Pub Date : 2025-12-11DOI: 10.1001/jamaophthalmol.2025.5068
Warren W Pan,Ian Waters,Jonah Yousif,Zachery R Reichert,Mark W Johnson,Jason Miller,K Thiran Jayasundera
{"title":"Acute and Substantial Vision Loss After Pembrolizumab Immunotherapy for Bladder Cancer.","authors":"Warren W Pan,Ian Waters,Jonah Yousif,Zachery R Reichert,Mark W Johnson,Jason Miller,K Thiran Jayasundera","doi":"10.1001/jamaophthalmol.2025.5068","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.5068","url":null,"abstract":"","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"6 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1001/jamaophthalmol.2025.5078
Gabriella De Salvo, Peter M. Maloca
This case report discusses a diagnosis of epiretinal hyperproliferative complex in a male patient aged 75 years with a history of multiple myeloma who reported blurred vision in his left eye persisting after cataract surgery.
本病例报告讨论一名75岁男性患者，有多发性骨髓瘤病史，白内障手术后左眼视力持续模糊。
{"title":"Epiretinal Hyperproliferative Complex","authors":"Gabriella De Salvo, Peter M. Maloca","doi":"10.1001/jamaophthalmol.2025.5078","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.5078","url":null,"abstract":"This case report discusses a diagnosis of epiretinal hyperproliferative complex in a male patient aged 75 years with a history of multiple myeloma who reported blurred vision in his left eye persisting after cataract surgery.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"15 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1001/jamaophthalmol.2025.5069
Adrian T. Fung, David Sarraf, Jose M. Carrillo, Alessandro Feo, Shahin Faghihi, Caroline M. Borie, Liam Lim, Alex P. Hunyor, Nicolas A. Yannuzzi
Importance Retinal toxic effects due to pentosan polysulfate sodium (PPS) have primarily been reported following oral administration of the drug. Because PPS can also be administered subcutaneously, it is important to determine whether this route of administration may also be associated with retinal toxic effects. Objective To characterize the exposure characteristics and clinical presentation of toxic maculopathy following subcutaneous administration of PPS for the treatment of arthritis. Design, Setting, and Participants This multi-institutional, retrospective case series examined 3 cases of pentosan polysulfate maculopathy (PPM) after subcutaneous administration of PPS for the treatment of arthritis at 3 centers in Miami, Florida; Los Angeles, California; and Sydney, Australia, between September 1, 2024, and July 8, 2025. Data were analyzed from July 9, 2025, to July 18, 2025. Exposure Subcutaneous administration of PPS. Main Outcomes and Measures The primary outcome was PPM after subcutaneous PPS administration for arthritis. Changes were assessed by examining drug dosage, visual acuity, and features of multimodal retinal imaging. Results Three patients with PPS toxic maculopathy presented following treatment for osteoarthritis or inflammatory arthritis. The cumulative dose was very low in all 3 cases and ranged from 45.5 to 96 g during a span of 7 to 10 years. The multimodal features in all 3 cases were classic for PPS retinal toxic effects. Conclusions and Relevance The findings of this case series suggest that PPS retinal toxic effects can occur with subcutaneous administration alone, at much lower doses than typically occurs with oral administration, potentially due to 10-fold higher bioavailability. Early recognition of this toxic maculopathy with multimodal imaging is important to limit exposure to this drug and avoid incorrect treatments. Given progression of maculopathy even following cessation, caution is advised when using subcutaneous PPS.
