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Malena Daich Varela, Thales Antonio Cabral de Guimaraes, Michalis Georgiou, Michel Michaelides | British Journal of Ophthalmology | Volume 6, Issue 4 | 12 March, 2021 Abstract 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. RPE65 -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- cis -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. Introduction Leber congenital amaurosis (LCA) represents one of the severest diagnoses a family can receive regarding a child’s eyesight. It is characterized by early-onset visual impairment, nystagmus or roving eyes and severe photoreceptor dysfunction. 1 LCA and early-onset severe retinal degeneration (EOSRD) belong to the same disease spectrum, with the latter being less severe; later onset of visual impairment, often better preserved visual acuity and decreased, but usually present electrophysiological responses. 1 LCA/EOSRD affect approximately 1 in 80 000 children worldwide. 2 Retinal examination can be unremarkable especially in the early stages or show mild signs such as retinal pigment epithelial mottling and vessel narrowing. 3 Salt and pepper retinopathy, optic disc pallor and retinal pigment clumping (including nummular and bone spicule) usually appear in older individuals. Link to full article

Won Gi Chung , Jiuk Jang , Gang Cui , Sanghoon Lee , Han Jeong , Haisu Kang , Hunkyu Seo , Sumin Kim , Enji Kim , Junwon Lee , Seung Geol Lee , Suk Ho Byeon , Jang-Ung Park  | Nature Nanotechnology | 15 January 2024 | Vol 19 | Pages 688–697 | Link to article Abstract Electronic retinal prostheses for stimulating retinal neurons are promising for vision restoration. However, the rigid electrodes of conventional retinal implants can inflict damage on the soft retina tissue. They also have limited selectivity due to their poor proximity to target cells in the degenerative retina. Here we present a soft artificial retina (thickness, 10 μm) where flexible ultrathin photosensitive transistors are integrated with three-dimensional stimulation electrodes of eutectic gallium–indium alloy. Platinum nanoclusters locally coated only on the tip of these three-dimensional liquid-metal electrodes show advantages in reducing the impedance of the stimulation electrodes. These microelectrodes can enhance the proximity to the target retinal ganglion cells and provide effective charge injections (72.84 mC cm−2) to elicit neural responses in the retina. Their low Young’s modulus (234 kPa), owing to their liquid form, can minimize damage to the retina. Furthermore, we used an unsupervised machine learning approach to effectively identify the evoked spikes to grade neural activities within the retinal ganglion cells. Results from in vivo experiments on a retinal degeneration mouse model reveal that the spatiotemporal distribution of neural responses on their retina can be mapped under selective localized illumination areas of light, suggesting the restoration of their vision. Main Retinal degenerative diseases, including retinitis pigmentosa and age-related macular degeneration, can cause gradual loss or permanent damage to photoreceptor cells, resulting in severe vision impairment 1 , 2 . However, the inner retinal neurons (ganglion and bipolar cells) can be preserved despite photoreceptor degeneration. An electronic retinal prosthesis, which electrically stimulates inner retinal neurons using photoresponsive devices, has emerged as a promising method to restore vision 3 , 4 , 5 , 6 . The electrical activation of retinal neurons can generate visual perceptions (phosphene) 7 , 8 , 9 , 10 , 11 , 12 , 13 . This device has been adapted to human subjects blind by retinal degeneration, although still being limited by low visual acuity. The subretinal prosthesis, placed between the retinal pigment epithelium and the degenerated photoreceptor layer, provides stable mechanical fixation of the device, but has a greater degree of surgical difficulty with a limited implant size. The risks associated with subretinal implantation also include residual photoreceptor loss and retinal pigment epithelium disruption. Although subretinal implantation is routinely done in vitreoretinal surgery, the epiretinal prosthesis, placed inside the vitreous and facing the retinal ganglion cell (RGC) side, has shown promise in both long- and short-term clinical observations. However, the