Alternative titles; symbols
SNOMEDCT: 193410003; ORPHA: 59181; DO: 0090114;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q12.3 | Sorsby fundus dystrophy | 136900 | Autosomal dominant | 3 | TIMP3 | 188826 |
A number sign (#) is used with this entry because of evidence that Sorsby fundus dystrophy (SFD) is caused by heterozygous mutation in the TIMP3 gene (188826) on chromosome 22q12.
Sorsby fundus dystrophy (SFD) is an autosomal dominant retinal dystrophy characterized by the loss of central vision as a result of macular disease by the fourth to fifth decade and peripheral visual loss in late life (summary by Wijesuriya et al., 1996).
Sorsby et al. (1949) described 5 families with a fundus dystrophy that occurred in several generations in a dominant pedigree pattern. It became manifest at about the age of 40 years, beginning as a central (macular) lesion showing edema, hemorrhage, and exudates. In the course of years, atrophy with pigmentation and extension peripherally occurred. The choroidal vessels became exposed and appeared somewhat sclerotic. Within about 35 years after onset the entire fundus was involved. The choroidal vessels disappeared by this stage and the terminal picture was one of extensive choroidal atrophy with pigmentation. Night blindness was not a feature at any stage. The authors considered the process to be primarily choroidal. Kalmus and Seedburgh (1976) established a genealogic link between one of the families originally reported from England by Sorsby et al. (1949) and one reported from Australia by Fraser and Wallace (1971).
Sandvig (1955) described 13 cases of central choroidal degeneration in 4 generations of a family. Krill and Archer (1971) described mother and 3 children with diffuse total choroidal vascular atrophy.
Forsius (1981), who referred to the condition as Sorsby hemorrhagic degeneration of the retina and choroid, described an instructive Finnish family with marriage of 2 affected persons whose 8 children were all affected. Bleeding occurred in the macula at about age 20 or 25 years, but the most severe case had onset at age 13 years. Drusen appeared in the midperiphery and the periphery became albinoid.
Follow-up studies of the families initially characterized by Sorsby et al. (1949) emphasized the occurrence of interfamilial phenotypic variation and raised the possibility of genetic heterogeneity. In his original report, Sorsby et al. (1949) noticed bilateral macular 'hemorrhage and exudates developing into mineralized choroidal atrophy with massive pigment proliferation.' Affected members of one of his families, the Kempster family, reported progressive difficulties with night vision for as long as 25 years before loss of visual acuity (Capon et al., 1988), whereas the Carver family had difficulties in adapting to sudden changes in ambient light (Polkinghorne et al., 1989), and the affected members of the Ewbanks family were asymptomatic before loss of visual acuity (Hoskin et al., 1981). Affected individuals in the last family experienced a sudden decrease in central vision triggered by subretinal macular neovascularization. In contrast, 2 patients from the Kempster family showed atrophic macular disease without choroidal neovascularization (CNV), whereas Carver family patients predominantly demonstrated a slow progression of the disease associated with chorioretinal atrophy.
Gliem et al. (2015) described 3 unrelated German families with SFD and mutations in the TIMP3 gene. In 2 families, metamorphopsia and/or decrease in visual acuity were the initial symptoms occurring at approximately the sixth decade of life, whereas in the third family, the presenting symptoms were dark adaptation problems and visual field defects occurring at approximately the third decade of life. The ocular phenotype in all 3 families included drusen-like deposits, rapidly progressive geographic atrophy, CNV, and polypoidal choroidal vasculopathy (PCV). Late disease manifestations were uniform, with widespread chorioretinal atrophy, fibrosis, and choroidal thinning. Patients with CNV or PCV showed a favorable response to therapy with intravitreally injected bevacizumab, a competitive inhibitor of VEGF (see 192240). Gliem et al. (2015) noted that 3 asymptomatic young carriers of a TIMP3 mutation with otherwise normal findings on funduscopy and retinal imaging showed a characteristically reduced fluorescence on late-phase indocyanine green-angiography (ICG-A) images. This phenotypic sign was more pronounced and widespread in later disease stages. The authors suggested that imaging using late-phase ICG-A could be useful for early identification of individuals at risk for developing SFD.
