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2. Argus II retinal prosthesis implantation with scleral flap and autogenous temporalis fascia as alternative patch graft material: a 4-year follow-up

Author

Matet A, Amar N, Mohand-Said S, Sahel JA, and Barale PO

Subjects
visual prosthesis, autograft, surgical procedure, conjunctiva, intraocular pressure, Ophthalmology, RE1-994
Abstract

Alexandre Matet,1,2 Nawel Amar,1,2 Saddek Mohand-Said,1–4 José-Alain Sahel,1–7 Pierre-Olivier Barale1,2 1INSERM and DHOS, CHNO des Quinze-Vingts, 2Sorbonne Universités, UPMC Univ Paris 6, Institut de la Vision, 3INSERM, 4CNRS, Paris, France; 5Institute of Ophthalmology, University College London, London, UK; 6Fondation Ophtalmologique Adolphe de Rothschild, 7Académie des Sciences, Institut de France, Paris, France Introduction: The Argus II retinal prosthesis is composed of an epiretinal electrode array positioned over the macula and connected to an extrascleral electronics case via a silicone cable, running through a sclerotomy. During implantation, the manufacturer recommends to cover the sclerotomy site with a patch of processed human pericardium to prevent postoperative hypotony and conjunctival erosion by the underlying electronics case. Due to biomedical regulations prohibiting the use of this material in France, we developed an alternative technique combining a scleral flap protecting the sclerotomy and an autogenous graft of superior temporalis fascia overlying the electronics case. Methods: The purpose of this study is to describe the 4-year outcomes of this modified procedure in three subjects who underwent Argus II Retinal Prosthesis System implantation. Clinical data consisting of intraocular pressure measurements and tolerance in terms of conjunctival erosion or inflammation were retrospectively assessed over a 4-year postoperative follow-up. Results: None of the three patients implanted with the modified technique developed ocular hypotony over 4 years. A normal, transient conjunctival inflammation occurred during the first postoperative month but conjunctival erosion was not observed in any of the three patients over 4 years. Four years after implantation, the autogenous temporalis fascia graft remained well tolerated and the retinal prosthesis was functional in all three patients. Conclusion: The combination of an autograft of superficial temporalis fascia and a scleral flap efficiently prevented leakage through the sclerotomy site, ocular hypotony, and conjunctival erosion by the extrascleral electronics case. This modified technique is suitable for the implantation of existing and forthcoming retinal prostheses. Superficial temporalis fascia may also be used as alternative to commercial tectonic tissues for scleral wound repair in clinical settings where they are not available. Keywords: visual prosthesis, retinitis pigmentosa, surgical procedure, conjunctiva, intraocular pressure

Published
2016

4. The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

Author

Black G. C., Sergouniotis P., Sodi A., Leroy B. P., Van Cauwenbergh C., Liskova P., Gronskov K., Klett A., Kohl S., Taurina G., Sukys M., Haer-Wigman L., Nowomiejska K., Marques J. P., Leroux D., Cremers F. P. M., De Baere E., Dollfus H., Ashworth J., Audo I., Bacci G., Balciuniene V. J., Bargiacchi S., Bertelsen M., Black G., Boon C., Bremond-Gignac D., Buzzonetti L., Calvas P., Thomsen A. C., Chirita-Emandi A., Chokoshvili D., Cremers F., Daly A., Downes S., Fasolo A., Fasser C., Fischer D., Fortunato P., Gelzinis A., Hall G., Hamann S., Heon E., Iarossi G., Iberg C., Jouanjan G., Kaariainen H., Kahn K., Keegan D., Laengsfeld M., Leon A., Leroux B., Lorenz B., Maggi R., Mauring L., Melico P., Meunier I., Mohand-Said S., Monterosso C., Morandi P., Parmeggiani F., Passerini I., Pelletier V., Peluso F., Perdomo Y., Rapizzi E., Roos L., Roosing S., Rozet J. -M., Simonelli F., Sowden J., Stingl K., Suppiej A., Testa F., Tracewska A., Traficante G., Valeina S., Wheeler-Schilling T., Yu-Wai-Man P., Zeitz C., Zemaitiene R., Leroux, Dorothée [0000-0002-1412-6611], Apollo - University of Cambridge Repository, Ophthalmology, ANS - Complex Trait Genetics, Black, G. C., Sergouniotis, P., Sodi, A., Leroy, B. P., Van Cauwenbergh, C., Liskova, P., Gronskov, K., Klett, A., Kohl, S., Taurina, G., Sukys, M., Haer-Wigman, L., Nowomiejska, K., Marques, J. P., Leroux, D., Cremers, F. P. M., De Baere, E., Dollfus, H., Ashworth, J., Audo, I., Bacci, G., Balciuniene, V. J., Bargiacchi, S., Bertelsen, M., Black, G., Boon, C., Bremond-Gignac, D., Buzzonetti, L., Calvas, P., Thomsen, A. C., Chirita-Emandi, A., Chokoshvili, D., Cremers, F., Daly, A., Downes, S., Fasolo, A., Fasser, C., Fischer, D., Fortunato, P., Gelzinis, A., Hall, G., Hamann, S., Heon, E., Iarossi, G., Iberg, C., Jouanjan, G., Kaariainen, H., Kahn, K., Keegan, D., Laengsfeld, M., Leon, A., Leroux, B., Lorenz, B., Maggi, R., Mauring, L., Melico, P., Meunier, I., Mohand-Said, S., Monterosso, C., Morandi, P., Parmeggiani, F., Passerini, I., Pelletier, V., Peluso, F., Perdomo, Y., Rapizzi, E., Roos, L., Roosing, S., Rozet, J. -M., Simonelli, F., Sowden, J., Stingl, K., Suppiej, A., Testa, F., Tracewska, A., Traficante, G., Valeina, S., Wheeler-Schilling, T., Yu-Wai-Man, P., Zeitz, C., and Zemaitiene, R.