results have proven that one of the main limitations is caused by the unconformities between the retina and the implant, since the threshold to elicit retinal responses depends on the electrode–cell distance 13 , 14 , 15 , 16 , 17 , 18 . Low proximity resulting from these unconformities can also induce the lateral spread of the electric field, decreasing the spatial resolution of stimulation 19 , 20 . This imprecise stimulation on the epiretinal surface can excite the RGC axons, which traverse between the device and RGCs, generating irregular visual perceptions to patients 21 . To enhance stimulation resolution and minimize axonal stimulation, it is important to establish a precise and stable contact and reduce the distance between the target RGC bodies and the stimulation electrodes, thereby reducing the activation thresholds of the RGC somas. However, patients with severe retinal degenerative diseases have locally non-uniform retinal surfaces, which can create an undesired geometrical gap between the retinal surface and stimulation electrodes 19 , 22 . To read entire article, click here References He, S., Dong, W., Deng, Q., Weng, S. & Sun, W. Seeing more clearly: recent advances in understanding retinal circuitry. Science 302, 408–411 (2003). Bloch, E., Luo, Y. & da Cruz, L. Advances in retinal prosthesis systems. Ther. Adv. Ophthalmol. 11, 2515841418817501 (2019). Lee, G. J., Choi, C., Kim, D.-H. & Song, Y. M. Bioinspired artificial eyes: optic components, digital cameras, and visual prostheses. Adv. Funct. Mater. 28, 1705202 (2018). Sahel, J.-A. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat. Med. 27, 1223–1229 (2021). Rao, Z. et al. Curvy, shape-adaptive imagers based on printed optoelectronic pixels with a kirigami design. Nat. Electron. 4, 513–521 (2021). Ko, H. C. et al. A hemispherical electronic eye camera based on compressible silicon optoelectronics. Nature 454, 748–753 (2008). Lorach, H. et al. Photovoltaic restoration of sight with high visual acuity. Nat. Med. 21, 476–482 (2015). Mathieson, K. et al. Photovoltaic retinal prosthesis with high pixel density. Nat. Photon. 6, 391–397 (2012). Tang, J. et al. Nanowire arrays restore vision in blind mice. Nat. Commun. 9, 786 (2018). Jang, J. et al. Implantation of electronic visual prosthesis for blindness restoration. Opt. Mater. Express 9, 3878–3894 (2019). Maya-Vetencourt, J. F. Subretinally injected semiconducting polymer nanoparticles rescue vision in a rat model of retinal dystrophy. Nat. Nanotechnol. 15, 30 (2020). Mandel, Y. et al. Cortical responses elicited by photovoltaic subretinal prostheses exhibit similarities to visually evoked potentials. Nat. Commun. 4, 1980 (2013). Sachs, H. G. & Gabel, V.-P. Retinal replacement—the development of microelectronic retinal prostheses—experience with subretinal implants and new aspects. Graefe ’ s Arch. Clin. Exp. Ophthalmol. 242, 717–723 (2004). Yue, L. et al. Ten-year follow-up of a blind patient chronically implanted with epiretinal prosthesis Argus I. Ophthalmology 122, 2545–2552.e1 (2015). Xie, H. et al. Monitoring cortical response and electrode-retina impedance under epiretinal stimulation in rats. IEEE Trans. Neural Syst. Rehabil. Eng. 29, 1178–1187 (2021). Lee, K.-W. et al. Pillar-shaped stimulus electrode array for high-efficiency stimulation of fully implantable epiretinal prosthesis. J. Micromech. Microeng. 22, 105015 (2012). Ahuja, A. K. et al. Factors affecting perceptual threshold in Argus II retinal prosthesis subjects. Trans. Vis. Sci. Technol. 2, 1 (2013). Ghani, N., Bansal, J., Naidu, A. & Chaudhary, K. M. Long term positional stability of the Argus II retinal prosthesis epiretinal implant. BMC Ophthalmol. 23, 70 (2023). Palanker, D., Vankov, A., Huie, P. & Baccus, S. Design of a high-resolution optoelectronic retinal prosthesis. J. Neural Eng. 2, S105–S120 (2005). Flores, T. et al. Optimization of pillar electrodes in subretinal prosthesis for enhanced proximity to target neurons. J. Neural Eng. 15, 036011 (2018). Esler, T. B. et al. Minimizing activation of overlying axons with epiretinal stimulation: the role of fiber orientation and electrode configuration. PLoS ONE 13, e0193598 (2018). Todorova, M. G., Scholl, H. P. N. & della Volpe Waizel, M. The impact of macular edema on microvascular and metabolic alterations in retinitis pigmentosa. Graefe’s Arch. Clin. Exp. Ophthalmol. 259, 643–652 (2021).

