Late-onset Retinal Degeneration Research Articles

Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Critical age for the initiation of photoreceptor loss ranged from 48years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25µm in the extrafoveal retina and 19µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

Longitudinal Changes of Retinal Structure in Molecularly Confirmed C1QTNF5 Patients With Late-Onset Retinal Degeneration.

The purpose of this study was to present our findings on the natural history of late-onset retinal degeneration (LORD) in patients with molecularly confirmed C1QTNF5 heterozygous pathogenic variants and assess suitability of retinal structure parameters for disease monitoring. Sixteen patients with C1QTNF5-LORD were retrospectively identified from Moorfields Eye Hospital, UK. Fundus autofluorescence (FAF), optical coherence tomography (OCT) scans, and best-corrected visual acuity (BCVA) were collected. Area of atrophy (AA) was manually drawn in FAF images. Ellipsoid zone (EZ) width and foveal retinal thickness of the whole retina and outer retina were extracted from OCT scans. Age-related changes were tested with linear-mixed models. Patients had median age of 62.3years (interquartile range [IQR]=58.8-65.4years) at baseline, and median follow-up of 5.1years (IQR=2.6-7.6years). AA, EZ width, and retinal thickness parameters remained unchanged until age 50years, but showed significant change with age thereafter (all P < 0.0001). AA and EZ width progressed rapidly (dynamic range normalized rates=4.3-4.5%/year) from age 53.9 and 50.8years (estimated inflection points), respectively. Retinal thickness parameters showed slower progression rates (range=1.6-2.5%/year) from age 60 to 62.3. BCVA (median=0.3 LogMAR, IQR=0.0-1.0 at baseline) showed a rapid decline (3.3%) from age 70years. Findings from patients with earlier disease showed FAF atrophy manifests in the temporal retina initially, and then progresses nasally. Patients with LORD remained asymptomatic until age 50years, before suffering rapid outer retinal degeneration. EZ width and AA showed rapid progression and high interocular correlation, representing promising outcome metrics. Clinical measures also capturing the temporal retina may be preferable, enabling earlier detection and better disease monitoring. Area of atrophy in FAF images and OCT-measured EZ width represent promising outcome metrics for disease monitoring in patients with C1QTNF5-LORD.

Application of Electrophysiology in Non-Macular Inherited Retinal Dystrophies.

Inherited retinal dystrophies encompass a diverse group of disorders affecting the structure and function of the retina, leading to progressive visual impairment and, in severe cases, blindness. Electrophysiology testing has emerged as a valuable tool in assessing and diagnosing those conditions, offering insights into the function of different parts of the visual pathway from retina to visual cortex and aiding in disease classification. This review provides an overview of the application of electrophysiology testing in the non-macular inherited retinal dystrophies focusing on both common and rare variants, including retinitis pigmentosa, progressive cone and cone-rod dystrophy, bradyopsia, Bietti crystalline dystrophy, late-onset retinal degeneration, and fundus albipunctatus. The different applications and limitations of electrophysiology techniques, including multifocal electroretinogram (mfERG), full-field ERG (ffERG), electrooculogram (EOG), pattern electroretinogram (PERG), and visual evoked potential (VEP), in the diagnosis and management of these distinctive phenotypes are discussed. The potential for electrophysiology testing to allow for further understanding of these diseases and the possibility of using these tests for early detection, prognosis prediction, and therapeutic monitoring in the future is reviewed.

Outer retinal corrugations in late-onset retinal degeneration: a diagnostic finding demonstrated with multimodal imaging

ObjectiveLate-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal degeneration that presents in the sixth decade and leads to severe visual loss. The objective of this paper is to...

LipidUNet-Machine Learning-Based Method of Characterization and Quantification of Lipid Deposits Using iPSC-Derived Retinal Pigment Epithelium.