{"title":"Pentosan Polysulfate Maculopathy Following Subcutaneous Injections for Arthritis","authors":"Adrian T. Fung, David Sarraf, Jose M. Carrillo, Alessandro Feo, Shahin Faghihi, Caroline M. Borie, Liam Lim, Alex P. Hunyor, Nicolas A. Yannuzzi","doi":"10.1001/jamaophthalmol.2025.5069","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.5069","url":null,"abstract":"Importance Retinal toxic effects due to pentosan polysulfate sodium (PPS) have primarily been reported following oral administration of the drug. Because PPS can also be administered subcutaneously, it is important to determine whether this route of administration may also be associated with retinal toxic effects. Objective To characterize the exposure characteristics and clinical presentation of toxic maculopathy following subcutaneous administration of PPS for the treatment of arthritis. Design, Setting, and Participants This multi-institutional, retrospective case series examined 3 cases of pentosan polysulfate maculopathy (PPM) after subcutaneous administration of PPS for the treatment of arthritis at 3 centers in Miami, Florida; Los Angeles, California; and Sydney, Australia, between September 1, 2024, and July 8, 2025. Data were analyzed from July 9, 2025, to July 18, 2025. Exposure Subcutaneous administration of PPS. Main Outcomes and Measures The primary outcome was PPM after subcutaneous PPS administration for arthritis. Changes were assessed by examining drug dosage, visual acuity, and features of multimodal retinal imaging. Results Three patients with PPS toxic maculopathy presented following treatment for osteoarthritis or inflammatory arthritis. The cumulative dose was very low in all 3 cases and ranged from 45.5 to 96 g during a span of 7 to 10 years. The multimodal features in all 3 cases were classic for PPS retinal toxic effects. Conclusions and Relevance The findings of this case series suggest that PPS retinal toxic effects can occur with subcutaneous administration alone, at much lower doses than typically occurs with oral administration, potentially due to 10-fold higher bioavailability. Early recognition of this toxic maculopathy with multimodal imaging is important to limit exposure to this drug and avoid incorrect treatments. Given progression of maculopathy even following cessation, caution is advised when using subcutaneous PPS.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"170 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145718240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.5070
Piotr K Kopinski,Paul Nathan,Mandeep S Sagoo
{"title":"Eye Safety Risks of Antibody-Drug Conjugate Cancer Therapies.","authors":"Piotr K Kopinski,Paul Nathan,Mandeep S Sagoo","doi":"10.1001/jamaophthalmol.2025.5070","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.5070","url":null,"abstract":"","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"12 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.5006
Omar A Mahroo,Shigeru Sato,Siying Lin
{"title":"A New Gene for Congenital Stationary Night Blindness.","authors":"Omar A Mahroo,Shigeru Sato,Siying Lin","doi":"10.1001/jamaophthalmol.2025.5006","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.5006","url":null,"abstract":"","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"93 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.4888
Sanja Boranijasevic,Vasily Smirnov,Julien Navarro,Martha Tjon-Fo-Sang,Christel Condroyer,Lonneke Haer-Wigman,Aline Antonio,Claire-Marie Dhaenens,Virginie J M Verhoeven,José-Alain Sahel,L Ingeborgh van den Born,Sabine Defoort,Isabelle Audo,Christina Zeitz
ImportanceCongenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches.ObjectiveTo describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families.Design, Setting and ParticipantsThis retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically.ExposuresComplete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES).Main Outcomes and MeasuresThe main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis.ResultsThe series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina.Conclusion and RelevanceThis case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.
{"title":"EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.","authors":"Sanja Boranijasevic,Vasily Smirnov,Julien Navarro,Martha Tjon-Fo-Sang,Christel Condroyer,Lonneke Haer-Wigman,Aline Antonio,Claire-Marie Dhaenens,Virginie J M Verhoeven,José-Alain Sahel,L Ingeborgh van den Born,Sabine Defoort,Isabelle Audo,Christina Zeitz","doi":"10.1001/jamaophthalmol.2025.4888","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.4888","url":null,"abstract":"ImportanceCongenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches.ObjectiveTo describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families.Design, Setting and ParticipantsThis retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically.ExposuresComplete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES).Main Outcomes and MeasuresThe main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis.ResultsThe series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina.Conclusion and RelevanceThis case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"75 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.4903
Zhuoling Lin, Haotian Lin
This case report discusses a diagnosis of Axenfeld-Rieger syndrome in an 8-month-old infant who presented with bilateral abnormal pupils, posterior embryotoxon, and dental abnormalities.