Margarita Sharova, Tatyana Markova, Maria Sumina, Marina Petukhova, Maria Bulakh, Oxana Ryzhkova, Tatyana Nagornova, Sofya Ionova, Andrey Marakhonov, Elena Dadali, Sergey Kutsev  |  Genes | 20 June 2023 | Vol 14 (8) | page 1553 | doi.org/10.3390/genes14081553 Abstract Here we present a patient with a cranioectodermal phenotype associated with pathogenic variants in the IFT140 gene. Most frequently, pathogenic variants in IFT140 correspond to the phenotype of Mainzer–Saldino syndrome. Only four patients have previously been described with this cranioectodermal phenotype and variants in IFT140 . In comparison to other IFT140-cranioectodermal patients, our proband had similar skeletal features among with early onset end-stage renal failure that required kidney transplantation but did not have common ophthalmological features such as retinopathy, optic nerve atrophy, or nystagmus. Following exome sequencing, a splicing variant and exons 27–30 tandem duplication were suspected and further validated. The two other patients with Mainzer–Saldino syndrome that we described displayed a typical clinical picture but a special diagnostic journey. In both cases, at first only one pathogenic variant was detected following panel or exome NGS sequencing. Further WGS was performed for one of them where tandem duplication was found. Screening the third patient for the same tandem duplication was successful and revealed the presence of this duplication. Thus, we suggest that the description of the clinical feature polymorphism in a rare IFT140-cranioectodermal phenotype is extremely important for providing genetic counseling for families, as well as the formation of the correct diagnostic path for patients with a variant in IFT140 . 1. Introduction The IFT140 gene encodes for the IFT140 protein, which is part of a large multi-protein complex called the intraflagellar transport (IFT) complex. This complex is essential for the formation, maintenance, and function of the cilia, which are hair-like structures that extend from the surface of diverse types of cells. Biallelic pathogenic variants in IFT140 or other IFT-A complex genes can cause defective retrograde cilial transport [ 1 ]. This can result in a range of disorders known as ciliopathies, which can affect multiple organ systems and cause a variety of symptoms, including vision and hearing loss, skeletal abnormalities, kidney disease, and developmental delay [ 2 , 3 ]. The IFT140 gene is associated with several different phenotypes, such as Short-rib thoracic dysplasia, type 9 syndrome (OMIM #266920), and Retinitis pigmentosa, type 80 (OMIM #617781), as per OMIM database. Short-rib thoracic dysplasia, type 9 syndrome encompasses phenotypic spectrum from less severe Mainzer–Saldino syndrome to asphyxiating thoracic dystrophy or Jeune syndrome. Mainzer–Saldino syndrome (MSS) is characterized by a combination of the cone-shaped epiphyses of the phalanges, early onset of renal failure, and retinal dystrophy. Symptoms of thoracic dysplasia are not dominant in the phenotype and patients can develop a narrow chest and recurrent respiratory infections without asphyxia or other severe symptoms. Occasionally, patients can present liver fibrosis, mild developmental delay, and cerebellar ataxia [ 4 , 5 ]. More than 40 variants in the IFT140 