased model performance, but that even the non-linear model left a substantial fraction of neural variability unexplained. The broad goal of this paper is to provide a much-needed theoretical framework to objectively quantify stimulus paradigms in terms of the types of neural responses that they elicit (linear vs. non-linear vs. stimulus-independent variability). In turn, this aids the prosthetic community in the search for optimal stimulus parameters that avoid indiscriminate retinal activation and adaptation caused by excessively large stimulus pulses, and avoid low fidelity responses (low signal-to-noise ratio) caused by excessively weak stimulus pulses

Solving a 50 year mystery of a missing OPA1 mutation: more insights from the first family diagnosed with autosomal dominant optic atrophy

Background: Up to the 1950s, there was an ongoing debate about the diversity of hereditary optic neuropathies, in particular as to whether all inherited optic atrophies can be ascribed to Leber's hereditary optic neuropathy (LHON) or represent different disease entities. In 1954 W. Jaeger published a detailed clinical and genealogical investigation of a large family with explicit autosomal dominant segregation of optic atrophy thus proving the existence of a discrete disease different from LHON, which is nowadays known as autosomal dominant optic atrophy (ADOA). Since the year 2000 ADOA is associated with genomic mutations in the OPA1 gene, which codes for a protein that is imported into mitochondria where it is required for mitochondrial fusion. Interestingly enough, the underlying mutation in this family has not been identified since then. Results: We have reinvestigated this family with the aim to identify the mutation and to further clarify the underlying pathomechanism. Patients showed a classical non-syndromic ADOA. The long term deterioration in vision in the two teenagers examined 50 years later is of particular note 5/20 to 6/120. Multiplex ligation probe amplification revealed a duplication of the OPA1 exons 7-9 which was confirmed by long distance PCR and cDNA analysis, resulting in an in-frame duplication of 102 amino acids. Segregation was verified in 53 available members of the updated pedigree and a penetrance of 88% was calculated. Fibroblast cultures from skin biopsies were established to assess the mitochondrial network integrity and to qualitatively and quantitatively study the consequences of the mutation on transcript and protein level. Fibroblast cultures demonstrated a fragmented mitochondrial network. Processing of the OPA1 protein was altered. There was no correlation of the OPA1 transcript levels and the OPA1 protein levels in the fibroblasts. Intriguingly an overall decrease of mitochondrial proteins was observed in patients' fibroblasts, while the OPA1 transcript levels were elevated. Conclusions: The thorough study of this family provides a detailed clinical picture accompanied by a molecular investigation of patients' fibroblasts. Our data show a classic OPA1-associated non-syndromic ADOA segregating in this family. Cell biological findings suggest that OPA1 is regulated by post-translational mechanisms and we would like to hypothesize that loss of OPA1 function might lead to impaired mitochondrial quality control. With the clinical, genetic and cell biological characterisation of a family described already more than 50 years ago, we span more than half a century of research in optic neuropathies

CDHR1 mutations in retinal dystrophies

We report ophthalmic and genetic findings in patients with autosomal recessive retinitis pigmentosa (RP), cone-rod dystrophy (CRD) or cone dystrophy (CD) harboring potential pathogenic variants in the CDHR1 gene. Detailed ophthalmic examination was performed in seven sporadic and six familial subjects. Mutation screening was done using a customized next generation sequencing panel targeting 105 genes implicated in inherited retinal disorders. In one family, homozygosity mapping with subsequent candidate gene analysis was performed. Stringent filtering for rare and potentially disease causing variants following a model of autosomal recessive inheritance led to the identification of eleven different CDHR1 variants in nine index cases. All variants were novel at the time of their identification. In silico analyses confirmed their pathogenic potential. Minigene assays were performed for two non-canonical splice site variants and revealed missplicing for the mutant alleles. Mutations in CDHR1 are a rare cause of retinal dystrophy. Our study further expands the mutational spectrum of this gene and the associated clinical presentation

Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations

Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy). Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included (1) screen-based standardized 2- or 4-alternative forced-choice (AFC) tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test), and Landolt C-rings; (2) gray level discrimination; (3) performance during activities of daily living (ADL-table tasks). Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA) assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 ± 0.8 (mean ± SD, n = 10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs) were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events (AEs) were transient and mostly of mild to moderate intensity. Conclusions: Psychophysical and subjective data show that RETINA IMPLANT Alpha AMS is reliable, well tolerated and can restore limited visual functions in blind patients with degenerations of the outer retina. Compared with the previous implant Alpha IMS, longevity of the new implant Alpha AMS has been considerably improved. Alpha AMS has meanwhile been certified as a commercially available medical device, reimbursed in Germany by the public health system

Extraocular Surgical Approach for Placement of Subretinal Implants in Blind Patients: Lessons from Cochlear-Implants

In hereditary retinal diseases photoreceptors progressively degenerate, often causing blindness without therapy being available. Newly developed subretinal implants can substitute functions of photoreceptors. Retina implant extraocular surgical technique relies strongly on cochlear-implant know-how. However, a completely new surgical approach providing safe handling of the photosensor array had to be developed. The Retina Implant Alpha IMS consisting of a subretinal microphotodiode array and cable linked to a cochlear-implant-like ceramic housing was introduced via a retroauricular incision through a subperiosteal tunnel above the zygoma into the orbit using a specially designed trocar. Implant housing was fixed in a bony bed within a tight subperiosteal pocket in all patients. Primary outcomes were patient short term safety as well as effectiveness. Nine patients participated in the first part of the multicenter trial and received the subretinal visual implant in one eye. In all cases microphotodiode array pull-through procedure and stable positioning were possible without affecting the device function. No intraoperative complications were encountered. The minimally invasive suprazygomatic tunneling technique for the sensor unit as well as a subperiosteal pocket fixation of the implant housing provides a safe extraocular implantation approach of a subretinal device with a transcutaneous extracorporeal power supply

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.Peer reviewe