{"title":"Axenfeld-Rieger Syndrome in an Infant","authors":"Zhuoling Lin, Haotian Lin","doi":"10.1001/jamaophthalmol.2025.4903","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.4903","url":null,"abstract":"This case report discusses a diagnosis of Axenfeld-Rieger syndrome in an 8-month-old infant who presented with bilateral abnormal pupils, posterior embryotoxon, and dental abnormalities.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"34 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.3159
Neel D Pasricha,Stella K Kim,Asim V Farooq,Ethan S Lindgren,Rongshan Yan,Gerami D Seitzman,Matilda F Chan,Jessica G Shantha,Dimitra Skondra,Bennie H Jeng,Winston D Chamberlain,Kathryn A Colby,Debra A Goldstein,Lucia Sobrin,Ivana K Kim,Kuldev Singh,Wiley A Chambers,William M Boyd,Jordyn Silverstein,Paula R Pohlmann,Janice Lu,Alexa C Glencer,Laura A Huppert,A Jo Chien,Hope S Rugo,Laura J Esserman
ImportanceThe current ocular Common Terminology Criteria for Adverse Events (CTCAE) mix eye signs with symptoms and lack standardized clinical photographs and experimental oncology drug dose modification recommendations. Robust reporting of ocular adverse events (AEs) is important to maintain patient safety and to guide the development of novel efficacious drugs.ObjectiveTo develop improved ocular AE grading scales to reliably evaluate and grade ocular AEs in patients on experimental oncology drug therapy and to provide clear drug dose modification recommendations.Design, Setting, and ParticipantsA collaborative multicenter interspecialty working group consisting of oncologists and academic ophthalmologists from 11 academic centers in the US and ophthalmologists from the US Food and Drug Administration was assembled in February 2023 to form a consensus on new experimental oncology drug-related ocular AE grading scales. The grading scales were released in June 2023.Main Outcomes and MeasuresExpert consensus on novel experimental oncology drug-related ocular AE grading scales.ResultsSix experimental oncology drug-related ocular AE grading scales were developed with agreement from ophthalmologists and oncologists for use in antibody-drug conjugate clinical trials: visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment.Conclusions and RelevanceThe new experimental oncology drug-related ocular AE grading scales developed by the consensus panel were developed to be more concise, containing photographs where applicable, and to provide clear drug dose modification recommendations compared with the previous CTCAE. Use of these ocular AE grading scales may allow for more objective and consistent incidence measurements of ocular AEs throughout clinical trials and postmarketing, potentially facilitating safe testing of novel agents that may cause eye toxicity.
{"title":"Multicenter Interspecialty Consensus on Experimental Oncology Drug-Related Ocular Adverse Event Reporting.","authors":"Neel D Pasricha,Stella K Kim,Asim V Farooq,Ethan S Lindgren,Rongshan Yan,Gerami D Seitzman,Matilda F Chan,Jessica G Shantha,Dimitra Skondra,Bennie H Jeng,Winston D Chamberlain,Kathryn A Colby,Debra A Goldstein,Lucia Sobrin,Ivana K Kim,Kuldev Singh,Wiley A Chambers,William M Boyd,Jordyn Silverstein,Paula R Pohlmann,Janice Lu,Alexa C Glencer,Laura A Huppert,A Jo Chien,Hope S Rugo,Laura J Esserman","doi":"10.1001/jamaophthalmol.2025.3159","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.3159","url":null,"abstract":"ImportanceThe current ocular Common Terminology Criteria for Adverse Events (CTCAE) mix eye signs with symptoms and lack standardized clinical photographs and experimental oncology drug dose modification recommendations. Robust reporting of ocular adverse events (AEs) is important to maintain patient safety and to guide the development of novel efficacious drugs.ObjectiveTo develop improved ocular AE grading scales to reliably evaluate and grade ocular AEs in patients on experimental oncology drug therapy and to provide clear drug dose modification recommendations.Design, Setting, and ParticipantsA collaborative multicenter interspecialty working group consisting of oncologists and academic ophthalmologists from 11 academic centers in the US and ophthalmologists from the US Food and Drug Administration