gene have been described in patients with MSS or other short-rib thoracic dysplasia phenotypes, according to the HGMD database to date (2022.1 version). Additionally, according to recent publications, the IFT140 gene is associated with another newly described phenotype called Cranioectodermal dysplasia or Sensenbrenner syndrome [ 6 , 7 , 8 ]. Cranioectodermal dysplasia (CED) is characterized by the combination of MSS symptoms with craniofacial abnormalities (frontal bossing, dolichocephaly, sagittal craniosynostosis, epicanthal folds, telecanthus, hypertelorism) and ectodermal anomalies (sparse and thin hair, dental hypoplasia, oligodontia, nail dysplasia) [ 9 , 10 ]. There are only a few patients described in the literature with CED associated with the IFT140 gene [ 6 , 7 , 8 ]. Here, we present the fifth patient with IFT140 CED phenotype. We compared this patient with two other MSS patients with IFT140 variants in our cohort and their diagnostic journeys. Click here to read entire article References Liem, K.F.; Ashe, A.; He, M.; Satir, P.; Moran, J.; Beier, D.; Wicking, C.; Anderson, K.V. The IFT-A Complex Regulates Shh Signaling through Cilia Structure and Membrane Protein Trafficking. J. Cell Biol. 2012, 197 , 789–800. Waters, A.M.; Beales, P.L. Ciliopathies: An Expanding Disease Spectrum. Pediatr. Nephrol. 2011, 26 , 1039–1056. Yeh, T.C.; Niu, D.M.; Cheng, H.C.; Chen, Y.R.; Chen, L.Z.; Tsui, S.P.; Liao, T.W.E.; Wang, A.G.; Yang, C.F. Novel Mutation of IFT140 in an Infant with Mainzer-Saldino Syndrome Presenting with Retinal Dystrophy. Mol. Genet. Metab. Rep. 2022, 33 , 100937. Perrault, I.; Saunier, S.; Hanein, S.; Filhol, E.; Bizet, A.A.; Collins, F.; Salih, M.A.M.; Gerber, S.; Delphin, N.; Bigot, K.; et al. Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations. Am. J. Hum. Genet. 2012, 90 , 864–870. Oud, M.M.; Latour, B.L.; Bakey, Z.; Letteboer, S.J.; Lugtenberg, D.; Wu, K.M.; Cornelissen, E.A.M.; Yntema, H.G.; Schmidts, M.; Roepman, R.; et al. Cellular Ciliary Phenotyping Indicates Pathogenicity of Novel Variants in IFT140 and Confirms a Mainzer-Saldino Syndrome Diagnosis. Cilia 2018, 7 , 1. Walczak-Sztulpa, J.; Posmyk, R.; Bukowska-Olech, E.M.; Wawrocka, A.; Jamsheer, A.; Oud, M.M.; Schmidts, M.; Arts, H.H.; Latos-Bielenska, A.; Wasilewska, A. Compound Heterozygous IFT140 Variants in Two Polish Families with Sensenbrenner Syndrome and Early Onset End-Stage Renal Disease. Orphanet J. Rare Dis. 2020, 15 , 36. Bayat, A.; Kerr, B.; Douzgou, S. The Evolving Craniofacial Phenotype of a Patient with Sensenbrenner Syndrome Caused by IFT140 Compound Heterozygous Mutations. Clin. Dysmorphol. 2017, 26 , 247–251. Walczak-Sztulpa, J.; Wawrocka, A.; Doornbos, C.; van Beek, R.; Sowińska-Seidler, A.; Jamsheer, A.; Bukowska-Olech, E.; Latos-Bieleńska, A.; Grenda, R.; Bongers, E.M.H.F.; et al. Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes—Challenges for the Accurate Diagnosis. Front. Genet. 2022, 13 , 931822. Zaffanello, M.; Diomedi-Camassei, F.; Melzi, M.L.; Torre, G.; Callea, F.; Emma, F. Sensenbrenner Syndrome: A New Member of the Hepatorenal Fibrocystic Family. Am. J. Hum. Genet. 2006, 221 , 212–221. Handa, A.; Voss, U.; Hammarsjö, A.; Grigelioniene, G.; Nishimura, G. Skeletal Ciliopathies: A Pattern Recognition Approach. Jpn. J. Radiol. 2020, 38 , 193–206.

