Sorsby Macular Dystrophy

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Disease Entity

Sorsby Macular Dystrophy (ICD10# H35.5 - Hereditary retinal dystrophy)


Sorsby Macular Dystrophy (SMD), also known as Sorsby Fundus Dystrophy, is a rare progressive autosomal dominant macular dystrophy, presenting between the third and sixth decades of life. First described in 1949, it is typically characterized by retinal atrophy and retinal detachment leading to a loss of central vision, then peripheral vision, and eventually blindness.[1] Although a clear prevalence of SMD has not been characterized, estimates predict its occurrence to be 1 in 220,000.[2] Common pathologic characteristics include thick drusen-like deposits between the inner collagenous layer of Bruch’s membrane and the basement membrane of the retinal pigment epithelium (RPE). Its underlying pathophysiology consists of an autosomal dominant mutation in the tissue inhibitor of the metalloproteinase-3 gene (TIMP3), due to which dysregulated TIMP3 proteins form deposits in Bruch’s membrane.[2][3] Common symptoms include progressive vision loss, sudden loss in visual acuity, or nyctalopia. Slit lamp examination may reflect drusen deposition in the posterior pole and along vascular arcades, reticular drusen, and progressive choroidal neovascular membranes. Although there are currently no effective treatment options, anti-VEGF treatment has shown clinical efficacy in treating secondary choroidal vascular membrane formation (SCVM).


SMD is an autosomal dominant genetic disorder. It has been linked to heterozygous mutations in the TIMP3 gene on chromosome 22q12, a gene encoding tissue inhibitor of metalloproteinases-3.[2]

Risk Factors

The limited reports of SMD make it unclear in the literature whether there are significant risk factors. Given its autosomal dominant nature, an associated family history remains the most significant risk factor.[1]

General Pathology

The general pathology of SMD is not clearly delineated due to the low prevalence of cases. Initial electron microscopy reported a key histopathologic marker of SMD to be a thickened Bruch’s membrane.[3] The proposed pathogenesis involves the formation of lipid-rich, thick protein deposits between the inner collagenous layer of Bruch’s membrane and the basement membrane of the retinal pigment epithelium (RPE). These deposits in SMD have been noted to be approximately 20-30 microns thick and confluent.[4] Certain reports have noted larger deposits of up to 60 microns. Notably, TIMP3, drusen, and reticular pseudo-drusen tend to accumulate in similar regions, thus implicating Bruch’s membrane in the pathology of SMD and similar diseases such as Age-related macular degeneration (AMD). Due to its location, these lipid-rich deposits in Bruch’s membrane likely interfere with diffusion of required molecules from the choriocapillaris to the RPE.[5]


The underlying pathophysiology of SMD originates from an autosomal dominant mutation in TIMP3.[6] This protein is typically produced by the RPE as well as choroidal endothelial cells. It functions in reducing inflammation, angiogenesis (via binding vascular endothelial growth factor receptor 2), and is pro-apoptotic by assisting in regulating extra-cellular matrix turnover.

TIMP3 protein normally accrues in Bruch’s membrane with age. In SMD, the presence of missense mutations in the TIMP3 gene leads to the addition of a cysteine residue in the sequence. Although resulting TIMP3 proteins remain unchanged, these dysregulated proteins form deposits in Bruch’s membranes at an accelerated rate.[7] Their congregation and resistance to breakdown contribute to the pathology of SMD, similar to more commonly observed diseases such as AMD.

Up to 16 mutations have been linked to SMD.[8] While these various TIMP3 mutations have been extensively reported on, their significance in terms of pathophysiology has remained unclear.[9][10]

Primary prevention

No effective primary prevention methods have been reported for SMD in the literature, although TIMP-3 mutation-induced retinal degeneration has been found to be reduced with smoking cessation and maintaining a balanced diet.[10][11]


While clinical manifestations may not be apparent at birth or in childhood, symptoms of central visual blurring prior to the age of 40 years old may be an indication of SMD. If initially present unilaterally, similar symptoms may develop within months or years in the opposing eye. The history of progressive symptoms may be variable but typically includes progressive central vision loss, nyctalopia, and metamorphosia in the fourth or fifth decade which may progress to affect peripheral vision in later decades.

