Macular Dystrophies 1

Stargardt Disease (Fundus Flavimaculatus)

Genetics / Epidemiology

• Autosomal recessive in \approx90\% of cases; sporadic or other inheritance patterns rare.

• Prevalence \approx1/20\,000 → technically a rare disease, yet the single most common hereditary macular dystrophy.

• Usually manifests in childhood (often <10 yrs).

Pathophysiology & Key Features

• Primary degeneration of the retinal pigment epithelium (RPE) with secondary photoreceptor loss.

• Lipofuscin (toxic bis-retinoid by-product of the visual cycle) accumulates in RPE and photoreceptors.

• Characteristic “silent (dark) choroid” on fluorescein angiography (blocked background choroidal fluorescence by lipofuscin).

Clinical Presentation

• Bilateral, symmetrical, painless central‐vision loss.

• Early stages may appear ophthalmoscopically normal → mislabelled as non-organic/"malingering".

• Visual acuity: slow decline to 6/12, then faster drop to 6/60 or worse (often by age 20).

• Macular atrophy (indication of disease progression)

Fundus Findings

• Macular ‘beaten bronze’ atrophy of RPE.

• Numerous yellow, pisciform (fish-tail) flecks spread over posterior pole → term Fundus flavimaculatus (FF).

Ancillary Tests

• ERG: normal early; later may show cone dysfunction.

• Fluorescein angiography (FA): central hyperfluorescent window defect + dark choroid. glowing background

  • silent choroid - surrounding region of hyperfluorescence.
    Due to lipofuscin pigment blocking fluorescence of choroidal vessels.

• OCT: outer-retinal thinning, loss of ellipsoid zone, hyper-reflective flecks.

  

• Fundus autofluorescence (FAF): Lipofuscin pigments in the retina exhibit auto fluorescent propertie

  • Flecks = hyper-autofluorescent.

  • Areas of macular atrophy = hypo-autofluorescent.

Management / Prognosis

• No proven disease-modifying therapy.

• Avoid high-dose vitamin A (may accelerate lipofuscin accumulation).

• Low vision services and support services

• Genetic counselling

• Gene therapy and stem cell trials have been initiated and show promising results as potential treatments in the future.

Best Vitelliform (Best Disease)

• uncommon hereditary, usually bilateral macular dystrophy

• mild vision loss, slow progression

Genetics / Epidemiology

• Autosomal dominant (mutation in VMD2/Bestrophin-1 on chromosome 11).

• Penetrance high but variable expressivity; family history almost always positive.

Pathophysiology

• Mutant bestrophin-1 alters RPE chloride conductance → impaired phagocytosis & lipofuscin build-up.

Classic Fundus Appearance

• Yellow material (lipofuscin) accumulates at the macula

• Solitary, well-circumscribed yellow “egg-yolk” lesion (1–2 disc diameters) at the fovea.

• Sometimes extra-foveal satellite lesions.

• Dark area on Fluorescein angiography

• Lesion is intensely hyper-autofluorescent; dark on FA due to blockage.

Electrodiagnostics

• Electro-oculogram (EOG) markedly abnormal (Arden ratio <1.5).

• ERG usually normal → helps distinguish from other macular dystrophies.

Stages (natural history)

1. Pre-vitelliform: normal fundus, abnormal EOG.

2. Vitelliform: classic “egg-yolk” lesion at macula.

3. Pseudohypopyon: Yellowish material may gravitate inferiorly.

4. Vitelli-ruptive: lesion breaks into “scrambled-egg”; acuity reduces.

5. Atrophic / cicatricial: appears as mottled RPE pigment and an oval area of atrophy

sub retinal neovascularisation can develop

OCT Correlates

• Hyper-reflective dome between RPE & photoreceptor layer (vitelliform material).

• Disruption of ellipsoid zone as disease advances.

Course / Management

• Onset in early childhood; many (over 75%) maintain \ge6/12 in one eye until >50 yrs.

  • strong family history

• Vision loss after CNV, scarring, or geographic atrophy ≥ middle age.

• No treatment available

  • monitor with OCT/FAF

  • treat CNV with anti-VEGF injections.

  • Amsler Grid

  • review every 12 months

• Low-vision aids; genetic counselling.