JOHN A. GERMILLER MD, PhD | Pediatric Otolaryngology | 2007 | doi.org/10.1016/B978-0-323-04855-2.50009-5 Usher Syndrome Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, SNHL, and variable vestibular system pathology. Various types exist. Usher syndrome type I is the most severe type, with profound deafness at birth and severe vestibular dysfunction. It is caused by mutations in the MYO7A gene, which encodes a protein involved in proper functioning of the stereociliary bundle on sensory hair cells. Patients with type II Usher syndrome have less severe hearing impairment than in type I disease. Type III Usher's syndrome is characterized by intact hearing at birth that progressively deteriorates throughout life, without balance disturbance. In all forms of Usher syndrome, early referral to an ophthalmologist is important to monitor for retinitis pigmentosa and its associated vision loss. Hearing loss must be monitored especially carefully and managed aggressively in this syndrome because of the additional disability possible from multiple sensory impairments. Click here to read chapter

Lucy S. French, Carla B. Mellough, Fred K. Chen, and Livia S. Carvalho | Frontiers Cell. Neuroscience | 09 July 2020 | Sec. Cellular Neuropathology | Volume 14 | 2020 | doi.org/10.3389/fncel.2020.00183 Abstract Usher syndrome is a genetic disorder causing neurosensory hearing loss and blindness from retinitis pigmentosa (RP). Adaptive techniques such as braille, digital and optical magnifiers, mobility training, cochlear implants, or other assistive listening devices are indispensable for reducing disability. However, there is currently no treatment to reduce or arrest sensory cell degeneration. There are several classes of treatments for Usher syndrome being investigated. The present article reviews the progress this research has made towards delivering commercial options for patients with Usher syndrome. Introduction Usher syndrome is a group of autosomal recessive disorders characterized by congenital neurosensory hearing loss, progressive night vision impairment, and constriction of the visual field due to retinitis pigmentosa (RP). Some forms of Usher syndrome may also have varying levels of vestibular dysfunction resulting in loss of balance. It is the most common form of inherited deaf-blindness (El-Amraoui and Petit, 2014) affecting an estimated 1 in 6,000 people worldwide (Kimberling et al., 2010). Usher subtypes (1, 2, and 3; Table 1) are graded according to the severity of symptoms and age of onset. Type 1 patients are born profoundly deaf and experience pre-pubertal onset of progressive vision loss caused by RP. The majority of type 1 patients also have developmental motor delays caused by vestibular dysfunction. Type 2 patients have mild to moderate congenital hearing loss with RP diagnosed during puberty. Hearing loss in type 3 patients is progressive and post-lingual, while RP onset may be delayed until mid-adulthood (Reiners et al., 2006). The clinical presentation of RP begins with night blindness caused by the degeneration of rod photoreceptor cells. Subsequent constriction of the visual field results in a “tunnel vision” effect caused by the centripetal progression of cone photoreceptor cell loss. In classical RP, the death of cones may be secondary to rod degeneration and this may ultimately lead to complete loss of vision in advanced age (Hartong et al., 2006). Many other inherited retinal diseases are associated with deafness (Table 2) such as cone-rod dystrophy and hearing loss-1 (CRDHL1, OMIM #617236), diabetes and deafness, maternally inherited (MIDD, OMIM #520000) and Leber congenital amaurosis (LCA) with early-onset deafness (LCAEOD, OMIM #617879). This review is limited to the combination of RP and deafness, the classical presentation of Usher syndrome. Click here to read source article.

