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To analyze the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies.Multicenter international retrospective cohort study.Review of clinical notes, ophthalmic images, and genetic testing results of 104 patients (91 probands) with disease-causing CRB1 variants. Macular optical coherence tomography (OCT) parameters, visual function, fundus characteristics, and associations between variables were the main outcome measures.The mean age of the cohort at the first visit was 19.8 ± 16.1 (median 15) years, with a mean follow-up of 9.6 ± 10 years. Based on history, imaging, and clinical examination, 26 individuals were diagnosed with retinitis pigmentosa (RP; 25%), 54 with early-onset severe retinal dystrophy / Leber congenital amaurosis (EOSRD/LCA; 52%), and 24 with macular dystrophy (MD; 23%). Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. Longitudinal analysis revealed a significant difference between baseline and follow-up best-corrected visual acuity in the 3 subcohorts. Macular thickness decreased in most patients with EOSRD/LCA and MD, whereas the majority of patients with RP had increased perifoveal thickness.A subset of individuals with CRB1 variants present with mild, adult-onset RP. EOSRD/LCA phenotype was significantly associated with null variants, and 167_169 deletion was exclusively present in the MD cohort. The poor OCT lamination may have a degenerative component, as well as being congenital. Disease symmetry and reasonable window for intervention highlight CRB1 retinal dystrophies as a promising target for trials of novel therapeutics.

PURPOSE: Cataract surgery, quantity and quality, is an indicator of ophthalmic care. A comprehensive assessment of cataract surgical services has never been carried out in Palestine, including West Bank, Gaza Strip and East Jerusalem. The objective of this study was to estimate the cataract surgical rate in 2015 to and to explore the modes of payment and referral systems. METHODS: A cross-sectional study conducted between June and August 2016. Medical Directors from Cataract Surgical Centres in Palestine were interviewed using a structured questionnaire to extract data on cataract output and surgical techniques. Additionally, data were collected on modes of payment for cataract services. The cataract surgical rate was calculated by dividing the total cataract output in 2015 by the estimated population of Palestine in millions. RESULTS: In 2015, 9908 cataract surgeries were carried out in 22 centres. The cataract surgical rate was 2,117 operations per million population. Phacoemulsification was the most common technique (73.4%), however in government centres 67% were performed by extracapsular cataract extraction.In the Gaza Strip, 56.6% of cataract surgeries were operated at government centres, and 42.8% were operated at NGO centres while in West Bank, only 12% of cataract surgeries were operated at government centres, with two-thirds of cataracts diagnosed at governmental centres being referred to private and NGO centres. Seventy eight percent of cataract surgeries were funded by insurance, of which the government insurance scheme contributed 65%. CONCLUSION: The cataract surgical rate in Palestine falls short of the required WHO target. The majority of cataract surgeries are funded by insurance.

Item does not contain fulltext PURPOSE: To report genetic and clinical findings in a case series of 10 patients from eight unrelated families diagnosed with Senior-Løken syndrome. METHODS: A retrospective study of patients with Senior-Løken syndrome. Data collected included clinical findings electroretinography and ocular imaging. Genetic analysis was based on molecular inversion probes, whole-exome sequencing (WES), and Sanger sequencing. RESULTS: All patients who underwent electrophysiology (8/10) had widespread photoreceptor degeneration. Genetic analysis revealed two mutations in NPHP1, two mutations in NPHP4, and two mutations in IQCB1 (NPHP5). Five of the six mutations identified in the current study were found in a single family each in our cohort. The IQCB1-p.R461* mutation has been identified in 3 families. Patients harboring mutations in IQCB1 were diagnosed with Leber congenital amaurosis, while patients with NPHP4 and NPHP1 mutations showed early and sector retinitis pigmentosa, respectively. Full-field electroretinography was extinct for 6 of 10 patients, moderately decreased for two, and unavailable for another 2 subjects. Renal involvement was evident in 7/10 patients at the time of diagnosis. Kidney function was normal (based on serum creatinine) in patients younger than 10 years. Mutations in IQCB1 were associated with high hypermetropia, whereas mutations in NPHP4 were associated with high myopia. CONCLUSION: Patients presenting with infantile inherited retinal degeneration are not universally screened for renal dysfunction. Modern genetic tests can provide molecular diagnosis at an early age and therefore facilitate early diagnosis of renal disease with recommended periodic screening beyond childhood and family planning.

Contains fulltext : 251966.pdf (Publisher’s version ) (Open Access) PURPOSE: The effect of noncoding variants is often unknown in the absence of functional assays. Here, we characterized an ABCA4 intron 7 variant, c.859-25A>G, identified in Palestinian probands with Stargardt disease (STGD) or cone-rod dystrophy (CRD). We investigated the effect of this variant on the ABCA4 mRNA and retinal phenotype, and its prevalence in Palestine. METHODS: The ABCA4 gene was sequenced completely or partially in 1998 cases with STGD or CRD. The effect of c.859-25A>G on splicing was investigated in silico using SpliceAI and in vitro using splice assays. Homozygosity mapping was performed for 16 affected individuals homozygous for c.859-25A>G. The clinical phenotype was assessed using functional and structural analyses including visual acuity, full-field electroretinography, and multimodal imaging. RESULTS: The smMIPs-based ABCA4 sequencing revealed c.859-25A>G in 10 Palestinian probands from Hebron and Jerusalem. SpliceAI predicted a significant effect of this putative branchpoint-inactivating variant on the nearby intron 7 splice acceptor site. Splice assays revealed exon 8 skipping and two partial inclusions of intron 7, each having a deleterious effect. Additional genotyping revealed another 46 affected homozygous or compound heterozygous individuals carrying variant c.859-25A>G. Homozygotes shared a genomic segment of 59.6 to 87.9 kb and showed severe retinal defects on ophthalmoscopic evaluation. CONCLUSIONS: The ABCA4 variant c.859-25A>G disrupts a predicted branchpoint, resulting in protein truncation because of different splice defects, and is associated with early-onset STGD1 when present in homozygosity. This variant was found in 25/525 Palestinian inherited retinal dystrophy probands, representing one of the most frequent inherited retinal disease-causing variants in West-Bank Palestine.

