Publications by authors named "Michel Michaelides"

283 Publications

Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts.

Eye (Lond) 2021 Aug 3. Epub 2021 Aug 3.

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

Background: Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.

Methods: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing.

Results: Family A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470-477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case.

Conclusions: We have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.
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http://dx.doi.org/10.1038/s41433-021-01711-xDOI Listing
August 2021

Agreement Between Spectral-Domain and Swept-Source Optical Coherence Tomography Retinal Thickness Measurements in Macular and Retinal Disease.

Ophthalmol Ther 2021 Jul 29. Epub 2021 Jul 29.

NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, London, Institute of Ophthalmology, University College London, 162 City Road, London, EC1V 2PD, UK.

Introduction: To assess inter-device agreement in optical coherence tomography-derived retinal thickness measurements in patients with known macular conditions between spectral-domain and swept-source optical coherence tomography (OCT).

Methods: Two hundred seventy-two subjects were included in the study. They consisted of 91 male (33.5%) and 181 female (66.5%) subjects, and 132 left (48.5%) and 140 right (51.5%) eyes. Each subject underwent spectral-domain OCT (SD-OCT, Spectralis, Heidelberg Engineering; RTVue XR Avanti XR HD, Optovue) and swept-source OCT (SS-OCT; DRI-OCT-1, Atlantis, Topcon) in a single imaging session performed by the same clinical trial-certified technician. The comparison of retinal thickness reproducibility between devices was performed using Bland-Altman analyses and across the entire data set using the intraclass correlation coefficient (ICC).

Results: The ICC of the retinal thickness measurements (95% confidence interval) made using all three OCT instruments was 0.81 (0.77-0.84). The mean difference in mean retinal thickness between Spectralis SD-OCT and Topcon SS-OCT was 59.1 μm (95% limit of agreement [LoA] -21.7 to 139.8 μm). The mean difference in mean retinal thickness between Optovue SD-OCT and Topcon SS-OCT was 21.8 μm (95% LoA -34.7  to 78.3 μm).

Conclusions: Retinal layer thickness measurements vary between SS-OCT and SD-OCT devices. We describe inter-device agreement in retinal thickness between SS-OCT and SD-OCT in patients with macular conditions. Clinicians should be aware of the differences in retinal thickness values when imaging patients using different OCT devices and should consider using the same OCT device model in order to monitor clinical change.

Trial Registration: ClinicalTrials.gov Identifier (NCT02828215).
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http://dx.doi.org/10.1007/s40123-021-00377-8DOI Listing
July 2021

Swept-source optical coherence tomography changes and visual acuity among Palestinian retinitis Pigmentosa patients: a cross-sectional study.

BMC Ophthalmol 2021 Jul 29;21(1):289. Epub 2021 Jul 29.

St. John of Jerusalem Eye Hospital Group, East Jerusalem, 91198, Palestine.

Background: Retinitis pigmentosa (RP) is a heterogeneous group of inherited ocular diseases that result in progressive retinal degeneration. This study aims to describe different Swept-source Optical Coherence Tomographic (SS-OCT) changes in Palestinian RP patients and to explore possible correlations with Visual Acuity (VA).

Methods: A cross-sectional observational study was conducted on Retinitis Pigmentosa patients diagnosed with RP in a tertiary eye hospital. Full history and ocular examination were made. SS-OCT imaging was done for all eyes assessing the presence of cystoid macular edema, epiretinal membrane, macular holes, and external limiting membrane, ellipsoid zone status. Also, central macular thickness and choroidal vascular thickness were measured.

Results: The study was run on 161 eyes of 81 patients; 53 males and 28 females. The average age at examination was 26.1 (6-78) years. Twenty-six eyes (16.1%) were of syndromic RP patients, mostly Usher syndrome; 20 eyes (12.4%). The mean Logaritmic minimal angle of resolution (LogMAR) of Best Corrected Visual Acuity (BCVA)of the study sample was 0.66 ± 0.7. The most prevalent change was cystoid macular edema [28 eyes, (17.4%)], followed by epiretinal membrane [17eye, (10.6%)]. A macular hole was noted only in one eye (0.6%). Ellipsoid zone and external limiting membrane were absent in 55 eyes (35.0%) and 60 eyes 37.5%. Vitreous hyperreflective foci were found in 35 eyes (43.8%). LogMAR of BCVA was associated significantly with cystoid macular edema (p = 0.001), ellipsoid zone(p = 0.001), and external limiting membrane (p = 0.001).

Conclusions: Detailed SS-OCT assessment in Palestinian patients diagnosed with RP identified different morphologies from other populations. Cystoid macular edema and vitreous hyperreflective foci may reflect signs of early or intermediate stages of the disease. Disease progression can be monitored by measuring the length/width (area) of ellipsoid zone +/- external limiting membrane and choroidal vascular thickness, which should be evaluated serially using high-resolution OCT.
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http://dx.doi.org/10.1186/s12886-021-02047-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320214PMC
July 2021

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

Foveal structure and visual function in nanophthalmos and posterior microphthalmos.

Br J Ophthalmol 2021 Jul 22. Epub 2021 Jul 22.