In a study of 16 patients from 4 unrelated families with SFD and TIMP3 mutations, Gliem et al. (2015) identified reticular pseudodrusen (RPD) in 5 of 7 patients in their sixties and in none of the 3 younger patients; the 6 patients aged 70 or older had widespread chorioretinal atrophy, subretinal fibrosis, or both, which did not allow reliable detection of RPD. The RPD were most abundant in the superior quadrant and spared the foveal region. RPD were yellowish round to oval (dot subtype) or confluent, wriggled (ribbon subtype) lesions, sometimes forming irregular networks. RPD were hyporeflective on near-infrared (NIR) reflectance and hypofluorescent on fundus autofluorescence (FAF) imaging. They appeared as subretinal deposits on spectral domain optical coherence tomography. Other lesions, such as peripheral pseudodrusen and soft drusen, were present less frequently. Gliem et al. (2015) concluded that the presence of RPD is a frequent finding in patients with SFD. They noted that the distribution and phenotype of RPD in the patients with SFD were similar to those in patients with age-related macular degeneration. Gliem et al. (2015) suggested that the association of RPD with SFD implicated Bruch membrane, Bruch membrane-retinal pigment epithelium interface, or both in the pathogenesis of RPD.
The transmission pattern of SFD in the families reported by Sorsby et al. (1949) was consistent with autosomal dominant inheritance.
The existence of an autosomal recessive form of Sorsby fundus dystrophy (264420) has been proposed. In a large, highly consanguineous Finnish family previously thought to have early-onset autosomal recessive SFD (Forsius et al., 1982), Felbor et al. (1997) examined the TIMP3 gene and identified a novel heterozygous gly166-to-cys mutation in the TIMP3 gene (188826.0004) in all affected individuals and provided strong evidence for autosomal dominant inheritance of the SFD phenotype in this family. These results, in conjunction with a critical review of reported cases, rendered the existence of a recessive mode of inheritance in SFD questionable. Considering all available data, they suggested that SFD is a genetically homogeneous, clinically variable, autosomal dominant disorder.
The mechanism of the visual loss in SFD was elucidated by Jacobson et al. (1995) who demonstrated that the night blindness was reversed by vitamin A in early stages of the disorder. A clue as to the pathophysiology had come from a morphologic study of the retina from eye donors with SFD that showed an abnormal lipid-containing deposit interposed between the photoreceptors and their blood supply, the choroid (Capon et al., 1989). This subretinal deposit, located within the Bruch membrane and present across the entire retina, was thought to be a possible barrier to diffusion of nutrients to the photoreceptors (Steinmetz et al., 1992). With the discovery of TIMP3 mutations in SFD, it was speculated that these mutations could lead to the abnormal subretinal deposit by disturbing the balance between buildup and breakdown of the extracellular matrix. A testable hypothesis was that the subretinal deposit acted as a diffusion barrier for entry of sufficient vitamin A into the photoreceptors. In patients at early stages of the disease, Jacobson et al. (1995) found that 50,000 IU/d vitamin A administered daily by mouth resulted in disappearance of night blindness. Efforts will be necessary to determine the lowest effective dose of vitamin A, since long-term use of high dosage has potential toxicity. The long-term effects on the natural history of the disease and the possibility of treating presymptomatic heterozygotes are all important issues for investigation.
Langton et al. (2005) expressed a range of SFD mutants from human retinal pigment epithelial cells, including S181C (188826.0001), S156C (188826.0003), and E139X (188826.0005). Resistance to turnover, resulting from intermolecular disulfide bond formation, was a common property of all the SFD mutants examined, providing a possible explanation for the increased deposition of the protein observed in eyes from SFD patients. In contrast, SFD mutants varied in their ability to inhibit cell-surface activation of MMP2 (120360), a potent mediator of angiogenesis, ranging from being fully active to totally inactive. Langton et al. (2005) concluded that increased deposition of active TIMP3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary initiating event in SFD.
In a single large SFD family, Weber et al. (1994) demonstrated linkage to markers on chromosome 22q13-qter between D22S275 and D22S274.