Regulates ciliary localization of Joubert syndrome-associated protein INPP5E Kollu N. Rao, Wei Zhang, Linjing Li, Manisha Anand, and Hemant Khanna, Human Molecular Genetics | Vol 25, Issue 20 | pgs. 4533 - 4545 | 15 Oct 2016 | https://doi.org/10.1093/hmg/ddw281 Abstract Ciliary trafficking defects underlie the pathogenesis of severe human ciliopathies, including Joubert Syndrome (JBTS), Bardet-Biedl Syndrome, and some forms of retinitis pigmentosa (RP). Mutations in the ciliary protein RPGR (retinitis pigmentosa GTPase regulator) are common causes of RP-associated photoreceptor degeneration worldwide. While previous work has suggested that the localization of RPGR to cilia is critical to its functions, the mechanism by which RPGR and its associated cargo are trafficked to the cilia is unclear. Using proteomic and biochemical approaches, we show that RPGR interacts with two JBTS-associated ciliary proteins: PDE6B (delta subunit of phosphodiesterase; a prenyl-binding protein) and INPP5E (inositol polyphosphate-5-phosphatase 5E). We find that PDE6B binds selectively to the C-terminus of RPGR and that this interaction is critical for RPGR’s localization to cilia. To read the original article, click here

ARVO Annual Meeting Ali Sakawa Sharif, Christin Hanke-Gogokhia, Jeanne M Frederick, Wolfgang Baehr | Investigative Ophthalmology & Visual Science | July 2018 | Vol.59 | 3068 Abstract Purpose Mutations in INPP5E are associated with Joubert syndrome and MORM disease (mental retardation, truncal obesity, retinal dystrophy and micropenis). Joubert syndrome is a syndromic ciliopathy that includes ataxia, hyperpnea, abnormal eye and tongue movements, polydactyly and retinitis pigmentosa. To date, the function of INPP5E is unclear. Germline deletion of INPP5E is embryonically lethal in mouse, therefore, we sought to study INPP5E function by generating retina- and photoreceptor-specific knockouts. Our goal is to identify the onset of degeneration and devise gene-based therapies to ameliorate or cure the retina disease. Methods Conditional Inpp5e knockout mice were generated by mating Inpp5eflox/flox mice with Six3-Cre, iCre75, or inducible ET-Cre transgenic mice. Mating of floxed mice with various Cre-expressing mice excises Inpp5e exons 2-6 in photoreceptor progenitors, rods or mature photoreceptors, respectively. Deletion of exons 2-6 removes much of the INPP5E phosphatase domain. Retina phenotypes are subsequently characterized by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT), rotarod performance test, OptoMotry, confocal immunohistochemistry using a battery of outer segment-related antibodies, transmission electron microscopy and immunoblotting. Click here to read original article To register for this year's ARVO Conference, click here.

detection of rare variants in syndromic and non-syndromic IRD Abstract 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. To read the original article, click here

Scheie Eye Institute | 51 North 39th Street | Philadelphia, PA 19104 | July 30, 2020 SUMMARY "Inherited retinal diseases (IRDs) refer to a heterogenous group of conditions where 300+ distinct single-gene defects act on rod or cone photoreceptors to cause vision loss. Worldwide prevalence of IRDs are thought to be 1 in 1000. One of the most common IRDs is autosomal dominant retinitis pigmentosa (adRP) caused by Rhodopsin (RHO) mutations. RHO is expressed in rod photoreceptors which provide us with night vision. Many aspects of the human RHO-associated adRP has been described by our group over the last 3 decades. "We have also investigated naturally occurring dogs, and genetically engineered pigs, rats, and mice with RHO mutations." "Our earlier work concentrated on understanding of disease phenotype, progression, and interaction with light. More recently we have directed our attention to gene-based treatments and outcome measures to be used in clinical trials." Click here to read original post. Cideciyan Lab Scheie Eye Institute 51 North 39th Street Philadelphia, PA 19104 215-662-9986

A Long-Term Follow-Up Study Nguyen, Xuan-Thanh-An MD | Talib, Mays MD | van Cauwenbergh, Caroline PhD; van Schooneveld, Mary J. MD, PhD | Fiocco, Marta PhD; Wijnholds, Jan PhD | ten Brink, Jacoline B. BAS | Florijn, Ralph J. PhD | Schalij-Delfos, Nicoline E. MD, PhD | Dagnelie, Gislin PhD | van Genderen, Maria M. MD, PhD | de Baere, Elfride MD, PhD†; Meester-Smoor, Magda A. PhD | De Zaeytijd, Julie MD | Balikova, Irina MD, PhD | Thiadens, Alberta A. MD, PhD | Hoyng, Carel B. MD, PhD | Klaver, Caroline C. MD, PhD | van den Born, L. Ingeborgh MD, PhD | Bergen, Arthur A. PhD | Leroy, Bart P. MD, PhD | Boon, Camiel J.F. MD, PhD Retina 41(1) | p 213-223 | January 2021 | DOI: 10.1097/IAE.0000000000002808 Purpose To investigate the natural history of RHO-associated retinitis pigmentosa (RP). Methods A multi-center, medical chart review of 100 patients with autosomal dominant RHO-associated RP. Results Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor–retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001). Conclusion: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies. Read entire article here. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.

