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2. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel–associated retinopathy

Author

Burkard, Markus, Kohl, Susanne, Krätzig, Timm, Tanimoto, Naoyuki, Brennenstuhl, Christina, Bausch, Anne E, Junger, Katrin, Reuter, Peggy, Sothilingam, Vithiyanjali, Beck, Susanne C, Huber, Gesine, Ding, Xi-Qin, Mayer, Anja K, Baumann, Britta, Weisschuh, Nicole, Zobor, Ditta, Hahn, Gesa-Astrid, Kellner, Ulrich, Venturelli, Sascha, Becirovic, Elvir, Issa, Peter Charbel, Koenekoop, Robert K, Rudolph, Günther, Heckenlively, John, Sieving, Paul, Weleber, Richard G, Hamel, Christian, Zong, Xiangang, Biel, Martin, Lukowski, Robert, Seeliger, Matthias W, Michalakis, Stylianos, Wissinger, Bernd, and Ruth, Peter

Subjects
Genetics, Neurosciences, Brain Disorders, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, Amino Acid Substitution, Animals, Color Vision Defects, Cyclic Nucleotide-Gated Cation Channels, Disease Models, Animal, HEK293 Cells, Heterozygote, Humans, Ion Channel Gating, Mice, Mice, Transgenic, Mutation, Mutation, Missense, Retinal Cone Photoreceptor Cells, Retinal Diseases, Molecular genetics, Ophthalmology, Retinopathy, Medical and Health Sciences, Immunology
Abstract

Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3-/-) mice to obtain triallelic Cnga3+/- Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling.

Published
2018

5. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.

Author

Kohl, Susanne, Zobor, Ditta, Chiang, Wei-Chieh, Weisschuh, Nicole, Staller, Jennifer, Gonzalez Menendez, Irene, Chang, Stanley, Beck, Susanne, Garcia Garrido, Marina, Sothilingam, Vithiyanjali, Seeliger, Mathias, Stanzial, Franco, Benedicenti, Francesco, Inzana, Francesca, Héon, Elise, Vincent, Ajoy, Beis, Jill, Strom, Tim, Rudolph, Günther, Roosing, Susanne, Hollander, Anneke, Cremers, Frans, Lopez, Irma, Ren, Huanan, Webster, Andrew, Michaelides, Michel, Koenekoop, Robert, Zrenner, Eberhart, Kaufman, Randal, Tsang, Stephen, Wissinger, Bernd, Moore, Anthony, and Lin, Jonathan

Subjects
Activating Transcription Factor 6, Adolescent, Adult, Aged, 80 and over, Animals, Child, Color Vision Defects, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Pedigree, Retinal Cone Photoreceptor Cells, Transcription, Genetic, Unfolded Protein Response, Young Adult
Abstract

Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.

Published
2015

7. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy

Author

Catarino, Claudia B., von Livonius, Bettina, Priglinger, Claudia, Banik, Rudrani, Matloob, Selma, Tamhankar, Madhura A., Castillo, Lorena, Friedburg, Christoph, Halfpenny, Christopher A., Lincoln, John A., Traber, Ghislaine L., Acaroglu, Gölge, Black, Graeme C. M., Doncel, Carlos, Fraser, Clare L., Jakubaszko, Joanna, Landau, Klara, Langenegger, Stefan J., Muñoz-Negrete, Francisco J., Newman, Nancy J., Poulton, Joanna, Scoppettuolo, Elisabetta, Subramanian, Prem, Toosy, Ahmed T., Vidal, Mariona, Vincent, Andrea L., Votruba, Marcela, Zarowski, Marcin, Zermansky, Adam, Lob, Felice, Rudolph, Günther, Mikazans, Oskars, Silva, Magda, Llòria, Xavier, Metz, Günther, and Klopstock, Thomas

Published
2020
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9. Assessment of retinopathy of prematurity regression and reactivation using an artificial intelligence–based vascular severity score

