Publications by authors named "Michalis Georgiou"

49 Publications

Characterization of Retinal Function using Microperimetry-Derived Metrics in both Adults and Children with RPGR-Associated Retinopathy.

Am J Ophthalmol 2021 Jul 22. Epub 2021 Jul 22.

UCL Institute of Ophthalmology, University College London, London, UK; Moorfields Eye Hospital, London, UK. Electronic address:

Purpose: To investigate microperimetry testing of RPGR-associated retinopathy in a cohort of children and adults.

Study Design: Prospective observational case series.

Methods: The coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated for mesopic microperimetry. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), MS, total volume (V), and central 3-degree field volume (V) from volumetric and topographic analyses were acquired.

Results: Seventy-six RPGR subjects (53 adults, 23 children) were recruited. The mean follow-up period was 2.8 years. The ICC values for MS, V and V were 0.982 dB (95% confidence intervals, CI 0.969 to 0.989), 0.970 dB-sr (95% CI -0.02658 to 0.03691) and 0.986 dB-sr (95% CI 0.978 to 0.991), respectively. The r values for interocular MS, V and V, were 0.97 (P<0.01), 0.97 (P<0.01) and 0.98 (P<0.01) respectively, indicating strong inter-ocular correlation. The interocular correlation of progression for MS, V and V was 0.81 (P<0.01), 0.64 (P<0.01) and 0.81 (P<0.01), respectively. There was no statistically significant difference in the interocular progression rates for MS or V. V did show a statistically significant difference. Most patients lost retinal sensitivity rapidly during their second and third decades of life.

Conclusions: The high degree of reproducibility of results and the good interocular correlation lends this modality to accurately monitoring disease progression, as well as supporting validation of the use of MP in assessing the outcomes of gene therapy clinical treatment trials.
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http://dx.doi.org/10.1016/j.ajo.2021.07.018DOI Listing
July 2021

Unilateral congenital non-syndromic retinal vessel dilation and tortuosity.

Am J Ophthalmol Case Rep 2021 Sep 7;23:101160. Epub 2021 Jul 7.

UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.

Purpose: To present a case of atypical unilateral developmental retinal vascular anomaly.

Observations: A 10-year-old girl presented to her paediatrician after an absent red reflex was noted in a photograph. She had right anisometropic amblyopia and right iris heterochromia, but was otherwise healthy, with no visual complaints. Fundus examination revealed abnormal right retinal vasculature in keeping with an arteriovenous malformation (AVM). OCTA performed at age 16, showed large aberrant veins in the right eye, whereas OCTA B-Scans showed that the same eye had significantly higher retinal blood perfusion than the unaffected eye.

Conclusions And Importance: OCTA is a valuable, non-invasive emerging method of evaluating patients with AVMs, with this patient having a unique unilateral presentation of a developmental anomaly, without evidence of progression or other vessel malformation. OCTA allowed assessment of flow between the affected and non-affected eye, quantifying the greater blood perfusion in the affected eye due to the AVM.
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http://dx.doi.org/10.1016/j.ajoc.2021.101160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271107PMC
September 2021

Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.

Ophthalmic Genet 2021 Jul 5:1-10. Epub 2021 Jul 5.

Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.

Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here, we characterize the clinical phenotype of disease caused by variants in , and .Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease-causing variants in , or .-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in showed mild retinal disease with progressive, non-congenital SNHL. variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. -related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe.This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients who have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.
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http://dx.doi.org/10.1080/13816810.2021.1946704DOI Listing
July 2021

Novel disease-causing variant in presenting with autosomal dominant retinitis pigmentosa.

Br J Ophthalmol 2021 May 24. Epub 2021 May 24.

Cell and Gene Therapy, University College London Institute of Ophthalmology, London, UK

Aim: To describe the clinical and molecular features of a novel, autosomal dominant -retinopathy.

Methods: Retrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.

Results: Eight family members were confirmed as affected by genotyping heterozygous for c.763delG. Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.

Conclusions: This novel heterozygous variant c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318034DOI Listing
May 2021

Structural evaluation in inherited retinal diseases.

Br J Ophthalmol 2021 May 12. Epub 2021 May 12.

