A mutation in CRX causing pigmented paravenous retinochoroidal atrophy

2020 ◽  
pp. 112067212095759
Author(s):  
Jin Kyun Oh ◽  
Yan Nuzbrokh ◽  
Winston Lee ◽  
Jose Ronaldo Lima de Carvalho ◽  
Nan Kai Wong ◽  
...  
Keyword(s):  
Vision Loss ◽  
Retinal Dystrophy ◽  
Cone Dystrophy ◽  
Full Field ◽  
Inherited Retinal Dystrophy ◽  
History Of ◽  
Pigmented Paravenous Retinochoroidal Atrophy ◽  
Retinal Thinning ◽  
Bull's Eye ◽  
Sd Oct

Introduction: Mutations in the cone-rod homeobox ( CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. Case description: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull’s eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. Conclusion: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

scholarly journals The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene

2019 ◽  
Vol 199 ◽  
pp. 58-70 ◽  
Author(s):  
Daniel C. Chung ◽  
Mette Bertelsen ◽  
Birgit Lorenz ◽  
Mark E. Pennesi ◽  
Bart P. Leroy ◽  
...  
Keyword(s):  
Natural History ◽  
Retinal Dystrophy ◽  
Inherited Retinal Dystrophy ◽  
History Of ◽  
Biallelic Mutations

scholarly journals Clinical Course and Electron Microscopic Findings in Lymphocytes of Patients with DRAM2-Associated Retinopathy

2020 ◽  
Vol 21 (4) ◽  
pp. 1331 ◽  
Author(s):  
Kazuki Kuniyoshi ◽  
Takaaki Hayashi ◽  
Shuhei Kameya ◽  
Satoshi Katagiri ◽  
Kei Mizobuchi ◽  
...  
Keyword(s):  
Night Blindness ◽  
Retinal Dystrophy ◽  
Visual Outcome ◽  
Systemic Effect ◽  
Cone Dystrophy ◽  
Electron Microscopic ◽  
Peripheral Lymphocytes ◽  
Transmission Electron ◽  
Inherited Retinal Dystrophy ◽  
Microscopic Findings

DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.

scholarly journals Early onset retinal dystrophies: clinical clues to diagnosis for pediatricians

2019 ◽  
Vol 45 (1) ◽  
Author(s):  
Agnese Suppiej ◽  
Silvia Marino ◽  
Maria Eleonora Reffo ◽  
Veronica Maritan ◽  
Giovanna Vitaliti ◽  
...  
Keyword(s):  
Vision Loss ◽  
Clinical Symptoms ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Primary Care Providers ◽  
Visual Development ◽  
Cone Dystrophy ◽  
Care Providers ◽  
Visual Symptoms ◽  
Retinal Dystrophies

Abstract Introduction Inherited retinal dystrophies are major cause of severe progressive vision loss in children. Early recognition and diagnosis are essential for timely visual rehabilitation during the appropriate stages of the visual development, as well as for genetic diagnosis and possible gene therapy. The aim of this study is to characterize a pattern of the initial visual symptoms, which could help the pediatricians and the primary care providers to suspect an inherited retinal disorder in its early stage. Methods We analyzed the initial clinical symptoms, based on parental report during the first visit to specialist, in 50 children diagnosed with retinal dystrophy confirmed by full-field electroretinography. The analysis included the age of symptoms onset and the type of visual symptoms, both in the total population and in the following diagnostic subgroups: rod-cone dystrophy (n.17), cone-rod dystrophy (n.12), achromatopsia (n.13), congenital stationary night blindness (n.6) and Leber’s congenital amaurosis (n.2). Results The majority of children (80%) had the onset of clinical symptoms before one year of age. The most frequent visual complaints reported by parents were nystagmus (76%), visual loss (28%) and photophobia (8%). Nystagmus was the first symptom reported by parents if the disease onset was before the age of six months, while the onset after the six months of age was more likely associated with the complain of vision loss. Conclusions Low vision and nystagmus observed by parents, particularly in the first year of life, may represent a red flag, prompting an appropriate ophthalmological workup for inherited retinal dystrophy.

scholarly journals Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration

2019 ◽  
pp. bjophthalmol-2018-313580 ◽  
Author(s):  
Abigail T Fahim ◽  
Zaina Bouzia ◽  
Kari H Branham ◽  
Neruban Kumaran ◽  
Mauricio E Vargas ◽  
...  
Keyword(s):  
Natural History ◽  
Retinal Degeneration ◽  
Early Onset ◽  
Vision Loss ◽  
Age Of Onset ◽  
Retinal Dystrophy ◽  
Loss Of Function ◽  
Phenotypic Data ◽  
History Of ◽  
Clinical Records

