Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy characterized by bilateral central vision loss, typically occurring in the fourth and fifth decades of life.1,2 It is caused by mutations in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene localized to 22a13-qter 3. It is postulated that accumulation of the abnormal protein product in Bruch's membrane leads to aberrant extracellular matrix remodeling, giving rise to choroidal neovascularization in conjunct with chorioretinal atrophy.4,5 Classically, the decline in central vision in SFD is attributed to choroidal neovascularization (CNV) and associated submacular scarring.5–7 However, phenotypic variability is increasingly reported surrounding this condition in the literature. Here we present a rare case of SFD manifesting with chorioretinal atrophy in the absence of CNV.
A 64-year-old male presented to our clinic for evaluation of suspected SFD. He reported 9 years of progressive, bilateral central vision loss and an extensive family history of a dominantly inherited macular dystrophy with molecularly confirmed SFD in his brother and sister (Figure 1). Past ocular history also included ocular hypertension in both eyes and mild myopia. Medications included dorzolamide-timolol (Cosopt; Akorn Pharmaceuticals, Lake Forest, IL) and bimatoprost drops for management of ocular hypertension, as well as AREDS 2 formula, lutein, and fish oil. Present or past tobacco use was denied. Due to the loss of central vision, the patient stopped driving 6 years prior to presentation. In the ensuing years, he underwent serial eye examinations with screening for CNV every 3 to 6 months by his local retina provider.
Pedigree depicting four generations of known ocular disease in the patient's (arrowhead) lineage. Notably, his paternal grandmother was blind. Of her children, three daughters and one son, the patient's father, were affected. The patient's father reported onset of metamorphopsia in the fourth decade, which progressed to blindness. Each of the patient's siblings have been diagnosed with molecularly confirmed Sorsby's fundus dystrophy, both possessing the same c.610A>T mutation. No other family members in this pedigree have undergone genetic testing. Neither of the patient's children has yet experienced visual symptoms.
At the time of our encounter, best-corrected visual acuity was 20/150 in the right eye and 20/200 in the left eye. Funduscopic exam was notable for moderate vessel attenuation, extensive center-involving macular atrophy, peripheral scalloped atrophic patches most prominent in the temporal periphery, and nasal drusen-like deposits in both eyes. Semiautomatic kinetic perimetry (Octopus 900 Pro; Haag-Streit Diagnostics, Köniz, Switzerland) revealed mild constriction of peripheral isopters with a central scotoma to the III4e test target in both eyes. Widefield fundus autofluorescence imaging showed coalescing hypoautofluorescent patches with hyperautofluorescent margins, corresponding to scalloped atrophic patches in the macula and periphery (Figures 2A and 2B). Optical coherence tomography (OCT) of the macula revealed diffuse retinal, retinal pigment epithelium (RPE), and choroidal atrophy (Figure 2C). There was no exudation, fibrovascular pigment epithelial detachment, subretinal scar, or other evidence of current or prior CNV in either eye. Full-field electroretinogram (ERG) testing with DTL electrodes demonstrated no detectable rod-isolated response and severely attenuated cone-isolated responses.
(A) Widefield pseudocolor scanning laser ophthalmoscopy revealed scalloped, atrophic patches in the macula and in the far periphery. (B) Widefield fundus autofluorescence imaging also reflected these findings with well-demarcated regions of hypoautofluorescence. (C) Optical coherence tomography imaging revealed diffuse atrophy of the outer retina, retinal pigment epithelium, and choroid. There was no evidence of current or prior choroidal neovascularization. Findings were comparable between eyes.
Based on prior testing results in his family, the patient underwent Clinical Laboratory Improvement Amendments-certified specific mutation analysis in the TIMP3 gene, confirming a pathogenic heterozygous mutation of p.Ser204Cys:c.610A>T. With molecular confirmation of SFD, the patient was advised to resume regular visits with his local retina specialist, with continued monitoring for CNV formation.