Moorfields Eye Hospital City Road Campus, London, UK

Ophthalmic genetics is a field that has been rapidly evolving over the last decade, mainly due to the flourishing of translational medicine for inherited retinal diseases (IRD). In this review, we will address the different methods by which retinal structure can be objectively and accurately assessed in IRD. We review standard-of-care imaging for these patients: colour fundus photography, fundus autofluorescence imaging and optical coherence tomography (OCT), as well as higher-resolution and/or newer technologies including OCT angiography, adaptive optics imaging, fundus imaging using a range of wavelengths, magnetic resonance imaging, laser speckle flowgraphy and retinal oximetry, illustrating their utility using paradigm genotypes with on-going therapeutic efforts/trials.
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http://dx.doi.org/10.1136/bjophthalmol-2021-319228DOI Listing
May 2021

Retinal imaging in inherited retinal diseases.

Ann Eye Sci 2020 Sep 15;5. Epub 2020 Sep 15.

UCL Institute of Ophthalmology, University College London, London, UK.

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRD, with the first approved gene therapy and the commencement of multiple therapy trials. The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD. Herein we present in a comprehensive and concise manner the imaging findings of: (I) macular dystrophies (MD) [Stargardt disease (), X-linked retinoschisis (), Best disease (), pattern dystrophy (), Sorsby fundus dystrophy (), and autosomal dominant drusen ()], (II) cone and cone-rod dystrophies (, , and ) (III) cone dysfunction syndromes [achromatopsia (], blue-cone monochromatism ( array), oligocone trichromacy, bradyopsia () and Bornholm eye disease (), (IV) Leber congenital amaurosis (, , , , , and ) (V) rod-cone dystrophies [retinitis pigmentosa, enhanced S-Cone syndrome (), Bietti crystalline corneoretinal dystrophy ()], (VI) rod dysfunction syndromes (congenital stationary night blindness, fundus albipunctatus () Oguchi disease (, ), and (VII) chorioretinal dystrophies [choroideremia (), gyrate atrophy ()].
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http://dx.doi.org/10.21037/aes-20-81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081382PMC
September 2020

Joubert syndrome diagnosed renally late.

Clin Kidney J 2021 Mar 12;14(3):1017-1019. Epub 2020 Mar 12.

Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK.

Joubert syndrome is a genetically heterogeneous multisystem disorder typically diagnosed in childhood. Nephronophthisis is the most common renal pathology in Joubert syndrome, and renal failure usually occurs in childhood or in young adults. We report a 61-year-old female diagnosed with -related oculorenal Joubert syndrome, who presented initially with decline in renal function in her 50s. Our report describes exceptionally late presentation of renal disease in Joubert syndrome and highlights the importance of continued renal function monitoring in older adults with Joubert syndrome.
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http://dx.doi.org/10.1093/ckj/sfaa007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986455PMC
March 2021

Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions.

Br J Ophthalmol 2021 Mar 19. Epub 2021 Mar 19.

Institute of Ophthalmology, University College London, London, London, UK

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis-something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318452DOI Listing
March 2021

KCNV2-Associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints-KCNV2 Study Group Report 2.

Am J Ophthalmol 2021 Mar 15;230:1-11. Epub 2021 Mar 15.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel.

Purpose: To describe the detailed retinal phenotype of KCNV2-associated retinopathy.

Study Design: Multicenter international retrospective case series.

Methods: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses.

Results: Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes.

Conclusions: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.
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http://dx.doi.org/10.1016/j.ajo.2021.03.004DOI Listing
March 2021

Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials.

Br J Ophthalmol 2021 Mar 12. Epub 2021 Mar 12.

UCL Institute of Ophthalmology, University College London, London, UK

Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. -related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11--retinal and cell therapy's aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318483DOI Listing
March 2021

Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy.

Orphanet J Rare Dis 2021 03 12;16(1):128. Epub 2021 Mar 12.

UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.

Purpose: To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease.

Methods: Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK).

Results: The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented.

Conclusions: The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.
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http://dx.doi.org/10.1186/s13023-021-01759-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953775PMC
March 2021

Inherited retinal diseases: Therapeutics, clinical trials and end points-A review.