Physical examination

In the initial stages of SMD, slit lamp examination typically reveals drusen deposition in the posterior pole and along vascular arcades, although reticular drusen may also be seen. These drusen are described as yellow, extracellular deposits between Bruch’s membrane and the RPE.[5][11] Certain reports also describe a secondary choroidal neovascular membrane (SCVM), geographic atrophy, or fibrotic lesions that are seen in later stages of SMD, though SCVMs have been noted at early stages.[12] Active SCVM in these patients may present with findings of subretinal hemorrhages, fluid, or intraretinal edema. Additionally, the presence of reticular drusen have often been correlated with a higher likelihood of SCVM development or geographic atrophy progression.[13][14][15] Patients with SMD may display macular lesions that have a “pseudo- inflammatory” appearance, geographic atrophy, and black pigmentation in a concentrated, clumped formation.

The wide variety of uncovered TIMP3 mutations may present variably in terms of clinical symptoms and visual acuity; thus, a relevant family history is vital for diagnostic purposes.

Signs & Symptoms

Patients with SMD may present with a variable disease progression. The common initial symptoms in patients with SMD include progressive vision loss, sudden loss in visual acuity, or nyctalopia. Patients may present with symptoms in their second decade, but the reported average age remains in the fourth or fifth decades.[16] Other reported symptoms include metamorphopsia, central scotomas, and loss of central vision.[16][17] Physical exam findings of choroidal neovascularization and pigment epithelial atrophy may contribute to these symptoms of vision loss. Further progression has shown involvement of the peripheral retina and loss of ambulatory vision even in a patient’s seventh decade, leading to bilateral loss of vision or blindness. Color vision may also be affected, though the data remains unclear given the low prevalence.[16][17]

Clinical diagnosis

SMD may be diagnosed in individuals with a pertinent positive family history (with autosomal dominant inheritance) and correlated findings on slit lamp examination.

Diagnostic procedures

Genetic testing for known TIMP3 mutations associated with SMD is imperative for a definitive diagnosis.

Although not diagnostic, the following findings have been reported in cases of SMD:

  • Indocyanine-green angiography (ICG) may present with reduced late-phase central macular fluorescence. These findings may be present in asymptomatic patients with otherwise unremarkable imaging (fundoscopy, fundus autofluorescence, OCT, FA). This may indicate its practicality for detecting early stages of SMD.[5]
  • Horizontal enhanced depth imaging (EDI) OCT may reflect choroidal thinning with significant chorio-retinal atrophy.[5]
  • OCT imaging may reveal increased reflectivity of the RPE and photoreceptor choroid complex. Presence of subretinal hemorrhages or edema associated with active SCVM development may be seen.

Laboratory test

In SMD, electron microscopy typically depicts a thickened Bruch’s membrane. Yellow, drusen-like deposits of variable thickness are seen and typically consist of multimerized TIMP-3 aggregated protein. These deposits have been noted to stain positive on a periodic acid Schiff stain (PAS).[3][18]

Differential diagnosis

Age-related macular degeneration (AMD)

An acquired retinal degeneration characterized by drusen, or extracellular deposits, and degeneration of photoreceptors as well as proximate tissue involvement.[19] Its etiology is complex, including degeneration due to age, genetics, and environmental factors. The clinical presentation of AMD may be similar to SMD with typical drusen and choroidal neovascular membrane formation, but features that suggest SMD include a pertinent family history, earlier onset of symptoms, and peripheral chorioretinal atrophy.[19]

Malattia Leventinese (ML; also known as familial dominant drusen or Doyne honeycomb retinal dystrophy)

A retinal dystrophy characterized by honeycombed (or grouped) white lesions (drusen) described around the macula and disc.[20] ML is due to a mutation in the EFEMP1 gene, which codes for the epidermal growth factor-containing extracellular matrix protein 1. Clinical symptoms include asymptomatic progression until around the fourth or fifth decade, during which symptoms of photopsia, metamorphopsia, and progressively decreasing visual acuity occur. Similar to SMD, ML may involve central vision later in the seventh and eight decades of age. Slip lamp examination typically reflects drusen deposits between Bruch’s membrane and the RPE that progress into a criss-crossing honeycombing structure.[20] Additionally, patients may form choroid neovascular membranes.

