The differential diagnosis includes disorders with an autosomal dominant (AD) mode of inheritance associated with macular atrophy and/or CNVM, including autosomal dominant drusen and late-onset retinal macular dystrophy. The possibility of these disorders, including SFD, should also be considered in any family with an AD form of presumed ‘age-related macular degeneration’.

The tissue inhibitor of metalloproteinase-3 (TIMP3 gene on chromosome 22q) is implicated in SFD [4–6]. Most of the known mutations in TIMP3, including Ser181Cys [4], Ser156Cys [5] and Tyr172Cys [6], introduce potentially unpaired cysteine residues in the C-terminus of the protein, thereby resulting in inappropriate disulphide bond formation and an abnormal tertiary protein structure. This may alter TIMP3-mediated extracellular matrix turnover leading to the thickening of Bruch’s membrane and the widespread accumulation of abnormal material beneath the retinal pigment epithelium (RPE) that is seen histologically [7–9]. The thickening of Bruch’s membrane is likely to alter the flow of nutrients and growth factors across it, leading to RPE/photoreceptor dysfunction.

The finding that treatment with high doses of oral vitamin A reverses night blindness in this disorder [10] suggests that early retinal dysfunction may be due to a reduction in the permeability of Bruch’s membrane, resulting in the hindrance of transport of vitamin A from the choriocapillaris to the photoreceptors by accumulated extracellular debris beneath the RPE. In addition, Majid et al. [11] have demonstrated that mutant TIMP3 can induce apoptosis of RPE cells suggesting that apoptosis may be the final pathway for cell death in this disorder. Furthermore, TIMP3 has been recently shown to be a potent inhibitor of angiogenesis, which may, in part, account for the complication of choroidal neovascularisation seen in SFD [12]. TIMP3 inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis, most probably by blockade of VEGF-2 receptors [12].

Further insights into the pathophysiology of SFD may follow the development of a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine TIMP3 gene [13]. Immunolabelling studies and biochemical data from these mice suggested that site-specific excess rather than absence or deficiency of functional TIMP3 may be the primary consequence of the known TIMP3 mutations [13].