Hae Rang Kim, Jinu Han, Yong Joon Kim, Hyun Goo Kang, Suk Ho Byeon, Sung Soo Kim, and Christopher Seungkyu Lee | Genes | 4 July 2022 | 13 (7) | pg. 1197 | https://doi.org/10.3390/genes13071197 Abstract Autosomal recessive bestrophinopathy (ARB) is a rare subtype of bestrophinopathy caused by biallelic mutations of the BEST1 gene. ARB is characterized by multifocal subretinal deposits accompanied by macular edema or subretinal fluid, hyperopia, co-existing narrow angle, and a marked decrease in electrooculogram. However, little is known about the genetic variants and specific clinical features of ARB. This is an observational case series of patients with a clinical and genetic diagnosis of ARB who underwent multimodal imaging. We describe ten patients from nine unrelated families with six known variants and three novel missense variants: c.236C→T, p.(Ser79Phe); C.452C→T, p.(Leu151Pro); and c.650C→T, p.(Trp217Met). The most common variant was c.584C→T, p.(Ala195Val), observed in six patients, without correlation to the severity of the phenotype. All patients manifested bilateral multifocal subretinal deposits and subretinal fluid throughout the follow-up period, while intraretinal fluid was found in approximately half of the eyes. The extent or chronicity of the fluid collection did not correlate with visual acuity. Angle-closure glaucoma was present in five eyes. Three patients had a genetically confirmed family history of ARB, and one patient had a clinically suspected family history. This study reveals novel mutations in the BEST1 gene and adds to the spectrum of clinical presentations of ARB. 1. Introduction Bestrophinopathy is a spectrum of inherited macular degenerations caused by mutations in the BEST1 gene [ 1 ]. BEST1 is located on chromosome 11q13 [ 2 , 3 ] and encodes bestrophin-1, a 585 amino-acid calcium-activated Cl− channel localized to the basolateral membrane of retinal pigment epithelium (RPE) [ 4 ]. Mutation in the BEST1 gene might result in abnormal functioning of the protein bestrophin-1, an anion channel in the RPE, leading to a variety of retinopathies [ 5 , 6 ]. The most prevalent variant, Best vitelliform macular dystrophy [VMD, also known as Best disease; Online Mendelian Inheritance in Man identifier (OMIM), 153700], is characterized by prominent central macular lesions that undergo consecutive morphologic changes from characteristic ‘egg-yolk’ appearance in the vitelliform stage to vitelliruptive stage, pseudohypopion state, and atrophic stage [ 7 ]. Since the first report in 1905 by Friedrich, a wide array of missense mutations in BEST1 variants have been reported [ 8 ]. Other subtypes include adult-onset vitelliform macular dystrophy (OMIM 153840), autosomal dominant vitreoretinochoroidopathy (OMIM 193220), retinitis pigmentosa 50 (OMIM 613194), and autosomal recessive bestrophinopathy (OMIM 611809) [ 7 ]. In 2006, Schatz et al. first reported two related patients with multifocal vitelliform dystrophy and compound heterozygous BEST1 variants. Burgess et al. then denominated the term “autosomal recessive bestrophinopathy” (ARB) as a new BEST1 -associated phenotype. Unlike missense mutations in autosomal dominant inheritance of VMD, ARB is caused by a homozygous or compound heterozygous BEST1 mutation with a modifier effect of the first on the second mutation in the latter [ 9 , 10 ]. ARB is characterized by multifocal diffuse subretinal deposits that appear hyperfluorescent on fundus autofluorescence imaging, accompanied by macular edema or subretinal fluid, hyperopia, and co-existing narrow angle. Electrophysiological characteristics include a marked decrease in light rise on electrooculography (EOG) and relatively preserved electroretinography (ERG) parameters unless photoreceptor cells are severely damaged. Although abnormal EOG findings are crucial