Clin Exp Ophthalmol 2021 Apr 20;49(3):270-288. Epub 2021 Mar 20.

UCL Institute of Ophthalmology, University College London, London, UK.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders characterised by photoreceptor degeneration or dysfunction. These disorders typically present with severe vision loss that can be progressive, with disease onset ranging from congenital to late adulthood. The advances in genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRDs, with the first approved gene therapy and the commencement of multiple clinical trials. The scope of this review is to familiarise clinicians and scientists with the current management and the prospects for novel therapies for: (1) macular dystrophies, (2) cone and cone-rod dystrophies, (3) cone dysfunction syndromes, (4) Leber congenital amaurosis, (5) rod-cone dystrophies, (6) rod dysfunction syndromes and (7) chorioretinal dystrophies. We also briefly summarise the investigated end points for the ongoing trials.
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http://dx.doi.org/10.1111/ceo.13917DOI Listing
April 2021

Optical Coherence Tomography Artifacts Are Associated With Adaptive Optics Scanning Light Ophthalmoscopy Success in Achromatopsia.

Transl Vis Sci Technol 2021 01 7;10(1):11. Epub 2021 Jan 7.

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM).

Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 and 51 ) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity.

Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success ( = 0.0002). Neither BCVA nor axial length was associated with AOSLO success ( = 0.07 and = 0.75, respectively).

Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging.

Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.
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http://dx.doi.org/10.1167/tvst.10.1.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804582PMC
January 2021

KCNV2-Associated Retinopathy: Genetics, Electrophysiology, and Clinical Course-KCNV2 Study Group Report 1.

Am J Ophthalmol 2021 05 11;225:95-107. Epub 2020 Dec 11.

Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

Purpose: To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults.

Study Design: This was a multicenter international clinical cohort study.

Methods: Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects.

Results: In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades.

Conclusion: In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajo.2020.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186730PMC
May 2021

Incidental unilateral idiopathic maculopathy in children.

J AAPOS 2020 12 26;24(6):357.e1-357.e6. Epub 2020 Nov 26.

Moorfields Eye Hospital, London, United Kingdom; UCL Institute of Ophthalmology, University College London, United Kingdom; Royal London Hospital, Whitechapel, London, United Kingdom.

Purpose: To investigate the clinical findings and differential diagnosis of incidental unilateral discoid maculopathy in a case series of children.

Methods: The medical records and retinal imaging of children referred to a single center for flat, well circumscribed, hypopigmented discoid macular lesion in the left eye were reviewed retrospectively.

Results: Three children (age range, 4-11 years; 2 female), with no subjective ophthalmic complaints, were referred for investigation of a flat, well-circumscribed, hypopigmented discoid macular lesion in the left eye. Case 1 had a history of viral mesenteric adenitis, and case 2 had a history of hand, foot, and mouth disease. For case 3, no previous history of systemic viral infection was established. Snellen visual acuity was 20/20 for all 3 children. The lesion was located superior to the fovea for case 1 and centered to the fovea for cases 2 and 3, all in the left eye. In all 3 patients, hyperautofluorescent changes were noted around the edges of the lesion, which was roughly discoid. OCT showed subtle changes of the interdigitation zone and retinal pigment epithelium (RPE) for cases 1 and 2. In case 3 the presence of hyperreflective, hypertrophic tissue at the level of the interdigitation zone and/or the RPE was noted.

Conclusions: In these 3 children with subclinical, unilateral discoid maculopathy sharing common features and identified incidentally, previous viral illness may have been causative. These cases may represent resolved unilateral acute idiopathic maculopathy.
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http://dx.doi.org/10.1016/j.jaapos.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020732PMC
December 2020

The genetic landscape of crystallins in congenital cataract.

Orphanet J Rare Dis 2020 11 26;15(1):333. Epub 2020 Nov 26.

Department of Genetics, UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.

Background: The crystalline lens is mainly composed of a large family of soluble proteins called the crystallins, which are responsible for its development, growth, transparency and refractive index. Disease-causing sequence variants in the crystallins are responsible for nearly 50% of all non-syndromic inherited congenital cataracts, as well as causing cataract associated with other diseases, including myopathies. To date, more than 300 crystallin sequence variants causing cataract have been identified.