BackgroundDefects in retinol dehydrogenase 12 (RDH12) account for 3.4%–10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration.MethodsA retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.Results57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.ConclusionsThis study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

scholarly journals Wavelength of light and photophobia in inherited retinal dystrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuki Otsuka ◽  
Akio Oishi ◽  
Manabu Miyata ◽  
Maho Oishi ◽  
Tomoko Hasegawa ◽  
...  
Keyword(s):  
Short Wavelength ◽  
Pathological Condition ◽  
Retinal Dystrophy ◽  
Ocular Pain ◽  
Bull’S Eye Maculopathy ◽  
Significant Difference ◽  
Inherited Retinal Dystrophy ◽  
Short Wavelength Light ◽  
Bull's Eye ◽  
Wavelength Filtering

Abstract Inherited retinal dystrophy (IRD) patients often experience photophobia. However, its mechanism has not been elucidated. This study aimed to investigate the main wavelength of light causing photophobia in IRD and difference among patients with different phenotypes. Forty-seven retinitis pigmentosa (RP) and 22 cone-rod dystrophy (CRD) patients were prospectively recruited. We designed two tinted glasses: short wavelength filtering (SWF) glasses and middle wavelength filtering (MWF) glasses. We classified photophobia into three types: (A) white out, (B) bright glare, and (C) ocular pain. Patients were asked to assign scores between one (not at all) and five (totally applicable) for each symptom with and without glasses. In patients with RP, photophobia was better relieved with SWF glasses {“white out” (p < 0.01) and “ocular pain” (p = 0.013)}. In CRD patients, there was no significant difference in the improvement wearing two glasses (p = 0.247–1.0). All RP patients who preferred MWF glasses had Bull’s eye maculopathy. Meanwhile, only 15% of patients who preferred SWF glasses had the finding (p < 0.001). Photophobia is primarily caused by short wavelength light in many patients with IRD. However, the wavelength responsible for photophobia vary depending on the disease and probably vary according to the pathological condition.

scholarly journals Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3

2021 ◽  
Vol 22 (5) ◽  
pp. 2607
Author(s):  
Michalitsa Diakatou ◽  
Gregor Dubois ◽  
Nejla Erkilic ◽  
Carla Sanjurjo-Soriano ◽  
Isabelle Meunier ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Dominant ◽  
Vision Loss ◽  
Retinal Dystrophy ◽  
Common Mutation ◽  
Wild Type ◽  
Inherited Retinal Dystrophy ◽  
Allele Specific ◽  
Induced Pluripotent ◽  
Overexpression System

Retinitis pigmentosa (RP) is an inherited retinal dystrophy that causes progressive vision loss. The G56R mutation in NR2E3 is the second most common mutation causing autosomal dominant (ad) RP, a transcription factor that is essential for photoreceptor development and maintenance. The G56R variant is exclusively responsible for all cases of NR2E3-associated adRP. Currently, there is no treatment for NR2E3-related or, other, adRP, but genome editing holds promise. A pertinent approach would be to specifically knockout the dominant mutant allele, so that the wild type allele can perform unhindered. In this study, we developed a CRISPR/Cas strategy to specifically knockout the mutant G56R allele of NR2E3 and performed a proof-of-concept study in induced pluripotent stem cells (iPSCs) of an adRP patient. We demonstrate allele-specific knockout of the mutant G56R allele in the absence of off-target events. Furthermore, we validated this knockout strategy in an exogenous overexpression system. Accordingly, the mutant G56R-CRISPR protein was truncated and mis-localized to the cytosol in contrast to the (peri)nuclear localizations of wild type or G56R NR2E3 proteins. Finally, we show, for the first time, that G56R iPSCs, as well as G56R-CRISPR iPSCs, can differentiate into NR2E3-expressing retinal organoids. Overall, we demonstrate that G56R allele-specific knockout by CRISPR/Cas could be a clinically relevant approach to treat NR2E3-associated adRP.

scholarly journals WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1624
Author(s):  
Elana Meer ◽  
Tomas S. Aleman ◽  
Ahmara G. Ross
Keyword(s):  
Visual Field ◽  
Vision Loss ◽  
Open Angle Glaucoma ◽  
Field Testing ◽  
Normal Tension Glaucoma ◽  
Visual Field Defects ◽  
Fiber Layer ◽  
Retinal Dysfunction ◽  
Full Field ◽  
History Of