Author

Eilts, Sonja K., Pfeil, Johanna M., Poschkamp, Broder, Krohne, Tim U., Eter, Nicole, Barth, Teresa, Guthoff, Rainer, Lagrèze, Wolf, Grundel, Milena, Bründer, Marie-Christine, Busch, Martin, Kalpathy-Cramer, Jayashree, Chiang, Michael F., Chan, R. V. Paul, Coyner, Aaron S., Ostmo, Susan, Campbell, J. Peter, Stahl, Andreas, Pfeil, Johanna M, Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf A, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G, Krohne, Tim U, Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R, Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Oberacher-Velten, Isabel, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Meltendorf, Synke, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Ehrt, Oliver, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Aisenbrey, Sabine, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Roider, Johann, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, Modlich, Simon, Jandeck, Isabel, Gerding, Heinrich, Smith, Lois E H, Eilts, Sonja K., Pfeil, Johanna M., Poschkamp, Broder, Krohne, Tim U., Eter, Nicole, Barth, Teresa, Guthoff, Rainer, Lagrèze, Wolf, Grundel, Milena, Bründer, Marie-Christine, Busch, Martin, Kalpathy-Cramer, Jayashree, Chiang, Michael F., Chan, R. V. Paul, Coyner, Aaron S., Ostmo, Susan, Campbell, J. Peter, Stahl, Andreas, Pfeil, Johanna M, Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf A, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G, Krohne, Tim U, Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R, Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Oberacher-Velten, Isabel, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Meltendorf, Synke, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Ehrt, Oliver, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Aisenbrey, Sabine, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Roider, Johann, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, Modlich, Simon, Jandeck, Isabel, Gerding, Heinrich, and Smith, Lois E H

Published
2023

10. Gene Therapy with Voretigene Neparvovec Improves Vision and Partially Restores Electrophysiological Function in Pre-School Children with Leber Congenital Amaurosis

Author

Gerhardt, Maximilian J., primary, Priglinger, Claudia S., additional, Rudolph, Günther, additional, Hufendiek, Karsten, additional, Framme, Carsten, additional, Jägle, Herbert, additional, Salchow, Daniel J., additional, Anschütz, Andreas, additional, Michalakis, Stylianos, additional, and Priglinger, Siegfried G., additional

Published
2022
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11. Evaluation of visual evoked potentials in dysthyroid optic neuropathy.

Author

Garip Kübler, Aylin, Halfter, Kathrin, Reznicek, Lukas, Klingenstein, Annemarie, Priglinger, Siegfried, Rudolph, Günther, and Hintschich, Christoph

Subjects
VISUAL evoked potentials, AUDITORY neuropathy, COLOR vision, NEUROPATHY, OPTIC nerve, EYE color
Abstract

To evaluate the findings of visual evoked potentials (VEP) in patients with dysthyroid optic neuropathy (DON). In this observational, cross-sectional study 40 eyes (22 patients) with a diagnosis of DON were included. We discovered that in 16 out of 37 eyes with pattern-VEP (p-VEP), the latency of P100 wave was normal in spite of having a diagnosis of DON. The same pattern was also observed in the measurement of the amplitude of P100 wave: in 28 out of 37 eyes with p-VEP the amplitudes were observed as normal. In 3 eyes of 3 patients p-VEP showed no response, therefore a flash-VEP (f-VEP) was performed. Flash-VEPs of those patients indicated a prolonged P100 latency with a reduced amplitude. The sensitivity of abnormal P100 latency was 56.8% (95%CI 39.5–72.9%); and that of reduced P100 amplitude was 24.3% (95%CI 11.8–41.2%). Also, in 40 eyes color vision test by Arden was performed. In 36 eyes (20 patients) the tritan value was pathological (based on a threshold of ≥8%). According our data, VEP seems to have a limited potential especially in patients with a good best-corrected visual acuity (BCVA ≤0.2 LogMAR) for identifying the optic nerve involvement. The fact that P100 latency and amplitude were normal even in cases with an optic nerve swelling makes us question the usefulness of the VEP for diagnosing cases of DON in daily clinical life. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Author