was assembled in February 2023 to form a consensus on new experimental oncology drug-related ocular AE grading scales. The grading scales were released in June 2023.Main Outcomes and MeasuresExpert consensus on novel experimental oncology drug-related ocular AE grading scales.ResultsSix experimental oncology drug-related ocular AE grading scales were developed with agreement from ophthalmologists and oncologists for use in antibody-drug conjugate clinical trials: visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment.Conclusions and RelevanceThe new experimental oncology drug-related ocular AE grading scales developed by the consensus panel were developed to be more concise, containing photographs where applicable, and to provide clear drug dose modification recommendations compared with the previous CTCAE. Use of these ocular AE grading scales may allow for more objective and consistent incidence measurements of ocular AEs throughout clinical trials and postmarketing, potentially facilitating safe testing of novel agents that may cause eye toxicity.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"25 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1001/jamaophthalmol.2025.4875
Mukhtar Ullah,Atta Ur Rehman,Madhur Shetty,Michael D Allen,Ehsan Ullah,Sabrina G Signorini,Cyril Burin des Roziers,Rosalie M Grijalva,Abdur Rashid,Asad Munir,Alessandra Pia Porretta,Enza Maria Valente,Aime R Agather,Ioannis Dimopoulos,Robert B Hufnagel,Edouard Malandain,Juliette Coursimault,Muhammad Ansar,Stylianos E Antonarakis,Andrea Superti-Furga,Sanaullah Jan,Brian P Brooks,Giacomo Calzetti,Bin Guan,Mathieu Quinodoz,L Keith Henry,Carlo Rivolta
ImportanceInherited retinal dystrophies are a group of disorders that may lead to progressive vision loss. Improved knowledge of their molecular genetics is important for accurate diagnosis or development of targeted therapies.ObjectiveTo identify pathogenic variants in the SLC6A6 gene (encoding TauT, the main transporter for taurine) and assess their role in the molecular pathogenesis of hereditary early-onset retinal dystrophy (EORD) in affected individuals from diverse ethnic backgrounds.Design, Setting, and ParticipantsThis was a retrospective, multicenter observational study conducted between June 2019 and March 2025, involving 7 affected and 10 unaffected individuals from 4 unrelated families recruited in Pakistan, Italy, the US, and France.ExposurePathogenic variants in SLC6A6 in individuals with EORD.Main Outcomes and MeasuresGenetic, clinical, and functional outcomes of pathogenic variants in SLC6A6 in individuals with Leber congenital amaurosis (LCA) and EORD. All patients underwent standard clinical examinations, including visual acuity, full-field electroretinography, and multimodal retinal imaging, followed by measurement of fasting plasma taurine levels. In vitro and ex vivo taurine transport and membrane trafficking assays in human embryonic kidney (HEK)-293 cells, as well as patient-derived fibroblasts, were also performed.ResultsAll 7 affected individuals exhibited LCA/EORD, with extraocular findings in some. Genetic analysis identified homozygous pathogenic SLC6A6 variants in all affected individuals, while unaffected relatives were heterozygous carriers. Families 1 and 2 carried missense variants p.(Thr249Ile) and p.(Ala294Thr), while families 3 and 4 carried truncating variants-a deletion of exon 11 and p.(Thr113Ter), respectively. Functional studies demonstrated that both missense variants are associated with complete loss of taurine transport in HEK-293 cells and patient-derived fibroblasts. Additionally, irrespective of the variants considered, plasma taurine levels in affected individuals were reduced compared with heterozygous carriers (difference between means, -31.7 µmol/L; 95% CI, -42.7 to -20.8; P < .001) and healthy control individuals (difference between means, -37.7 µmol/L; 95% CI -41.6 to -33.8; P < .001).Conclusions and RelevanceThese findings confirm and expand the role of biallelic variants in SLC6A6 in association with LCA/EORD due to impaired taurine transport. These findings suggest that patients with a diagnosis of SLC6A6-related LCA/EORD may be candidates for investigational oral taurine supplementation.
