Retinal Degeneration In Patients Research Articles

Leukemia Inhibitory Factor Protects against Degeneration of Cone Photoreceptors Caused by RPE65 Deficiency.

Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber's congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65. LIF was administered to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting. Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection. LIF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.

Survival and Functional Integration of Human Embryonic Stem Cell-Derived Retinal Organoids After Shipping and Transplantation into Retinal Degeneration Rats.

Because derivation of retinal organoids (ROs) and transplantation are frequently split between geographically distant locations, we developed a special shipping device and protocol capable of the organoids' delivery to any location. Human embryonic stem cell (hESC)-derived ROs were differentiated from the hESC line H1 (WA01), shipped overnight to another location, and then transplanted into the subretinal space of blind immunodeficient retinal degeneration (RD) rats. Development of transplants was monitored by spectral-domain optical coherence tomography. Visual function was accessed by optokinetic tests and superior colliculus (SC) electrophysiology. Cryostat sections through transplants were stained with hematoxylin and eosin; or processed for immunohistochemistry to label human donor cells, retinal cell types, and synaptic markers. After transplantation, ROs integrated into the host RD retina, formed functional photoreceptors, and improved vision in rats with advanced RD. The survival and vision improvement are comparable with our previous results of hESC-ROs without a long-distance delivery. Furthermore, for the first time in the stem cell transplantation field, we demonstrated that the response heatmap on the SC showed a similar shape to the location of the transplant in the host retina, which suggested the point-to-point projection of the transplant from the retina to SC. In conclusion, our results showed that using our special device and protocol, the hESC-derived ROs can be shipped over long distance and are capable of survival and visual improvement after transplantation into the RD rats. Our data provide a proof-of-concept for stem cell replacement as a therapy for RD patients.

GMFB/AKT/TGF-β3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1β (Il-1β) in diabetic retinas. Tgf-β3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-β3 protein level via the AKT pathway. The protective effect of TGF-β3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-β3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-β3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Detailed analysis of an enriched deep intronic ABCA4 variant in Irish Stargardt disease patients

Over 15% of probands in a large cohort of more than 1500 inherited retinal degeneration patients present with a clinical diagnosis of Stargardt disease (STGD1), a recessive form of macular dystrophy caused by biallelic variants in the ABCA4 gene. Participants were clinically examined and underwent either target capture sequencing of the exons and some pathogenic intronic regions of ABCA4, sequencing of the entire ABCA4 gene or whole genome sequencing. ABCA4 c.4539 + 2028C > T, p.[= ,Arg1514Leufs*36] is a pathogenic deep intronic variant that results in a retina-specific 345-nucleotide pseudoexon inclusion. Through analysis of the Irish STGD1 cohort, 25 individuals across 18 pedigrees harbour ABCA4 c.4539 + 2028C > T and another pathogenic variant. This includes, to the best of our knowledge, the only two homozygous patients identified to date. This provides important evidence of variant pathogenicity for this deep intronic variant, highlighting the value of homozygotes for variant interpretation. 15 other heterozygous incidents of this variant in patients have been reported globally, indicating significant enrichment in the Irish population. We provide detailed genetic and clinical characterization of these patients, illustrating that ABCA4 c.4539 + 2028C > T is a variant of mild to intermediate severity. These results have important implications for unresolved STGD1 patients globally with approximately 10% of the population in some western countries claiming Irish heritage. This study exemplifies that detection and characterization of founder variants is a diagnostic imperative.

Natural Disease Course in Usher Syndrome Patients Harboring USH2A Variant p.Cys870* in Exon 13, Amenable to Exon Skipping Therapy.