Solaki, Maria, Baumann, Britta, Reuter, Peggy, Andreasson, Sten, Audo, Isabelle, Ayuso, Carmen, Balousha, Ghassan, Benedicenti, Francesco, Birch, David, Bitoun, Pierre, Blain, Delphine, Bocquet, Beatrice, Branham, Kari, Català-Mora, Jaume, De Baere, Elfride, Dollfus, Helene, Falana, Mohammed, Giorda, Roberto, Golovleva, Irina, Gottlob, Irene, Heckenlively, John R., Jacobson, Samuel G., Jones, Kaylie, Jägle, Herbert, Janecke, Andreas R., Kellner, Ulrich, Liskova, Petra, Lorenz, Birgit, Martorell-Sampol, Loreto, Messias, André, Meunier, Isabelle, Belga Ottoni Porto, Fernanda, Papageorgiou, Eleni, Plomp, Astrid S., de Ravel, Thomy J. L., Reiff, Charlotte M., Renner, Agnes B., Rosenberg, Thomas, Rudolph, Günther, Salati, Roberto, Sener, E. Cumhur, Sieving, Paul A., Stanzial, Franco, Traboulsi, Elias I., Tsang, Stephen H., Varsanyi, Balázs, Weleber, Richard G., Zobor, Ditta, Stingl, Katarina, Wissinger, Bernd, Kohl, Susanne, Solaki, Maria, Baumann, Britta, Reuter, Peggy, Andreasson, Sten, Audo, Isabelle, Ayuso, Carmen, Balousha, Ghassan, Benedicenti, Francesco, Birch, David, Bitoun, Pierre, Blain, Delphine, Bocquet, Beatrice, Branham, Kari, Català-Mora, Jaume, De Baere, Elfride, Dollfus, Helene, Falana, Mohammed, Giorda, Roberto, Golovleva, Irina, Gottlob, Irene, Heckenlively, John R., Jacobson, Samuel G., Jones, Kaylie, Jägle, Herbert, Janecke, Andreas R., Kellner, Ulrich, Liskova, Petra, Lorenz, Birgit, Martorell-Sampol, Loreto, Messias, André, Meunier, Isabelle, Belga Ottoni Porto, Fernanda, Papageorgiou, Eleni, Plomp, Astrid S., de Ravel, Thomy J. L., Reiff, Charlotte M., Renner, Agnes B., Rosenberg, Thomas, Rudolph, Günther, Salati, Roberto, Sener, E. Cumhur, Sieving, Paul A., Stanzial, Franco, Traboulsi, Elias I., Tsang, Stephen H., Varsanyi, Balázs, Weleber, Richard G., Zobor, Ditta, Stingl, Katarina, Wissinger, Bernd, and Kohl, Susanne

Abstract

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying “likely disease-causing” variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as “likely disease-causing” according to ACMG/AMP criteria. We report 48 novel “likely disease-causing” variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.

Published
2022
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14. Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia

Author

Solaki, Maria, primary, Baumann, Britta, additional, Reuter, Peggy, additional, Andreasson, Sten, additional, Audo, Isabelle, additional, Ayuso, Carmen, additional, Balousha, Ghassan, additional, Benedicenti, Francesco, additional, Birch, David, additional, Bitoun, Pierre, additional, Blain, Delphine, additional, Bocquet, Beatrice, additional, Branham, Kari, additional, Català‐Mora, Jaume, additional, De Baere, Elfride, additional, Dollfus, Helene, additional, Falana, Mohammed, additional, Giorda, Roberto, additional, Golovleva, Irina, additional, Gottlob, Irene, additional, Heckenlively, John R., additional, Jacobson, Samuel G., additional, Jones, Kaylie, additional, Jägle, Herbert, additional, Janecke, Andreas R., additional, Kellner, Ulrich, additional, Liskova, Petra, additional, Lorenz, Birgit, additional, Martorell‐Sampol, Loreto, additional, Messias, André, additional, Meunier, Isabelle, additional, Belga Ottoni Porto, Fernanda, additional, Papageorgiou, Eleni, additional, Plomp, Astrid S., additional, de Ravel, Thomy J. L., additional, Reiff, Charlotte M., additional, Renner, Agnes B., additional, Rosenberg, Thomas, additional, Rudolph, Günther, additional, Salati, Roberto, additional, Sener, E. Cumhur, additional, Sieving, Paul A., additional, Stanzial, Franco, additional, Traboulsi, Elias I., additional, Tsang, Stephen H., additional, Varsanyi, Balázs, additional, Weleber, Richard G., additional, Zobor, Ditta, additional, Stingl, Katarina, additional, Wissinger, Bernd, additional, and Kohl, Susanne, additional

Published
2022
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17. Gene Therapy with Voretigene Neparvovec Improves Vision and Partially Restores Electrophysiological Function in Pre-School Children with Leber Congenital Amaurosis.

