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1. Characteristics of autosomal dominant WFS1-associated optic neuropathy and its comparability to OPA1-associated autosomal dominant optic atrophy

Author

de Muijnck, Cansu, Haer-Wigman, Lonneke, van Everdingen, Judith A. M., Lushchyk, Tanya, Heutinck, Pam A. T., van Dooren, Marieke F., Kievit, Anneke J. A., Verhoeven, Virginie J. M., Simon, Marleen E. H., Wasmann, Rosemarie A., Notting, Irene C., De Baere, Elfride, Walraedt, Sophie, De Zaeytijd, Julie, Van den Broeck, Filip, Leroy, Bart P., Boon, Camiel J. F., and van Genderen, Maria M.

Published
2024
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3. Efficacy of Carbonic Anhydrase Inhibitors on Cystoid Fluid Collections and Visual Acuity in Patients with X-Linked Retinoschisis

Author

Hensman, Jonathan, Hahn, Leo C., van Schooneveld, Mary J., Diederen, Roselie M.H., ten Brink, Jacoline B., Florijn, Ralph J., Bergen, Arthur A., Strubbe, Ine, Heutinck, Pam, van Genderen, Maria M., van den Born, L. Ingeborgh, Thiadens, Alberta A., de Zaeytijd, Julie, Leroy, Bart P., Hoyng, Carel B., and Boon, Camiel J.F.

Published
2024
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7. A clinical and molecular characterisation of CRB1-associated maculopathy

Author

Khan, Kamron N, Robson, Anthony, Mahroo, Omar AR, Arno, Gavin, Inglehearn, Chris F, Armengol, Monica, Waseem, Naushin, Holder, Graham E, Carss, Keren J, Raymond, Lucy F, Webster, Andrew R, Moore, Anthony T, McKibbin, Martin, van Genderen, Maria M, Poulter, James A, Michaelides, Michel, and UK Inherited Retinal Disease Consortium

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Clinical Research, Rare Diseases, Neurosciences, Neurodegenerative, Genetics, Eye Disease and Disorders of Vision, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Eye, Adolescent, Adult, Alleles, Child, Child, Preschool, Electronic Health Records, Eye Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Infant, Infant, Newborn, Macular Degeneration, Male, Membrane Proteins, Nerve Tissue Proteins, Retinal Photoreceptor Cell Outer Segment, Young Adult, UK Inherited Retinal Disease Consortium, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Published
2018

9. Mutations in NSUN3, a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy

Author

Oogheelkunde Onderzoek, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Child Health, de Muijnck, Cansu, Brink, Jacoline B.ten, de Haan, Hugoline G., Rodenburg, Richard J., Wolf, Nicole I., Bergen, Arthur A., Boon, Camiel J.F., van Genderen, Maria M., Oogheelkunde Onderzoek, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Child Health, de Muijnck, Cansu, Brink, Jacoline B.ten, de Haan, Hugoline G., Rodenburg, Richard J., Wolf, Nicole I., Bergen, Arthur A., Boon, Camiel J.F., and van Genderen, Maria M.

Published
2024

10. Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A

Author

Oogheelkunde Onderzoek, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Child Health, de Muijnck, Cansu, van Schooneveld, Mary J., Plomp, Astrid S., Rodenburg, Richard J., van Genderen, Maria M., Boon, Camiel J.F., Oogheelkunde Onderzoek, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Child Health, de Muijnck, Cansu, van Schooneveld, Mary J., Plomp, Astrid S., Rodenburg, Richard J., van Genderen, Maria M., and Boon, Camiel J.F.

Published
2024

11. Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement

Author

MS Oogheelkunde, Child Health, Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van Der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H.M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elizabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C.M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, Hennekam, Raoul C., MS Oogheelkunde, Child Health, Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van Der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H.M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elizabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C.M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, and Hennekam, Raoul C.

Published
2024

12. Reply to: Pitfalls in the genetic testing of the OPN1LW-OPN1MW gene cluster in human subjects

Author

Zorgeenheid Oogheelkunde Medisch, Child Health, Haer-Wigman, Lonneke, den Ouden, Amber, Derks, Ronny, van Genderen, Maria M., Lugtenberg, Dorien, Verheij, Joke, Vijzelaar, Raymon, Yntema, Helger G., Vissers, Lisenka E.L.M., Neveling, Kornelia, Zorgeenheid Oogheelkunde Medisch, Child Health, Haer-Wigman, Lonneke, den Ouden, Amber, Derks, Ronny, van Genderen, Maria M., Lugtenberg, Dorien, Verheij, Joke, Vijzelaar, Raymon, Yntema, Helger G., Vissers, Lisenka E.L.M., and Neveling, Kornelia

Published
2024

13. Diagnosis and management in Rubinstein-Taybi syndrome:first international consensus statement

Author

Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van Der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H.M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elizabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C.M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, Hennekam, Raoul C., Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van Der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H.M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elizabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C.M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, and Hennekam, Raoul C.

Abstract

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Published
2024

14. Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort: The RD5000 Consortium

Author

Genetica Klinische Genetica, Child Health, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Heutinck, Pam A.T., van den Born, L. Ingeborgh, Vermeer, Maikel, Iglesias Gonzales, Adriana I., Hoyng, Carel B., Pott, Jan Willem R., Kroes, Hester Y., van Schooneveld, Mary J., Boon, Camiel J.F., van Genderen, Maria M., Plomp, Astrid S., de Jong-Hesse, Yvonne, van Egmond-Ebbeling, Michelle B., Hoefsloot, Lies H., A Bergen, Arthur, Klaver, Caroline C.W., Meester-Smoor, Magda A., Thiadens, Alberta A.H.J., Verhoeven, Virginie J.M., Genetica Klinische Genetica, Child Health, Zorgeenheid Oogheelkunde Medisch, MS Oogheelkunde, Heutinck, Pam A.T., van den Born, L. Ingeborgh, Vermeer, Maikel, Iglesias Gonzales, Adriana I., Hoyng, Carel B., Pott, Jan Willem R., Kroes, Hester Y., van Schooneveld, Mary J., Boon, Camiel J.F., van Genderen, Maria M., Plomp, Astrid S., de Jong-Hesse, Yvonne, van Egmond-Ebbeling, Michelle B., Hoefsloot, Lies H., A Bergen, Arthur, Klaver, Caroline C.W., Meester-Smoor, Magda A., Thiadens, Alberta A.H.J., and Verhoeven, Virginie J.M.