{"title":"Early-Onset Retinopathy in Patients With Variants in SLC6A6 Leading to Impaired Taurine Transport.","authors":"Mukhtar Ullah,Atta Ur Rehman,Madhur Shetty,Michael D Allen,Ehsan Ullah,Sabrina G Signorini,Cyril Burin des Roziers,Rosalie M Grijalva,Abdur Rashid,Asad Munir,Alessandra Pia Porretta,Enza Maria Valente,Aime R Agather,Ioannis Dimopoulos,Robert B Hufnagel,Edouard Malandain,Juliette Coursimault,Muhammad Ansar,Stylianos E Antonarakis,Andrea Superti-Furga,Sanaullah Jan,Brian P Brooks,Giacomo Calzetti,Bin Guan,Mathieu Quinodoz,L Keith Henry,Carlo Rivolta","doi":"10.1001/jamaophthalmol.2025.4875","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.4875","url":null,"abstract":"ImportanceInherited retinal dystrophies are a group of disorders that may lead to progressive vision loss. Improved knowledge of their molecular genetics is important for accurate diagnosis or development of targeted therapies.ObjectiveTo identify pathogenic variants in the SLC6A6 gene (encoding TauT, the main transporter for taurine) and assess their role in the molecular pathogenesis of hereditary early-onset retinal dystrophy (EORD) in affected individuals from diverse ethnic backgrounds.Design, Setting, and ParticipantsThis was a retrospective, multicenter observational study conducted between June 2019 and March 2025, involving 7 affected and 10 unaffected individuals from 4 unrelated families recruited in Pakistan, Italy, the US, and France.ExposurePathogenic variants in SLC6A6 in individuals with EORD.Main Outcomes and MeasuresGenetic, clinical, and functional outcomes of pathogenic variants in SLC6A6 in individuals with Leber congenital amaurosis (LCA) and EORD. All patients underwent standard clinical examinations, including visual acuity, full-field electroretinography, and multimodal retinal imaging, followed by measurement of fasting plasma taurine levels. In vitro and ex vivo taurine transport and membrane trafficking assays in human embryonic kidney (HEK)-293 cells, as well as patient-derived fibroblasts, were also performed.ResultsAll 7 affected individuals exhibited LCA/EORD, with extraocular findings in some. Genetic analysis identified homozygous pathogenic SLC6A6 variants in all affected individuals, while unaffected relatives were heterozygous carriers. Families 1 and 2 carried missense variants p.(Thr249Ile) and p.(Ala294Thr), while families 3 and 4 carried truncating variants-a deletion of exon 11 and p.(Thr113Ter), respectively. Functional studies demonstrated that both missense variants are associated with complete loss of taurine transport in HEK-293 cells and patient-derived fibroblasts. Additionally, irrespective of the variants considered, plasma taurine levels in affected individuals were reduced compared with heterozygous carriers (difference between means, -31.7 µmol/L; 95% CI, -42.7 to -20.8; P < .001) and healthy control individuals (difference between means, -37.7 µmol/L; 95% CI -41.6 to -33.8; P < .001).Conclusions and RelevanceThese findings confirm and expand the role of biallelic variants in SLC6A6 in association with LCA/EORD due to impaired taurine transport. These findings suggest that patients with a diagnosis of SLC6A6-related LCA/EORD may be candidates for investigational oral taurine supplementation.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"20 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImportanceAs new chemotherapy agents emerge, ophthalmologists may play a role in identifying vision-threatening adverse effects. Inherited retinal degenerations can offer insight into the changes that may result from pharmacologic inhibition of the signaling pathways involved in these conditions.ObjectiveTo present a case of a patient treated with a yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor who developed chorioretinal findings that resemble those seen in helicoid peripapillary chorioretinal degeneration (HPCD, also known as Sveinsson chorioretinal atrophy), an autosomal dominant disease caused by loss-of-function variants in TEAD1.Design, Setting, and ParticipantCase report of a single patient at a large university hospital.ExposuresThe patient was treated with VT3989, a YAP/TEAD inhibitor, for 5 cycles.Main Outcomes and MeasuresClinical evaluation and description of the