The retinal pigment epithelium (RPE) is a monolayer of hexagonal cells located at the back of the eye. It provides nourishment and support to photoreceptors and choroidal capillaries, performs phagocytosis of photoreceptor outer segments (POS), and secretes cytokines in a polarized manner for maintaining the homeostasis of the outer retina. Dysfunctional RPE, caused by mutations, aging, and environmental factors, results in the degeneration of other retinal layers and causes vision loss. A hallmark phenotypic feature of degenerating RPE is intra and sub-cellular lipid-rich deposits. These deposits are a common phenotype across different retinal degenerative diseases. To reproduce the lipid deposit phenotype of monogenic retinal degenerations in vitro, induced pluripotent stem cell-derived RPE (iRPE) was generated from patients' fibroblasts. Cell lines generated from patients with Stargardt and Late-onset retinal degeneration (L-ORD) disease were fed with POS for 7 days to replicate RPE physiological function, which caused POS phagocytosis-induced pathology in these diseases. To generate a model for age-related macular degeneration (AMD), a polygenic disease associated with alternate complement activation, iRPE was challenged with alternate complement anaphylatoxins. The intra and sub-cellular lipid deposits were characterized using Nile Red, boron-dipyrromethene (BODIPY), and apolipoprotein E (APOE). To quantify the density of lipid deposits, a machine learning-based software, LipidUNet, was developed. The software was trained on maximum-intensity projection images of iRPE on culture surfaces. In the future, it will be trained to analyze three-dimensional (3D) images and quantify the volume of lipid droplets. The LipidUNet software will be a valuable resource for discovering drugs that decrease lipid accumulation in disease models.

Microperimetry in Foveal Sparing Atrophic Late-Onset Retinal Degeneration.

To understand the baseline and longitudinal microperimetry (MP) characteristics in foveal sparing atrophic Late-Onset Retinal Degeneration (L-ORD). Prospective, cross-sectional, longitudinal study in which patients from the retina clinics of two academic teaching hospitals were included. Mesopic microperimetry was performed using a Nidek MP-1 micro-perimeter. Mean total, foveal, inner ring, and outer ring sensitivities were analyzed. A total of 20 eyes from 10 patients had baseline data. The subset of 10 eyes from 5 patients had follow-up data. The mean baseline macular sensitivity was 10.02 dB (+/- 5.26) with findings showing symmetry between both eyes. In the follow-up cohort, there was a significant loss of outer ring (0.83 dB per year, p= 0.0001), inner ring (0.67 dB per year, p=0.034), and foveal sensitivity (0.92dB loss per year, p= 0.015), while the mean sensitivity decreased significantly (0.66 dB per year, p = 0.0008) at 4-year follow-up. The drop in mean sensitivity was associated with significant increases in the number of deep scotoma points (6.20, p=0.037) and a decrease in the number of normal points (-6.30, p=0.022). Microperimetry is a useful tool for macular function follow-up to measure disease progression in L-ORD.

Establishment and characterization of an iPSC line (UCLi023-A) derived from a Late-Onset Retinal Degeneration patient carrying a founder mutation in C1QTNF5

Late-Onset Retinal Degeneration (L-ORD) is a rare autosomal dominant macular disease, with most cases being caused by a founder mutation in C1QTNF5. Initial symptoms, which generally occur during or after the sixth decade, include abnormal dark adaptation and changes in peripheral vision. Over time, the build-up of sub-retinal pigment epithelium (RPE) deposits leads to macular atrophy and bilateral central vision loss1. Here, we describe the generation of a human induced pluripotent stem cell (iPSC) line from dermal fibroblasts of a 61-year-old L-ORD Caucasian male patient carrying the founder mutation (c.489C>G, p.Ser163Arg), using episomal reprogramming.

Anterior segment phenotypic changes in late-onset retinal degeneration with Ser163Arg mutation in CTRP5/C1QTNF5.

