67 Sorsby’s Fundus Dystrophy

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I 1949, S and Mason described five families with a dominantly inherited central retinal dystrophy leading to visual loss in the fifth decade.34 Visual loss occurred either because of subretinal neovascular membranes leading to disciform scarring or because of chorioretinal atrophy at the macula. There was gradual progression of the condition to involve the retinal periphery, such that ambulatory vision was lost up to 35 years later.34 The condition has become known as Sorsby’s fundus dystrophy (SFD). For general and electrophysiological reviews, see Berninger,5 Iannaccone,22 and Scullica and Falsini.32

Clinical features

Family members who have been studied before the onset of the macular lesion demonstrate drusen, pigment epithelial atrophy,21 and a yellow subretinal deposit throughout the fundus.7 Night blindness is a feature in some patients.17,22

The onset of central visual loss has subsequently been noted from the third17 to the seventh23 decades. Distortion and sudden loss of vision occur in the presence of a subretinal neovascular membrane (figure 67.1), but gradual visual failure due to macular atrophy is equally common31 (figure 67.2).

Densely packed drusen and angioid streaks are noted in some patients.21 The disciform scars are always large (see figure 67.1) and become pigmented in late stages.7 As the scar flattens, atrophy occurs, leading to choroidal sclerosis. One fortunate patient has been reported with a small island of preserved central vision.28 Subsequent gradual loss of peripheral vision is the rule. There are no associated systemic health problems.11

Electrophysiology

Capon et al. found normal electroretinograms (ERGs) in eyes with normal vision.7 There was no abnormality of a- or b-wave amplitudes, latencies, or waveforms under scotopic or photopic conditions. Electro-oculograms (EOGs) showed a reduced light rise in all cases, with a range from 120% to 165%. Hoskin et al. found normal ERGs and EOGs in eight patients, all under the age of 45, at 50% risk of having SFD.21 Felbor et al. found the ERG to be normal initially in one patient but subnormal four years after presentation with visual loss in one eye.16 The same authors reported early-onset disease associated with subbnormal ERGs and EOGs. Also reported, albeit in a single-case study, is the finding that the EOG may be affected before the onset of symptoms.28

Other studies of patients with central visual loss have demonstrated attenuated ERGs, more marked under scotopic than photopic conditions24,39 (see figures 67.3 through 67.5). No effect was observed on response implicit time. Clarke et al.12 have also shown that pattern ERGs (PERGs) are markedly abnormal in most patients with central visual loss (see figures 67.6 and 67.7), but even in the case in which a small central island of vision is preserved, the PERG is significantly reduced.28 A mouse model of SFD has so far shown normal ERGs throughout life.39

Color vision

Both deuteranomaly18 and tritanomaly6,7 have been described in different members of British families who are now known to have the same causative mutation. Other families have had normal color vision.21

Histopathology

The few eyes that have been studied histopathologically have had end-stage pathology. There is a widespread eosinophilic deposit at the level of Bruch’s membrane, atrophy of the choriocapillaris, and, at the macula, either photoreceptor and pigment epithelial atrophy or disciform scarring associated with breaks in Bruch’s membrane.3

Psychophysics

Dark adaptation is usually abnormal from an early stage in SFD, and the abnormality worsens with age. The rod-cone break is delayed, as is the return to prebleach rod sensitivity.7,10,16,25,36 The abnormality is worse centrally than peripherally before the onset of central vision loss.25 A member of one of the original families described by Sorsby, however, showed abnormal but nonprogressive dark adaptation.28

F 67.1 Left fundus of a patient with SFD showing large disciform scar. (See also color plate 35.)

F 67.2 Left fundus of a patient with SFD showing atrophy of the retinal pigment epithelium and choriocapillaris at the posterior pole. (See also color plate 36.)

F 67.4 Scattergram of age versus photopic b-wave amplitude for control subjects and patients with SFD. Each data point for the SFD cases is labeled with the specific gene mutation for that patient.

F 67.5 Scattergram of age versus scotopic b-wave amplitude for control subjects and patients with SFD.

Visual fields

Central and paracentral scotomas have been reported,19,28 although a tiny central island has been shown to be preserved in one case.28 These latter authors have also commented that the underreporting of field losses in the literature may misrepresent the nature and extent of such loss in the condition.