Author

Gerhardt, Maximilian J., Priglinger, Claudia S., Rudolph, Günther, Hufendiek, Karsten, Framme, Carsten, Jägle, Herbert, Salchow, Daniel J., Anschütz, Andreas, Michalakis, Stylianos, and Priglinger, Siegfried G.

Subjects
PRESCHOOL children, GENE therapy, BLINDNESS, ELECTROPHYSIOLOGY, HEALTH facilities, DIABETIC retinopathy, LOW vision
Abstract

Leber congenital amaurosis caused by mutations in the RPE65 gene belongs to the most severe early-onset hereditary childhood retinopathies naturally progressing to legal blindness. The novel gene therapy voretigene neparvovec is the first approved causative treatment option for this devastating eye disease and is specifically designed to treat RPE65-mediated retinal dystrophies. Herein, we present a follow-up of the youngest treated patients in Germany so far, including four pre-school children who received treatment with voretigene neparvovec at a single treatment center between January 2020 and May 2022. All patients underwent pars plana vitrectomy with circumferential peeling of the internal limiting membrane at the injection site and subretinal injection of voretigene neparvovec. Pre- and postoperative diagnostics included imaging (spectral domain optical coherence tomography, fundus autofluorescence, fundus wide-angle imaging), electrophysiologic examination (ERG), retinal light sensitivity measurements (FST) and visual acuity testing. Behavioral changes were assessed using a questionnaire and by observing the children's vision-guided behavior in different levels of illumination. All children showed marked increase in vision-guided behavior shortly after therapy, as well as marked increase in visual acuity in the postoperative course up to full visual acuity in one child. Two eyes showed partial electrophysiological recovery of an ERG that was undetectable before treatment—a finding that has not been described in humans before. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Author

Newman, Nancy J., primary, Yu-Wai-Man, Patrick, additional, Carelli, Valerio, additional, Moster, Mark L., additional, Biousse, Valerie, additional, Vignal-Clermont, Catherine, additional, Sergott, Robert C., additional, Klopstock, Thomas, additional, Sadun, Alfredo A., additional, Barboni, Piero, additional, DeBusk, Adam A., additional, Girmens, Jean François, additional, Rudolph, Günther, additional, Karanjia, Rustum, additional, Taiel, Magali, additional, Blouin, Laure, additional, Smits, Gerard, additional, Katz, Barrett, additional, Sahel, José-Alain, additional, Vignal, Catherine, additional, Hage, Rabih, additional, Catarino, Claudia B., additional, Priglinger, Claudia, additional, Priglinger, Siegfried, additional, Thurau, Stephan, additional, von Livonius, Bettina, additional, Muth, Daniel, additional, Wolf, Armin, additional, Al-Tamami, Jasmina, additional, Pressler, Angelika, additional, Schertler, Cosima, additional, Hildebrandt, Martin, additional, Neuenhahn, Michael, additional, Heilweil, Gad, additional, Tsui, Irena, additional, Hubbard, G. Baker, additional, Hendrick, Andrew, additional, Dattilo, Michael, additional, Peragallo, Jason, additional, Hawy, Eman, additional, DuBois, Med, Lindreth, additional, Gibbs, Deborah, additional, Filho, Alcides Fernandes, additional, Dobbs, Jannah, additional, Carbonelli, Michele, additional, Di Vito, Lidia, additional, Contin, Manuela, additional, Mohamed, Susan, additional, La Morgia, Chiara, additional, Silvestri, Sara, additional, Acheson, James, additional, Eleftheriadou, Maria, additional, Esposti, Simona, additional, Gemenetzi, Maria, additional, Leitch-Devlin, Lauren, additional, Tucker, William R., additional, Jurkute, Neringa, additional, SantaMaria, Melissa, additional, Tollis, Heather, additional, Haller, Julie A., additional, and Massini, Maria, additional