Subjects
0301 basic medicine, Eye Diseases, lcsh:Medicine, CHILDREN, Position statement, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], MOLECULAR-GENETICS, 0302 clinical medicine, HISTORY, Health care, Medicine and Health Sciences, Genetics(clinical), Pharmacology (medical), Child, Genetics (clinical), medicine.diagnostic_test, General Medicine, Genomics, Europe, TRIALS, ERN-EYE, Rare eye diseases, medicine.symptom, Genetic and genomic testing, Human, medicine.medical_specialty, Visual impairment, LEBER CONGENITAL AMAUROSIS, Socio-culturale, DIAGNOSIS, 03 medical and health sciences, Rare Diseases, medicine, Humans, Genetic Testing, Intensive care medicine, Genetic testing, business.industry, CLINICAL-FEATURES, lcsh:R, Rare eye disease, Eye Disease, Human genetics, Clinical trial, 030104 developmental biology, Genomic, 030221 ophthalmology & optometry, Personalized medicine, business, Rare disease
Abstract

Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

Published
2021

5. Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study

Author

Garweg, Jg, Stefanickova, J, Hoyng, C, Schmelter, T, Niesen, T, Sowade, O, Sivaprasad, S, Adan, A, Alexik, M, Ali, F, Amaro, M, Balciuniene, V, Bandello, Fm, Arias Barquet, L, Beck, A, Bell, K, Boscia, F, Bures, A, Carneiro, A, Chow, Dr, Cimbalas, A, Dahlke, C, Deepali, V, Dickinson, Jd, Dollin, M, Eandi, C, Emmerich, K, Feltgen, N, Pereira Figueira, J, Findl, O, Gajdosova, M, Gale, Rp, John Galic, I, Garweg, J, Gasser-Steiner, V, Giunta, M, Gonder, Jr, Grzybowski, A, Hamouz, J, Hattenbach, L, Holz, Fg, Jesia, H, Kaluzny, J, Kerenyi, A, Kertes, Pj, Koch, F, Kodjikan, L, Lederer, De, Liehneova, I, Lorenz, K, Lotery, Aj, Mckibbin, M, Menon, Gv, Michalewska, Z, Midena, E, Nicolo, M, Papp, A, Pavlovicova, G, Peiretti, E, Vaz-Pereira, S, Perri, P, Petropoulos, I, Queguiner, F, Raczynska, K, Sararols-Ramsay, L, Rekas, M, Ricci, F, Romanowska-Dixon, B, Sachs, Hg, Mohand-Said, S, Sandner, D, Schmidt-Erfurth, U, Sekundo, W, Seres, A, Souied, E, Castro de Sousa, J, Stankiewicz, A, Struharova, K, Studnicka, J, Cervera Taulet, E, Taylor, S, Teper, S, Vajas, A, Cava Valenciano, C, Varsanyi, B, Viola, F, Virgili, G, Wagenfeld, L, Walters, G, Wiedemann, P, Zarnowski, T, Garweg, J. G., Stefanickova, J., Hoyng, C., Schmelter, T., Niesen, T., Sowade, O., Sivaprasad, S., Adan, A., Alexik, M., Ali, F., Amaro, M., Balciuniene, V. -J., Bandello, F. M., Arias Barquet, L., Beck, A., Bell, K., Boscia, F., Bures, A., Carneiro, A., Chow, D. R., Cimbalas, A., Dahlke, C., Deepali, V., Dickinson, J. D., Dollin, M., Eandi, C., Emmerich, K. -H., Feltgen, N., Pereira Figueira, J., Findl, O., Gajdosova, M., Gale, R. P., John Galic, I., Garweg, J., Gasser-Steiner, V., Giunta, M., Gonder, J. R., Grzybowski, A., Hamouz, J., Hattenbach, L. -O., Holz, F. G., Jesia, H., Kaluzny, J., Kerenyi, A., Kertes, P. J., Koch, F., Kodjikan, L., Lederer, D. E., Liehneova, I., Lorenz, K., Lotery, A. J., Mckibbin, M., Menon, G. V., Michalewska, Z., Midena, E., Nicolo, M., Papp, A., Pavlovicova, G., Peiretti, E., Vaz-Pereira, S., Perri, P., Petropoulos, I., Queguiner, F., Raczynska, K., Sararols-Ramsay, L., Rekas, M., Ricci, F., Romanowska-Dixon, B., Sachs, H. G., Mohand-Said, S., Sandner, D., Schmidt-Erfurth, U., Sekundo, W., Seres, A., Souied, E., Castro de Sousa, J., Stankiewicz, A., Struharova, K., Studnicka, J., Cervera Taulet, E., Taylor, S., Teper, S., Vajas, A., Cava Valenciano, C., Varsanyi, B., Viola, F., Virgili, G., Wagenfeld, L., Walters, G., Wiedemann, P., and Zarnowski, T.

