Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes

To report novel TIMP3 mutations, and to characterize the ocular phenotype of Sorsby fundus dystrophy (SFD), including a novel early sign for the disease and to report the effect of anti-VEGF therapy.

Twenty-one probands of three unrelated families with SFD were investigated using wide-field imaging, confocal laser scanning ophthalmoscopy with autofluorescence imaging, optical coherence tomography (OCT), indocyanine green-angiography (ICG-A), and molecular diagnostic for causative mutations.

Molecular genetic analysis revealed two novel (p.Tyr174Cys, p.Tyr177Cys) and one previously described (p.Tyr182Cys) missense mutations in TIMP3. In families with p.Tyr177Cys and p.Tyr182Cys, metamorphopsia and/or decrease in visual acuity were the initial symptoms occurring at approximately the sixth decade of life. The p.Tyr174Cys mutation carriers had first symptoms at approximately the third decade with dark adaptation problems and visual field defects. The ocular phenotype included drusen-like deposits, rapidly progressive geographic atrophy, choroidal neovascularization (CNV), and polypoidal choroidal neovascularization (PCV). Late disease manifestations were uniform with widespread chorioretinal atrophy, fibrosis, and choroidal thinning. Three asymptomatic young carriers of a TIMP3 mutation with otherwise normal findings on funduscopy and retinal imaging showed a characteristically reduced fluorescence on late-phase ICG-A images. This phenotypic sign was more pronounced and widespread in later disease stages. Patients with CNV or PCV showed a favorable response to therapy with intravitreally injected bevacizumab.

This study expands the spectrum of mutations in the TIMP3 gene and associated phenotypic findings. Imaging using late-phase ICG-A may be useful for early identification of individuals at risk for developing SFD. Intravitreal anti-VEGF therapy if initiated timely is effective in SFD patients with CNV.