In 2 SFD pedigrees, Weber et al. (1994) studied TIMP3 as a candidate gene on the basis of its chromosomal location at 22q12.1-q13.2 and its pivotal physiologic role in extracellular matrix remodeling. They identified heterozygous point mutations in the TIMP3 gene (188826.0001-188826.0002) in affected members of both pedigrees. The mutations predicted disruption of the tertiary structure and thus the functional properties of the mature protein.
In affected members of a family with SFD, Langton et al. (2000) identified a heterozygous nonsense mutation in the TIMP3 gene (188826.0005).
Ayyagari et al. (2000) described a 4-generation pedigree with autosomal dominant hemorrhagic macular degeneration. The phenotype overlapped that of SFD and was characterized by atrophy of the choriocapillaris and retinal pigment epithelium with abnormal accumulation of confluent lipid-containing material in the inner layer of Bruch membrane. Several family members developed recurrent choroidal neovascular membranes, also a feature observed in SFD. The authors reviewed the mutations reported in all SFD pedigrees to that time: all families in the literature showed mutations in the TIMP3 gene, all involving exon 5 or the intron 4/exon 5 junction. Despite the phenotypic similarities to SFD, the large kindred studied by these authors showed no involvement of the TIMP3 gene by linkage, haplotype, or mutation analysis. They concluded that exclusion of the TIMP3 gene in this family indicates genetic heterogeneity of autosomal dominant hemorrhagic macular dystrophy.
Ayyagari, R., Griesinger, I. B., Bingham, E., Lark, K. K., Moroi, S. E., Sieving, P. A. Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3 gene. Arch. Ophthal. 118: 85-92, 2000. [PubMed: 10636420] [Full Text: https://doi.org/10.1001/archopht.118.1.85]
Capon, M. R. C., Marshall, J., Krafft, J. I., Alexander, R. A., Hirscott, P. S., Bird, A. C. Sorsby's fundus dystrophy: a light and electron microscopic study. Ophthalmology 96: 1769-1777, 1989. [PubMed: 2482957] [Full Text: https://doi.org/10.1016/s0161-6420(89)32664-9]
Capon, M. R. C., Polkinghorne, P. J., Fitzke, F. W., Bird, A. C. Sorsby's pseudoinflammatory macula dystrophy: Sorsby's fundus dystrophies. Eye 2: 114-122, 1988. [PubMed: 2457521] [Full Text: https://doi.org/10.1038/eye.1988.23]
Felbor, U., Suvanto, E. A., Forsius, H. R., Eriksson, A. W., Weber, B. H. F. Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. Am. J. Hum. Genet. 60: 57-62, 1997. [PubMed: 8981947]
Forsius, H. R., Eriksson, A. W., Suvanto, E. A., Alanko, H. I. Pseudoinflammatory fundus dystrophy with autosomal recessive inheritance. Am. J. Ophthal. 94: 634-649, 1982. [PubMed: 7148944] [Full Text: https://doi.org/10.1016/0002-9394(82)90009-5]
Forsius, H. Personal Communication. Oulu, Finland 6/1/1981.