Published
2021
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26. A duplication on chromosome 16q12 affecting the IRXB gene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect

Author

Kohl, Susanne, primary, Llavona, Pablo, additional, Sauer, Alexandra, additional, Reuter, Peggy, additional, Weisschuh, Nicole, additional, Kempf, Melanie, additional, Dehmelt, Florian Alexander, additional, Arrenberg, Aristides B, additional, Sliesoraityte, Ieva, additional, Zrenner, Eberhart, additional, van Schooneveld, Mary J, additional, Rudolph, Günther, additional, Kühlewein, Laura, additional, and Wissinger, Bernd, additional

Published
2021
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29. Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy

Author

Yu-Wai-Man, Patrick, primary, Newman, Nancy J., additional, Carelli, Valerio, additional, Moster, Mark L., additional, Biousse, Valerie, additional, Sadun, Alfredo A., additional, Klopstock, Thomas, additional, Vignal-Clermont, Catherine, additional, Sergott, Robert C., additional, Rudolph, Günther, additional, La Morgia, Chiara, additional, Karanjia, Rustum, additional, Taiel, Magali, additional, Blouin, Laure, additional, Burguière, Pierre, additional, Smits, Gerard, additional, Chevalier, Caroline, additional, Masonson, Harvey, additional, Salermo, Yordak, additional, Katz, Barrett, additional, Picaud, Serge, additional, Calkins, David J., additional, and Sahel, José-Alain, additional

Published
2020
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31. CDHR1 mutations in retinal dystrophies

Author

Stingl, Katarina, Mayer, Anja K., Llavona, Pablo, Mulahasanovic, Lejla, Rudolph, Günther, Jacobson, Samuel G., Zrenner, Eberhart, Kohl, Susanne, Wissinger, Bernd, and Weisschuh, Nicole

Subjects
Science, Cadherin Related Proteins, High-Throughput Nucleotide Sequencing, Nerve Tissue Proteins, Cadherins, Article, Mutation, Humans, Medicine, Cone-Rod Dystrophies, Genetic Association Studies, Retinitis Pigmentosa
Abstract

We report ophthalmic and genetic findings in patients with autosomal recessive retinitis pigmentosa (RP), cone-rod dystrophy (CRD) or cone dystrophy (CD) harboring potential pathogenic variants in the CDHR1 gene. Detailed ophthalmic examination was performed in seven sporadic and six familial subjects. Mutation screening was done using a customized next generation sequencing panel targeting 105 genes implicated in inherited retinal disorders. In one family, homozygosity mapping with subsequent candidate gene analysis was performed. Stringent filtering for rare and potentially disease causing variants following a model of autosomal recessive inheritance led to the identification of eleven different CDHR1 variants in nine index cases. All variants were novel at the time of their identification. In silico analyses confirmed their pathogenic potential. Minigene assays were performed for two non-canonical splice site variants and revealed missplicing for the mutant alleles. Mutations in CDHR1 are a rare cause of retinal dystrophy. Our study further expands the mutational spectrum of this gene and the associated clinical presentation.

