Sorsby Fundus Dystrophy

Key points at a glance

Key Points at a Glance

• Sorsby fundus dystrophy (SFD) is an autosomal dominant macular dystrophy caused by mutations in the TIMP3 gene.
• It typically presents in relatively young individuals in their 30s to 40s and leads to rapid vision loss.
• Choroidal neovascularization (CNV) and macular atrophy are the main lesions, progressing bilaterally.
• The prevalence is rare, affecting approximately 1 in 220,000 people.
• Anti-VEGF therapy is effective for CNV; molecular targeted therapy and CRISPR editing are under research.
• The core pathology involves Bruch’s membrane thickening due to TIMP-3 protein accumulation and impaired choroidal perfusion.

1. What is Sorsby Fundus Dystrophy?

Sorsby fundus dystrophy (SFD) is a rare hereditary macular disease first reported by Sorsby et al. in 1949. It is caused by mutations in the TIMP3 (Tissue Inhibitor of Metalloproteinases-3) gene located on chromosome 22q12.1-q13.2. It follows an autosomal dominant inheritance pattern with high penetrance²⁾.

The prevalence is estimated at approximately 1 in 220,000 people. To date, more than 18 pathogenic mutations have been identified, all clustered in exon 5²⁾. These mutations affect odd-numbered cysteine residues, leading to abnormal protein structure.

Disease Overview

First report: Reported in 1949.

Inheritance: Autosomal dominant; high penetrance.

Age of onset: Typically 30s to 40s.

Prevalence

Frequency: Approximately 1 in 220,000 people (rare disease).

Bilateral: Lesions occur in both eyes as the disease progresses.

Causative Gene

Locus: 22q12.1-q13.2.

Gene: TIMP3 (tissue inhibitor of metalloproteinases 3).

Number of mutations: More than 18 types have been identified²⁾.

Q Is Sorsby macular dystrophy the same disease as age-related macular degeneration?

A

They are different diseases. SFD is a hereditary disease caused by mutations in the TIMP3 gene, characterized by onset at a young age (30s–40s). In contrast, age-related macular degeneration mainly occurs after age 60 and is a multifactorial disease. Both present with CNV and macular atrophy, making them clinically similar, but their causes, age of onset, and genetic background are fundamentally different.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Onset is often bilateral in the 30s–40s. The following symptoms appear from the early to advanced stages.

• Vision loss: May progress rapidly with the onset of CNV. In advanced stages, severe visual impairment occurs.
• Night blindness (difficulty seeing in the dark): May be present as an early symptom, sometimes preceding visual field defects.
• Metamorphopsia: Straight lines appear distorted when CNV forms, reflecting morphological abnormalities of the macula.
• Central scotoma: Central visual field loss occurs as macular atrophy progresses.

Clinical Findings

Fundus examination reveals various findings depending on the disease stage.

Early Findings

Drusen-like deposits: Distributed from the perimacular area to the posterior pole.

Bruch’s membrane thickening: A characteristic finding confirmed by EDI-OCT.

Yellow deposits: Lipid-like deposits beneath the retinal pigment epithelium (RPE).

Advanced Findings

Choroidal neovascularization (CNV): Presents as exudative maculopathy, leading to rapid vision loss.

Macular atrophy: Atrophy of the RPE and photoreceptors, leading to loss of central visual function.

Geographic atrophy: Extensive atrophic lesions in the posterior pole.

As a case report, the use of adalimumab for SFD with CNV has been reported ¹⁾. Additionally, cases where early onset and CNV led to genetic diagnosis have also been documented ²⁾.

Q Why does night blindness occur?

A

Thickening of Bruch’s membrane due to accumulation of TIMP-3 protein impairs nutrient supply and waste removal from the choroid to the retina. This dysfunction is thought to interfere with vitamin A metabolism necessary for rhodopsin regeneration, leading to night blindness due to reduced rod function.

3. Causes and Risk Factors

SFD is a monogenic disease, and mutations in TIMP3 are the only established cause. Currently, more than 18 mutations have been reported, all concentrated in exon 5 ²⁾.