Subjects
Male, Vascular Endothelial Growth Factor A, Diabetic Retinopathy, Recombinant Fusion Proteins, Visual Acuity, Angiogenesis Inhibitors, Middle Aged, Macular Edema, Diabetes Mellitus, Type 1, Receptors, Vascular Endothelial Growth Factor, Diabetes Mellitus, Type 2, Settore MED/30, Sickness Impact Profile, Surveys and Questionnaires, Intravitreal Injections, Quality of Life, Humans, Female, Single-Blind Method, Tomography, Optical Coherence, Vision, Ocular, Aged
Abstract

Purpose: To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). Design: AQUA was a multicenter, open-label, single-arm, phase 4 study. Participants: Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. Methods: Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. Main Outcome Measures: The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. Results: A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was –175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. Conclusions: Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.

Published
2019

6. An ontological foundation for ocular phenotypes and rare eye diseases

Author

Sergouniotis, Panagiotis I., Maxime, Emmanuel, Leroux, Dorothée, Olry, Annie, Thompson, Rachel, Rath, Ana, Robinson, Peter N., Dollfus, Hélèneashworth, Jl, Audo, I, Balciuniene, Vj, Banin, E, Black, Gc, Böhringer, D, Boon, Cjf, Bremond-Gignac, D, Calvas, P, Castela, G, Dagnelie, G, Dollfus, H, Downes, Sm, Fasolo, A, Fasser, C, Gelzinis, A, Goetz, K, Hamann, S, Héon, E, Iarossi, G, Kawasaki, A, Keegan, D, Kessel, L, Khan, K, Klett, A, Köhler, S, Leroux, D, Leroy, Bp, Lisch, W, Liskova, P, Lorenz, B, Maggi, R, Maxime, E, Meunier, I, Mohand-Said, S, Nowomiejska, K, Perdomo, Y, Petzold, A, Preising, M, Robinson, Pn, Scholl, Hpn, Sergouniotis, Pi, Sodi, A, Stingl, K, Studer, F, Suppiej, A, Thompson, R, Touitou, V, Traboulsi, E, Trumpaitis, J, Tuft, Sj, Vaclavik, V, Valeina, S, Van Cauwenbergh, C, Verloes, A, Vighetto, A, Wheeler, R, Wheeler-Schilling, T, Yu-Wai-Man, P, Zobor, D, Zrenner, E., Sergouniotis, Panagiotis I [0000-0003-0986-4123], Apollo - University of Cambridge Repository, University of Manchester [Manchester], Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Newcastle University [Newcastle], The Jackson Laboratory for Genomic Medicine, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and European Project: 0305444(2003)

Subjects
0301 basic medicine, Eye Diseases, Computer science, Evidence-based precision medicine, Rare eye disease, Human phenotype ontology, Orphanet rare disease ontology, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030105 genetics & heredity, Ontology (information science), Terminology, NO, Open Biomedical Ontologies, MESH: Eye Diseases / classificationHumans Precision Medicine / methods* Rare Diseases / classification, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Human Phenotype Ontology, Eye Diseases/classification, Humans, Pharmacology (medical), Precision Medicine, Letter to the Editor, MESH: Humans Precision Medicine / methods, Genetics (clinical), Information exchange, Evidence-Based Medicine, Orphanet rare disease ontology, Rare Diseases/classification, MESH: Computational Biology / methods, lcsh:R, Computational Biology, Human phenotype ontology, Biological Ontologies, Precision Medicine/methods, General Medicine, Evidence-based medicine, Rare eye disease, Computational Biology/methods, Data science, MESH: Rare Diseases / classification, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evidence-based precision medicine, Eye disorder, MESH: Biological Ontologies, MESH: Evidence-Based Medicine, 030217 neurology & neurosurgery
Abstract

