title: Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology University Hospital of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gliem
authors.affiliation: Department of Ophthalmology University Hospital of Bonn, Bonn, Germany.
authors.forename: Philipp L
authors.initials: PL
authors.lastname: Müller
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Department of Ophthalmology University Hospital of Bonn, Bonn, Germany.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.affiliation: Center for Human Genetics, Ingelheim, Germany 4Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
authors.affiliation: Institute for Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Stöhr
authors.affiliation: Institute for Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.affiliation: Department of Ophthalmology University Hospital of Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D004247:DNA / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009887:Ophthalmoscopy; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D012160:Retina / Q000473:pathology*; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D004247:DNA