Published
2017

33. Real-World Clinical Experience With Idebenone in the Treatment of Leber Hereditary Optic Neuropathy

Author

Catarino, Claudia B, von Livonius, Bettina, Priglinger, Claudia, Banik, Rudrani, Matloob, Selma, Tamhankar, Madhura A, Castillo, Lorena, Friedburg, Christoph, Halfpenny, Christopher A, Lincoln, John A, Traber, Ghislaine L, Acaroglu, Gölge, Black, Graeme C M, Doncel, Carlos, Fraser, Clare L, Jakubaszko, Joanna, Landau, Klara, Langenegger, Stefan J, Muñoz-Negrete, Francisco J, Newman, Nancy J, Poulton, Joanna, Scoppettuolo, Elisabetta, Subramanian, Prem, Toosy, Ahmed T, Vidal, Mariona, Vincent, Andrea L, Votruba, Marcela, Zarowski, Marcin, Zermansky, Adam, Lob, Felice, Rudolph, Günther, Mikazans, Oskars, Silva, Magda, Lloria, Xavier, Metz, Günther, Klopstock, Thomas, Catarino, Claudia B, von Livonius, Bettina, Priglinger, Claudia, Banik, Rudrani, Matloob, Selma, Tamhankar, Madhura A, Castillo, Lorena, Friedburg, Christoph, Halfpenny, Christopher A, Lincoln, John A, Traber, Ghislaine L, Acaroglu, Gölge, Black, Graeme C M, Doncel, Carlos, Fraser, Clare L, Jakubaszko, Joanna, Landau, Klara, Langenegger, Stefan J, Muñoz-Negrete, Francisco J, Newman, Nancy J, Poulton, Joanna, Scoppettuolo, Elisabetta, Subramanian, Prem, Toosy, Ahmed T, Vidal, Mariona, Vincent, Andrea L, Votruba, Marcela, Zarowski, Marcin, Zermansky, Adam, Lob, Felice, Rudolph, Günther, Mikazans, Oskars, Silva, Magda, Lloria, Xavier, Metz, Günther, and Klopstock, Thomas

Abstract

BACKGROUND: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. RESULTS: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. CONCLUSIONS: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings

Published
2020

36. Deep‐intronic variants in CNGB3 cause achromatopsia by pseudoexon activation

Author

Weisschuh, Nicole, primary, Sturm, Marc, additional, Baumann, Britta, additional, Audo, Isabelle, additional, Ayuso, Carmen, additional, Bocquet, Beatrice, additional, Branham, Kari, additional, Brooks, Brian P., additional, Catalá‐Mora, Jaume, additional, Giorda, Roberto, additional, Heckenlively, John R., additional, Hufnagel, Robert B., additional, Jacobson, Samuel G., additional, Kellner, Ulrich, additional, Kitsiou‐Tzeli, Sofia, additional, Matet, Alexandre, additional, Martorell Sampol, Loreto, additional, Meunier, Isabelle, additional, Rudolph, Günther, additional, Sharon, Dror, additional, Stingl, Katarina, additional, Streubel, Berthold, additional, Varsányi, Balázs, additional, Wissinger, Bernd, additional, and Kohl, Susanne, additional

Published
2019
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38. Comparing alternative ranibizumab dosages for safety and efficacy in retinopathy of prematurity : a randomized clinical trial

Author

Stahl, Andreas, Krohne, Tim U., Eter, Nicole, Oberacher-Velten, Isabel, Guthoff, Rainer, Meltendorf, Synke, Ehrt, Oliver, Aisenbrey, Sabine, Roider, Johann, Gerding, Heinrich, Jandeck, Claudia, Smith, Lois E. H., Walz, Johanna M., Bühler, Anima, Daniel, Moritz, Felzmann, Susanne, Gross, Nicolai, Horn, Stefanie, Lagrèze, Wolf, Molnár, Fanni, Müller, Claudia, Reichl, Sabine, Reiff, Charlotte, Richter, Olga, Stech, Milena, Hentschel, Roland, Stavropolou, Dimitria, Tautz, Juliane, Bartsch, Kerstin, Braunstein, Jennifer, Brinken, Ralf, Brinkmann, Christian Karl, Czauderna, Joanna, Dralle, Wiebke, Gliem, Martin, Goebel, Arno, Heymer, Philipp, Hofmann, Martina, Holz, Frank G., Kupitz, David, Müller, Philipp, Petrak, Michael, Schmitz, Eva Janine, Schmitz-Valckenberg, Steffen, Schröder, Moritz, Steinberg, Julia, Supé, Julia, Kant, Evelyn, Kunze, Diana, Müller, Andreas, Adorf, Adeline, Alex, Anne, Alten, Florian, Clemens, Christoph R., Falkenau, Silvia, Friedhoff, Caroline, Loos, Desiree Sandra, Mihailovic, Natasa, Termühlen, Julia, Uhlig, Constantin, Hörnig-Franz, Isabell, Rieger-Fackeldey, Esther, Tekaat, Maria, Werner, Claudius, Altmann, Mathias, Barth, Theresa, Blecha, Christiane, Brandl-Rühle, Sabine, Helbig, Horst, Hufendiek, Karsten, Jägle, Herbert, Konrad, Julia, Kopetzky, Eva, Lehmann, Fabian, Keller-Wackerbauer, Annette, Kittel, Jochen, Segerer, Hugo, Ackermann, Phillip, Benga, Jemina, Guthoff, Tanja, Kleinert, Elena, Mayatepek, Ertan, Schrader, Stefan, Völker, Magdalena, Höhn, Thomas, Lohmeier, Klaus, Sabir, Hemmen, Brevis, Francisco, Mönig, Tina, Schwarz, Simone, Ehmer, Angela, Schuart, Claudia, Avenarius, Stefan, Böttger, Ralf, Apel, Christoph, Bergmann, Anne, Herrmann, Karsten, Ockert-Schön, Franziska, Wegener, Sabine, Nentwich, Martin, Pressler, Angelika, Rudolph, Günther, Genzel-Boroviczeny, Orsolya, Schmidt, Susanne, Münch, Hans-Georg, Thilmany, Claude, Bruckmann, Anna, Dimopoulos, Spyridon, Hagemann, Ulrike, Inhoffen, Werner, Partsch, Michael, Schrader, Merle, Süsskind, Daniela, Völker, Michael, Bialkowski, Anja, Müller-Hansen, Ingo, Gerberth, Andrea, Hasselbach, Heike Christine, Lindemann, Solveig, Purtskhvanidze, Konstantine, Raffel, Yvonne, Schröder, Greta, Szymanek, Beke, Tode, Jan, Bendiks, Meike, and Modlich, Simon