Background The optical accessibility of the eye and technological advances in ophthalmic diagnostics have put ophthalmology at the forefront of data-driven medicine. The focus of this study is rare eye disorders, a group of conditions whose clinical heterogeneity and geographic dispersion make data-driven, evidence-based practice particularly challenging. Inter-institutional collaboration and information sharing is crucial but the lack of standardised terminology poses an important barrier. Ontologies are computational tools that include sets of vocabulary terms arranged in hierarchical structures. They can be used to provide robust terminology standards and to enhance data interoperability. Here, we discuss the development of the ophthalmology-related component of two well-established biomedical ontologies, the Human Phenotype Ontology (HPO; includes signs, symptoms and investigation findings) and the Orphanet Rare Disease Ontology (ORDO; includes rare disease nomenclature/nosology). Methods A variety of approaches were used including automated matching to existing resources and extensive manual curation. To achieve the latter, a study group including clinicians, patient representatives and ontology developers from 17 countries was formed. A broad range of terms was discussed and validated during a dedicated workshop attended by 60 members of the group. Results A comprehensive, structured and well-defined set of terms has been agreed on including 1106 terms relating to ocular phenotypes (HPO) and 1202 terms relating to rare eye disease nomenclature (ORDO). These terms and their relevant annotations can be accessed in http://www.human-phenotype-ontology.org/ and http://www.orpha.net/; comments, corrections, suggestions and requests for new terms can be made through these websites. This is an ongoing, community-driven endeavour and both HPO and ORDO are regularly updated. Conclusions To our knowledge, this is the first effort of such scale to provide terminology standards for the rare eye disease community. We hope that this work will not only improve coding and standardise information exchange in clinical care and research, but also it will catalyse the transition to an evidence-based precision ophthalmology paradigm. Electronic supplementary material The online version of this article (10.1186/s13023-018-0980-6) contains supplementary material, which is available to authorized users.

Published
2019

7. Pathway Analysis Integrating Genome-Wide and Functional Data Identifies PLCG2 as a Candidate Gene for Age-Related Macular Degeneration

Author

Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Waksmunski, AR, Grunin, M, Kinzy, TG, Igo, RP, Haines, JL, Bailey, JNC, Fritsche, LG, Igl, W, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, M, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Ouyang, H, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Stark, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-A, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, S, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, A, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

PURPOSE: Age-related macular degeneration (AMD) is the worldwide leading cause of blindness among the elderly. Although genome-wide association studies (GWAS) have identified AMD risk variants, their roles in disease etiology are not well-characterized, and they only explain a portion of AMD heritability. METHODS: We performed pathway analyses using summary statistics from the International AMD Genomics Consortium's 2016 GWAS and multiple pathway databases to identify biological pathways wherein genetic association signals for AMD may be aggregating. We determined which genes contributed most to significant pathway signals across the databases. We characterized these genes by constructing protein-protein interaction networks and performing motif analysis. RESULTS: We determined that eight genes (C2, C3, LIPC, MICA, NOTCH4, PLCG2, PPARA, and RAD51B) "drive" the statistical signals observed across pathways curated in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and Gene Ontology (GO) databases. We further refined our definition of statistical driver gene to identify PLCG2 as a candidate gene for AMD due to its significant gene-level signals (P < 0.0001) across KEGG, Reactome, GO, and NetPath pathways. CONCLUSIONS: We performed pathway analyses on the largest available collection of advanced AMD cases and controls in the world. Eight genes strongly contributed to significant pathways from the three larger databases, and one gene (PLCG2) was central to significant pathways from all four databases. This is, to our knowledge, the first study to identify PLCG2 as a candidate gene for AMD based solely on genetic burden. Our findings reinforce the utility of integrating in silico genetic and biological pathway data to investigate the genetic architecture of AMD.

Published
2019

8. ERN-EYE: the European Reference Network dedicated to European patients with Rare Eye Diseases

Author

Leroux, D., Dollfus, H., Ashworth, J., Black, G., Bohringer, D., Boon, C.J., Cremers, F., Daly, A., Fasser, C., Fischer, D., Keegan, D., Khan, K., Larkin, F., Larsen, M., Leroy, B.P., Liskova, P., Lorenz, B., Martinho, C., Mohand-Said, S., Petzold, A., Preising, M., Reinhart, T., Wheeler-Schilling, T., Wong, S., Zrenner, E., and All ERN-EYE Members