Published
2024

15. Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort:The RD5000 Consortium

Author

Heutinck, Pam A.T., van den Born, L. Ingeborgh, Vermeer, Maikel, Iglesias Gonzales, Adriana I., Hoyng, Carel B., Pott, Jan Willem R., Kroes, Hester Y., van Schooneveld, Mary J., Boon, Camiel J.F., van Genderen, Maria M., Plomp, Astrid S., de Jong-Hesse, Yvonne, van Egmond-Ebbeling, Michelle B., Hoefsloot, Lies H., A Bergen, Arthur, Klaver, Caroline C.W., Meester-Smoor, Magda A., Thiadens, Alberta A.H.J., Verhoeven, Virginie J.M., Heutinck, Pam A.T., van den Born, L. Ingeborgh, Vermeer, Maikel, Iglesias Gonzales, Adriana I., Hoyng, Carel B., Pott, Jan Willem R., Kroes, Hester Y., van Schooneveld, Mary J., Boon, Camiel J.F., van Genderen, Maria M., Plomp, Astrid S., de Jong-Hesse, Yvonne, van Egmond-Ebbeling, Michelle B., Hoefsloot, Lies H., A Bergen, Arthur, Klaver, Caroline C.W., Meester-Smoor, Magda A., Thiadens, Alberta A.H.J., and Verhoeven, Virginie J.M.

Abstract

Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children. This study investigated the frequency of these in pediatric IRD with the aim of highlighting relevant groups for future therapy. Methods:Diagnostic, genetic, and demographic data, collected from medical charts of patients with IRD aged up to 20 years (n = 624, 63% male), registered in the Dutch RD5000 database, were analyzed to determine frequencies of phenotypes and genetic causes. Phenotypes were categorized as nonsyndromic (progressive and stationary IRD) and syndromic IRD. Genetic causes, mostly determined by whole-exome sequencing (WES), were examined. Additionally, we investigated the utility of periodic reanalysis of WES data in genetically unresolved cases.Results: Median age at registration was 13 years (interquartile range, 9-16). Retinitis pigmentosa (RP; n = 123, 20%), Leber congenital amaurosis (LCA; n = 97, 16%), X-linked retinoschisis (n = 64, 10%), and achromatopsia (n = 63, 10%) were the most frequent phenotypes. The genetic cause was identified in 76% of the genetically examined patients (n = 473). The most frequently disease-causing genes were RS1 (n = 32, 9%), CEP290 (n = 28, 8%), CNGB3 (n = 21, 6%), and CRB1 (n = 17, 5%). Diagnostic yield after reanalysis of genetic data increased by 7%. Conclusions: As in most countries, RP and LCA are the most prominent pediatric IRDs in the Netherlands, and variants in RS1 and CEP290 were the most prominent IRD genotypes. Our findings can guide therapy development to target the diseases and genes with the greatest needs in young patients.

Published
2024

16. Quality of life in patients with CRB1-associated retinal dystrophies: A longitudinal study

Author

Karuntu, Jessica S, Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Meester-Smoor, Magda A, van den Born, L Ingeborgh, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, van Nispen, Ruth M A, Boon, Camiel J F, Karuntu, Jessica S, Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Meester-Smoor, Magda A, van den Born, L Ingeborgh, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, van Nispen, Ruth M A, and Boon, Camiel J F

Abstract

PURPOSE: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies.METHODS: A longitudinal questionnaire study included 22 patients with pathogenic CRB1 variants. The National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up. Classical test theory was performed to obtain subdomain scores and in particular 'near activities' and 'total composite' scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales.RESULTS: In total, 22 patients with pathogenic CRB1 variants were included, with a median age of 25.0 years (IQR: 13-31 years) at baseline and mean follow-up of 4.0 ± 0.3 years. A significant decline at 4 years was observed for 'near activities' (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and 'total composite' (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the 'visual functioning' scale significantly decreased after 4 years (-0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). The 'socio-emotional' scale also showed a significant decline after 2 years (-0.78 logits, p = 0.033) and 4 years (-0.83 logits, p = 0.021).CONCLUSION: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy.

Published
2024

17. Quality of life in patients with CRB1-associated retinal dystrophies:A longitudinal study

Author

Karuntu, Jessica S., Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., van Nispen, Ruth M.A., Boon, Camiel J.F., Karuntu, Jessica S., Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., van Nispen, Ruth M.A., and Boon, Camiel J.F.