Pattern dystrophy

A collective of autosomal dominant disorders that were commonly linked to mutations in the PRPH2 gene, which codes for peripherin-2.[21] This protein is a glycoprotein that is implicated in stabilizing outer segment discs; however, a variety of genes have since been implicated in similar maculopathies. Slit-lamp observations may include deposition of various sized pigment (lipofuscin) in the macula, particularly the RPE. Patients with pattern dystrophies may present with progressive central vision loss in their fourth and fifth decade of life, metamorphopsia, and mild loss of visual acuity.[21] Patients may also present with choroidal neovascularization, similar to SMD. The key differentiating factor lies in the progressive nature of its symptoms, such as nyctalopia, and physical exam findings of drusen deposition.[21]

Best disease

Multiple inherited diseases that are a consequence of BEST gene mutations.[22] These inherited diseases include the common “Best vitelliform macular dystrophy,” which may present similarly to SMD. This autosomal dominant disease with incomplete penetrance is specifically due to the bestrophin 1 protein (BEST1) and appears as an egg yolk-like yellow lesion on the macula; this may involve the RPE as well.[22] Clinical symptoms vary dependent on the stage of disease but may appear as early as the first to second decade of life and present with minimal changes of visual acuity in its early stages. Progression of the disease may present with significantly diminished visual acuity in the later stages and may also present with symptoms such as metamorphopsia, central scotoma, or rapid visual decline.[22]

Central serous chorioretinopathy

A common retinopathy that typically presents during middle age, from the second to fifth decade of life.[23] Although the pathophysiology is not completely understood, patients may initially present with progressive loss of central vision, metamorphopsia, hyperopia, central scotoma, or diminished color saturation. Patients may present with formation of a choroidal neovascular membrane and loss of the RPE.[23] On further examination, patients may have round macular detachments and similar yellow deposits or fluid in the sub-retinal region. The RPE may be seen as detached, which may reflect evidence of leakage of sub-retinal fluid or a localized depression.[23]


Medical therapy

SMD and its associated TIMP-3 mutations do not have an effective or definitive treatment regimen yet. Prior medical therapies for SMD included vitamin A, thermal photocoagulation, and photodynamic therapy (PDT) with verteporfin; however, all treatment modalities showed low efficacy with some development of adverse effects.[24][25] Vitamin A was hypothesized to combat nyctalopia, but low doses were not effective, while high doses provoked noxious liver injury. Thermal photocoagulation was initially utilized to combat choroidal neovascular membrane (CNV) formation but did not lead to clinical improvement and paradoxically worsened membrane formation. PDT verteporfin was either utilized as monotherapy or in conjunction with corticosteroid injections, but due to reduced clinical efficacy, was stopped.[24][25]

Anti-vascular endothelial growth factor (anti-VEGF) treatment has shown clinical efficacy in treating secondary choroidal vascular membrane formation (SCVM). One systematic review compiled 14 studies with a total of 31 SMD patients and found that 51% of eyes with SMD maintained a logmar visual acuity of 0.5 if assicuated SCVM was treated early.[25] Treatment with an anti-VEGF regimen found 67% of these eyes with SCVM were able to remain functional with a visual acuity of 0.2 or better. However, limited utility was noted if patients presented with disciform scarring prior to treatment. Additionally, treatment with anti- VEGF regimen did not protect patients from further macular scar formation, and 5-year follow- up of these patients did in visual acuity (the overall follow-up time for the patients in this review was 54 months).[25]

Various studies have reinforced the efficacy of an anti-VEGF regimen in SMD patients, but do not specify a scheduled regimen. While certain studies advocate for a treat and extend protocol, others were not predisposed towards one approach.

A single report of SMD has also detailed the use of triamcinolone injections and adalimumab in the use of preserving vision.[24]

Given the low prevalence of patients with SMD and lack of effective treatment regimens, it is vital to host patient-centered discussions with the patients’ interests in the forefront. Various approaches may be time-intensive, ineffective, or cost-prohibitive; these should be taken into consideration before potential treatment.


There have been no studied or published effective surgical treatment options for SMD to date.


Overall, the prognosis of patients with SMD may be variable and should be approached on an individual basis. Patients may begin to see progressive symptoms of vision loss (either acute or progressive), nyctalopia, metamorphopsia, loss of central vision, and potentially a loss of color vision beginning as early as their second decade of life, but more often in their fourth or fifth decade. These symptoms are attributable to the development of choroidal neovascularization and pigment epithelial atrophy, which may progress to affect peripheral vision if left untreated. These symptoms may present unilaterally but may eventually progress to affect bilateral vision.

Previously, choroidal neovascular membrane formation led to rapid central vision loss as well as blindness. The introduction of anti-VEGF treatment has assisted in preserving vision in cases of SMD associated with SCVM. Patients should be included in their care and taught about potential symptoms of nyctalopia or metamorphopsia, and utilization of an Amsler grid may be considered.

Additional Resources


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