Published
2018

9. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, L.G., Igl, W., Bailey, J.N., Grassmann, F., Sengupta, S, Bragg-Gresham, J.L., Burdon, K.P., Hebbring, S.J., Wen, C., Gorski, M., Kim, I.K., Cho, D., Zack, D., Souied, E., Scholl, H.P., Bala, E., Lee, K.E., Hunter, D.J., Sardell, R.J., Mitchell, P., Merriam, J.E., Cipriani, V., Hoffman, J.D., Schick, T., Lechanteur, Y.T., Guymer, R.H., Johnson, M.P., Jiang, Y., Stanton, C.M., Buitendijk, G.H., Zhan, X., Kwong, A.M., Boleda, A., Brooks, M., Gieser, L., Ratnapriya, R., Branham, K.E., Foerster, J.R., Heckenlively, J.R., Othman, M.I., Vote, B.J., Liang, H.H., Souzeau, E., McAllister, I.L., Isaacs, T., Hall, J., Lake, S., Mackey, D.A., Constable, I.J., Craig, J.E., Kitchner, T.E., Yang, Z, Su, Z., Luo, H., Chen, D., Ouyang, H., Flagg, K., Lin, D., Mao, G., Ferreyra, H., Stark, K., Strachwitz, C.N. von, Wolf, A., Brandl, C., Rudolph, G., Olden, M., Morrison, M.A., Morgan, D.J., Schu, M., Ahn, J., Silvestri, G., Tsironi, E.E., Park, K.H., Farrer, L.A., Orlin, A., Brucker, A., Li, M., Curcio, C.A., Mohand-Said, S., Sahel, J.A., Audo, I., Benchaboune, M., Cree, A.J., Rennie, C.A., Goverdhan, S.V., Grunin, M., Hagbi-Levi, S., Campochiaro, P., Katsanis, N., Holz, F.G., Blond, F., Blanche, H., Deleuze, J.F., Igo, R.P., Jr., Truitt, B., Peachey, N.S., Meuer, S.M., Myers, C.E., Moore, E.L., Klein, R., Hollander, A.I. den, Saksens, N.T.M., Hoyng, C.B., Jong, E.K. de, et al., Fritsche, L.G., Igl, W., Bailey, J.N., Grassmann, F., Sengupta, S, Bragg-Gresham, J.L., Burdon, K.P., Hebbring, S.J., Wen, C., Gorski, M., Kim, I.K., Cho, D., Zack, D., Souied, E., Scholl, H.P., Bala, E., Lee, K.E., Hunter, D.J., Sardell, R.J., Mitchell, P., Merriam, J.E., Cipriani, V., Hoffman, J.D., Schick, T., Lechanteur, Y.T., Guymer, R.H., Johnson, M.P., Jiang, Y., Stanton, C.M., Buitendijk, G.H., Zhan, X., Kwong, A.M., Boleda, A., Brooks, M., Gieser, L., Ratnapriya, R., Branham, K.E., Foerster, J.R., Heckenlively, J.R., Othman, M.I., Vote, B.J., Liang, H.H., Souzeau, E., McAllister, I.L., Isaacs, T., Hall, J., Lake, S., Mackey, D.A., Constable, I.J., Craig, J.E., Kitchner, T.E., Yang, Z, Su, Z., Luo, H., Chen, D., Ouyang, H., Flagg, K., Lin, D., Mao, G., Ferreyra, H., Stark, K., Strachwitz, C.N. von, Wolf, A., Brandl, C., Rudolph, G., Olden, M., Morrison, M.A., Morgan, D.J., Schu, M., Ahn, J., Silvestri, G., Tsironi, E.E., Park, K.H., Farrer, L.A., Orlin, A., Brucker, A., Li, M., Curcio, C.A., Mohand-Said, S., Sahel, J.A., Audo, I., Benchaboune, M., Cree, A.J., Rennie, C.A., Goverdhan, S.V., Grunin, M., Hagbi-Levi, S., Campochiaro, P., Katsanis, N., Holz, F.G., Blond, F., Blanche, H., Deleuze, J.F., Igo, R.P., Jr., Truitt, B., Peachey, N.S., Meuer, S.M., Myers, C.E., Moore, E.L., Klein, R., Hollander, A.I. den, Saksens, N.T.M., Hoyng, C.B., Jong, E.K. de, and et al.

Abstract

Item does not contain fulltext, Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 x 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 x 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016

10. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Author

Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, Heid, IM, Fritsche, LG, Igl, W, Bailey, JNC, Grassmann, F, Sengupta, S, Bragg-Gresham, JL, Burdon, KP, Hebbring, SJ, Wen, C, Gorski, M, Kim, IK, Cho, D, Zack, D, Souied, E, Scholl, HPN, Bala, E, Lee, KE, Hunter, DJ, Sardell, RJ, Mitchell, P, Merriam, JE, Cipriani, V, Hoffman, JD, Schick, T, Lechanteur, YTE, Guymer, RH, Johnson, MP, Jiang, Y, Stanton, CM, Buitendijk, GHS, Zhan, X, Kwong, AM, Boleda, A, Brooks, M, Gieser, L, Ratnapriya, R, Branham, KE, Foerster, JR, Heckenlively, JR, Othman, MI, Vote, BJ, Liang, HH, Souzeau, E, McAllister, IL, Isaacs, T, Hall, J, Lake, S, Mackey, DA, Constable, IJ, Craig, JE, Kitchner, TE, Yang, Z, Su, Z, Luo, H, Chen, D, Hong, O, Flagg, K, Lin, D, Mao, G, Ferreyra, H, Starke, K, von Strachwitz, CN, Wolf, A, Brandl, C, Rudolph, G, Olden, M, Morrison, MA, Morgan, DJ, Schu, M, Ahn, J, Silvestri, G, Tsironi, EE, Park, KH, Farrer, LA, Orlin, A, Brucker, A, Li, M, Curcio, CA, Mohand-Said, S, Sahel, J-M, Audo, I, Benchaboune, M, Cree, AJ, Rennie, CA, Goverdhan, SV, Grunin, M, Hagbi-Levi, S, Campochiaro, P, Katsanis, N, Holz, FG, Blond, F, Blanche, H, Deleuze, J-F, Igo, RP, Truitt, B, Peachey, NS, Meuer, SM, Myers, CE, Moore, EL, Klein, R, Hauser, MA, Postel, EA, Courtenay, MD, Schwartz, SG, Kovach, JL, Scott, WK, Liew, G, Tan, AG, Gopinath, B, Merriam, JC, Smith, RT, Khan, JC, Shahid, H, Moore, AT, McGrath, JA, Laux, R, Brantley, MA, Agarwal, A, Ersoy, L, Caramoy, A, Langmann, T, Saksens, NTM, de Jong, EK, Hoyng, CB, Cain, MS, Richardson, AJ, Martin, TM, Blangero, J, Weeks, DE, Dhillon, B, van Duijn, CM, Doheny, KF, Romm, J, Klaver, CCW, Hayward, C, Gorin, MB, Klein, ML, Baird, PN, den Hollander, AI, Fauser, S, Yates, JRW, Allikmets, R, Wang, JJ, Schaumberg, DA, Klein, BEK, Hagstrom, SA, Chowers, I, Lotery, AJ, Leveillard, T, Zhang, K, Brilliant, MH, Hewitt, AW, Swaroop, A, Chew, EY, Pericak-Vance, MA, DeAngelis, M, Stambolian, D, Haines, JL, Iyengar, SK, Weber, BHF, Abecasis, GR, and Heid, IM

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Published
2016

11. Transcriptome analysis of the rd1 mouse

Author

Leveillard, T., Lavedan, C., Mohand-Said, S., Dressman, M., Dolemeyer, A., Lambrou, G., and Sahel, J.

Subjects
Human genetics -- Research, Genetic disorders -- Research, Retina -- Abnormalities, Retinal degeneration -- Physiological aspects, Rods (Photoreceptors), Biological sciences
Published
2001

12. Detection of human faces by blind patients implanted with the Argus® II Retinal Prosthesis System

Author

Guerra, Stefania, Stanga, P., Merlini, F., Sahel, J., Mohand-Said, S., Da Cruz, L., Caspi, A., and Greenberg, R.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Purpose: To investigate whether Argus II subjects can locate human faces with their systems using a facial detection algorithm and whether detection speed improves when field of view that is mapped onto the Argus II implant is changed (i.e. demagnified). Methods: To date, more than 50 patients [for full text, please go to the a.m. URL], Artificial Vision 2013

Published
2014

13. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome

Author

Bujakowska, K.M., Zhang, Q, Siemiatkowska, A.M., Liu, Q., Place, E., Falk, M.J., Consugar, M., Lancelot, M.E., Antonio, A., Lonjou, C., Carpentier, W., Mohand-Said, S., Hollander, A.I. den, Cremers, F.P.M., Leroy, B.P., Gai, X., Sahel, J.A., Born, L.I. van den, Collin, R.W.J., Zeitz, C., Audo, I., Pierce, E.A., Bujakowska, K.M., Zhang, Q, Siemiatkowska, A.M., Liu, Q., Place, E., Falk, M.J., Consugar, M., Lancelot, M.E., Antonio, A., Lonjou, C., Carpentier, W., Mohand-Said, S., Hollander, A.I. den, Cremers, F.P.M., Leroy, B.P., Gai, X., Sahel, J.A., Born, L.I. van den, Collin, R.W.J., Zeitz, C., Audo, I., and Pierce, E.A.

Abstract

Item does not contain fulltext, Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog [IFT172 (Chlamydomonas)] that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.

Published
2015

14. Argus II users’ maximum visual acuity enhancement via the Acuboost™

Author

Sahel, JA, Merlini, F, Mohand-Said, S, Stanga, P, Caspi, A, Greenberg, RJ, and Cosendai, G

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Purpose: To demonstrate that magnification and image processing in retinal prosthesis with an external camera and processor can enable a visual acuity well beyond the limit set by theoretical resolution of the implanted array. Methods: To date, more than 60 patients blinded by outer retinal dystrophies[for full text, please go to the a.m. URL], 26. Internationaler Kongress der Deutschen Ophthalmochirurgen

Published
2013
Full Text
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21. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies

Author

Manes, G., Meunier, I., Avila-Fernandez, A., Banfi, S., Meur, G. Le, Zanlonghi, X., Corton, M., Simonelli, F., Brabet, P., Labesse, G., Audo, I., Mohand-Said, S., Zeitz, C., Sahel, J.A., Weber, M., Dollfus, H., Dhaenens, C.M., Allorge, D., Baere, E. de, Koenekoop, R.K., Kohl, S., Cremers, F.P.M., Hollyfield, J.G., Senechal, A., Hebrard, M., Bocquet, B., Garcia, C.A., Hamel, C.P., Manes, G., Meunier, I., Avila-Fernandez, A., Banfi, S., Meur, G. Le, Zanlonghi, X., Corton, M., Simonelli, F., Brabet, P., Labesse, G., Audo, I., Mohand-Said, S., Zeitz, C., Sahel, J.A., Weber, M., Dollfus, H., Dhaenens, C.M., Allorge, D., Baere, E. de, Koenekoop, R.K., Kohl, S., Cremers, F.P.M., Hollyfield, J.G., Senechal, A., Hebrard, M., Bocquet, B., Garcia, C.A., and Hamel, C.P.