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, genetic structures, Bevacizumab, Medizin, Angiogenesis Inhibitors, Pilot Projects, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Germany, Ranibizumab, Internal medicine, Clinical endpoint, Humans, Medicine, Retinopathy of Prematurity, Dosing, Original Investigation, Dose-Response Relationship, Drug, business.industry, Standard treatment, Infant, Newborn, Retinopathy of prematurity, Odds ratio, medicine.disease, Treatment Outcome, Pediatrics, Perinatology and Child Health, 030221 ophthalmology & optometry, Female, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Importance Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49;P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration clinicaltrials.gov Identifier:NCT02134457and clinicaltrialsregister.eu Identifier:2013-002539-13.

Published
2018

39. The Clinical Phenotype of CNGA3 -Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial

Author

Zobor, Ditta, Werner, Annette, Stanzial, Franco, Benedicenti, Francesco, Rudolph, Günther, Kellner, Ulrich, Hamel, Christian, Andréasson, Sten, Zobor, Gergely, Strasser, Torsten, Wissinger, Bernd, Kohl, Susanne, Zrenner, Eberhart, Consortium, RD-CURE, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
0301 basic medicine, Male, Pathology, Visual acuity, Achromatopsia, genetic structures, Visual Acuity, Color Vision Defects, chemistry.chemical_compound, 0302 clinical medicine, Contrast (vision), Prospective Studies, Child, media_common, medicine.diagnostic_test, Middle Aged, Visual field, Phenotype, Sensory Thresholds, Female, medicine.symptom, Color Perception, Tomography, Optical Coherence, Photopic vision, Adult, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Cyclic Nucleotide-Gated Cation Channels, Dark Adaptation, Biology, Retina, 03 medical and health sciences, Young Adult, Ophthalmology, medicine, Electroretinography, Psychophysics, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retinal, Genetic Therapy, medicine.disease, eye diseases, 030104 developmental biology, chemistry, 030221 ophthalmology & optometry, sense organs, Visual Fields, Microperimetry
Abstract

International audience; Purpose:The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial.Methods:Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT).Results:Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic responses were nondetectable in cACHM patients, but residual cone responses were observed in the iACHM patients. Scotopic responses were altered referring to anomalies of photoreceptor and postreceptor signaling, whereas in voltage versus intensity functions, Vmax was significantly below normal values (P < 0.05). In contrast, slope (n) and semisaturation intensity (K) were found to be within normal limits. Spectral-domain OCT examination showed no specific changes in 14.7%, disruption of the ellipsoid zone (EZ) at the fovea in 38.2%, absent EZ in 17.7%, a hyporeflective zone in 20.5%, and outer retinal atrophy in 8.9% of all cases and foveal hypoplasia in 29 patients (85%). No correlation of retinal morphology with visual function or with a specific genotype was found. The severity of morphologic and functional changes lacked a robust association with age.Conclusions:Our extended investigations prove that even among such a genetically homogenous group of patients, no specific correlations regarding function and morphology severity and age can be observed. Therefore, the therapeutic window seems to be wider than previously indicated.