Mutant proteins form incorrect dimers due to abnormal disulfide bonds and do not function normally ²⁾. Additionally, mutant TIMP-3 binds strongly to extracellular matrix components of Bruch’s membrane, making it resistant to degradation and turnover ²⁾. This accumulation causes thickening and dysfunction of Bruch’s membrane.

TIMP3 is also involved in extracellular matrix regulation outside the eye. TIMP3 knockout models show extraocular tissue abnormalities such as alveolar enlargement, highlighting the importance of therapeutic strategies that selectively suppress mutant alleles ²⁾.

About Genetic Counseling

Since SFD is inherited in an autosomal dominant pattern, first-degree relatives of a patient have a 50% chance of inheriting the mutation. If there is a family history, consultation with a genetic specialist and consideration of genetic testing are recommended. Regular ophthalmologic examinations before symptom onset are also useful for early detection.

4. Diagnosis and Testing Methods

The diagnosis of SFD is based on a combination of clinical findings, imaging, and genetic testing. SFD should be strongly suspected in cases of bilateral macular degeneration, CNV, and a positive family history at a young age.

Genetic testing is important for definitive diagnosis, directly identifying mutations in TIMP3 exon 5 ²⁾. Next-generation sequencing (NGS) panel analysis is currently the standard approach.

Findings from various imaging tests are as follows:

Test	Main Findings
EDI-OCT	Bruch’s membrane thickening, sub-RPE fluid
OCTA	Noninvasive visualization of CNV vascular network
ICG Angiography	Assessment of choroidal circulation impairment and CNV extent

• EDI-OCT (Enhanced Depth Imaging OCT): Can evaluate Bruch’s membrane thickening in vivo. Also useful for detecting RPE thinning, sub-RPE fluid, and intraretinal fluid.
• OCTA (Optical Coherence Tomography Angiography): Can evaluate CNV morphology and extent without fluorescein angiography. Suitable for regular monitoring.
• ICG Angiography: Evaluates choroidal perfusion. In SFD, characteristic choroidal circulatory disturbances are observed.

5. Standard Treatment

No clinical guidelines for SFD have been established in Japan. Current treatment strategies are based on evidence from case reports and small clinical trials.

Anti-VEGF Therapy

Anti-VEGF drugs for cases with CNV have also been reported effective in SFD. Treatment with aflibercept has been reported to suppress CNV activity for up to 3 years ²⁾. It is positioned as first-line therapy for cases with exudative lesions.

Anti-TNFα Therapy

Anti-TNFα therapy with adalimumab (40 mg subcutaneous injection every other week) has been reported effective. Spaide et al. reported a case in which CNV activity was not observed for 18 months after adalimumab administration ¹⁾.

Local administration of triamcinolone (corticosteroid) has also been reported for the purpose of suppressing inflammation ¹⁾.

Anti-VEGF Therapy

Drug example: Aflibercept, etc.

Indication: Cases with CNV.

Effect: Suppression of CNV activity ²⁾.

Anti-TNFα Therapy

Drug: Adalimumab 40 mg every other week.

Report: No CNV activity for 18 months¹⁾.

Status: Adjunctive therapy / research stage.

CRISPR Editing

Method: Adenine base editing (ABE).

Target: Correction of TIMP3 pathogenic variant²⁾.

Current status: Preclinical research stage.

Key features of the main treatments are shown below.

Treatment	Target	Current Status
Anti-VEGF drugs	VEGF	Standard option for CNV
Adalimumab	TNFα	Case reports exist / research stage
CRISPR-ABE	TIMP3 mutation	Preclinical stage

Treatment considerations

• Currently, no drugs are approved for SFD. Anti-VEGF therapy is also used off-label.
• Anti-TNFα therapy (adalimumab) is a systemic drug with risks such as infection and demyelinating diseases, and its initiation by ophthalmology alone requires caution.
• Gene editing using CRISPR is at the research stage and cannot currently be received as general medical treatment.

Q How many injections of anti-VEGF treatment are needed to be effective?