Abstract

Purpose: To assess the longitudinal vision-related quality of life among patients with CRB1-associated inherited retinal dystrophies. Methods: In this longitudinal questionnaire study, the National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ-39) was applied at baseline, two-year follow-up, and 4-year follow-up in patients with pathogenic CRB1 variants. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] Classical test theory was performed to obtain subdomain scores and in particular ‘near activities’ and ‘total composite’ scores. The Rasch analysis based on previous calibrations of the NEI VFQ-25 was applied to create visual functioning and socio-emotional subscales. Results: In total, 22 patients with a CRB1-associated retinal dystrophy were included, […] with a median age of 25.0 years (interquartile range: 13–31 years) at baseline and mean follow-up of 4.0 ± 0.3 years. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] A significant decline at 4 years was observed for ‘near activities’ (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and ‘total composite’ (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch-scaled scores, the ‘visual functioning’ scale significantly decreased after 2 years (−0.89 logits; p = 0.012), but not at 4-year follow-up (+0.01 logits; p = 0.975). [Correction added on 20 November 2023, after first online publication: In the preceding sentence, “…after 4 years…” has been corrected to “…after 2 years…” in this version.] The ‘socio-emotional’ scale also showed a significant decline after 2 years (−0.78 logits, p = 0.033) and 4 years (−0.83 logits, p = 0.021). Conclusion: In the absence of an intervention, a decline in vision-related quality of life is present in patients with pathogenic CRB1 variants at 4-year follow-up. Patient-reported outcome measures shoul

Published
2024

18. Quality of life in patients with CRB1-associated retinal dystrophies: A longitudinal study

Author

MS Oogheelkunde, Child Health, Karuntu, Jessica S., Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., van Nispen, Ruth M.A., Boon, Camiel J.F., MS Oogheelkunde, Child Health, Karuntu, Jessica S., Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., van Nispen, Ruth M.A., and Boon, Camiel J.F.

Published
2024

19. Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement

Author

Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean-Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H. M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elisabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C. M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, Hennekam, Raoul C., Lacombe, Didier, Bloch-Zupan, Agnès, Bredrup, Cecilie, Cooper, Edward B., Houge, Sofia Douzgou, García-Miñaúr, Sixto, Kayserili, Hülya, Larizza, Lidia, Lopez Gonzalez, Vanesa, Menke, Leonie A., Milani, Donatella, Saettini, Francesco, Stevens, Cathy A., Tooke, Lloyd, Van der Zee, Jill A., Van Genderen, Maria M., Van-Gils, Julien, Waite, Jane, Adrien, Jean-Louis, Bartsch, Oliver, Bitoun, Pierre, Bouts, Antonia H. M., Cueto-González, Anna M., Dominguez-Garrido, Elena, Duijkers, Floor A., Fergelot, Patricia, Halstead, Elisabeth, Huisman, Sylvia A., Meossi, Camilla, Mullins, Jo, Nikkel, Sarah M., Oliver, Chris, Prada, Elisabetta, Rei, Alessandra, Riddle, Ilka, Rodriguez-Fonseca, Cristina, Rodríguez Pena, Rebecca, Russell, Janet, Saba, Alicia, Santos-Simarro, Fernando, Simpson, Brittany N., Smith, David F., Stevens, Markus F., Szakszon, Katalin, Taupiac, Emmanuelle, Totaro, Nadia, Valenzuena Palafoll, Irene, Van Der Kaay, Daniëlle C. M., Van Wijk, Michiel P., Vyshka, Klea, Wiley, Susan, and Hennekam, Raoul C.

Abstract

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Published
2024

20. Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement

Author

Lacombe, Didier, primary, Bloch-Zupan, Agnès, additional, Bredrup, Cecilie, additional, Cooper, Edward B, additional, Houge, Sofia Douzgou, additional, García-Miñaúr, Sixto, additional, Kayserili, Hülya, additional, Larizza, Lidia, additional, Lopez Gonzalez, Vanesa, additional, Menke, Leonie A, additional, Milani, Donatella, additional, Saettini, Francesco, additional, Stevens, Cathy A, additional, Tooke, Lloyd, additional, Van der Zee, Jill A, additional, Van Genderen, Maria M, additional, Van-Gils, Julien, additional, Waite, Jane, additional, Adrien, Jean-Louis, additional, Bartsch, Oliver, additional, Bitoun, Pierre, additional, Bouts, Antonia H M, additional, Cueto-González, Anna M, additional, Dominguez-Garrido, Elena, additional, Duijkers, Floor A, additional, Fergelot, Patricia, additional, Halstead, Elizabeth, additional, Huisman, Sylvia A, additional, Meossi, Camilla, additional, Mullins, Jo, additional, Nikkel, Sarah M, additional, Oliver, Chris, additional, Prada, Elisabetta, additional, Rei, Alessandra, additional, Riddle, Ilka, additional, Rodriguez-Fonseca, Cristina, additional, Rodríguez Pena, Rebecca, additional, Russell, Janet, additional, Saba, Alicia, additional, Santos-Simarro, Fernando, additional, Simpson, Brittany N, additional, Smith, David F, additional, Stevens, Markus F, additional, Szakszon, Katalin, additional, Taupiac, Emmanuelle, additional, Totaro, Nadia, additional, Valenzuena Palafoll, Irene, additional, Van Der Kaay, Daniëlle C M, additional, Van Wijk, Michiel P, additional, Vyshka, Klea, additional, Wiley, Susan, additional, and Hennekam, Raoul C, additional

Published
2024
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22. Quality of life in patients with CRB1‐associated retinal dystrophies: A longitudinal study.

Author

Karuntu, Jessica S., Nguyen, Xuan‐Thanh‐An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij‐Delfos, Nicoline E., Klaver, Caroline C. W., Meester‐Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A. H. J., Bergen, Arthur A., van Nispen, Ruth M. A., and Boon, Camiel J. F.