Methods: Here we aimed to identify the genetic basis of disease in five multi-generation British families and five sporadic cases with autosomal dominant congenital cataract using whole exome sequencing, with identified variants validated using Sanger sequencing. Following bioinformatics analysis, rare or novel variants with a moderate to damaging pathogenicity score, were filtered out and tested for segregation within the families.

Results: We have identified 10 different heterozygous crystallin variants. Five recurrent variants were found: family-A, with a missense variant (c.145C>T; p.R49C) in CRYAA associated with nuclear cataract; family-B, with a deletion in CRYBA1 (c.272delGAG; p.G91del) associated with nuclear cataract; and family-C, with a truncating variant in CRYGD (c.470G>A; W157*) causing a lamellar phenotype; individuals I and J had variants in CRYGC (c.13A>C; T5P) and in CRYGD (c.418C>T; R140*) causing unspecified congenital cataract and nuclear cataract, respectively. Five novel disease-causing variants were also identified: family D harboured a variant in CRYGC (c.179delG; R60Qfs*) responsible for a nuclear phenotype; family E, harboured a variant in CRYBB1 (c.656G>A; W219*) associated with lamellar cataract; individual F had a variant in CRYGD (c.392G>A; W131*) associated with nuclear cataract; and individuals G and H had variants in CRYAA (c.454delGCC; A152del) and in CRYBB1 (c.618C>A; Y206*) respectively, associated with unspecified congenital cataract. All novel variants were predicted to be pathogenic and to be moderately or highly damaging.

Conclusions: We report five novel variants and five known variants. Some are rare variants that have been reported previously in small ethnic groups but here we extend this to the wider population and record a broader phenotypic spectrum for these variants.
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http://dx.doi.org/10.1186/s13023-020-01613-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691105PMC
November 2020

Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration.

Sci Rep 2020 10 16;10(1):17520. Epub 2020 Oct 16.

UCL Institute of Ophthalmology, University College London, 11 - 43 Bath Street, London, EC1V 9EL, UK.

Disease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy.
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http://dx.doi.org/10.1038/s41598-020-74516-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567831PMC
October 2020

Autosomal Recessive Bestrophinopathy: Clinical Features, Natural History, and Genetic Findings in Preparation for Clinical Trials.

Ophthalmology 2021 May 8;128(5):706-718. Epub 2020 Oct 8.

Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address:

Purpose: To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults.

Design: Retrospective case series.

Participants: Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center.

Methods: Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing.

Main Outcome Measures: Visual acuity (VA), retinal imaging, and electrophysiologic changes over time.

Results: Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results.

Conclusions: Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.
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http://dx.doi.org/10.1016/j.ophtha.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062850PMC
May 2021

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

Am J Hum Genet 2020 11 5;107(5):802-814. Epub 2020 Oct 5.

University of Cape Town/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, 7935, South Africa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675008PMC
November 2020

Long-Term Investigation of Retinal Function in Patients with Achromatopsia.

Invest Ophthalmol Vis Sci 2020 09;61(11):38

UCL Institute of Ophthalmology, University College London, London, United Kingdom.

Purpose: To investigate the long-term natural history of retinal function of achromatopsia (ACHM).

Methods: Subjects with molecularly confirmed ACHM were recruited in a prospective cohort study of mesopic microperimetry. Coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated. Best-corrected visual acuity (BCVA), bivariate contour ellipse area (BCEA), contrast sensitivity (CS), MS, total volume (VTOT), and central field volume (V5°) from volumetric and topographic analyses were acquired. Correlation of functional parameters with structural findings from optical coherence tomography (OCT) was performed.

Results: Eighteen subjects were recruited. Mean follow-up was 7.2 years. The MS test-retest repeatability coefficient was 1.65 decibels (dB), and the ICC was 0.973 (95% confidence interval, 0.837-0.98). Mean MS was similar for right and left eyes (16.97dB and 17.14dB, respectively). A negative significant correlation between logMAR BCVA and the retinal sensitivity indices (MS, VTOT, V5°) was found. A significant negative correlation between logCS and MS, VTOT, and V5° was also observed. BCVA and BCEA improved during follow-up. Mean CS, MS, VTOT, and V5° at final follow-up were similar to baseline. MS was similar between CNGA3- and CNGB3-ACHM. Patients with and without the presence of a foveal ellipsoid zone on OCT had similar MS (16.64 dB and 17.17 dB, respectively).