The aim of the study was to determine the rate of retinal degeneration in patients with c.2610C>A (p.Cys870*) in USH2A exon 13, amenable to exon skipping therapy. There were nine patients from seven families, three of whom were male (two were homozygous). Seven patients had follow-up data (median of 11 years). Analysis included best corrected visual acuity (BCVA, decimal Snellen), visual field (Goldmann perimetry target II/4), fundus autofluorescence (FAF), optical coherence tomography (OCT), and microperimetry (MP). The median age at the onset of nyctalopia was 20 years (range, 8-35 years of age). At the first exam, at a median age of 42 years, the median BCVA was 0.5 (0.2-1.0), and the median visual field diameter was 23° (5°-114°). Imaging showed a hyperautofluorescent ring delineating preserved foveal photoreceptors in 78% (7/9) of patients, while 22% (2/9) had a hyperautofluorescent patch or atrophy, reflecting advanced disease. Survival analysis predicted that 50% of patients reach legal blindness based on a visual field diameter < 20° at the age of 52 (95% CI, 45-59) and legal blindness based on a BCVA ≤ 0. 1 (20/200) at the age of 55 (95% CI, 46-66). Visual field constriction occurred at the median rate of radial 1.5 deg/year, and hyperautofluorescent ring constriction occurred at the median rate of 34 μm/year. A non-null second allele was found in two patients: p.Thr4315Pro and p.Arg303His; the patient with p.Arg303His had a milder disease. The rates of progression will be useful in the design and execution of clinical trials.

Current Management of Inherited Retinal Degeneration Patients in Europe: Results of a 2-Year Follow-Up Multinational Survey by the European Vision Institute Clinical Research Network – EVICR.net

Introduction: An increasing number of gene-specific therapies are being developed for inherited retinal degenerations (IRDs). Identification of well-characterized patients is an emerging need. We conducted the second multinational survey among the EVICR.net and ERN-EYE members to understand the management and treatment of IRDs in Europe and compared it to the 2019 survey. Methods: An electronic survey questionnaire was developed and sent to 124 clinical centers (25 countries) by June/July 2021. Statistical analysis was performed with Excel and R. Results: The overall response rate was 44% but varied among countries. Only 9% of responding centers do not see IRD patients (2019 survey 14%), 42% follow at least 200 patients per year, 18% follow 500–999, and 2% more than 1,000. Databases exist in 86% of the centers (local 86%; national web based 12%). IRD patients are referred to EVICR.net and ERN-EYE centers mainly by general ophthalmologists, patient self-referral, or medical retina specialists. Most IRD patients are first seen as adults. Signs and symptoms depend on age of onset: in infancy, nystagmus; at older age, night blindness and reduced visual field; reduced visual acuity is described at any age. Comprehensive ophthalmic examination always includes visual acuity and almost always visual field multimodal retinal imaging, electrophysiology, color vision testing, and refraction. Identification of genotypes is successful in 72% of centers in 40–80% of cases (2019 survey 69% of centers). The time for confirmation of the genetic diagnosis varies from 2–4 weeks to 24 months (2019 survey >4 weeks ≤10 years). Genetic testing is covered by public health service in 83%, private health insurance in 29%, research funds in 24%; 5% do not have access to genetic testing (2019 survey 15%). The most striking result is the high increase in the involvement of centers in natural history and gene therapy trials that more than doubled for the latter. Discussion: This second multinational survey on management of IRDs in Europe highlights persistent important differences in the number of IRD patients managed per center, comparable diagnostic work-up, and increasing genotyping in diagnostic laboratories. The important increase in involvement of centers in natural history and gene therapy trials reflects the rapidly evolving field of gene therapy development. The survey provides important follow-up data for researchers, clinicians, caregivers, patient advocate groups, pharmaceutical companies, and investors.

Ongoing retinal degeneration despite intraventricular enzyme replacement therapy with cerliponase alfa in late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2 disease)

Background/aimsLate-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative, blinding lysosomal storage disorder. The purpose of the current study was to characterise the progression of CLN2-associated retinal degeneration in...