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.

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.

PurposePathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity.MethodsTargeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation.ResultsFourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers.ConclusionsThe study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases. Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Whelan, Laura. Trinity College; Estados Unidos Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: De Baere, Elfride. University of Ghent; Bélgica Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel Fil: Bauwens, Miriam. University of Ghent; Bélgica Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos Fil: Defoort, Sabine. Universite Lille; Francia Fil: Devos, Aurore. Universite Lille; Francia Fil: Dockery, Adrian. Trinity College; Estados Unidos Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa Fil: Fakin, Ana. Charles University and General University Hospital; República Checa Fil: Farrar, G. Jane. Trinity College; Estados Unidos Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Glavac, Damjan. University of Ljubljana; Eslovenia Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania Fil: Jägle, Herbert. University Regensburg; Alemania Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia Fil: Kellner, Ulrich. No especifíca; Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa Fil: Lamey, Tina M.. University of Western Australia; Australia Fil: MacDonald, Ian M.. University of Alberta; Canadá Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: McLaren, Terri L.. University of Western Australia; Australia Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Meunier, Isabelle. Université Montpellier II; Francia Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Newman, Hadas. Universitat Tel Aviv; Israel Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica Fil: Oldak, Monika. No especifíca; Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Puech, Bernard. Universite Lille; Francia Fil: Ramesar, Raj. University of Cape Town; Sudáfrica Fil: Rüther, Klaus. No especifíca; Fil: Salameh, Manar. No especifíca; Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia Fil: Spital, Georg. No especifíca; Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Szaflik, Jacek P.. No especifíca; Fil: Thompson, Jennifer A.. No especifíca; Fil: Thuillier, Caroline. Universite Lille; Francia Fil: Tracewska, Anna M.. No especifíca; Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda Fil: Zanlonghi, Xavier. No especifíca; Fil: Liskova, Petra. Charles University and General University Hospital; República Checa Fil: Stöhr, Heidi. Universitat Regensburg; Alemania Fil: De Roach, John N.. University of Western Australia; Australia Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España Fil: Roberts, Lisa. University of Cape Town; Sudáfrica Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania Fil: Dhaenens, Claire Marie. Universite Lille; Francia Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos

Precise genetic and phenotypic characterization of congenital stationary night blindness (CSNB) patients is needed for future therapeutic interventions. The aim of this study was to estimate the prevalence of CSNB in our populations and to study clinical and genetic aspects of the autosomal recessive (AR) form of CSNB. This is a retrospective cohort study of Palestinian and Israeli CSNB patients harboring mutations in TRPM1 underwent comprehensive ocular examination. Genetic analysis was performed using homozygosity mapping and sequencing. 161 patients (from 76 families) were recruited for this study, leading to a prevalence of 1:6210 in the vicinity of Jerusalem, much higher than the worldwide prevalence. 61% of the families were consanguineous with AR inheritance pattern. Biallelic pathogenic TRPM1 mutations were identified in 36 families (72 patients). Two founder mutations explain the vast majority of cases: a nonsense mutation c.880A>T (p.Lys294*) identified in 22 Palestinian families and a large genomic deletion (36,445 bp) encompassing exons 2–7 of TRPM1 present in 13 Ashkenazi Jewish families. Most patients were myopic (with mean BCVA of 0.40 LogMAR) and all had absent rod responses in full field electroretinography. To the best of our knowledge, this is the largest report of a clinical and genetic analysis of patients affected with CSNB due to TRPM1 mutations.

PURPOSE To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses. METHODS Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES). RESULTS Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjogren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2. CONCLUSION Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.

Purpose Preeclampsia is a multisystem disorder defined as new onset of hypertension and proteinuria during the second half of pregnancy. Serous retinal detachment (SRD) is a known complication of preeclampsia caused by choroidal ischemia and subsequent disruption of blood-retinal barrier. Poor perfusion of the choriocapillaris causes Elschnig's spots. We aim to describe distinctive optical coherence tomography (OCT) features of a cluster of Elschnig's spots in a patient with severe preeclampsia during the acute and remission stages. We also present a summary of OCT features of preeclampsia patients with SRD. Methods Descriptive case report. Results V-shaped adhesions were observed at the location of each of the Elschnig's spots, the center of which showed disruption of the outer retinal bands (external limiting membrane, inner segment/outer segment junction layer), and the V-shaped outer parts remained tethered to retinal pigment epithelium (RPE)-Bruch's complex by hyperreflective exudate on the surface of RPE. These features parallel the histopathologic features described earlier. In an experimental model, Elschnig's spots showed a gradient of RPE damage from the center to the periphery, where RPE was necrotic in the center and edematous in the periphery. Three months later, spectral-domain OCT (SD-OCT) showed focal RPE elevations at the location of each of the Elschnig's spots. Conclusions We illustrate the distinctive SD-OCT features of a cluster of Elschnig's spots in the acute and chronic stages of preeclampsia and demonstrate the correlation with the previously described histopathologic features. Despite the favorable visual outcome, irreversible tissue damage may occur, necessitating prompt diagnosis and immediate therapeutic intervention.