Subjects
RETINAL degeneration, QUALITY of life, CLASSICAL test theory, PATIENT reported outcome measures, LONGITUDINAL method
Abstract

Purpose: To assess the longitudinal vision‐related quality of life among patients with CRB1‐associated inherited retinal dystrophies. Methods: In this longitudinal questionnaire study, the National Eye Institute Visual Function Questionnaire (39 items, NEI VFQ‐39) was applied at baseline, two‐year follow‐up, and 4‐year follow‐up in patients with pathogenic CRB1 variants. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] Classical test theory was performed to obtain subdomain scores and in particular 'near activities' and 'total composite' scores. The Rasch analysis based on previous calibrations of the NEI VFQ‐25 was applied to create visual functioning and socio‐emotional subscales. Results: In total, 22 patients with a CRB1‐associated retinal dystrophy were included, [...] with a median age of 25.0 years (interquartile range: 13–31 years) at baseline and mean follow‐up of 4.0 ± 0.3 years. [Correction added on 20 November 2023, after first online publication: The preceding sentence has been updated in this version.] A significant decline at 4 years was observed for 'near activities' (51.0 ± 23.8 vs 35.4 ± 14.7, p = 0.004) and 'total composite' (63.0 ± 13.1 vs 52.0 ± 12.1, p = 0.001) subdomain scores. For the Rasch‐scaled scores, the 'visual functioning' scale significantly decreased after 2 years (−0.89 logits; p = 0.012), but not at 4‐year follow‐up (+0.01 logits; p = 0.975). [Correction added on 20 November 2023, after first online publication: In the preceding sentence, "...after 4 years..." has been corrected to "...after 2 years..." in this version.] The 'socio‐emotional' scale also showed a significant decline after 2 years (−0.78 logits, p = 0.033) and 4 years (−0.83 logits, p = 0.021). Conclusion: In the absence of an intervention, a decline in vision‐related quality of life is present in patients with pathogenic CRB1 variants at 4‐year follow‐up. Patient‐reported outcome measures should be included in future clinical trials, as they can be a potential indicator of disease progression and treatment efficacy. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Mutations in NSUN3 , a Mitochondrial Methyl Transferase Gene, Cause Inherited Optic Neuropathy.

Author

de Muijnck, Cansu, Brink, Jacoline B. ten, de Haan, Hugoline G., Rodenburg, Richard J., Wolf, Nicole I., Bergen, Arthur A., Boon, Camiel J. F., and van Genderen, Maria M.

Subjects
CELL respiration, CONSANGUINITY, GENETIC testing, GENETIC variation, NEUROPATHY
Abstract

Inherited optic neuropathies (IONs) are rare genetic diseases characterized by progressive visual loss due the atrophy of optic nerves. The standard diagnostic workup involving next-generation sequencing panels has a diagnostic yield of about forty percent. In the other 60% of the patients with a clinical diagnosis of ION, the underlying genetic variants remain unknown. In this case study, we describe a potentially new disease-associated gene, NSUN3, for IONs. The proband was a young woman with consanguineous parents. She presented with bilateral optic atrophy and nystagmus at the age of seven years. Genetic testing revealed the homozygous variant c.349_352dup p.(Ala118Glufs*45) in NSUN3, with a segregation in the family compatible with autosomal recessive inheritance. Additional functional analysis showed decreased NSUN3 mRNA levels, slightly diminished mitochondrial complex IV levels, and decreased cell respiration rates in patient fibroblasts compared to healthy controls. In conclusion, pathogenic variants in NSUN3 can cause optic neuropathy. Trio whole-exome sequencing should be considered as a diagnostic strategy in ION cases where standard diagnostic analysis does not reveal disease-causing variants. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Efficacy of Carbonic Anhydrase Inhibitors on Cystoid Fluid Collections and Visual Acuity in Patients with X-Linked Retinoschisis

Author

Hensman, Jonathan, primary, Hahn, Leo C., additional, van Schooneveld, Mary J., additional, Diederen, Roselie M.H., additional, ten Brink, Jacoline B., additional, Florijn, Ralph J., additional, Bergen, Arthur A., additional, Strubbe, Ine, additional, Heutinck, Pam, additional, van Genderen, Maria M., additional, van den Born, L. Ingeborgh, additional, Thiadens, Alberta A., additional, de Zaeytijd, Julie, additional, Leroy, Bart P., additional, Hoyng, Carel B., additional, and Boon, Camiel J.F., additional

Published
2023
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27. Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism

Author

Poulter, James A, Al-Araimi, Musallam, Conte, Ivan, van Genderen, Maria M, Sheridan, Eamonn, Carr, Ian M, Parry, David A, Shires, Mike, Carrella, Sabrina, Bradbury, John, Khan, Kamron, Lakeman, Phillis, Sergouniotis, Panagiotis I, Webster, Andrew R, Moore, Anthony T, Pal, Bishwanath, Mohamed, Moin D, Venkataramana, Anandula, Ramprasad, Vedam, Shetty, Rohit, Saktivel, Murugan, Kumaramanickavel, Govindasamy, Tan, Alex, Mackey, David A, Hewitt, Alex W, Banfi, Sandro, Ali, Manir, Inglehearn, Chris F, and Toomes, Carmel

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Eye Disease and Disorders of Vision, Pediatric, Neurosciences, Congenital Structural Anomalies, Clinical Research, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Albinism, Amino Acid Transport Systems, Neutral, Animals, Child, Consanguinity, DNA Mutational Analysis, Female, Fovea Centralis, Genes, Recessive, Homozygote, Humans, Male, Mutation, Optic Nerve, Pedigree, Phenotype, Syndrome, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

Published
2013

28. CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study

Author

Nguyen, Xuan-Thanh-An, Talib, Mays, van Cauwenbergh, Caroline, van Schooneveld, Mary J., Fiocco, Marta, Wijnholds, Jan, ten Brink, Jacoline B., Florijn, Ralph J., Schalij-Delfos, Nicoline E., Dagnelie, Gislin, van Genderen, Maria M., de Baere, Elfride, Meester-Smoor, Magda A., De Zaeytijd, Julie, Balikova, Irina, Thiadens, Alberta A., Hoyng, Carel B., Klaver, Caroline C., van den Born, L. Ingeborgh, Bergen, Arthur A., Leroy, Bart P., and Boon, Camiel J.F.