Adult-Onset Vitelliform Dystrophy (AOVD)

• Form of vitelliform dystrophy that develops in adulthood

• Presents in middle age or older

• Consistent with normal vision, at least in the early stages, followed by often mild deterioration

• Vitelliform lesions usually smaller than in Best’s disease

• Regarded as one of the ‘pattern dystrophies’

  • A group of rare dystrophies of the RPE, characterised by accumulation of lipofuscin at the RPE (yellow, whitish, or grey deposits at the macula in a variety of morphologies).

X-Linked Juvenile Retinoschisis (XLRS)

• X-linked recessive → males affected, carrier females clinically silent.

• Intraretinal splitting (schisis) at nerve-fiber layer & inner nuclear layer; impaired cell adhesion.

Clinical Features

• Onset: first decade with unexplained central‐vision loss (~6/9–6/12).

• Stellate or cartwheel-shaped (spokes) series of cystoid spaces at the maculae which do not leak on fluorescein angiograph

• Half of all cases have a peripheral schisis as well (usually inferotemporal fundus)

• ERG: “negative” pattern – markedly reduced b-wave, relatively preserved a-wave.

• reduced central vision

OCT

• Cystic cavities within the neurosensory retina; retinal splitting plane visible.

Course

• Usually presents in first decade with unexplained loss of central vision (~6/9-6/12)

• Vision slowly declines, reaching 6/18-6/24 by age 20

• May well be 6/60 by late middle age.

• If peripheral retinoschisis, can potentially be complicated by:

  • Vitreous haemorrhage

  • Retinal detachment

Management

• No treatment alters the natural course of the disease.

• However, topical dorzolamide and oral acetazolamide have been shown to reduce cystic spaces and foveal thickness with an increase in visual acuity.

• Gene therapy is under investigation, with potential for restoring visual function in future

• Low vision services may be needed.

Cone Dystrophies

Group of conditions characterised by early onset, bilateral, slowly progressive loss of central vision, due to progressive deterioration of cone photoreceptor function.

Definition & Genetics

• Heterogeneous group with progressive primary cone photoreceptor dysfunction.

• Inheritance: sporadic or autosomal dominant most frequent; autosomal recessive & X-linked forms exist.

• Some evolve into cone-rod dystrophy when rods later affected.

Symptoms

• Early blurred central vision, photophobia.

• Marked colour vision loss (often red-green); frequent nystagmus.

• Central/paracentral scotoma; peripheral field usually spared until late.

Signs & Imaging

• Classic ‘bull’s-eye’ maculopathy: concentric RPE atrophy with central sparing.

• Fundus may exhibit non-specific central pigmentary changes at macula

• central atrophic changes in later stage disease

• FAF: ring of hyper- or hypo-autofluorescence outlining bull’s-eye.

• OCT: attenuation / loss of inner segment–ellipsoid (IS/ELM) band; foveal thinning.

• ERG: photopic (cone) responses reduced/absent; scotopic (rod) normal early, deteriorate later if cone-rod dystrophy develops.

Course

• Visual decline may start in 1st decade

• VA falls to 6/12–6/18, colour vision usually impaired.

• Typically reaches 6/60 (or worse) by 3rd–4th decade.

Management

• No treatment currently available

• Electrophysiology (ERG – abnormal cone response) important for specific diagnosis

• Genetic counselling

• Low vision services

  • Tinted spectacle to reduce glare difficulties

Cross-Topic Connections & Practical Considerations

• All conditions emphasise importance of multimodal imaging (OCT, FAF, FA) + electrophysiology (ERG/EOG) for accurate phenotyping.

• Lipofuscin accumulation (Stargardt, vitelliform group) is central → avoidance of vitamin A excess, exploration of pharmacological visual-cycle modulators.

• Gene therapy is a recurring future avenue (ABCA4, BEST1, RS1, cone-specific genes); raises pharmacoeconomic & ethical questions regarding access, long-term surveillance, and germline editing avoidance.

• Early genetic diagnosis enables informed family planning, carrier testing, and enrolment in natural-history or interventional trials.

• Low-vision rehabilitation, psychosocial support, and educational accommodations remain cornerstone care across all dystrophies.