Sorsby fundus dystrophy:Insights from the past and looking to the future
Open accessAbstract
Sorsby fundus dystrophy (SFD), an autosomal dominant, fully penetrant, degenerative disease of the macula, is manifested by symptoms of night blindness or sudden loss of visual acuity, usually in the third to fourth decades of life due to choroidal neovascularization (CNV). SFD is caused by specific mutations in the Tissue Inhibitor of Metalloproteinase‐3, (TIMP3) gene. The predominant histo‐pathological feature in the eyes of patients with SFD are confluent 20–30 m thick, amorphous deposits found between the basement membrane of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane. SFD is a rare disease but it has generated significant interest because it closely resembles the exudative or “wet” form of the more common age‐related macular degeneration (AMD). In addition, in both SFD and AMD donor eyes, sub‐retinal deposits have been shown to accumulate TIMP3 protein. Understanding the molecular functions of wild‐type and mutant TIMP3 will provide significant insights into the patho‐physiology of SFD and perhaps AMD. This review summarizes the current knowledge on TIMP3 and how mutations in TIMP3 cause SFD to provide insights into how we can study this disease going forward. Findings from these studies could have potential therapeutic implications for both SFD and AMD.
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Treatment with vitamin A in retinal diseases associated with vitamin A is not straight-forward because of fear of accumulation of excessive amounts of toxic retinoids formed as byproducts of vitamin A pathways.
“Treatment with vitamin A in these cases is not straight-forward, as there is a fear of accumulation of excessive amounts of toxic retinoids that are formed as byproducts of vitamin A pathways.”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [77]
The Clinical Disease > Treatment section (page unavailable) says vitamin A has not become a widely used treatment for Sorsby fundus dystrophy because of potential toxicity from long-term high doses and limited efficacy at lower doses in advanced disease. It does not identify accumulation of toxic retinoids formed through vitamin A pathways as the reason, or extend this concern to retinal diseases generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPathogenic variants in TIMP3 result in thickening of Bruch's membrane, leading to reduced exchange of nutrients and waste products between RPE and choriocapillaris, including vitamin A, resulting in local vitamin A deficiency.
“Pathogenic variants in the TIMP3 gene result in thickening of the Bruch’s membrane, leading to reduced exchange of nutrients and waste products between RPE and choriocapillaris, including vitamin A, resulting in local vitamin A deficiency [77,187].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [77]
The Pathology section (page unavailable) describes markedly thickened Bruch’s membrane in an eye with a Sorsby-associated TIMP3 mutation. The Treatment section (page unavailable) reports a proposed explanation in which thickening deprives photoreceptors of vitamin A. It does not establish reduced exchange of nutrients and waste products generally, and presents vitamin A deprivation as a hypothesis rather than a demonstrated consequence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEarly attempts of Sorsby fundus dystrophy treatment with vitamin A did not become widely used due to potential long-term toxicity of high doses of vitamin A and lack of lower doses efficacy.
“Although initial results were promising, treatment did not become widely used due to the potential long-term toxicity of high doses of vitamin A and lack of lower doses efficacy [77,189].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [77]
In ABCA4-retinopathy, toxic products of vitamin A accumulate excessively in the retina.
“A good example of this toxicity is ABCA4-retinopathy where toxic products of vitamin A accumulate excessively in the retina [9,23,76,77,78].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [77]
The Clinical Disease > Treatment section discusses vitamin A deprivation and supplementation in Sorsby fundus dystrophy, while the molecular-mechanisms section discusses lipofuscin accumulation in a different retinal disease. Searches for ABCA4-retinopathy and vitamin A–derived toxic products found no passage addressing their accumulation in ABCA4-retinopathy. (LLM, conf=0.77)
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References 91 · Cited by 45
Research works printed but not linked: 1
- Jacobson SG, Cideciyan AV, Regunath G, Rodriguez FJ, Vandenburgh K, Sheffield VV, 1995b Night blindness in Sorsby’s fundus dystrophy is reversed by vitamin A. Nature Genetics 11, 27– 32. 7550309
- Authors
- Anand‐Apte, B., Chao, J. R., Singh, R., & Stöhr, H.
- Affiliations
- Cleveland Clinic (US)
- University of Washington (US)
- University of Rochester Medicine (US)
- University of Regensburg (DE)
- Corresponding author
- Anand‐Apte, Bela
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2018-08-21
- Volume
- 97
- Issue
- 1
- Pages
- 88-97
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- PMC
- PMC6241301
- OpenAlex
- W2888067574
- Cited by
- 45
- References
- 91
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 11 · 2021: 4 · 2020: 4 · 2019: 4
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- BrightFocus Foundation (MDR Grant)
- Center for Scientific Review (P30EY001730, P30EY025585, RO1EY026030, RO1EY026181, RO1EY027083, RO1EY028167, T32EY024236)
- Foundation Fighting Blindness (Center Grant, Individual Investigator Award)
- Research to Prevent Blindness (Career Development Award, Unrestricted Grant)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- Sorsby fundus dystrophy, TIMP-3, choroidal neovascularization, macular degeneration, retinal pigment epithelium, Bruch's membrane, subretinal deposits, age-related macular degeneration, genetic mutations, disease pathophysiology, therapeutic target
- MeSH terms
- Animals, Humans, Macular Degeneration, Mutation, Retina, Tissue Inhibitor of Metalloproteinase-3, Retinal Pigment Epithelium
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