Late-onset retinal degeneration (L-ORD) is a rare retinal dystrophy with anterior segment (AS) abnormalities, including long anterior zonules (LAZ) and iris atrophy. This investigation evaluates AS changes in a L-ORD cohort. Prospective, longitudinal study including L-ORD individuals (Ser163Arg) with ocular exam and standard slit-lamp photographs between 2011 and 2022. AS images were merged and assessed for LAZ number and zonule-free zone (ZFZ) radius. Further clinical findings such as iris atrophy patterns were reported descriptively. Twelve eyes of 6 patients (4 males, median age = 60.5years) were included, showing a median of 160 (11-372) LAZs, mainly localized superiorly (39%) and inferiorly (24%). There was a high inter-ocular correlation (rs = 0.94, p < 0.01), no difference in LAZ count between eyes (p = 0.82), and an inverse relationship between LAZ and age (r = - 0.82; p < 0.05). The ZFZ had median 2.1mm (1.3-5.4), with no inter-ocular difference (p = 0.31). Iris transillumination defects occurred in 11/12 eyes, with 4 major patterns identified: pupillary ruff rarefaction (10/12), patchy atrophy (6/12), notched defects (6/12), and radial streaks (2/12). In a short-term follow-up of 5.9years, 4 eyes showed a reduction in LAZ count to median 139.5 (67-169) (p = 0.50) and a concomitant increase in ZFZ measurement to median 2.2 (1.7-2.6) (p = 0.17). This study confirms symmetric LAZs count and ZFZ in L-ORD, with ZFZ measurements smaller than in previous cohorts. A reduction in LAZs count and an increase in ZFZ with age were suggested longitudinally, yet findings need further evaluation as follow-up was limited to two cases.

Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.

Usher syndrome (USH) is the most common syndromic inherited retinal disease, causing retinitis pigmentosa and sensorineural hearing loss. We reported previously that a nonsense mutation in the centrosome-associated protein CEP250 gene (encoding C-Nap1) causes atypical USH in patients of Iranian Jewish origin. To better characterize CEP250, we aimed to generate and study a knockout (KO) mouse model for Cep250. Mice heterozygous for a "knockout-first" Cep250 construct were generated and bred with Cre recombinase mice to generate the null allele and produce homozygous Cep250 KO mice. Retinal function was evaluated by full-field electroretinography (ffERG) at variable ages, and retinal structure changes were examined using histological analysis. Hearing thresholds were detected using auditory brainstem response (ABR) at the age of 20 months. The Cep250 KO mouse model was generated by activating a construct harboring a deletion of exons 6 and 7. At 6 months, the ffERG was normal, but it decreased gradually with age. For both photopic and scotopic ffERG responses, very low amplitudes were evident at 20 months. Histological analysis confirmed late-onset retinal degeneration. ABR tests illustrated that hearing threshold significantly increased at the age of 20 months. Although most USH animal models have normal retinal function and structure, the Cep250 KO mouse model shows both retinal degeneration and hearing loss with a relatively late age of onset. This model may shed more light on CEP250-associated retinal and hearing deficits and represents an efficient platform for the development of treatment modalities for USH. Our study demonstrates better understanding of Cep250-associated retinal and hearing disease in a mouse model and may help in developing more efficient gene therapy modalities.

A Novel Mouse Model for Late-Onset Retinal Degeneration (L-ORD) Develops RPE Abnormalities Due to the Loss of C1qtnf5/Ctrp5.

Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular dystrophy resulting from mutations in the gene CTRP5/C1QTNF5. A mouse model (Ctrp5+/-) for the most common S163R developed many features of human clinical disease. We generated a novel homozygous Ctrp5 gene knock-out (Ctrp5-/-) mouse model to further study the mechanism of L-ORD. The retinal morphology of these mice was evaluated by retinal imaging, light microscopy, and transmission electron microscopy (TEM) at 6, 11, and 18.5 mo. Expression of Ctrp5 was analyzed using immunostaining and qRT-PCR. The Ctrp5-/- mice showed lack of both Ctrp5 transcript and protein. Presence of a significantly larger number of autofluorescent spots was observed in Ctrp5-/- mice compared to the WT (P<0.0001) at 19 mo. Increased RPE stress with vacuolization and thinning was observed as early as 6 mo in Ctrp5-/- mice. Further, ultrastructural analyses revealed a progressive accumulation of basal laminar sub-RPE deposits in Ctrp5-/- mice from 11 mo. The Ctrp5-/- mice shared retinal and RPE pathology that matches with that previously described for Ctrp5+/- mice suggesting that pathology in these mice results from the loss of functional CTRP5 and that the presence of CTRP5 is critical for normal RPE and retinal function.