This unique case illustrates the extent to which chorioretinal atrophy in advanced SFD may lead to vision loss in the absence of CNV. This patient manifested extensive, coalescing patches of atrophy in the macula and periphery. Per our review of the literature, no reports of the p.Ser204Cys:c.610A>T mutation displaying a similar phenotype currently exist.8,9 However, cases of SFD with chorioretinal atrophy in the absence of CNV have been attributed to other TIMP3 mutations. There is one similar report in a 2015 case series by Gliem et al., which describes a 61-year-old with a p.Tyr177Cys:c.530A>G mutation with progressive chorioretinal atrophy in the absence of CNV. Interestingly, other affected individuals in this pedigree exhibited CNV.1
Although this is an atypical manifestation of SFD, this case may soon resemble the norm in the present era of increasingly employed anti-vascular endothelial growth factor therapies in which prompt treatment may prevent many of the long-term visual consequences of CNV formation. Further, it draws attention to efforts to develop therapies for atrophic macular disease such as geographic atrophy and highlights the potential role that existing TIMP3 mutant animal models may serve in these efforts. Indeed, there is a documented correlation between TIMP3 content in Bruch's membrane and diagnosis of age-related macular degeneration (AMD), and certain TIMP3 variants appear to confer susceptibility to AMD.11,12
In summary, although SFD is classically characterized by exuberant neovascularization and a subsequent cicatricial response, some cases follow an atrophic course in the absence of CNV formation. This case highlights the extent to which atrophic degeneration can lead to visual disability in late-stage SFD. Although this presentation is unique, it may soon represent the norm as antiangiogenic therapies are increasingly utilized to control the neovascular complications of this rare disease.
- Gliem M, Müller PL, Mangold E, et al. Sorsby fundus dystrophy: Novel mutations, novel phenotypic characteristics, and treatment outcomes. Invest Ophthalmol Vis Sci. 2015;56(4):2664–2676. doi:10.1167/iovs.14-15733 [CrossRef]
- Szental JA, Harper CA, Baird PN, Michalova K, Guymer RH. Sorsby's fundus dystrophy: A case report to raise awareness of the disease and potential future treatments. Clin Exp Ophthalmol. 2009;37(3):325–327. doi:10.1111/j.1442-9071.2009.02025.x [CrossRef]
- Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet. 1994;8(4):352–356. doi:10.1038/ng1294-352 [CrossRef]
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- Stohr H, Anand-Apte B. A review and update on the molecular basis of pathogenesis of Sorsby fundus dystrophy. Adv Exp Med Biol. 2012;723:261–267. doi:10.1007/978-1-4614-0631-0_34 [CrossRef]
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- Hoskin A, Sehmi K, Bird AC. Sorsby's pseudoinflammatory macular dystrophy. Br J Ophthalmol. 1981;65(12):859–865. doi:10.1136/bjo.65.12.859 [CrossRef]
- Almuhtaseb H, Pilli S, Lotery AJ. Long term follow up of Sorsby fundus dystrophy patients treated with intravitreal bevacizumab. Invest Ophthalmol Vis Sci. 2015;56(7):3839–3839.
- Balaskas K, Hovan M, Mahmood S, Bishop P. Ranibizumab for the management of Sorsby fundus dystrophy. Eye (Lond). 2013;27(1):101–102. doi:10.1038/eye.2012.221 [CrossRef]
- Warwick A, Gibson J, Sood R, Lotery A. A rare penetrant TIMP3 mutation confers relatively late onset choroidal neovascularisation which can mimic age-related macular degeneration. Eye (Lond). 2016;30(3):488–491. doi:10.1038/eye.2015.204 [CrossRef]
- Kamei M, Hollyfield JG. TIMP-3 in Bruch's membrane: Changes during aging and in age-related macular degeneration. Invest Ophthalmol Vis Sci. 1999;40(10):2367–2375.
- Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010;107(16):7401–7406. doi:10.1073/pnas.0912702107 [CrossRef]