A

There is no established guideline for the optimal number and interval of injections for SFD. A case of CNV activity suppression with aflibercept over 3 years has been reported²⁾, but treatment is adjusted according to individual lesion activity. Regular monitoring with OCT and OCTA is important.

6. Pathophysiology and detailed pathogenesis

The core of SFD pathology is the dysfunction and accumulation of TIMP-3 protein.

Normal function of TIMP-3

TIMP-3 (tissue inhibitor of metalloproteinases 3) is a protein that binds to the extracellular matrix of Bruch’s membrane and has the following functions.

• Inhibition of MMPs (matrix metalloproteinases): Prevents excessive degradation of the extracellular matrix²⁾.
• Regulation of VEGFR2 signaling: Modulates the activation of vascular endothelial growth factor receptor 2 (VEGFR2) and controls angiogenesis²⁾.
• Inhibition of ADAM17: ADAM17 is a sheddase that cleaves and activates TNFα, and TIMP-3 inhibits it, thereby suppressing TNFα signaling¹⁾.

Pathogenesis caused by mutant TIMP-3

TIMP3 mutations are concentrated in exon 5, and the mutant protein causes pathogenesis through the following pathways.

1. Abnormal dimer formation: Mutations create extra cysteine residues, leading to abnormal dimer formation via disulfide bonds²⁾.
2. Accumulation in Bruch’s membrane: Mutant TIMP-3 binds strongly to the extracellular matrix of Bruch’s membrane and accumulates, resisting turnover²⁾.
3. Enhanced inhibition of matrix metalloproteinases: Excessive accumulation of TIMP-3 impairs normal remodeling of Bruch’s membrane²⁾.

Involvement of the TNFα pathway

Loss of ADAM17 inhibition by TIMP-3 leads to increased TNFα production. TNFα has pro-inflammatory and pro-angiogenic effects, exacerbating CNV formation and retinal damage¹⁾. This pathway is the target of adalimumab (anti-TNFα antibody).

---

7. Latest research and future perspectives (research-stage reports)

For patients: Please read

The following content is currently at the research stage or in clinical trials, and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

CRISPR adenine base editing (ABE)

Elsayed et al. (2022) reported the potential of CRISPR adenine base editing (ABE) for SFD-causing mutations²⁾. ABE achieves A→G base conversion without double-strand DNA breaks and is considered safer than conventional CRISPR-Cas9. Among 18 SFD mutations, several were identified as correctable by ABE, and feasibility of mutation correction has been demonstrated in preclinical models using iPS cells.

Elsayed et al. (2022) systematically analyzed 18 SFD-associated mutations and identified those targetable by ABE²⁾. These findings provide a foundation for developing ABE-based gene therapy for SFD.

Molecular targeted therapy with adalimumab

Spaide et al. (2022) reported the efficacy of adalimumab therapy targeting the TIMP-3/ADAM17/TNFα pathway¹⁾.

Spaide et al. (2022) reported that in SFD patients, subcutaneous adalimumab 40 mg every other week resulted in no CNV activity over 18 months¹⁾. This result clinically supports the role of the TNFα pathway in the pathogenesis of SFD.

Anti-TNFα therapy is an approach that repurposes existing biologics, with the advantage of abundant safety data as an approved drug. There is no formal approval or trial for SFD, and future prospective studies are expected.

Q When will CRISPR gene therapy become available?

A

Currently, it is at the preclinical research stage, and the timing of clinical application is undetermined. Although efficacy has been reported in cell models²⁾, clinical trials are needed to confirm safety and efficacy in humans. For progress, consultation with a specialist and checking the latest information are important.

---

8. References

1. Spaide RF. Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication. Eye (Lond). 2022;36(9):1810-1812. PMID:34376817.
2. Elsayed MEAA, Kaukonen M, Kiraly P, Kapetanovic JC, MacLaren RE. Potential CRISPR Base Editing Therapeutic Options in a Sorsby Fundus Dystrophy Patient. Genes (Basel). 2022;13(11):2103. PMID:36421778. PMCID:PMC9690532. doi:10.3390/genes13112103.