Retinal Degeneration in Patients with Wilson's Disease: An OCT Study in Asian Indian Population.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. We aimed to study the abnormalities in the retinal layers in patients with WD using optical coherence tomography (OCT). The study is a chart review of 16 patients with WD (six females) who underwent OCT at our hospital during follow-up visits. Spectral-domain OCT was performed in all subjects to assess the thickness of macula and retinal nerve fiber layer (RNFL) and the data was compared with 14 healthy controls (three females). The mean age of the patients was 20.81 ± 7.47 years and controls was 26.86 ± 9.95 years. The mean age at the onset of the illness was 16.25 ± 5.57 years (range 11-28 years) with the mean duration of illness being 4.81 ± 3.31 years at the final follow-up examination. The mean macular thickness was found to be significantly reduced in patients (232.13 ± 19.39) when compared to controls (271.30 ± 17.32 μm; P = 0.01). There was a significant difference in the ganglion cell and inner plexiform (GCIP) layer between the patients (86.83 ± 8.20 μm) and controls (97.72 ± 5.31 μm; P = 0.01). In addition, the outer nuclear layer with the photoreceptor layer (ONL + PRL) thickness was also reduced in WD (93.90 ± 10.23 μm vs. 108.43 ± 10.00 μm; P = 0.01) There was no change in the RNFL thickness, between the two groups (P = 0.53). Abnormalities of the retinal layers were observed in the patients with WD. OCT is a non-invasive tool to identify and quantify the abnormalities of the retinal layers.

The antiparkinsonian drug safinamide is not harmful for the human retina. A neurophysiological study

Safinamide is a selective MAO-B inhibitor, indicated for the treatment of Parkinson's disease (PD). The European patient information leaflet warns about the “Potential for retinal degeneration in patients with presence/prior history of retinal disease: Safinamide should not be administered to patients with ophthalmological history that would put them at increased risk for potential retinal effects”. The available literature, however, misses any data concerning this potential retinal toxicity. This prompted us to implement a neurophysiological study concerning a possible drug-related retinal damage.

Sensitive quantification of m.3243A>G mutational proportion in non-retinal tissues and its relationship with visual symptoms.

The m.3243A>G mutation in the mitochondrial genome commonly causes retinal degeneration in patients with maternally inherited diabetes and deafness and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. Like other mitochondrial mutations, m.3243A>G is inherited from the mother with a variable proportion of wild type and mutant mitochondrial genomes in different cells. The mechanism by which the m.3243A>G variant in each tissue relates to the manifestation of disease phenotype is not fully understood. Using a digital PCR assay, we found that the % m.3243G in skin derived dermal fibroblasts was positively correlated with that of blood from the same individual. The % m.3243G detected in fibroblast cultures remained constant over multiple passages and was negatively correlated with mtDNA copy number. Although the % m.3243G present in blood was not correlated with severity of vision loss, as quantified by Goldmann visual field, a significant negative correlation between % m.3243G and the age of onset of visual symptoms was detected. Altogether, these results indicate that precise measurement of % m.3243G in clinically accessible tissues such as skin and blood may yield information relevant to the management of retinal m.3243A>G-associated disease.

Retinal Neurodegeneration in Diabetic Peripheral Neuropathy by Optical Coherence Tomography: A Systematic Review and Meta-analysis

ABSTRACT Purpose The optical coherence tomography (OCT) has been used to evaluate the changes of retinal degeneration in patients with diabetic peripheral neuropathy (DPN) in recent years, but the results of previous studies were controversial. Therefore, systematic review and meta-analysis were performed to evaluate the degree of retinal neurodegeneration in DPN measured by OCT. Methods A comprehensive search of PubMed, Embase, Web of Science, Scopus, China Biomedical Literature (CBM), China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases were performed to identify studies that evaluate retinal neurodegeneration in DPN by using OCT. The included studies were critically reviewed and meta-analyses were performed to evaluate differences of the OCT-derived parameters between the DPN and non-DPN patients. Results Twelve studies were included in the final meta-analysis, involving a total of 1,807 eyes (573 in the DPN group and 1,229 in the non-DPN group). The mean peripapillary retinal nerve fiber layer (pRNFL) thickness was significantly lower in the DPN group than in the non-DPN group (weighted mean difference [WMD] = −8.37 μm; 95% CI: −11.00, −5.74). The reduction of pRNFL thickness was the most pronounced in the inferior quadrant, and the differences in the nasal and temporal quadrants were also statistically significant, with WMD (95% CI) being −4.63 μm (−7.51, −1.76) and −3.92 μm (−6.86, −0.98), respectively. Similar results were observed for macular parameters, with WMD and 95% CI being −1.0 μm (−1.5, −0.5) for macular retinal nerve fiber layer (mRNFL), −2.7 μm (−10.7, −5.3) for macular ganglion cell-inner plexiform layer (mGCIPL), and −2.2 μm (−4.4, −0.04) for macular ganglion cell complex (mGCC), respectively. Conclusions Patients with DPN present with significant retinal neurodegeneration, with reduced pRNFL, mRNFL, mGCIPL, and mGCC thickness. Measurements of OCT parameters may serve as a biomarker for diagnosing and monitoring DPN.