Application of multicolour reflectance imaging for the characterisation of inherited retinal disorders.

To describe the role of multicolour reflectance images (MCI) in the phenotypic diagnosis of inherited retinal disorders (IRDs). A retrospective review of consecutive patients affected by IRDs examined with MCI techniques from January to December 2019 at a tertiary care referral centre. All patients had MCI, fundus autofluorescence and optical coherence tomography taken at the same time point. The ability of each modality to highlight clinical features was assessed. Lesions' size was also measured and compared among imaging modalities. Thirty eyes of 15 patients were included in the study, 6 males and 9 females, with a mean age of 44 years (range: 19-57.5). The most frequent clinical diagnosis were: pattern dystrophies, and late-onset retinal degeneration. Next-generation or Sanger sequencing analysis was carried out in all patients. Blue and green reflectance were relevant in highlighting peripheral mottling in fundus albipunctatus, pseudoreticular drusen in late-onset retinal degeneration, parafoveal hyperreflective area in bull's eye maculopathy and crystals in Bietti's crystalline dystrophy. Likewise, it is to mention the ability of infrared reflectance to detect hyperreflective patches in posterior pole in neurofibromatosis type 1 and retinal changes in pattern dystrophies and cone dystrophies. Multicolour imaging technique enables the detection of clinical features that could be overlooked by other imaging modalities, allowing accurate phenotypic characterisation of IRDs and guiding genetic diagnose, and may become a meaningful monitoring tool for future treatments.

Distinct Phenotypic Consequences of Pathogenic Mutants Associated with Late-Onset Retinal Degeneration

A pathologic feature of late-onset retinal degeneration caused by the S163R mutation in C1q-tumor necrosis factor-5 (C1QTNF5) is the presence of unusually thick deposits between the retinal pigmented epithelium (RPE) and the vascular choroid, considered a hallmark of this disease. Following its specific expression in mouse RPE, the S163R mutant exhibits a reversed polarized distribution relative to the apically secreted wild-type C1QTNF5, and forms widespread, prominent deposits that gradually increase in size with aging. The current study shows that S163R deposits expand to a considerable thickness through a progressive increase in the basolateral RPE membrane, substantially raising the total RPE height, and enabling their clear imaging as a distinct hyporeflective layer by noninvasive optical coherence tomography in advanced age animals. This phenotype bears a striking resemblance to ocular pathology previously documented in patients harboring the S163R mutation. Therefore, a similar viral vector-based gene delivery approach was used to also investigate the behavior of P188T and G216C, two novel pathogenic C1QTNF5 mutants recently reported in patients for which histopathologic data are lacking. Both mutants primarily impacted the RPE/photoreceptor interface and did not generate basal laminar deposits. Distinct distribution patterns and phenotypic consequences of C1QTNF5 mutants were observed invivo, which suggested that multiple pathobiological mechanisms contribute to RPE dysfunction and vision loss in this disorder.

Late-Onset Retinal Degeneration: Clinical Perspectives.

Late-onset retinal degeneration (L-ORD) is a type of retinal dystrophy marked by nyctalopia and subretinal pigment epithelium deposits, which eventually promote retinal atrophy with final visual compromise. L-ORD may also present with changes in the anterior segment, notably long anterior zonules and iris atrophy, distinguishing it from other inherited eye conditions. Although it can clinically simulate age-related macular degeneration, L-ORD has a different course of progression and prognosis, requiring adequate diagnosis for patient counseling. This review summarizes the main clinical, genetic, pathophysiological, diagnostic, and therapeutic aspects of L-ORD to help ophthalmologists identify and manage this rare ocular disease.

Specific ablation of Hippo signalling component Yap1 in retinal progenitors and Müller cells results in late onset retinal degeneration.