Published
2021
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29. Quality of life in patients with CRB1‐associated retinal dystrophies: A longitudinal study

Author

Karuntu, Jessica S., primary, Nguyen, Xuan‐Thanh‐An, additional, Talib, Mays, additional, van Schooneveld, Mary J., additional, Wijnholds, Jan, additional, van Genderen, Maria M., additional, Schalij‐Delfos, Nicoline E., additional, Klaver, Caroline C. W., additional, Meester‐Smoor, Magda A., additional, van den Born, L. Ingeborgh, additional, Hoyng, Carel B., additional, Thiadens, Alberta A. H. J., additional, Bergen, Arthur A., additional, van Nispen, Ruth M. A., additional, and Boon, Camiel J. F., additional

Published
2023
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33. CRB1-Associated Retinal Dystrophy Patients Have Expanded Lewis Glycoantigen-Positive T Cells

Author

Oogheelkunde Onderzoek, Infection & Immunity, MS Oogheelkunde, Child Health, Moekotte, Lude, Kuiper, Jonas J.W., Hiddingh, Sanne, Nguyen, Xuan Thanh An, Boon, Camiel J.F., van den Born, L. Ingeborgh, de Boer, Joke H., van Genderen, Maria M., Oogheelkunde Onderzoek, Infection & Immunity, MS Oogheelkunde, Child Health, Moekotte, Lude, Kuiper, Jonas J.W., Hiddingh, Sanne, Nguyen, Xuan Thanh An, Boon, Camiel J.F., van den Born, L. Ingeborgh, de Boer, Joke H., and van Genderen, Maria M.

Published
2023

34. Visual impairment due to retinopathy of prematurity and concomitant disabilities in the Netherlands

Author

MS Neonatologie, Child Health, MS Oogheelkunde, Trzcionkowska, Kasia, Termote, Jacqueline U.M., van Genderen, Maria M., de Vries, Meindert J., van Sorge, Arlette J., Schalij-Delfos, Nicoline E., MS Neonatologie, Child Health, MS Oogheelkunde, Trzcionkowska, Kasia, Termote, Jacqueline U.M., van Genderen, Maria M., de Vries, Meindert J., van Sorge, Arlette J., and Schalij-Delfos, Nicoline E.

Published
2023

35. Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies

Author

Oogheelkunde Onderzoek, Infection & Immunity, MS Oogheelkunde, Child Health, Nguyen, Xuan Thanh An, Moekotte, Lude, Plomp, Astrid S., Bergen, Arthur A., van Genderen, Maria M., Boon, Camiel J.F., Oogheelkunde Onderzoek, Infection & Immunity, MS Oogheelkunde, Child Health, Nguyen, Xuan Thanh An, Moekotte, Lude, Plomp, Astrid S., Bergen, Arthur A., van Genderen, Maria M., and Boon, Camiel J.F.

Published
2023

38. CLINICAL AND GENETIC CHARACTERISTICS OF MALE PATIENTS WITH RPGR-ASSOCIATED RETINAL DYSTROPHIES: A Long-Term Follow-up Study

Author

Talib, Mays, van Schooneveld, Mary J., Thiadens, Alberta A., Fiocco, Marta, Wijnholds, Jan, Florijn, Ralph J., Schalij-Delfos, Nicoline E., van Genderen, Maria M., Putter, Hein, Cremers, Frans P. M., Dagnelie, Gislin, ten Brink, Jacoline B., Klaver, Caroline C. W., van den Born, L. Ingeborgh, Hoyng, Carel B., Bergen, Arthur A., and Boon, Camiel J. F.

Published
2019
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40. Impact of Bevacizumab on Visual Function, Tumor Size, and Toxicity in Pediatric Progressive Optic Pathway Glioma: A Retrospective Nationwide Multicentre Study

Author

Bennebroek, Carlien A. M., primary, van Zwol, Judith, additional, Porro, Giorgio L., additional, Oostenbrink, Rianne, additional, Dittrich, Anne T. M., additional, Groot, Annabel L. W., additional, Pott, Jan W., additional, Janssen, Etienne J. M., additional, Bauer, Noël J., additional, van Genderen, Maria M., additional, Saeed, Peerooz, additional, Lequin, Maarten H., additional, de Graaf, Pim, additional, and Schouten-van Meeteren, Antoinette Y. N., additional

Published
2022
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41. The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene

Author

Hahn, Leo C., primary, Georgiou, Michalis, additional, Almushattat, Hind, additional, van Schooneveld, Mary J., additional, de Carvalho, Emanuel R., additional, Wesseling, Nieneke L., additional, ten Brink, Jacoline B., additional, Florijn, Ralph J., additional, Lissenberg-Witte, Birgit I., additional, Strubbe, Ine, additional, van Cauwenbergh, Caroline, additional, de Zaeytijd, Julie, additional, Walraedt, Sophie, additional, de Baere, Elfride, additional, Mukherjee, Rajarshi, additional, McKibbin, Martin, additional, Meester-Smoor, Magda A., additional, Thiadens, Alberta A.H.J., additional, Al-Khuzaei, Saoud, additional, Akyol, Engin, additional, Lotery, Andrew J., additional, van Genderen, Maria M., additional, Ossewaarde-van Norel, Jeannette, additional, van den Born, L. Ingeborgh, additional, Hoyng, Carel B., additional, Klaver, Caroline C.W., additional, Downes, Susan M., additional, Bergen, Arthur A., additional, Leroy, Bart P., additional, Michaelides, Michel, additional, and Boon, Camiel J.F., additional