Abstract

Item does not contain fulltext, Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507( *)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.

Published
2013

22. Genotyping microarray for CSNB-associated genes.

Author

Zeitz, C., Labs, S., Lorenz, B., Forster, U., Uksti, J., Kroes, H.Y., Baere, E. de, Leroy, B.P., Cremers, F.P.M., Wittmer, M., Genderen, M. van, Sahel, J.A., Audo, I., Poloschek, C.M., Mohand-Said, S., Fleischhauer, J.C., Huffmeier, U., Moskova-Doumanova, V., Levin, A.V., Hamel, C.P., Leifert, D., Munier, F.L., Schorderet, D.F., Zrenner, E., Friedburg, C., Wissinger, B., Kohl, S., Berger, W., Zeitz, C., Labs, S., Lorenz, B., Forster, U., Uksti, J., Kroes, H.Y., Baere, E. de, Leroy, B.P., Cremers, F.P.M., Wittmer, M., Genderen, M. van, Sahel, J.A., Audo, I., Poloschek, C.M., Mohand-Said, S., Fleischhauer, J.C., Huffmeier, U., Moskova-Doumanova, V., Levin, A.V., Hamel, C.P., Leifert, D., Munier, F.L., Schorderet, D.F., Zrenner, E., Friedburg, C., Wissinger, B., Kohl, S., and Berger, W.

Abstract

Contains fulltext : 80582.pdf (publisher's version ) (Closed access), PURPOSE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disease. Although electroretinographic (ERG) measurements can discriminate clinical subgroups, the identification of the underlying genetic defects has been complicated for CSNB because of genetic heterogeneity, the uncertainty about the mode of inheritance, and time-consuming and costly mutation scanning and direct sequencing approaches. METHODS: To overcome these challenges and to generate a time- and cost-efficient mutation screening tool, the authors developed a CSNB genotyping microarray with arrayed primer extension (APEX) technology. To cover as many mutations as possible, a comprehensive literature search was performed, and DNA samples from a cohort of patients with CSNB were first sequenced directly in known CSNB genes. Subsequently, oligonucleotides were designed representing 126 sequence variations in RHO, CABP4, CACNA1F, CACNA2D4, GNAT1, GRM6, NYX, PDE6B, and SAG and spotted on the chip. RESULTS: Direct sequencing of genes known to be associated with CSNB in the study cohort revealed 21 mutations (12 novel and 9 previously reported). The resultant microarray containing oligonucleotides, which allow to detect 126 known and novel mutations, was 100% effective in determining the expected sequence changes in all known samples assessed. In addition, investigation of 34 patients with CSNB who were previously not genotyped revealed sequence variants in 18%, of which 15% are thought to be disease-causing mutations. CONCLUSIONS: This relatively inexpensive first-pass genetic testing device for patients with a diagnosis of CSNB will improve molecular diagnostics and genetic counseling of patients and their families and gives the opportunity to analyze whether, for example, more progressive disorders such as cone or cone-rod dystrophies underlie the same gene defects.

Published
2009

23. Genotyping Microarray for CSNB-Associated Genes

Author

Zeitz, C, Labs, S, Lorenz, B, Forster, U, Üksti, J, Kroes, H Y, De Baere, E, Leroy, B P, Cremers, F P M, Wittmer, M, van Genderen, M M, Sahel, J A, Audo, I, Poloschek, C M, Mohand-Said, S, Fleischhauer, J C, Hüffmeier, U, Moskova-Doumanova, V, Levin, A V, Hamel, C P, Leifert, D, Munier, F L, Schorderet, D F, Zrenner, E, Friedburg, C, Wissinger, B, Kohl, S, Berger, W, Zeitz, C, Labs, S, Lorenz, B, Forster, U, Üksti, J, Kroes, H Y, De Baere, E, Leroy, B P, Cremers, F P M, Wittmer, M, van Genderen, M M, Sahel, J A, Audo, I, Poloschek, C M, Mohand-Said, S, Fleischhauer, J C, Hüffmeier, U, Moskova-Doumanova, V, Levin, A V, Hamel, C P, Leifert, D, Munier, F L, Schorderet, D F, Zrenner, E, Friedburg, C, Wissinger, B, Kohl, S, and Berger, W