Current Management of Inherited Retinal Degeneration Patients in Europe: Results of a Multinational Survey by the European Vision Institute Clinical Research Network

Purpose: An increasing number of gene therapies are developed for Inherited Retinal Degenerations (IRD). To date, 1 treatment has been approved for clinical use (FDA USA 2017, EMA Europe 2018, MoHAP UAE 2019, SFDA Saudi Arabia 2019, Swiss Medic Switzerland 2020, TGA Australia 2020, and BFR Brazil 2020). While such therapies do not provide complete cure, they may halt degeneration or partially restore function. Identification of well-characterized patients is an emerging need. We conducted the first multinational survey to understand the management of IRDs in Europe. Methods: An electronic survey questionnaire containing 112 questions was developed and sent to the 101 EVICR.net clinical centers (14 European countries and Israel). Results: The overall response rate was 49%. Only 14% of responding centers do not see IRD patients; 52% that manage IRD patients follow ≥200 patients, 16% > 1,000. Databases exist in 86% of the centers; of these, 75% are local files, 28% local Web-based database, and 19% national Web-based. IRD patients are referred to EVICR.net centers mainly by general ophthalmologists, patient self-referrals, and medical retina specialists. Most IRD patients are first seen in adulthood. Most prominent signs and symptoms depend on the age of onset, for example, nystagmus in infancy, or night blindness, and reduced visual acuity at older age. The time from inquiring for first appointment and clinical diagnosis varies among countries: in 29% of centers, the mean time is <4 weeks, although can be up to 35 months in others. The time to genetic diagnosis is ≥4 weeks, the maximum 10 years, likely depending on access to genetic testing, and the improvement of the tests available. Comprehensive eye examination always includes autofluorescence imaging and perimetry (86% static, 76% kinetic, and 21% microperimetry), and frequently optical coherence tomography (OCT) (95%), electroretinography (93%), and fundus photography (93%). Identified genotypes were reported in 40–80% patients by 69% of centers, and in 80–100% by 5%. Genetic testing is provided by public health insurance in 77% of centers, private health insurance in 38%, center budget in 13%, research funds in 18%; and 15% of centers do not have access to genetic testing. Conclusion: At the start of this era of ocular gene therapy for IRD patients, this first international survey on management of IRDs in Europe highlights significant heterogeneity between centers and across countries and provides important baseline data for researchers, clinicians, pharmaceutical companies, and investors.

A Ketogenic & Low-Protein Diet Slows Retinal Degeneration in rd10 Mice.