Published
2017
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40. Clinical Phenotype and Course of PDE6A-Associated Retinitis Pigmentosa Disease, Characterized in Preparation for a Gene Supplementation Trial.

Author

Kuehlewein, Laura, Zobor, Ditta, Andreasson, Sten Olof, Ayuso, Carmen, Banfi, Sandro, Bocquet, Beatrice, Bernd, Antje S., Biskup, Saskia, Boon, Camiel J. F., Downes, Susan M., Fischer, M. Dominik, Holz, Frank G., Kellner, Ulrich, Leroy, Bart P., Meunier, Isabelle, Nasser, Fadi, Rosenberg, Thomas, Rudolph, Günther, Stingl, Katarina, and Thiadens, Alberta A. H. J.

Published
2020
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43. Deep‐intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Author

Weisschuh, Nicole, Sturm, Marc, Baumann, Britta, Audo, Isabelle, Ayuso, Carmen, Bocquet, Beatrice, Branham, Kari, Brooks, Brian P., Catalá‐Mora, Jaume, Giorda, Roberto, Heckenlively, John R., Hufnagel, Robert B., Jacobson, Samuel G., Kellner, Ulrich, Kitsiou‐Tzeli, Sofia, Matet, Alexandre, Martorell Sampol, Loreto, Meunier, Isabelle, Rudolph, Günther, and Sharon, Dror

Abstract

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty‐seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663–1205G>A, found in 14 subjects, and variant c.1663‐2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663–1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease‐causing variant. [ABSTRACT FROM AUTHOR]

Published
2020
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46. Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

Author

Weisschuh, Nicole, primary, Mayer, Anja K., additional, Strom, Tim M., additional, Kohl, Susanne, additional, Glöckle, Nicola, additional, Schubach, Max, additional, Andreasson, Sten, additional, Bernd, Antje, additional, Birch, David G., additional, Hamel, Christian P., additional, Heckenlively, John R., additional, Jacobson, Samuel G., additional, Kamme, Christina, additional, Kellner, Ulrich, additional, Kunstmann, Erdmute, additional, Maffei, Pietro, additional, Reiff, Charlotte M., additional, Rohrschneider, Klaus, additional, Rosenberg, Thomas, additional, Rudolph, Günther, additional, Vámos, Rita, additional, Varsányi, Balázs, additional, Weleber, Richard G., additional, and Wissinger, Bernd, additional

Published
2016
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50. Will experience support use of first-ever retinal gene therapy? Recent reports of retinal atrophy have raised concerns about potential long-term safety.

Author

Gerhardt, Maximilian J., Michalakis, Stylianos, Rudolph, Günther, Priglinger, Claudia, and Priglinger, Siegfried

Subjects
WORK experience (Employment), THERAPEUTICS, BLINDNESS, INJECTIONS, GENETIC mutation, MOLECULAR diagnosis, ATTITUDE (Psychology), MEDICAL personnel, TREATMENT effectiveness, RISK assessment, ATROPHY, GENE therapy, PSYCHOSOCIAL factors, VISION, RETINAL diseases, EARLY diagnosis, DISEASE risk factors, DISEASE complications, SYMPTOMS
Abstract

The article discusses voretigene neparvovec as the first causal treatment for biallelic RPE65 mutation-associated retinal disease which regularly progresses to legal blindness. Topics covered include the aim of the retinal gene therapy to deliver the correct coding sequence of the human RPE65 to the retinal pigment epithelium, the performance of the treatment via subretinal injection following vitrectomy, and concerns about its potential long-term safety following reports of retinal atrophy.

Published
2022

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