Yes-associated protein (YAP) is a major component of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations in humans result in autosomal dominant coloboma. Here, we generated a conditional knockout mouse model in which Yap1 was specifically deleted in embryonic retinal progenitor cells (RPCs) and in mature Müller cells using a Chx10-Cre driver. Our data demonstrated that the conditional ablation of Yap1 in embryonic RPCs does not prevent normal retinal development and caused no gross changes in retinal structure during embryonic and early postnatal life. Nevertheless, Yap1 deficient in retinal Müller cells in adult mice leads to impaired visual responses and extensive late-onset retinal degeneration, characterized by reduced cell number in all retinal layers. Immunofluorescence data further revealed the degeneration and death of rod and cone photoreceptors, bipolar cells, horizontal cells, amacrine cells and ganglion cells to varying degrees in aged knockout mice. Moreover, alteration of glial homeostasis and reactive gliosis were also observed. Finally, cell proliferation and TUNEL assay revealed that the broad retinal degeneration is mainly caused by enhanced apoptosis in late period. Together, this work uncovers that YAP is essential for the normal vision and retinal maintenance, highlighting the crucial role of YAP in retinal function and homeostasis.

Single-cell–resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity

Regional phenotypic and functional differences in the retinal pigment epithelium (RPE) monolayer have been suggested to account for regional susceptibility in ocular diseases such as age-related macular degeneration (AMD), late-onset retinal degeneration (L-ORD), and choroideremia (CHM). However, a comprehensive description of human topographical RPE diversity is not yet available, thus limiting the understanding of regional RPE diversity and degenerative disease sensitivity in the eye. To develop a complete morphometric RPE map of the human eye, artificial intelligence–based software was trained to recognize, segment, and analyze RPE borders. Five statistically different, concentric RPE subpopulations (P1 to P5) were identified using cell area as a parameter, including a subpopulation (P4) with cell area comparable to that of macular cells in the far periphery of the eye. This work provides a complete reference map of human RPE subpopulations and their location in the eye. In addition, the analysis of cadaver non-AMD and AMD eyes and ultra-widefield fundus images of patients revealed differential vulnerability of the five RPE subpopulations to different retinal diseases.

AMPK modulation ameliorates dominant disease phenotypes of CTRP5 variant in retinal degeneration

Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder caused by a missense substitution in CTRP5. Distinctive clinical features include sub-retinal pigment epithelium (RPE) deposits, choroidal neovascularization, and RPE atrophy. In induced pluripotent stem cells-derived RPE from L-ORD patients (L-ORD-iRPE), we show that the dominant pathogenic CTRP5 variant leads to reduced CTRP5 secretion. In silico modeling suggests lower binding of mutant CTRP5 to adiponectin receptor 1 (ADIPOR1). Downstream of ADIPOR1 sustained activation of AMPK renders it insensitive to changes in AMP/ATP ratio resulting in defective lipid metabolism, reduced Neuroprotectin D1(NPD1) secretion, lower mitochondrial respiration, and reduced ATP production. These metabolic defects result in accumulation of sub-RPE deposits and leave L-ORD-iRPE susceptible to dedifferentiation. Gene augmentation of L-ORD-iRPE with WT CTRP5 or modulation of AMPK, by metformin, re-sensitize L-ORD-iRPE to changes in cellular energy status alleviating the disease cellular phenotypes. Our data suggests a mechanism for the dominant behavior of CTRP5 mutation and provides potential treatment strategies for L-ORD patients.

MASSIVE ADVANCING NONEXUDATIVE TYPE 1 CHOROIDAL NEOVASCULARIZATION IN CTRP5 LATE-ONSET RETINAL DEGENERATION: Longitudinal Findings on Multimodal Imaging and Implications for Age-Related Macular Degeneration.