PurposeTreatments that delay retinal cell death regardless of genetic causation are needed for inherited retinal degeneration (IRD) patients. The ketogenic diet is a high-fat, low-carbohydrate diet, used to treat epilepsy, and has beneficial effects for neurodegenerative diseases. This study aimed to determine whether the ketogenic diet could slow retinal degeneration.MethodsEarly weaned, rd10 and wild-type (WT) mice were placed on either standard chow, a ketogenic diet, or a ketogenic & low-protein diet. From postnatal day (PD) 23 to PD50, weight and blood β-hydroxybutyrate levels were recorded. Retinal thickness, retinal function, and visual performance were measured via optical coherence tomography, electroretinography (ERG), and optokinetic tracking (OKT). At PD40, serum albumin, rhodopsin protein, and phototransduction gene expression were measured.ResultsBoth ketogenic diets elicited a systemic induction of ketosis. However, rd10 mice on the ketogenic & low-protein diet had significant increases in photoreceptor thickness, ERG amplitudes, and OKT thresholds, whereas rd10 mice on the ketogenic diet showed no photoreceptor preservation. In both rd10 and WT mice, the ketogenic & low-protein diet was associated with abnormal weight gain and decreases in serum albumin levels, 27% and 56%, respectively. In WT mice, the ketogenic & low-protein diet was also associated with an ∼20% to 30% reduction in ERG amplitudes.ConclusionsThe ketogenic & low-protein diet slowed retinal degeneration in a clinically relevant IRD model. In WT mice, the ketogenic & low-protein diet was associated with a decrease in phototransduction and serum albumin, which could serve as a protective mechanism in the rd10 model. Although ketosis was associated with protection, its role remains unclear.Translational RelevanceNeuroprotective mechanisms associated with the ketogenic & low-protein diet have potential to slow retinal degeneration.

Long-term lutein administration attenuates retinal inflammation and functional deficits in early diabetic retinopathy using the Ins2Akita/+ mice

IntroductionLutein is a carotenoid whose protective effects in the retina have been reported in various studies. The effect of lutein has not been reported in the retina of the Ins2Akita/+...

Spontaneous Feedforward Connectivity in Electrically Stimulated Retinal Degeneration Mice.

Retinal degeneration (Rd) is a neurodegenerative disorder primarily associated with the degeneration of the retina neurons and culminates in the eventual loss of visual perception or blindness. Decrease in fronto-, parietal and occipital brain connectivity have been reported in a number of neurodegeneration diseases involving cognitive decline. However, cortical communication in the brain of retinal degeneration patients remains largely unknown and strategies to remediate observed dysfunctional brain connectivity in such instance have not be thoroughly investigated. We used rd10 mice as a model to study brain connectivity in the human retinal degeneration disease, retinitis pigmentosa. Rd10 mice with sham matched controls were electrically stimulated at varying stimulation frequencies and the consequent perturbations in feedforward brain connectivity were studied in the visual cortex and pre-frontal cortex using electrocorticography (ECoG) and normalized symbolic transfer entropy (NSTE). Contra Vcx - contra PFx feed forward connectivity significantly (p<0.05) increased in theta, alpha and beta oscillatory bands of 2 Hz and 10 Hz stimulated rd10 respectively in comparison with sham group. Also, this increase was significantly maintained even after the end of the stimulation period.

Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease

Mutations in the CLN2 gene lead to a neurodegenerative and blinding lysosomal storage disorder: late infantile neuronal ceroid lipofucinosis, also known as "CLN2 disease." The purpose of the current study was to characterize the evolution of CLN2-associated retinal manifestations using the Weill Cornell Batten Scale (WCBS) and the age association of the retinal degeneration using central subfield thickness (CST) measurements and then correlate these findings with fundus photography and OCT to determine a critical period for retinal intervention. Retrospective, single-center cohort. Eighty-four eyes of 42 treatment-naïve patients with CLN2 disease. Clinical records, fundus photographs, and OCT imaging for patients with CLN2 disease collected during examinations under anesthesia were reviewed. Imaging was categorized per WCBS criteria by 3 masked graders. CLN2-associated retinopathy assessed using WCBS scores, fundus photographs, and OCT imaging, correlated with patient age. Eighty-four eyes of 42 patients had baseline fundus photographs, with baseline OCT in 31 eyes of 16 patients. Fundus photographs were obtained serially for 26 eyes of 13 patients, and serial OCT scans were obtained in 10 eyes of 5 patients. At baseline, bilateral WCBS scores were highly correlated for OCT and fundus photographs (r = 0.96 and 0.82, respectively). Central subfield thickness was negatively correlated with left and right eye WCBS OCT scores (r = -0.92 and-0.83, respectively; P < 0.001) and fundus photograph scores (r = -0.80 and-0.83, respectively; P < 0.001). OCT thickness was symmetrical between each eye. Baseline OCT data with age fit using a sigmoid function demonstrated a period of accelerated loss between 48 and 72 months of age. Retinal degeneration associated with CLN2 disease manifests as a progressive, symmetrical decline, which appears to accelerate during a critical period at 48 to 72 months of age, suggesting intervention with retina-specific CLN2 gene therapy should occur ideally before or as early as possible within this critical period. The WCBS is a valuable tool and is highly correlated with the extent of retinal degeneration observed in OCT or fundus photographs; by using the fellow eye as a control, this grading scale can be used to monitor the effect of CLN2 gene therapy in future trials.

GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress

Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca2+-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca2+-free form at photoreceptor inner segments. We here show that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in rd3 mice, it takes 8 months to halve in rd3/rd3 GCAPs−/− mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in rd3 mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca2+-free-phosphorylated state in rd3 mice, we infer that the [Ca2+]i at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca2+-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of rd3 retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber’s congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.

Cone Spacing Correlates With Retinal Thickness and Microperimetry in Patients With Inherited Retinal Degenerations.

PurposeTo determine whether high-resolution retinal imaging measures of macular structure correlate with visual function over 36 months in retinal degeneration (RD) patients and normal subjects.MethodsTwenty-six eyes of 16 RD patients and 16 eyes of 8 normal subjects were studied at baseline; 15 eyes (14 RD) and 11 eyes (6 normal) were studied 36 months later. Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) was used to identify regions of interest (ROIs) with unambiguous cones at baseline to measure cone spacing. AOSLO images were aligned with spectral-domain optical coherence tomography (SD-OCT) and fundus-guided microperimetry results to correlate structure and function at the ROIs. SD-OCT images were segmented to measure inner segment (IS) and outer segment (OS) thickness. Correlations between cone spacing, IS and OS thickness and sensitivity were assessed using Spearman correlation coefficient ρ with bootstrap analyses clustered by person.ResultsCone spacing (ρ = 0.57, P < 0.001) and macular sensitivity (ρ = 0.19, P = 0.14) were significantly correlated with eccentricity in patients. Controlling for eccentricity, cone spacing Z-scores were inversely correlated with IS (ρ = −0.29, P = 0.002) and OS thickness (ρ = −0.39, P < 0.001) in RD patients only, and with sensitivity in normal subjects (ρ = −0.22, P < 0.001) and RD patients (ρ = −0.38, P < 0.001). After 36 months, cone spacing increased (P < 0.001) and macular sensitivity decreased (P = 0.007) compared to baseline in RD patients.ConclusionsCone spacing increased and macular sensitivity declined significantly in RD patients over 36 months. High resolution images of cone structure correlated with retinal sensitivity, and may be appropriate outcome measures for clinical trials in RD.

Evaluation of Progressive Visual Dysfunction and Retinal Degeneration in Patients With Parkinson's Disease.

To quantify changes in visual function parameters and in the retinal nerve fiber layer and macular thickness over a 5-year period in patients with Parkinson's disease (PD). Thirty patients with PD and 30 healthy subjects underwent a complete ophthalmic evaluation, including assessment of visual acuity, contrast sensitivity vision, color vision, and retinal evaluation with spectral-domain optical coherence tomography (SD-OCT). All subjects were reevaluated after 5 years to quantify changes in visual function parameters, the retinal nerve fiber layer, and macular thickness. Association between progressive ophthalmologic changes and disease progression was analyzed. Changes were detected in visual function parameters and retinal nerve fiber layer thickness in patients compared with controls. Greater changes were found during the follow-up in the PD group than healthy subjects in visual acuity, contrast sensitivity, Lanthony color test (P < 0.016), in superotemporal and temporal retinal nerve fiber layer sectors (P < 0.001), and in macular thickness (all sectors except inner superior and inner inferior sectors, P < 0.001). Progressive changes in the retinal nerve fiber layer were associated with disease progression (r = 0.389, P = 0.028). Progressive visual dysfunction, macular thinning, and axonal loss can be detected in PD. Analysis of the macular thickness and the retinal nerve fiber layer by SD-OCT can be useful for evaluating Parkinson's disease progression.

Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center.

Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.