Fraser, H. B., Wallace, D. C. Sorsby's familial pseudoinflammatory macular dystrophy. Am. J. Ophthal. 71: 1216-1220, 1971. [PubMed: 5314577] [Full Text: https://doi.org/10.1016/0002-9394(71)90965-2]
Gliem, M., Muller, P. L., Mangold, E., Bolz, H. J., Stohr, H., Weber, B. H. F., Holz, F. G., Issa, P. C. Reticular pseudodrusen in Sorsby fundus dystrophy. Ophthalmology 122: 1555-1562, 2015. [PubMed: 26077580] [Full Text: https://doi.org/10.1016/j.ophtha.2015.04.035]
Gliem, M., Muller, P. L., Mangold, E., Holz, F. G., Bolz, H. J., Stohr, H., Weber, B. H. F., Issa, P. C. Sorsby fundus dystrophy : novel mutations, novel phenotypic characteristics, and treatment outcomes. Invest. Ophthal. Vis. Sci. 56: 2664-2676, 2015. [PubMed: 25766588] [Full Text: https://doi.org/10.1167/iovs.14-15733]
Hoskin, A., Sehmi, K., Bird, A. C. Sorsby's pseudoinflammatory macular dystrophy. Brit. J. Ophthal. 65: 859-865, 1981. [PubMed: 7317334] [Full Text: https://doi.org/10.1136/bjo.65.12.859]
Jacobson, S. G., Cideciyan, A. V., Regunath, G., Rodriguez, F. J., Vandenburgh, K., Sheffield, V. C., Stone, E. M. Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. Nature Genet. 11: 27-32, 1995. [PubMed: 7550309] [Full Text: https://doi.org/10.1038/ng0995-27]
Kalmus, H., Seedburgh, D. Probable common origin of a hereditary fundus dystrophy (Sorsby's familial pseudoinflammatory macular dystrophy) in an English and Australian family. J. Med. Genet. 13: 271-276, 1976. [PubMed: 1085369] [Full Text: https://doi.org/10.1136/jmg.13.4.271]
Krill, A. E., Archer, D. Classification of the choroidal atrophies. Am. J. Ophthal. 72: 562-585, 1971. [PubMed: 5315093] [Full Text: https://doi.org/10.1016/0002-9394(71)90854-3]
Langton, K. P., McKie, N., Curtis, A., Goodship, J. A., Bond, P. M., Barker, M. D., Clarke, M. A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy. J. Biol. Chem. 275: 27027-27031, 2000. [PubMed: 10854443] [Full Text: https://doi.org/10.1074/jbc.M909677199]
Langton, K. P., McKie, N., Smith, B. M., Brown, N. J., Barker, M. D. Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum. Molec. Genet. 14: 3579-3586, 2005. [PubMed: 16223891] [Full Text: https://doi.org/10.1093/hmg/ddi385]
Polkinghorne, P. J., Capon, M. R. C., Berninger, T., Lyness, A. L., Sehmi, K., Bird, A. C. Sorsby's fundus dystrophy: a clinical study. Ophthalmology 96: 1763-1768, 1989. [PubMed: 2622621] [Full Text: https://doi.org/10.1016/s0161-6420(89)32654-6]
Sandvig, K. Familial, central, areolar, choroidal atrophy of autosomal dominant inheritance. Acta Ophthal. 33: 71-78, 1955. [PubMed: 13410569] [Full Text: https://doi.org/10.1111/j.1755-3768.1955.tb05111.x]
Sorsby, A., Mason, M. E. J., Gardner, N. A fundus dystrophy with unusual features (late onset and dominant inheritance of a central retinal lesion showing oedema, haemorrhage and exudates developing into generalized choroidal atrophy with massive pigment proliferation). Brit. J. Ophthal. 33: 67-97, 1949. [PubMed: 18111349] [Full Text: https://doi.org/10.1136/bjo.33.2.67]
Steinmetz, R. L., Polkinghorne, P. C., Fitzke, F. W., Kemp, C. M., Bird, A. C. Abnormal dark adaptation and rhodopsin kinetics in Sorsby's fundus dystrophy. Invest. Ophthal. Vis. Sci. 33: 1633-1636, 1992. [PubMed: 1559761]
Weber, B. H. F., Vogt, G., Pruett, R. C., Stohr, H., Felbor, U. Mutations in the tissue inhibitor metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nature Genet. 8: 352-356, 1994. [PubMed: 7894485] [Full Text: https://doi.org/10.1038/ng1294-352]
Weber, B. H. F., Vogt, G., Wolz, W., Ives, E. J., Ewing, C. C. Sorsby's fundus dystrophy is genetically linked to chromosome 22q13-qter. Nature Genet. 7: 158-161, 1994. [PubMed: 7920634] [Full Text: https://doi.org/10.1038/ng0694-158]
Wijesuriya, S. D., Evans, K., Jay, M. R., Davison, C., Weber, B. H. F., Bird, A. C., Bhattacharya, S. S., Gregory, C. Y. Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes. Genome Res. 6: 92-101, 1996. [PubMed: 8919688] [Full Text: https://doi.org/10.1101/gr.6.2.92]