Conclusions: We demonstrate a highly reproducible assessment of MS. Retinal function including MS, volumetric indices, and CS are stable in ACHM. Improvement of fixation stability and small changes of BCVA over time may be part of the natural history of the disease.
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http://dx.doi.org/10.1167/iovs.61.11.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509756PMC
September 2020

Preservation of the Foveal Avascular Zone in Achromatopsia Despite the Absence of a Fully Formed Pit.

Invest Ophthalmol Vis Sci 2020 08;61(10):52

Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.

Purpose: To examine the foveal avascular zone (FAZ) in patients with congenital achromatopsia (ACHM).

Methods: Forty-two patients with genetically confirmed ACHM were imaged either with Optovue's AngioVue system or Zeiss's Plex Elite 9000, and the presence or absence of a FAZ was determined. For images where a FAZ was present and could be confidently segmented, FAZ area, circularity index, and roundness were measured and compared with previously published normative values. Structural optical coherence tomography images were acquired to assess the degree of foveal hypoplasia (number and thickness of inner retinal layers present at the fovea).

Results: A FAZ was present in 31 of 42 patients imaged (74%), although no determination could be made for 11 patients due to poor image quality (26%). The mean ± SD FAZ area for the ACHM retina was 0.281 ± 0.112 mm2, which was not significantly different from the previously published normative values (P = 0.94). However, their FAZs had decreased circularity (P < 0.0001) and decreased roundness (P < 0.0001) compared to the normative cohort. In the patients with ACHM examined here, the FAZ area decreased as the number and thickness of the retained inner retinal layers increased.

Conclusions: Our data demonstrate that despite the presence of foveal hypoplasia, patients with ACHM can have a FAZ. This is distinct from other conditions associated with foveal hypoplasia, which generally show an absence of the FAZ. In ACHM, FAZ formation does not appear to be sufficient for complete pit formation, contrary to some models of foveal development.
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http://dx.doi.org/10.1167/iovs.61.10.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463179PMC
August 2020

Intraobserver Repeatability and Interobserver Reproducibility of Foveal Cone Density Measurements in and -Associated Achromatopsia.

Transl Vis Sci Technol 2020 06 26;9(7):37. Epub 2020 Jun 26.

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: To examine repeatability and reproducibility of foveal cone density measurements in patients with and -associated achromatopsia (ACHM) using split-detection adaptive optics scanning light ophthalmoscopy (AOSLO).

Methods: Thirty foveae from molecularly confirmed subjects with ACHM, half of whom harbored disease-causing variants in and half in underwent nonconfocal split-detection AOSLO imaging. Cone photoreceptors within the manually delineated rod-free zone were manually identified twice by two independent observers. The coordinates of the marked cones were used for quantifying foveal cone density. Cone density and difference maps were generated to compare cone topography between trials.

Results: We observed excellent intraobserver repeatability in foveal cone density estimates, with intraclass correlation coefficients (ICCs) ranging from 0.963 to 0.991 for and subjects. Interobserver reproducibility was also excellent for both (ICC = 0.952; 95% confidence interval [CI], 0.903-1.0) and (ICC = 0.968; 95% CI, 0.935-1.0). However, Bland-Altman analysis revealed bias between observers.

Conclusions: Foveal cone density can be measured using the described method with good repeatability and reproducibility both for - and -associated ACHM. Any degree of bias observed among the observers is of uncertain clinical significance but should be evaluated on a study-specific basis.

Translational Relevance: This approach could be used to explore disease natural history, as well as to facilitate stratification of patients and monitor efficacy of interventions for ongoing and upcoming ACHM gene therapy trials.
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http://dx.doi.org/10.1167/tvst.9.7.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414701PMC
June 2020

Sector Retinitis Pigmentosa: Extending the Molecular Genetics Basis and Elucidating the Natural History.

Am J Ophthalmol 2021 01 12;221:299-310. Epub 2020 Aug 12.

