What are the management options and genetic implications for individuals diagnosed with macular dystrophy?

Macular Dystrophy: Management and Genetic Implications

Macular dystrophies are a heterogeneous group of inherited retinal disorders requiring genetic testing for diagnosis, genetic counseling for family planning, and condition-specific management ranging from nutritional supplementation to emerging gene therapies, with most forms having no curative treatment currently available. 1, 2

Genetic Inheritance Patterns

Macular dystrophies demonstrate variable inheritance patterns depending on the specific condition 2:

• Best vitelliform macular dystrophy: Autosomal dominant inheritance due to BEST1 gene mutations 1
• Autosomal recessive bestrophinopathy: Also caused by BEST1 gene mutations but with recessive inheritance 1
• Stargardt disease (STGD1): Caused by ABCA4 gene mutations, representing the most common inherited macular dystrophy 3
• Central areolar choroidal dystrophy: Autosomal dominant inheritance due to PRPH2 gene mutations 1
• RP1L1-associated occult macular dystrophy: Autosomal dominant inheritance with RP1L1 gene mutation 1
• Adult-onset foveomacular vitelliform dystrophy: Variable genetic inheritance, though autosomal dominance with variable penetrance has been suggested 4

Diagnostic Approach

Clinical Features to Identify

Stargardt Disease 3:

• Progressive bilateral central vision loss typically beginning in childhood or adolescence
• Yellow-white flecks at the level of the retinal pigment epithelium
• Accumulation of toxic bisretinoids and lipofuscin in the retina and RPE

Best Vitelliform Macular Dystrophy 1:

• Vitelliform lesion on fundoscopy centered in the fovea
• Serous detachment on OCT filled with hyperreflective material
• Hyperautofluorescence on fundus autofluorescence (FAF)
• Absent or markedly decreased light rise on electro-oculography
• Positive family history with symmetrical bilateral disease

Adult-Onset Foveomacular Vitelliform Dystrophy 4:

• Onset between 30-50 years of age
• Bilateral, symmetrical, grayish-yellow, round or oval-shaped lesions
• Lesions one-third to one-half disc diameter in size
• Blurred vision or mild metamorphopsia
• Normal or mildly subnormal electro-oculogram

Central Areolar Choroidal Dystrophy 1:

• Moderate atrophic RPE changes in early stages (stage 1-2)
• Geographic atrophy in advanced stages (stage 3-4)
• Highly symmetrical FAF abnormalities
• No leakage on fluorescein angiography

Diagnostic Testing Algorithm

1. Multimodal retinal imaging 2:

   • Optical coherence tomography (OCT) to assess retinal architecture
   • Fundus autofluorescence (FAF) to evaluate RPE health
   • Fluorescein angiography (FA) and indocyanine green angiography (ICGA) to exclude leakage

2. Electrophysiological testing 4:

   • Electro-oculogram (EOG) particularly for Best disease diagnosis
   • Full-field electroretinography when indicated

3. Genetic testing 2:

   • Targeted gene panel testing for known macular dystrophy genes
   • Whole exome sequencing if initial testing is negative
   • Essential for confirming diagnosis and enabling genetic counseling

Management Options

Condition-Specific Treatments

Best Vitelliform Macular Dystrophy 1:

• No treatment available for the primary disease process
• Intravitreal anti-VEGF injections if choroidal neovascularization develops

Stargardt Disease 3:

• Visual cycle modulators under investigation: C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, A1120
• Complement inhibitors: Avacincaptad pegol (C5 inhibitor) may reduce inflammation-related RPE damage
• Gene therapy: ABCA4 gene augmentation therapy in phase I/II trials
• Stem cell transplantation: Phase I/II trial data suggest potential biologic plausibility
• Note: Fenretinide and emixustat failed to halt geographic atrophy progression in AMD trials

Central Areolar Choroidal Dystrophy 1:

• No treatment currently available

RP1L1-Associated Occult Macular Dystrophy 1:

• No treatment currently available

Adult-Onset Foveomacular Vitelliform Dystrophy 4:

• Monitor for subfoveal choroidal neovascularization, which can cause dramatic vision loss
• Anti-VEGF therapy if CNV develops

General Supportive Management

Vision Rehabilitation 5:

• Optical or electronic magnifying devices
• Bright lights and electronic reading aids
• Referral to low vision services for patients with functional impairment

Monitoring Protocol 4:

• Regular comprehensive eye examinations to detect complications
• Amsler grid for home monitoring of metamorphopsia 5
• OCT at follow-up visits to assess disease progression 2

Genetic Counseling Implications

Family Screening Recommendations 4:

• Comprehensive eye examinations for first-degree relatives, particularly for autosomal dominant conditions
• Earlier screening for at-risk family members based on inheritance pattern
• Genetic testing for at-risk relatives after proband diagnosis confirmed

Recurrence Risk Counseling 1:

• Autosomal dominant conditions: 50% risk for each offspring
• Autosomal recessive conditions: 25% risk if both parents are carriers
• Variable penetrance in some conditions (e.g., adult-onset foveomacular vitelliform dystrophy) complicates risk assessment

Prenatal and Reproductive Options:

• Preimplantation genetic diagnosis available for known familial mutations
• Prenatal testing possible once causative mutation identified
• Genetic counseling should address reproductive options and family planning

Critical Clinical Pitfalls

Avoid misdiagnosis with age-related macular degeneration 1, 5:

• Macular dystrophies present with bilateral symmetrical disease, typically at younger ages
• AMD shows asymmetric disease with drusen and age-related changes
• Genetic testing distinguishes inherited conditions from AMD

Do not delay genetic testing 2:

• Early genetic diagnosis enables accurate prognostication
• Allows enrollment in clinical trials for emerging therapies
• Essential for family planning and cascade screening

Monitor for choroidal neovascularization 4:

• Can develop in Best disease, adult-onset foveomacular vitelliform dystrophy, and other conditions
• Requires prompt anti-VEGF treatment to prevent severe vision loss
• Patients should report sudden vision changes immediately

Recognize that most macular dystrophies lack effective treatment 1, 3:

• Counsel patients realistically about prognosis
• Emphasize that peripheral vision is typically preserved
• Connect patients with support organizations and low vision services early