Published
2022
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42. The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences

Author

Kruijt, Charlotte C, Gradstein, Libe, Bergen, Arthur A, Florijn, Ralph J, Arveiler, Benoit, Lasseaux, Eulalie, Zanlonghi, Xavier, Bagdonaite-Bejarano, Laura, Fulton, Anne B, Yahalom, Claudia, Blumenfeld, Anat, Perez, Yonatan, Birk, Ohad S, de Wit, Gerard C, Schalij-Delfos, Nicoline E, van Genderen, Maria M, Kruijt, Charlotte C, Gradstein, Libe, Bergen, Arthur A, Florijn, Ralph J, Arveiler, Benoit, Lasseaux, Eulalie, Zanlonghi, Xavier, Bagdonaite-Bejarano, Laura, Fulton, Anne B, Yahalom, Claudia, Blumenfeld, Anat, Perez, Yonatan, Birk, Ohad S, de Wit, Gerard C, Schalij-Delfos, Nicoline E, and van Genderen, Maria M

Abstract

Purpose: The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism.Subjects and Methods: We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43).Results: Patients with FHONDA had a total of 15 different mutations in SLC38A8, of which 6 were novel. Excluding missing data, all patients had moderate to severe visual impairment (median visual acuity [VA] = 0.7 logMAR, interquartile range [IQR] = 0.6-0.8), nystagmus (28/28), and grade 4 foveal hypoplasia (17/17). Misrouting was present in all nine tested patients. None of the patients had any signs of hypopigmentation of skin and hair. VA in albinism was better (median = 0.5 logMAR, IQR = 0.3-0.7, P 0.006) and the phenotypes were more variable: 14 of 132 without nystagmus, foveal hypoplasia grades 1 to 4, and misrouting absent in 16 of 74.Conclusions: Compared to albinism, the FHONDA syndrome appears to have a more narrow phenotypic spectrum, consisting of nonprogressive moderately to severely reduced VA, nystagmus, severe foveal hypoplasia, and misrouting. The co-occurrence of nystagmus, foveal hypoplasia, and misrouting in the absence of hypopigmentation implies that these abnormalities are not caused by lack of melanin, which has important implications for understanding the pathogenesis of these features.

Published
2022

43. CRB1-associated retinal dystrophies: a prospective natural history study in anticipation of future clinical trials

Author

Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Talsma, Herman E, Fiocco, Marta, Florijn, Ralph J, Ten Brink, Jacoline B, Cremers, Frans P M, Meester-Smoor, Magda A, Ingeborgh van den Born, L, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, Boon, Camiel J F, Nguyen, Xuan-Thanh-An, Talib, Mays, van Schooneveld, Mary J, Wijnholds, Jan, van Genderen, Maria M, Schalij-Delfos, Nicoline E, Klaver, Caroline C W, Talsma, Herman E, Fiocco, Marta, Florijn, Ralph J, Ten Brink, Jacoline B, Cremers, Frans P M, Meester-Smoor, Magda A, Ingeborgh van den Born, L, Hoyng, Carel B, Thiadens, Alberta A H J, Bergen, Arthur A, and Boon, Camiel J F

Abstract

PURPOSE: To describe the natural disease course of CRB1-associated retinal dystrophies, and to identify clinical endpoints for future clinical trials.DESIGN: Single center, prospective case series.METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using ETDRS charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography (ERG), full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography and fundus autofluorescence imaging.RESULTS: Based on genetic, clinical and electrophysiological data, patients were diagnosed with retinitis pigmentosa (n = 19; 86%), cone-rod dystrophy (n = 2; 9%) or isolated macular dystrophy (n = 1; 5%). Two-year analysis of the entire cohort showed no significant changes in BCVA (p = 0.069) or V4e isopter seeing retinal areas (p = 0.616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at 2-year follow-up (p < 0.001). FST responses were measurable in patients with non-recordable ERGs. On average, FST responses remained stable during follow-up.CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up, and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical endpoint in future human treatment trials for CRB1-associated retinal dystrophies.

Published
2022

44. Impact of Bevacizumab on Visual Function, Tumor Size, and Toxicity in Pediatric Progressive Optic Pathway Glioma:A Retrospective Nationwide Multicentre Study

Author

Bennebroek, Carlien A.M., van Zwol, Judith, Porro, Giorgio L., Oostenbrink, Rianne, Dittrich, Anne T.M., Groot, Annabel L.W., Pott, Jan W., Janssen, Etienne J.M., Bauer, Noël J., van Genderen, Maria M., Saeed, Peerooz, Lequin, Maarten H., de Graaf, Pim, Schouten-van Meeteren, Antoinette Y.N., Bennebroek, Carlien A.M., van Zwol, Judith, Porro, Giorgio L., Oostenbrink, Rianne, Dittrich, Anne T.M., Groot, Annabel L.W., Pott, Jan W., Janssen, Etienne J.M., Bauer, Noël J., van Genderen, Maria M., Saeed, Peerooz, Lequin, Maarten H., de Graaf, Pim, and Schouten-van Meeteren, Antoinette Y.N.