Institute of Ophthalmology, University College London, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom. Electronic address:

Purpose: To determine the genetic background of sector retinitis pigmentosa (RP) natural history to better inform patient counseling.

Design: Retrospective case series.

Methods: Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing were performed in patients with sector RP from a single tertiary referral center. Main outcomes measured were demographic data, signs and symptoms, visual acuity, molecular genetics; and ERG, FAF, and OCT findings.

Results: Twenty-six molecularly confirmed patients from 23 different families were identified harboring likely disease-causing variants in 9 genes. The modes of inheritance were autosomal recessive (AR, n=6: USH1C, n=2; MYO7A, n=2; CDH3, n=1; EYS, n=1), X-linked (XL, n=4: PRPS1, n=1; RPGR, n=3), and autosomal dominant (AD, n=16: IMPDH1, n=3; RP1, n=3; RHO, n=10), with a mean age of disease onset of 38.5, 30.5, and 39.0 years old, respectively. Five of these genes have not previously been reported to cause sector RP (PRPS1, MYO7A, EYS, IMPDH1, and RP1). Inferior and nasal predilection was common across the different genotypes, and patients tended to maintain good central vision. Progression on serial FAF was observed in RPGR, MYO7A, CDH23, EYS, IMPDH1, RP1, and RHO-associated sector RP.

Conclusions: The genotypic spectrum of the disease is broader than previously reported. The longitudinal data provided will help to make accurate patient prognoses and counseling as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments.
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http://dx.doi.org/10.1016/j.ajo.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772805PMC
January 2021

Macula-predominant retinopathy associated with biallelic variants in .

Ophthalmic Genet 2020 12 13;41(6):612-615. Epub 2020 Aug 13.

UCL Institute of Ophthalmology, University College London , London, UK.

Purpose: To describe the clinical, electrophysiological, and molecular features of an unusual macula-predominant retinopathy in two unrelated probands with biallelic variants in .

Methods: Retrospective case series.

Results: A 29-year-old female presented with visual loss since the age of 14 years. Retinal examination revealed symmetric outer retinal atrophy in the posterior pole with peripapillary sparing. Fundus autofluorescence (AF) showed patchy loss of AF in the posterior pole, with hyper-autofluorescent borders. Optical coherence tomography (OCT) showed loss of the macular outer retinal layers. Pattern electroretinography (PERG) showed macular dysfunction and full-field ERG indicated mild loss of photoreceptor function. Next-generation sequencing (NGS) identified two variants in : p.(Arg234His) and c.448 + 1 G > A in . The second patient was a 10-year-old male with bilateral macular changes and visual loss. Retinal examination showed bilateral macular cloverleaf-like outer retinal changes, with relative foveal sparing. Fundus AF showed bilateral macular hypo-autofluorescent patches with a border of increased signal and preserved foveal AF. OCT showed attenuation of the perifoveal outer retinal layers in the regions of reduced AF signal. PERG showed macular dysfunction, but the full-field ERG was normal. NGS and whole-genome sequencing identified two variants in : p.(Arg234His) and p.(Cys245_Leu247deI) in .

Conclusions: Disease-causing variants in are typically associated with early-onset severe retinal dystrophy with significant macular involvement. Hypomorphic alleles of this gene cause relatively mild retinopathy with predominant macular involvement. This phenotype demonstrates the vulnerability of the macular photoreceptors to certain perturbations of .
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http://dx.doi.org/10.1080/13816810.2020.1802763DOI Listing
December 2020

Subfoveal retinal detachment associated with dome-shaped macula in a 6 year-old child: Comparison with other case reports and systematic review of the literature regarding dome-shaped macula in children.

Am J Ophthalmol Case Rep 2020 Sep 8;19:100821. Epub 2020 Jul 8.

Moorfields Eye Hospital, London, EC1 2PD, UK.

Purpose: To describe the case of an asymptomatic 6-year-old girl, who was found to have bilateral dome-shaped macula, associated with left serous macular detachment and left optic disc pit, and no evidence of posterior staphyloma in either eye, and to review the literature regarding dome-shaped macula in children and compare our patient's findings with similar case reports.

