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Sorsby syndrome: for professionals

Overview

Prevalence1 in 220,000
InheritanceAutosomal dominant
Genes involved (OMIM No.)TIMP3 (#602194)
SymptomsBilateral progressive central vision loss starting between 4th and 5th decade of life Central scotomas Nyctalopia Metamorphopsia
Ocular FeaturesDrusen Reticular pseudodrusen Choroidal neovascularisation Macula atrophy
Systemic featuresPrimarily has ocular effects
Key investigationsFundus examination Fundus autofluorescence Optical coherence tomography Fundus fluorescein angiography (if CNV suspected) Visual field testing Electroretinography
Molecular diagnosisWhole genome sequencing with retinal panel
ManagementOcular Anti-VEGF injections if CNV detected Regular ophthalmic monitoring Systemic Smoking cessation Antioxidants in diet Supportive measures with genetic counsellor
Therapies under ResearchNatural history studies

Clinical Phenotype

Sorsby syndrome, also known as Sorsby fundus dystrophy (SFD), is a rare inherited macular dystrophy.

Presenting features

  • Onset: Patients typically present between the ages of 20-40. This distinguishes it from age-related macular degeneration (AMD) which occurs later in life.
  • Sudden and progressive central vision loss
  • Delayed dark adaptation
  • Central scotomas
  • Metamorphopsia
  • Nyctalopia
  • Symmetrical effect in both eyes

Ocular signs

  • Drusen
  • Choroidal neovascularization (CNV) develops in the majority of patients
  • Macular atrophy

Associated systemic features

  • Cardiovascular health: although Sorsby syndrome primarily affects the eyes, ongoing research explores potential links with cardiovascular issues.

Fundus appearance

  • Drusen deposits distributed in the posterior pole and along vascular arcades.
  • There are also reticular drusen deposits, which appear as subretinal deposits between the photoreceptor outer segments (POS) and the RPE’s apical surface. These reticular pseudodrusen are best visualized through fundus autofluorescence (FAF) imaging, displaying a distinctive reticular pattern. Unlike drusen, reticular pseudodrusen are linked to worse visual function and an increased risk of progressing to choroidal neovascularization (CNV) and geographic atrophy.
  • Areas of atrophy in the macular region, often associated with loss of retinal tissue and reduced pigmentation. Macular atrophy significantly contributes to central vision loss in affected individuals. This is particularly seen on FAF.
  • Choroidal neovascularization lesions appear as greyish or reddish subretinal masses. Fundus fluorescein angiography can be employed to visualize leakage from these neovascular membranes, confirming the presence of CNV.
  • Fundus findings are mostly symmetrical in both eyes.

Genetics

  • Gene: TIMP3 gene (tissue inhibitor of metalloproteinases 3), located on chromosome 22q12.3.
  • OMIM: #136900
  • Genotype-phenotype correlation: TIMP3 encodes tissue inhibitor of metalloproteinases-3, a protein crucial for regulating the activity of enzymes involved in tissue remodelling and maintenance of the extracellular matrix integrity. In the eyes, TIMP3 protein maintains the integrity of Bruch’s membrane. Disruptions in this gene therefore compromise Bruch’s membrane, leading to retinal degeneration and vision impairment.

Key Investigations

  • Fundus examination: subretinal drusen deposits, pigmentary changes, macular atrophy, and choroidal neovascularization
  • Fundus autofluorescence (FAF): drusen deposits and macular atrophy.
  • Optical coherence tomography (OCT): high-resolution retinal imaging revealing macular thinning, retinal pigment epithelium (RPE) disruption, subretinal fluid in the presence of choroidal neovascularization and a thickened Bruch’s membrane.
  • Fundus fluorescein angiography (FFA): choroidal neovascularization detection and assessment of its leakage pattern.
  • Visual field testing: central scotomas are common, indicating impaired central vision. Peripheral visual field defects may also be present.
  • Electroretinography (ERG): abnormal ERG responses, especially in scotopic (low-light) conditions, reflecting retinal dysfunction, a hallmark of Sorsby syndrome.
  • Genetic testing: Identification of pathogenic mutations in the TIMP3 gene is crucial for diagnosis confirmation and allows for informed genetic counselling.

Differential diagnoses

  • AMD: Sorsby syndrome can be distinguished from AMD through its earlier presentation and genetic testing.
  • Other macular dystrophies: differential diagnosis involves ruling out other inherited macular dystrophies that may present with central vision loss.

Patient management

1. Medical management:

  • Regular ophthalmic follow-up: monitor disease progression, assess treatment efficacy, and identify any complications promptly. Patients should also be informed to regularly monitor their mono-ocular acuity and Amsler grid tests at home and present to eye casualty if they notice any change in vision.
  • Intravitreal anti-VEGF injections: for active CNV-related complications (e.g. ranibizumab, aflibercept).

2. Lifestyle modifications:

  • Smoking cessation: smoking has been linked to the exacerbation of Sorsby syndrome. Encouraging affected individuals to quit smoking is vital to slow down the disease process.
  • Healthy diet and exercise: a balanced diet rich in antioxidants and regular physical activity can contribute to overall health. Studies have investigated the use of Vitamin A to improve nyctalopia, however lower doses lack efficacy and high doses increase the risk of hepatotoxicity.

3. Supportive measures:

  • Low vision rehabilitation: to enhance visual function and maximize independence in daily activities. Utilize low vision aids (e.g., magnifiers, telescopes), provide orientation and mobility training, and offer adaptive technology solutions.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic Counsellors (GCs) and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They inform patients of the diagnosis in a private room and provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

Current research

Gene therapy

Researchers are exploring gene therapy strategies to replace or repair the faulty timp-3 gene. Viral vectors are engineered to deliver functional timp-3 genes into affected retinal cells, aiming to halt or slow down disease progression. Although there are no clinical trials using gene therapy for Sorsby syndrome, a recent study from Oxford explored the potential use of CRISPR DNA base editing for future treatments.

Anti-angiogenic therapies

Ongoing studies are evaluating the efficacy of various anti-angiogenic agents to suppress CNV in Sorsby syndrome. A recent systematic review showed early diagnosis and immediate anti-VEGF therapy upon symptom onset resulted in favourable responses, with visual acuity improvements in some cases, emphasizing the importance of prompt intervention.

Updated on February 11, 2024

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