Researchers highlight the risk of misdiagnosing geographic atrophy

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Australian investigators identified a potential misdiagnosis rate of geographic atrophy (GA) of 1.9%. While this is low, they advised clinicians of the potential for dystrophies that mimic age-related macular degeneration (AMD) and other atrophic macular pathologies to be incorrectly diagnosed. Incorrect diagnosis can lead to inappropriate treatment,¹ reported first author Demi Markakis, who was associated with Cabrini Hospital and the Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Australia, when the study was undertaken and is now with The Alfred Hospital, Prahran, Australia.

Although inherited retinal diseases (IRDs) have distinct disease processes compared to AMD, IRDs may present with similar clinical phenotype (“phenocopy”), the investigators explained.

“Some develop chorioretinal atrophy, with a similar appearance to GA, the subject of this study. Some IRD phenocopies of GA include drusen,² including EFEMP1-associated autosomal dominant drusen,³ and CFH loss of function,⁴ and heterozygous variants. Some AMD phenocopies develop reticular pseudodrusen including Sorsby fundus dystrophy,⁵ autosomal recessive bestrophinopathy, pseudoxanthoma elasticum, late-onset retinal degeneration associated with a mutation in C1QTNF5,⁶ and possibly extensive macular atrophy with a pseudodrusen-like appearance.⁷ Systemic genetic and acquired complement disorders such as C3 glomerulonephropathy can be another phenocopy of drusen in AMD.⁸ Abetalipoproteinaemia has been described as a cause of isolated macular atrophy simulating late GA.⁹”

Clinical trials are being conducted to evaluate ocular gene therapy for more than 20 types of IRDs,^10-12 which, unlike AMD, typically appear within the first 3 decades of life. However, the investigators pointed out that differentiating GA secondary to AMD from IRDs is challenging, especially in older patients.^2,13

“With treatment options becoming available for both GA and IRDs and diagnosis complicated by the phenotypical similarities shared between the two diseases, ensuring patients receive an accurate diagnosis and therefore treatment, is more important than ever, as this will inform the possible treatment modalities. Even though research studies have evaluated the prevalence of some IRD genes in AMD cohorts,^2,13 no studies have looked at this in a real-world clinical setting,” Markakis and colleagues explained.

In light of that, the investigators wanted to determine the possible frequency of misdiagnosis when considering people with a diagnosis of GA secondary to AMD by performing an audit of real-world clinical records from a large ophthalmology practice in Australia.

They conducted a retrospective clinical review of medical records of patients diagnosed with AMD between 1995 and 2023 to identify those diagnosed with GA without drusen, that was further assessed for a potentially missed IRD with macular atrophy. Experts in AMD and IRD then reviewed the identified cases to establish a most-likely diagnosis.

A total of 1136 cases were flagged and reviewed. The authors reported a possible rate of misdiagnosis of 1.9%, with 1.0% representing potentially missed IRDs, most commonly pattern dystrophy (0.5%), they pointed out.

They advised using a multi-modal approach that includes clinical features and patient history, both to limit the potential to misdiagnosis GA and identify a subset of patients who could benefit from genetic testing before considering possible treatments.

References:

1. Markakis D, Britten-Jones AC, Guymer RH, et al. Retrospective audit reviewing accuracy of clinical diagnosis of geographic atrophy in a single centre private tertiary retinal practice in Australia. Sci Rep. 2025;15:8528. https://doi.org/10.1038/s41598-025-90516-z

2. Saksens NT, Fleckenstein M, Schmitz-Valckenberg S, et al. Macular dystrophies mimicking age-related macular degeneration. Prog Retin Eye Res. 2014;39, 23–57. https://doi.org/10.1016/j.preteyeres.2013.11.001

3. de Guimaraes TAC, Kalitzeos A, Mahroo OA, et al. A long-term retrospective natural history study of EFEMP1-associated autosomal dominant drusen. Invest Ophthalmol Vis Sci. 2024;65:31. https://doi.org/10.1167/iovs.65.6.31.

4. Taylor RL, Poulter JA, Downes SM, et al. Loss-of-function mutations in the CFH gene affecting alternatively encoded factor H-like 1 protein cause dominant early-onset macular drusen. Ophthalmology. 2019;126:1410–1421. https://doi.org/10.1016/j.ophtha.2019.03.013

5. Gliem M, Muller PL, Mangold E, et al. Reticular pseudodrusen in Sorsby fundus dystrophy. Ophthalmology. 2015;122:1555–1562. https://doi.org/10.1016/j.ophtha.2015.04.035

6. Cukras C, Flamendorf J, Wong WT, et al. Longitudinal structural changes in late-onset retinal degeneration. Retina. 2016;36:2348–2356. https://doi.org/10.1097/IAE.0000000000001113

7. Antropoli A, Bianco L, Condroyer C, et al. Extensive macular atrophy with pseudodrusen-like appearance (EMAP): progression kinetics and late-stage findings. Ophthalmology. 2024;https://doi.org/10.1016/j.ophtha.2024.04.001 (2024).

8. Savige J, Amos L, Ierino F, et al. Retinal disease in the C3 glomerulopathies and the risk of impaired vision. Ophthalmic Genet. 2016;37:369–376. https://doi.org/10.3109/13816810.2015.1101777

9. Alshareef RA, Bansal AS, Chiang A, Kaiser RS. Macular atrophy in a case of abetalipoproteinemia as only ocular clinical feature. Can J Ophthalmol. 2015;50:e43–46. https://doi.org/10.1016/j.jcjo.2014.12.016

10. Garafalo AV, Cideciyan AV, Heon E, et al. Progress in treating inherited retinal diseases: early subretinal gene therapy clinical trials and candidates for future initiatives. Prog Retin Eye Res. 2020;77:100827. https://doi.org/10.1016/j.preteyeres.2019.100827

11. Fuller-Carter PI, Basiri H, Harvey AR, Carvalho LS. Focused update on AAV-based gene therapy clinical trials for inherited retinal degeneration. BioDrugs. 2020;34:763–781. https://doi.org/10.1007/s40259-020-00453-8.

12. Brar AS, Parameswarappa DC, Takkar B, et al. Gene therapy for inherited retinal diseases: from laboratory bench to patient bedside and beyond. Ophthalmol Ther. 2024;13:21–50. https://doi.org/10.1007/s40123-023-00862-2

13. Kersten E, Geerlings MJ, Pauper M, et al. Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration. Clin Genet. 2018;94:569–574. https://doi.org/10.1111/cge.13447