Abstract

Backgrounds: Bevacizumab (BVZ) is used as a subsequent line of treatment for pediatric optic pathway glioma (OPG) in the case of progression. Data on the treatment effect concerning tumor progression and visual function are scarce and nationwide studies are lacking. Methods: We performed a retrospective, nationwide, multicentre cohort study including all pediatric patients with OPG treated with BVZ in the Netherlands (2009–2021). Progression-free survival, change in visual acuity and visual field, MRI-based radiologic response, and toxicity were evaluated. Results: In total, 33 pediatric patients with OPG were treated with BVZ (median 12 months). Visual acuity improved in 20.5%, remained stable in 74.4%, and decreased in 5.1% of 39 of all analysed eyes. The monocular visual field improved in 73.1%, remained stable in 15.4%, and decreased in 7.7% of 25 analysed eyes. Radiologic response at the end of therapy showed a partial response in 7 patients (21.9%), minor response in 7 (21.9%), stable disease in 15 (46.9%), and progressive disease in 3 (9.3%). Progression-free survival at 18 and 36 months after the start of BVZ reduced from 70.9% to 38.0%. Toxicity (≥grade 3 CTCAE) during treatment was observed in five patients (15.2%). Conclusion: Treatment of BVZ in pediatric patients with OPG revealed stabilisation in the majority of patients, but was followed by progression at a later time point in more than 60% of patients. This profile seems relatively acceptable given the benefits of visual field improvement in more than 70% of analysed eyes and visual acuity improvement in more than 20% of eyes at the cessation of BVZ.

Published
2022

45. Genotypic and Phenotypic Spectrum of Foveal Hypoplasia:A Multicenter Study

Author

Kuht, Helen J., Maconachie, Gail D.E., Han, Jinu, Kessel, Line, van Genderen, Maria M., McLean, Rebecca J., Hisaund, Michael, Tu, Zhanhan, Hertle, Richard W., Grønskov, Karen, Bai, Dayong, Wei, Aihua, Li, Wei, Jiao, Yonghong, Smirnov, Vasily, Choi, Jae Hwan, Tobin, Martin D., Sheth, Viral, Purohit, Ravi, Dawar, Basu, Girach, Ayesha, Strul, Sasha, May, Laura, Chen, Fred K., Heath Jeffery, Rachael C., Aamir, Abdullah, Sano, Ronaldo, Jin, Jing, Brooks, Brian P., Kohl, Susanne, Arveiler, Benoit, Montoliu, Lluis, Engle, Elizabeth C., Proudlock, Frank A., Nishad, Garima, Pani, Prateek, Varma, Girish, Gottlob, Irene, Thomas, Mervyn G., Kuht, Helen J., Maconachie, Gail D.E., Han, Jinu, Kessel, Line, van Genderen, Maria M., McLean, Rebecca J., Hisaund, Michael, Tu, Zhanhan, Hertle, Richard W., Grønskov, Karen, Bai, Dayong, Wei, Aihua, Li, Wei, Jiao, Yonghong, Smirnov, Vasily, Choi, Jae Hwan, Tobin, Martin D., Sheth, Viral, Purohit, Ravi, Dawar, Basu, Girach, Ayesha, Strul, Sasha, May, Laura, Chen, Fred K., Heath Jeffery, Rachael C., Aamir, Abdullah, Sano, Ronaldo, Jin, Jing, Brooks, Brian P., Kohl, Susanne, Arveiler, Benoit, Montoliu, Lluis, Engle, Elizabeth C., Proudlock, Frank A., Nishad, Garima, Pani, Prateek, Varma, Girish, Gottlob, Irene, and Thomas, Mervyn G.

Abstract

Purpose: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). Design: Multicenter, observational study. Participants: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). Methods: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. Main Outcome Measures: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS–), molecular diagnosis, and visual acuity (VA). Results: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS– (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky–Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. Conclusions: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms

Published
2022

46. CRB1-Associated Retinal Dystrophies:A Prospective Natural History Study in Anticipation of Future Clinical Trials

Author

Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Talsma, Herman E., Fiocco, Marta, Florijn, Ralph J., ten Brink, Jacoline B., Cremers, Frans P.M., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., Boon, Camiel J.F., Nguyen, Xuan Thanh An, Talib, Mays, van Schooneveld, Mary J., Wijnholds, Jan, van Genderen, Maria M., Schalij-Delfos, Nicoline E., Klaver, Caroline C.W., Talsma, Herman E., Fiocco, Marta, Florijn, Ralph J., ten Brink, Jacoline B., Cremers, Frans P.M., Meester-Smoor, Magda A., van den Born, L. Ingeborgh, Hoyng, Carel B., Thiadens, Alberta A.H.J., Bergen, Arthur A., and Boon, Camiel J.F.

Abstract

PURPOSE: To investigate the natural disease course of retinal dystrophies associated with crumbs cell polarity complex component 1 (CRB1) and identify clinical end points for future clinical trials. DESIGN: Single-center, prospective case series. METHODS: An investigator-initiated nationwide collaborative study that included 22 patients with CRB1-associated retinal dystrophies. Patients underwent ophthalmic assessment at baseline and 2 years after baseline. Clinical examination included best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts, Goldmann kinetic perimetry (V4e isopter seeing retinal areas), microperimetry, full-field electroretinography, full-field stimulus threshold (FST), fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: Based on genetic, clinical, and electrophysiological data, patients were diagnosed with retinitis pigmentosa (19 [86%]), cone-rod dystrophy (2 [9%]), or isolated macular dystrophy (1 [5%]). Analysis of the entire cohort at 2 years showed no significant changes in BCVA (P = .069) or V4e isopter seeing retinal areas (P = .616), although signs of clinical progression were present in individual patients. Macular sensitivity measured on microperimetry revealed a significant reduction at the 2-year follow-up (P < .001). FST responses were measurable in patients with nonrecordable electroretinograms. On average, FST responses remained stable during follow-up. CONCLUSION: In CRB1-associated retinal dystrophies, visual acuity and visual field measures remain relatively stable over the course of 2 years. Microperimetry showed a significant decrease in retinal sensitivity during follow-up and may be a more sensitive progression marker. Retinal sensitivity on microperimetry may serve as a functional clinical end point in future human treatment trials for CRB1-associated retinal dystrophies.