ocular condition via fundus photography and fundus autofluorescence.ResultsA woman in her 50s with metastatic mesothelioma diagnosed several years previously presented for evaluation. Nine months before presentation, she had undergone several cycles of treatment with chemotherapy agent VT3989, which inhibits the interaction of the YAP and TEAD proteins that form the terminal transcriptional effector complex of the Hippo pathway, which is involved in control of cell fate, proliferation, apoptosis, and tissue regeneration. She developed visual decline associated with radially oriented areas of retinal pigment epithelium atrophy extending around both optic nerves, along with small scattered atrophic flecks elsewhere. Given the atypical nature of the peripapillary findings and the resemblance to a mild form of HPCD, which is caused by loss-of-function variants in TEAD1, these changes were presumed to be secondary to treatment with the YAP/TEAD inhibitor VT3989.Conclusions and RelevanceDownregulation of the Hippo signaling pathway via YAP/TEAD inhibition in an adult patient may result in a phenotype resembling a mild form of HPCD (Sveinsson chorioretinal atrophy), underscoring the importance of this pathway in maintenance of the adult retina and retinal pigment epithelium. As novel cancer therapeutics continue to emerge, it may be important to ensure ophthalmologic monitoring of patients on drugs targeting the Hippo pathway.
{"title":"Pharmacologic Inhibition of YAP/TEAD and Development of New Chorioretinal Atrophy.","authors":"Lindsay K Kozek,Isaac Bleicher,Edward Lu,Mohamed Ashraf,David J Kwiatkowski,Paul Arrigg,Aaron Nagiel,Dean Eliott","doi":"10.1001/jamaophthalmol.2025.4213","DOIUrl":"https://doi.org/10.1001/jamaophthalmol.2025.4213","url":null,"abstract":"ImportanceAs new chemotherapy agents emerge, ophthalmologists may play a role in identifying vision-threatening adverse effects. Inherited retinal degenerations can offer insight into the changes that may result from pharmacologic inhibition of the signaling pathways involved in these conditions.ObjectiveTo present a case of a patient treated with a yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor who developed chorioretinal findings that resemble those seen in helicoid peripapillary chorioretinal degeneration (HPCD, also known as Sveinsson chorioretinal atrophy), an autosomal dominant disease caused by loss-of-function variants in TEAD1.Design, Setting, and ParticipantCase report of a single patient at a large university hospital.ExposuresThe patient was treated with VT3989, a YAP/TEAD inhibitor, for 5 cycles.Main Outcomes and MeasuresClinical evaluation and description of the ocular condition via fundus photography and fundus autofluorescence.ResultsA woman in her 50s with metastatic mesothelioma diagnosed several years previously presented for evaluation. Nine months before presentation, she had undergone several cycles of treatment with chemotherapy agent VT3989, which inhibits the interaction of the YAP and TEAD proteins that form the terminal transcriptional effector complex of the Hippo pathway, which is involved in control of cell fate, proliferation, apoptosis, and tissue regeneration. She developed visual decline associated with radially oriented areas of retinal pigment epithelium atrophy extending around both optic nerves, along with small scattered atrophic flecks elsewhere. Given the atypical nature of the peripapillary findings and the resemblance to a mild form of HPCD, which is caused by loss-of-function variants in TEAD1, these changes were presumed to be secondary to treatment with the YAP/TEAD inhibitor VT3989.Conclusions and RelevanceDownregulation of the Hippo signaling pathway via YAP/TEAD inhibition in an adult patient may result in a phenotype resembling a mild form of HPCD (Sveinsson chorioretinal atrophy), underscoring the importance of this pathway in maintenance of the adult retina and retinal pigment epithelium. As novel cancer therapeutics continue to emerge, it may be important to ensure ophthalmologic monitoring of patients on drugs targeting the Hippo pathway.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"30 1","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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