WDR36 is one of a number of genes implicated in the pathogenesis of adult-onset primary open angle glaucoma (POAG). Here we describe in detail the phenotype of a patient with pathogenic variation in WDR36 who presented with a protracted history of central vision loss. On exam visual acuities were at 20/100 level, had a tritan color defect and showed central arcuate visual field defects on visual field testing. Enlarged cup-to-disk ratios with normal intraocular pressures were associated with severe thinning of the ganglion cell layer (GCL) and retinal nerve fiber layer consistent with a clinical diagnosis of normal tension glaucoma. Full-field electroretinograms revealed a severe inner retinal dysfunction with reduced amplitudes and remarkably delayed timings of the b-wave, but preserved photoreceptor (a-wave) function. The pattern described herein recapitulates some of the findings of an animal model of WDR36-associated POAG and suggests a mechanism of disease that involves a retina-wide inner retinal dysfunction and neurodegeneration beyond the GCL. Further detailed structural and functional characterizations of patients with a pathogenic variant in the WDR36 gene are required to confirm these findings.

scholarly journals Notch inhibition promotes regeneration and immunosuppression supports cone survival in a zebrafish model of inherited retinal dystrophy

2021 ◽  
Author(s):  
Joseph Fogerty ◽  
Ping Song ◽  
Patrick Boyd ◽  
Sarah Grabinski ◽  
Thanh Hoang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Vision Loss ◽  
Retinal Dystrophy ◽  
Photoreceptor Degeneration ◽  
Zebrafish Model ◽  
Reactive Microglia ◽  
Multipotent Progenitors ◽  
Inherited Retinal Dystrophy ◽  
Ability To Regenerate ◽  
Mature Neurons

Photoreceptor degeneration leads to irreversible vision loss in humans with retinal dystrophies such as Retinitis Pigmentosa. Whereas photoreceptor loss is permanent in mammals, zebrafish possesses the ability to regenerate retinal neurons and restore visual function. Following acute damage, Muller glia (MG) re-enter the cell cycle and produce multipotent progenitors whose progeny differentiate into mature neurons. Both MG reprogramming and proliferation of retinal progenitor cells require reactive microglia and associated inflammatory signaling. Paradoxically, MG in zebrafish models of photoreceptor degeneration fail to re-enter the cell cycle and regenerate lost cells. Here, we used the zebrafish cep290 mutant to demonstrate that progressive cone degeneration generates an immune response but does not stimulate MG proliferation. Acute light damage triggered photoreceptor regeneration in cep290 mutants but cones were only restored to pre-lesion densities. Using irf8 mutant zebrafish, we found that the chronic absence of microglia reduced inflammation and rescued cone degeneration in cep290 mutants. Finally, single-cell RNA-sequencing revealed sustained expression of notch3 in MG of cep290 mutants and inhibition of Notch signaling induced MG to re-enter the cell cycle. Our findings provide new insights on the requirements for MG to proliferate and the potential for immunosuppression to prolong photoreceptor survival.

Methoxsalen-induced advanced bull’s eye maculopathy

2020 ◽  
pp. 112067212090731
Author(s):  
Ratnesh Ranjan ◽  
George J Manayath ◽  
Romit Salian ◽  
Venkatapathy Narendran
Keyword(s):  
Multifocal Electroretinogram ◽  
Fundus Examination ◽  
Ultraviolet A ◽  
Bull’S Eye Maculopathy ◽  
History Of ◽  
Flying Saucer ◽  
Retinal Thinning ◽  
Bull's Eye ◽  
Foveal Sparing ◽  
Defective Vision

A number of systemic medications are known to cause macular toxicity, and bull’s eye maculopathy is caused by some of them like hydroxychloroquine and clofazimine. A 55-year-old female, known case of vitiligo with history of undergoing methoxsalen–ultraviolet A therapy, presented with painless defective vision in both eyes. Fundus examination and autofluorescence showed macular degeneration with bull’s eye configuration. Optical coherence tomography showed perifoveal loss of photoreceptors and outer retinal thinning with foveal sparing appearing as ‘flying saucer’. Multifocal electroretinogram showed pan-macular suppression of waveforms. Patient was diagnosed as case of methoxsalen-induced advanced macular toxicity. This is the first reported case of methoxsalen-induced advanced bull’s eye maculopathy.

scholarly journals Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

2021 ◽  
Vol 22 (12) ◽  
pp. 6410
Author(s):  
Vasily Smirnov ◽  
Olivier Grunewald ◽  
Jean Muller ◽  
Christina Zeitz ◽  
Carolin D. Obermaier ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Copy Number Variants ◽  
Cone Dystrophy ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Large Deletions ◽  
Gene Panels ◽  
Generation Sequencing

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

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