for the diagnosis of bestrophinopathy, mutation analysis is necessary to confirm the diagnosis of a specific subtype of bestrophinopathy. The prevalence of ARB is estimated to be 1/1,000,000 [ 9 ]. In Korea, only two patients with ARB from a single family were reported in 2015 [ 11 ]. Herein, we report on ten patients with ARB due to mutations in BEST1 , characterizing their clinical features and genetic mutations . Click here to read more References Lee, J.H.; Oh, J.O.; Lee, C.S. Induced Pluripotent Stem Cell Modeling of Best Disease and Autosomal Recessive Bestrophinopathy. Yonsei Med. J. 2020, 61 , 816–825. Forsman, K.; Graff, C.; Nordström, S.; Johansson, K.; Westermark, E.; Lundgren, E.; Gustavson, K.H.; Wadelius, C.; Holmgren, G. The gene for Best’s macular dystrophy is located at 11q13 in a Swedish family. Clin. Genet. 1992, 42 , 156–159. Stone, E.M.; Nichols, B.E.; Streb, L.M.; Kimura, A.E.; Sheffield, V.C. Genetic linkage of vitelliform macular degeneration (Best’s disease) to chromosome 11q13. Nat. Genet. 1992, 1 , 246–250. Marmorstein, A.D.; Marmorstein, L.Y.; Rayborn, M.; Wang, X.; Hollyfield, J.G.; Petrukhin, K. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proc. Natl. Acad. Sci. USA 2000, 97 , 12758–12763. Yang, T.; Justus, S.; Li, Y.; Tsang, S.H. BEST1: The Best Target for Gene and Cell Therapies. Mol. Ther. 2015, 23 , 1805–1809. Xiao, Q.; Hartzell, H.C.; Yu, K. Bestrophins and retinopathies. Pflugers Arch. 2010, 460 , 559–569. Boon, C.J.; Klevering, B.J.; Leroy, B.P.; Hoyng, C.B.; Keunen, J.E.; den Hollander, A.I. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog. Retin Eye Res. 2009, 28 , 187–205. Best, F., II. Über eine hereditäre Maculaaffektion. Ophthalmologica 1905, 13 , 199–212. Habibi, I.; Falfoul, Y.; Todorova, M.G.; Wyrsch, S.; Vaclavik, V.; Helfenstein, M.; Turki, A.; Matri, K.E.; Matri, L.E.; Schorderet, D.F. Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB). Genes 2019, 10 , 953. Burgess, R.; Millar, I.D.; Leroy, B.P.; Urquhart, J.E.; Fearon, I.M.; De Baere, E.; Brown, P.D.; Robson, A.G.; Wright, G.A.; Kestelyn, P.; et al. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am. J. Hum. Genet. 2008, 82 , 19–31. Lee, C.S.; Jun, I.; Choi, S.I.; Lee, J.H.; Lee, M.G.; Lee, S.C.; Kim, E.K. A Novel BEST1 Mutation in Autosomal Recessive Bestrophinopathy. Investig. Ophthalmol. Vis. Sci. 2015, 56 , 8141–8150.

Zeinab Fadaie ,  Laura Whelan ,  Adrian Dockery ,  Catherina H Z Li ,  L Ingeborgh van den Born ,  Carel B Hoyng ,  Christian Gilissen ,  Jordi Corominas ,  Charlie Rowlands ,  Roly Megaw ,  Anne K Lampe ,  Frans P M Cremers ,  Gwyneth Jane Farrar ,  Jamie M Ellingford ,  Paul F Kenna ,  Susanne Roosing | Journal Medical Genetics | 2022 May | 59(5) | pgs. 438-444 | doi: 10.1136/jmedgenet-2020-107626 Background Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 ( BBS1 ) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in BBS1 and assessed its pathogenicity by in vitro functional analysis. Methods Whole genome sequencing was performed for three unrelated monoallelic BBS1 cases with non-syndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in BBS1 . After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of Bardet-Biedl syndrome. Results Clinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritization, two pathogenic variants in BBS1 , the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>G and c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial in-frame deletion of exon 8. Conclusion A putative severe branchpoint variant in BBS1 , together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis. Click here to read entire article and see references _____________________________ Correspondence to Susanne Roosing, Department of Human Genetics, Radboudumc, Nijmegen 6525 GA, The Netherlands; Susanne.Roosing@radboudumc.nl