To describe longitudinal multimodal imaging findings of nonexudative choroidal neovascularization in CTRP5 late-onset retinal degeneration. Four patients with CTRP5-positive late-onset retinal degeneration underwent repeated ophthalmoscopic examination and multimodal imaging. All four patients (two siblings and their cousins, from a pedigree described previously) had the heterozygous S163R mutation. All four patients demonstrated large subretinal lesions in the mid-peripheral retina of both eyes. The lesions were characterized by confluent hypercyanescence with hypocyanescent borders on indocyanine green angiography, faintly visible branching vascular networks with absent/minimal leakage on fluorescein angiography, Type 1 neovascularization on optical coherence tomography angiography, and absent retinal fluid, consistent with nonexudative choroidal neovascularization. The neovascular membranes enlarged substantially over time and the birth of new membranes was observed, but all lesions remained nonexudative/minimally exudative. Without treatment, all involved retinal areas remained free of atrophy and subretinal fibrosis. We report the existence of massive advancing nonexudative Type 1 choroidal neovascularization in CTRP5 late-onset retinal degeneration. These findings have implications for age-related macular degeneration. They provide a monogenic model system for studying the mechanisms underlying the distinct events of choroidal neovascularization development, enlargement, progression to exudation, and atrophy in age-related macular degeneration. They suggest that choroidal hypoperfusion precedes neovascularization and that nonexudative neovascularization may protect against atrophy.

QUANTITATIVE ANALYSIS OF LONGITUDINAL CHANGES IN MULTIMODAL IMAGING OF LATE-ONSET RETINAL DEGENERATION.

To quantitatively analyze clinically relevant features on longitudinal multimodal imaging of late-onset retinal degeneration to characterize disease progression. Fundus autofluorescence (FAF), infrared reflectance, and optical coherence tomography imaging of 4 patients with late-onset retinal degeneration were acquired over 3 to 15 years (20 visits total). Corresponding regions of interest were analyzed on FAF (reticular pseudodrusen [RPD], "speckled FAF," and chorioretinal atrophy) and infrared reflectance (hyporeflective RPD and target RPD) using quantitative measurements, including contour area, distance to fovea, contour overlap, retinal thickness, and texture features. Cross-sectional analysis revealed a moderate correlation (RPD FAF ∩ RPD infrared reflectance = 63%) between contour area across modalities. Quantification of retinal thickness and texture analysis of areas contoured on FAF objectively differentiated the contour types. A longitudinal analysis of aligned images demonstrates that the contoured region of atrophy both encroaches toward the fovea and grows monotonically with a rate of 0.531 mm/year to 1.969 mm/year (square root of area, n = 5 eyes). A retrospective analysis of precursor lesions of atrophy reveals quantifiable progression from RPD to speckled FAF to atrophy. Image analysis of time points before the development of atrophy reveals consistent patterns over time and space in late-onset retinal degeneration that may provide useful outcomes for this and other degenerative retinal diseases.

Familial Drusen, Doyne Honeycomb Retinal Dystrophy (Malattia Leventinese), Pigmented Paravenous Chorioretinal Atrophy and Late-Onset Retinal Degeneration

Inherited retinal diseases are a group of rare, heterogeneous eye disorders caused by gene mutations that result in degeneration of the retina. Malattia Leventinese, also known as familial drusen, dominant drusen, or Doyne honeycomb retinal dystrophy, was first described in patients living in the Levantine Valley in canton Ticino of southern Switzerland in 1925. Characteristic clinical findings include radial macular drusen, large confluent drusen, and juxtapapillary drusen. Especially early visual symptoms typically starting in the 3rd and 5th decades include reduced central vision, photophobia, and metamorphopsia. Pigmented paravenous retinochoroidal atrophy (PPRCA) is an uncommon disease characterized by perivenous aggregations of pigment clumps associated with peripapillary and radial zones of retinochoroidal atrophy that are distributed along the retinal veins. Patients are usually asymptomatic and the disease process is non-progressive or slow and subtly progressive. It is commonly bilateral and symmetric. The autosomal- dominant late-onset retinal degeneration (L-ORD), caused by C1QTNF5 gene mutations, shows typical retinal abnormalities that can extend beyond the macula, and patients can report night blindness in addition to central vision loss. Interestingly, L-ORD patients can have long anteriorly inserted lens zonules and loss of iris pigment.

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant.

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.