Published
2022

47. Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA

Author

AIOS Anesthesiologie, MS Oogheelkunde, Child Health, Genetica Klinische Genetica, Haer-Wigman, Lonneke, den Ouden, Amber, van Genderen, Maria M, Kroes, Hester Y, Verheij, Joke, Smailhodzic, Dzenita, Hoekstra, Attje S, Vijzelaar, Raymon, Blom, Jan, Derks, Ronny, Tjon-Pon-Fong, Menno, Yntema, Helger G, Nelen, Marcel R, Vissers, Lisenka E L M, Lugtenberg, Dorien, Neveling, Kornelia, AIOS Anesthesiologie, MS Oogheelkunde, Child Health, Genetica Klinische Genetica, Haer-Wigman, Lonneke, den Ouden, Amber, van Genderen, Maria M, Kroes, Hester Y, Verheij, Joke, Smailhodzic, Dzenita, Hoekstra, Attje S, Vijzelaar, Raymon, Blom, Jan, Derks, Ronny, Tjon-Pon-Fong, Menno, Yntema, Helger G, Nelen, Marcel R, Vissers, Lisenka E L M, Lugtenberg, Dorien, and Neveling, Kornelia

Published
2022

48. Impact of Bevacizumab on Visual Function, Tumor Size, and Toxicity in Pediatric Progressive Optic Pathway Glioma: A Retrospective Nationwide Multicentre Study

Author

MS Oogheelkunde, Brain, Cancer, MS Radiologie, Circulatory Health, Bennebroek, Carlien A M, van Zwol, Judith, Porro, Giorgio L, Oostenbrink, Rianne, Dittrich, Anne T M, Groot, Annabel L W, Pott, Jan W, Janssen, Etienne J M, Bauer, Noël J, van Genderen, Maria M, Saeed, Peerooz, Lequin, Maarten H, de Graaf, Pim, Schouten-van Meeteren, Antoinette Y N, MS Oogheelkunde, Brain, Cancer, MS Radiologie, Circulatory Health, Bennebroek, Carlien A M, van Zwol, Judith, Porro, Giorgio L, Oostenbrink, Rianne, Dittrich, Anne T M, Groot, Annabel L W, Pott, Jan W, Janssen, Etienne J M, Bauer, Noël J, van Genderen, Maria M, Saeed, Peerooz, Lequin, Maarten H, de Graaf, Pim, and Schouten-van Meeteren, Antoinette Y N

Published
2022

49. Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study

Author

MS Oogheelkunde, Child Health, Kuht, Helen J., Maconachie, Gail D.E., Han, Jinu, Kessel, Line, van Genderen, Maria M., McLean, Rebecca J., Hisaund, Michael, Tu, Zhanhan, Hertle, Richard W., Gronskov, Karen, Bai, Dayong, Wei, Aihua, Li, Wei, Jiao, Yonghong, Smirnov, Vasily, Choi, Jae Hwan, Tobin, Martin D., Sheth, Viral, Purohit, Ravi, Dawar, Basu, Girach, Ayesha, Strul, Sasha, May, Laura, Chen, Fred K., Heath Jeffery, Rachael C., Aamir, Abdullah, Sano, Ronaldo, Jin, Jing, Brooks, Brian P., Kohl, Susanne, Arveiler, Benoit, Montoliu, Lluis, Engle, Elizabeth C., Proudlock, Frank A., Nishad, Garima, Pani, Prateek, Varma, Girish, Gottlob, Irene, Thomas, Mervyn G., MS Oogheelkunde, Child Health, Kuht, Helen J., Maconachie, Gail D.E., Han, Jinu, Kessel, Line, van Genderen, Maria M., McLean, Rebecca J., Hisaund, Michael, Tu, Zhanhan, Hertle, Richard W., Gronskov, Karen, Bai, Dayong, Wei, Aihua, Li, Wei, Jiao, Yonghong, Smirnov, Vasily, Choi, Jae Hwan, Tobin, Martin D., Sheth, Viral, Purohit, Ravi, Dawar, Basu, Girach, Ayesha, Strul, Sasha, May, Laura, Chen, Fred K., Heath Jeffery, Rachael C., Aamir, Abdullah, Sano, Ronaldo, Jin, Jing, Brooks, Brian P., Kohl, Susanne, Arveiler, Benoit, Montoliu, Lluis, Engle, Elizabeth C., Proudlock, Frank A., Nishad, Garima, Pani, Prateek, Varma, Girish, Gottlob, Irene, and Thomas, Mervyn G.

Published
2022

50. The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences

Author

Child Health, MS Oogheelkunde, Kruijt, Charlotte C., Gradstein, Libe, Bergen, Arthur A., Florijn, Ralph J., Arveiler, Benoit, Lasseaux, Eulalie, Zanlonghi, Xavier, Bagdonaite-Bejaran, Laura, Fulton, Anne B., Yahalom, Claudia, Blumenfeld, Anat, Perez, Yonatan, Birk, Ohad S., De Wit, Gerard C., Schalij-Delfos, Nicoline E., Van Genderen, Maria M., Child Health, MS Oogheelkunde, Kruijt, Charlotte C., Gradstein, Libe, Bergen, Arthur A., Florijn, Ralph J., Arveiler, Benoit, Lasseaux, Eulalie, Zanlonghi, Xavier, Bagdonaite-Bejaran, Laura, Fulton, Anne B., Yahalom, Claudia, Blumenfeld, Anat, Perez, Yonatan, Birk, Ohad S., De Wit, Gerard C., Schalij-Delfos, Nicoline E., and Van Genderen, Maria M.

Published
2022

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