Abstract

PURPOSE. Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disease. Although electroretinographic (ERG) measurements can discriminate clinical subgroups, the identification of the underlying genetic defects has been complicated for CSNB because ofgenetic heterogeneity, the uncertainty about the mode of inheritance, and time-consuming and costly mutation scanning and direct sequencing approaches. METHODS. To overcome these challenges and to generate a time- and cost-efficient mutation screening tool, the authors developed a CSNB genotyping microarray with arrayed primer extension (APEX) technology. To cover as many mutations as possible, a comprehensive literature search was performed, and DNA samples from a cohort of patients with CSNB were first sequenced directly in known CSNB genes. Subsequently, oligonucleotides were designed representing 126 sequence variations in RHO, CABP4, CACNA1F, CACNA2D4, GNAT1,GRM6, NYX, PDE6B, and SAG and spotted on the chip. RESULTS. Direct sequencing of genes known to be associated with CSNB in the study cohort revealed 21 mutations (12 novel and 9 previously reported). The resultant microarray containing oligonucleotides, which allow to detect 126 known and novel mutations, was 100% effective in determining the expected sequence changes in all known samples assessed. In addition, investigation of 34 patients with CSNB who were previously not genotyped revealed sequence variants in 18%, of which 15% are thought to be disease-causing mutations. CONCLUSIONS. This relatively inexpensive first-pass genetic testing device for patients with a diagnosis of CSNB will improve molecular diagnostics and genetic counseling of patients and their families and gives the opportunity to analyze whether, for example, more progressive disorders such as cone or cone–rod dystrophies underlie the same gene defects.

Published
2009

47. Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse

Author

Frasson M, Serge Picaud, Léveillard T, Simonutti M, Mohand-Said S, Dreyfus H, Hicks D, and Sabel J

Subjects
Mice, Inbred C3H, Cell Survival, Reverse Transcriptase Polymerase Chain Reaction, Retinal Degeneration, Rod Opsins, Gene Expression, Cell Count, Nerve Tissue Proteins, Mice, Mutant Strains, Cell Line, Mice, Inbred C57BL, Mice, Neuroprotective Agents, Retinal Rod Photoreceptor Cells, Electroretinography, Animals, Glial Cell Line-Derived Neurotrophic Factor, Nerve Growth Factors, RNA, Messenger, Fluorescent Antibody Technique, Indirect, Neuroglia
Abstract

To evaluate the neuroprotective potential of glial cell line-derived neurotrophic factor (GDNF) in the retinal degeneration (rd/rd) mouse model of human retinitis pigmentosa.Subretinal injections of GDNF were made into rd/rd mice at 13 and 17 days of age and electroretinograms (ERGs) recorded at 22 days. Control mice received saline vehicle injections or underwent no procedure. At 23 days of age, retinas from treated and control mice were fixed and processed for wholemount immunohistochemistry using an anti-rod opsin antibody, and rod numbers were estimated using an unbiased stereological systematic random approach. Subsequent to counting, immunolabeled retinas were re-embedded and sectioned in a transverse plane and the numbers of rods recalculated.Although ERGs could not be recorded from sham-operation or nonsurgical rd/rd mice at 22 days of age, detectable responses (both a- and b-waves) were observed in 4 of 10 GDNF-treated mice. Stereological assessment of immunolabeled rods at 23 days showed that control rd/rd retinas contained 41,880+/-3,890 (mean +/- SEM; n = 6), phosphate-buffered saline (PBS)-injected retinas contained 61,165+/-4,932 (n = 10; P0.001 versus control retinas) and GDNF-injected retinas contained 89,232+/-8,033 (n = 10; P0.001 versus control retinas, P0.002 versus PBS). This increase in rod numbers after GDNF treatment was confirmed by cell counts obtained from frozen sections.GDNF exerts both histologic and functional neuroprotective effects on rod photoreceptors in the rd/rd mouse. Thus rescue was demonstrated in an animal model of inherited retinal degeneration in which the gene defect was located within the rods themselves, similar to most forms of human retinitis pigmentosa. GDNF represents a candidate neurotrophic factor for palliating some forms of hereditary human blindness.

49. [A new mode of recording retinal activity: multifocal ERG]

Author

Mack, G., Dolfus, H., Flament, J., Mohand-Said, S., and José-Alain Sahel

Subjects
Adult, Retinal Diseases, Electroretinography, Image Processing, Computer-Assisted, Evoked Potentials, Visual, Humans, Retina
Abstract

Global ERG recordings are only modified in conditions with diffuse or extensive retinal involvement. The use, over the last 6 months, of a new functional testing device: VERIS (visual evoked response imaging system) allows accurate detection and quantification of localized retinal function defects. Our preliminary experience shows that a careful preparation of subjects, standardized testing protocols and a good understanding of the device technology, especially software parameters are mandatory. We report our results on a series of 28 normal volunteers, grouped by age and describe the various graphic presentation of data collected. This technology should allow accurate detection and quantification of retinal functional defects in patients with age related macular degeneration as well as evaluation of visual function in retinitis pigmentosa patients before and after photoreceptor transplantation.

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