Observations: Our patient presented with bilateral dome-shaped macula and several other accompanying features, already described in previous reports in children her age.

Conclusions And Importance: Dome-shaped macula is a relatively new entity, which has been mainly described in highly myopic adults. Since its description, an increasing number of studies have been published to help characterise this condition and to elucidate its nature, causes, epidemiology and associated findings. Although the majority of the available data relate to adults, there are a number of studies that describe dome-shaped macula in children and adolescents. In this paper, we discuss the association of dome-shaped macula in children with posterior staphyloma, myopia, and suggest a possible developmental aetiology for this entity.
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http://dx.doi.org/10.1016/j.ajoc.2020.100821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387773PMC
September 2020

Oliver McFarlane syndrome and choroidal neovascularisation: a case report.

Ophthalmic Genet 2020 10 25;41(5):451-456. Epub 2020 Jun 25.

Moorfields Eye Hospital , London, UK.

Background: Oliver McFarlane syndrome (OMS) is a rare autosomal recessive disorder characterised by pigmentary chorioretinal atrophy with no previous reports of choroidal neovascularisation (CNV).

Material And Methods: We describe the history, findings of clinical examination, retinal imaging and electrodiagnostic studies, and the treatment of a patient with CNV secondary to OMS.

Case Description: CNV secondary to OMS was diagnosed in a ten-year-old white female who presented with reduced visual acuity and a macular haemorrhage in her right eye. CNV was confirmed on optical coherence tomography. She was initially treated with a single injection of intravitreal bevacizumab and 2 years later with an injection of intravitreal ranibizumab for a recurrence. Although macular scarring secondary to the CNV was observed, her vision has stabilised and she continues to be closely monitored.

Conclusion: We report the first case of CNV secondary to OMS and its successful treatment with intravitreal anti-vascular endothelial growth factor injections.
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http://dx.doi.org/10.1080/13816810.2020.1783689DOI Listing
October 2020

retinopathy: clinical features, molecular genetics and directions for future therapy.

Ophthalmic Genet 2020 06 22;41(3):208-215. Epub 2020 May 22.

UCL Institute of Ophthalmology, University College London , London, UK.

Kcnv2: -associated retinopathy or "cone dystrophy with supernormal rod responses" is an autosomal recessive cone-rod dystrophy with pathognomonic ERG findings. This gene encodes Kv8.2, a voltage-gated potassium channel subunit that acts as a modulator by shifting the activation range of the K channels in photoreceptor inner segments. Currently, no treatment is available for the condition. However, there is a lack of prospective long-term data in large molecularly confirmed cohorts, which is a prerequisite for accurate patient counselling/prognostication, to identify an optimal window for intervention and outcome measures, and ultimately to design future therapy trials. Herein we provide a detailed review of the clinical features, retinal imaging, electrophysiology and psychophysical studies, molecular genetics, and briefly discuss future prospects for therapy trials.
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http://dx.doi.org/10.1080/13816810.2020.1766087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446039PMC
June 2020

Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom.

Ophthalmology 2020 10 16;127(10):1384-1394. Epub 2020 Apr 16.

UCL Institute of Ophthalmology, University College London, London, United Kingdom; Genetics Service, Moorfields Eye Hospital, London, United Kingdom; Section of Ophthalmology, King's College London, St. Thomas' Hospital Campus, London, United Kingdom; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Purpose: In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene.

Design: Retrospective study of electronic patient records.

Participants: Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified.

Methods: Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource (https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94).

Main Outcome Measures: We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length.

Results: We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 (P = 0.025) overall and 0.27 (P = 0.017), -0.17 (P = 0.46), and 0.71 (P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively.

Conclusions: Our findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).
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http://dx.doi.org/10.1016/j.ophtha.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520514PMC
October 2020

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Invest Ophthalmol Vis Sci 2020 04;61(4):47

,.

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals.

Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated.

Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30.

Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).
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http://dx.doi.org/10.1167/iovs.61.4.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401957PMC
April 2020

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions.

Br J Ophthalmol 2021 02 8;105(2):151-157. Epub 2020 Apr 8.

UCL Institute of Ophthalmology, University College London, London, UK

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848059PMC
February 2021
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