Moorfields Eye Hospital NHS Foundation Trust, London, UK

Background/aims: The reason for visual impairment in patients with nanophthalmos and posterior microphthalmos is not completely understood. Therefore, this study aims to investigate foveal structure, and the impact of demographic, clinical and imaging parameters on best-corrected visual acuity (BCVA) in these conditions.

Methods: Sixty-two eyes of 33 patients with nanophthalmos (n=40) or posterior microphthalmos (n=22), and 114 eyes of healthy controls with high-resolution retinal imaging including spectral-domain or swept-source optical coherence tomography images were included in this cross-sectional case-control study. Foveal retinal layer thickness was determined by two independent readers. A mixed-effect model was used to perform structure-function correlations and predict the BCVA based on subject-specific variables.

Results: Most patients (28/33) had altered foveal structure associated with loss of foveal avascular zone and impaired BCVA. However, widening of outer nuclear layer, lengthening of photoreceptor outer segments, normal distribution of macular pigment and presence of Henle fibres were consistently found. Apart from the presence of choroidal effusion, which had significant impact on BCVA, the features age, refractive error, axial length and retinal layer thickness at the foveal centre explained 61.7% of the variability of BCVA.

Conclusion: This study demonstrates that choroidal effusion, age, refractive error, axial length and retinal layer thickness are responsible for the majority of interindividual variability of BCVA as well as the morphological foveal heterogeneity in patients with nanophthalmos or posterior microphthalmos. This might give further insights into the physiology of foveal development and the process of emmetropisation, and support clinicians in the assessment of these disease entities.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318717DOI 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

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD.

NPJ Genom Med 2021 Jun 29;6(1):53. Epub 2021 Jun 29.

Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.
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http://dx.doi.org/10.1038/s41525-021-00214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242099PMC
June 2021

Examining Whether AOSLO-Based Foveal Cone Metrics in Achromatopsia and Albinism Are Representative of Foveal Cone Structure.

Transl Vis Sci Technol 2021 05;10(6):22

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

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable.

Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable.

Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups.

Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients.

Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.
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http://dx.doi.org/10.1167/tvst.10.6.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132001PMC
May 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

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

Cell Rep 2021 Apr;35(3):109022

UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Kellogg Eye Centre, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA. Electronic address:

Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.
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http://dx.doi.org/10.1016/j.celrep.2021.109022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065177PMC
April 2021

CNGB1-related rod-cone dystrophy: A mutation review and update.

Hum Mutat 2021 Jun 16;42(6):641-666. Epub 2021 May 16.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.

Cyclic nucleotide-gated channel β1 (CNGB1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at noncanonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications, and 1 gross deletion. According to the American College of Medical Genetics and Genomics classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases, which, overall, are in line with previous findings suggesting that this form of RP has long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials.
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http://dx.doi.org/10.1002/humu.24205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218941PMC
June 2021

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

Panel-based genetic testing for inherited retinal disease screening 176 genes.

Mol Genet Genomic Med 2021 Mar 22:e1663. Epub 2021 Mar 22.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: This case series reports the performance of a next-generation sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with inherited retinal disease (IRD).

Methods: Subjects are patients who underwent genetic testing between 1 August 2016 and 1 January 2018 at Moorfields Eye Hospital, London, UK. Panel-based genetic testing was performed unless a specific gene (e.g., RS1) or small group of genes (e.g., ABCA4, PRPH2) were suspected. If a novel variant was identified, a further comment on their predicted pathogenicity and evolutionary conservation was offered and segregation studies performed. The main outcome measure is the likelihood of obtaining a genetic diagnosis using NGS 176.

Results: 488 patients were included. A molecular diagnosis was obtained for 59.4% of patients. Younger patients were more likely to receive a molecular diagnosis; with 92% of children under the age of 6 years receiving a conclusive result. There was a change in their initially assigned inheritance pattern in 8.4% of patients following genetic testing. Selected IRD diagnoses (e.g., achromatopsia, congenital stationary night blindness) were associated with high diagnostic yields.

Conclusion: This study confirms that NGS 176 is a useful first-tier genetic test for most IRD patients. Age and initial clinical diagnosis were strongly associated with diagnostic yield.
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http://dx.doi.org/10.1002/mgg3.1663DOI Listing
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 Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy.

Ophthalmology 2021 Jun 1;128(6):952-955. Epub 2020 Nov 1.

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

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http://dx.doi.org/10.1016/j.ophtha.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162661PMC
June 2021

The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline.

Transl Vis Sci Technol 2020 10 8;9(11). Epub 2020 Oct 8.

Baylor College of Medicine, Houston, TX, USA.

Purpose: The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 ()-related Retinal Degeneration (RUSH2A) multicenter study.

Methods: Participants had Usher syndrome type 2 (USH2, = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP,  = 47) associated with biallelic variants in the gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models.

Results: In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV;  = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated ( = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders ( = 0.04) and duration of visual loss ( < 0.001) also were associated with FST white stimulus.

Conclusions: USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression.

Translational Relevance: Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with mutations.
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http://dx.doi.org/10.1167/tvst.9.11.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552938PMC
October 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
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