Genetics

Inheritance is autosomal-dominant with high penetrance, and males and females are affected equally. The discovery of mutations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) gene in some families labeled as SFD indicated that it was truly a separate disorder40 and not just the severe end of the spectrum of dominant drusen (also known as Doyne’s honeycomb degeneration or malattia Leventinese). Seven mutations have been described in the TIMP-3 gene. All of

these mutations are in exon 5, apart from one that is in the intron/exon junction and may cause abnormal splicing of TIMP-3 mRNA.37 This mutation has been found in a Japanese family and is associated with a later onset of central visual loss.23 All but one of the mutations in exon 5 cause a cysteine substitution, which is thought to lead to aberrant disulphide bonding that causes oligomerization of the TIMP-3 protein. The exception is the E139X mutation described in a British family, which causes truncation of the TIMP-3 protein.11

The TIMP-3 protein is part of a family of metalloproteinase enzyme inhibitors that are involved in the turnover of the extracellular matrix. There are four very similar tissue inhibitors of metalloproteinases (TIMPs)2 composing a gene family with 12 highly conserved cysteine residues that form six disulphide bridges essential for correct protein folding and function. TIMPs consist of two domains, each stabilized by three disulphide bonds, an amino terminal inhibitory domain through which they bind to an active matrix metalloproteinase, and a carboxy terminal domain that is involved in interactions with proform matrix metalloproteinases and with binding to the extracellular matrix.26

Immunohistochemistry of human eyes shows TIMP-3- specific staining in Bruch’s membrane, particularly in the basement membranes of retinal pigment epithelial and endothelial cells.14 The eosinophilic deposit that is seen histologically in eyes with SFD stains for TIMP-3.13 The mechanism by which mutations in TIMP-3 give rise to retinal disease is not known but is unlikely to be due to loss of TIMP- 3 function, as expression studies have shown all known disease causing mutants to be functional metalloproteinase inhibitors.27 TIMP-3 has antiangiogenic properties in vitro,1 and overexpression of TIMP-3 in transfected rat retinal pigment epithelium inhibits experimental choroidal neovascularization.38 TIMP-3 is expressed in subretinal neovascular membranes.35 TIMP-3 is known to express apoptotic properties when overexpressed in vitro,4,29 and an altenative mechanism, particularly for the patients with atrophic maculopathy, could be apoptosis of photoreceptor and retinal pigment epithelial cells induced by accumulation of dimerized TIMP-3. The TIMP-3 deposit seen in SFD may represent an insoluble dimerized form of the inhibitor produced by abnormal disulphide bond formation by the mutated protein, which may be associated with elastin.9 Dimerization of the protein product of S181C, S156C, G166C, and E139X has been demonstrated.27 One possible mechanism for retinal disease may therefore be impairment of the nutrition and metabolism of the outer retina because of abnormal deposition of dimerized TIMP-3 in Bruch’s membrane.

Treatment

Laser treatment has generally been ineffective in controlling subretinal neovascularization in SFD,20,33 although one study

F 67.6 Representative transient PERGs (elicited to ISCEV PERG Standard 2000) to 25¢ check size, four reversals per second

stimulation. The responses from the left eye of a 48-year-old male control subject (A) and a 52-year-old patient with SFD (B) are shown.

F 67.7 Scattergram of age versus PERG P50/N95 amplitude for control subjects and patients with SFD.

reported benefit.8 Jacobson et al. demonstrated reversal of night blindness in SFD by treatment with high-dose vitamin A.25 Peripheral rod sensitivity returned to normal or near normal, and rod ERGs improved in one patient. The doses that are used, however, are associated with significant side effects, including liver damage and teratogenicity, and the regime is not generally employed in the treatment of SFD.

Relationship to age-related macular degeneration

SFD is of particular interest because the macular lesions closely resemble those seen in age-related macular degeneration (ARMD). Mutations in TIMP-3 have been excluded as causative in ARMD.15,30 However, the possibility exists that the accumulation of TIMP-3 protein that occurs in Bruch’s membrane as part of normal aging may be important in the etiology of ARMD.

Conclusion

It appears that the SFD phenotype arises following a gradual accumulation of TIMP-3 protein over many years. For unknown reasons, presumably related to the biochemistry of the mutant protein, the S156C mutation has an earlier onset of central visual loss, and the splice site mutation seen at the intron4/exon5 junction has a later onset. The EOG seems to be affected early in the course of the disease, which may be expected, as the site of deposition of TIMP-3 is in Bruch’s membrane. Dark adaptation appears to be next affected in the time course of the condition, with accompanying and progressive effects on the ERG being observed. The latter seems to be a function of the duration of the disease, indicating a gradual deterioration of photoreceptor function, with rods being affected first.

Color vision and central/paracentral field abnormalities may also be noted in some patients. As macular function becomes compromised, allied effects on the PERG are also to be expected. Further studies of SFD are likely to develop our understanding of the pathogenesis of ARMD.

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