Pattern Dystrophy

Key Points at a Glance

Highlights of This Disease

• Pattern dystrophy is a group of inherited macular diseases characterized by lipofuscin accumulation in the retinal pigment epithelium (RPE).
• It is mainly caused by mutations in the PRPH2 (peripherin) gene, but multiple genes such as BEST1, IMPG1/2 are also involved.
• The prevalence is estimated at 1/7,400–8,200, and onset is most common in the 50s–70s. ¹⁾
• It is classified into five subtypes: AOFVD, butterfly-shaped, reticular, Stargardt-like, and fundus pulverulentus.
• Important complications include choroidal neovascularization (CNV) and geographic atrophy (GA), occurring in 2.1–11.7% and 21.3–26.9% of cases, respectively. ¹⁾
• No curative treatment currently exists. Anti-VEGF therapy is effective for CNV, preventing a loss of 3 or more lines of visual acuity in 87.5% of cases. ¹⁾
• Clinically, differentiation from age-related macular degeneration (AMD) and Best disease is important.

1. What is Pattern Dystrophy?

Pattern dystrophies of the RPE are a group of inherited macular degenerations characterized by yellowish to gray-yellow patterned lesions due to lipofuscin accumulation in the retinal pigment epithelium (RPE).

The prevalence is estimated at 1/7,400–8,200. ¹⁾ Onset is most common in the 50s–70s, with females accounting for 57–66% of cases. ¹⁾ Inheritance is often autosomal dominant (AD), but sporadic cases also occur.

The subtypes are broadly classified into the following five types. Adult-onset foveomacular vitelliform dystrophy (AOFVD) is the most frequent and most studied.

AOFVD

Adult-onset foveomacular vitelliform dystrophy: The most common subtype. It forms a gray-yellow round vitelliform lesion in the macula.

4 stages: previtelliform → vitelliform → pseudohypopyon → atrophic. ¹⁾

Butterfly-shaped dystrophy

Butterfly-shaped dystrophy: Presents a butterfly-wing pigment pattern in the macula.

Features: Yellow, orange, and black pigment accumulation at the RPE level arranged in a butterfly shape.

Reticular dystrophy

Reticular dystrophy: Presents a net-like pigment arrangement. Also associated with Sjögren-Larsson syndrome.

Benign concentric annular MD: A rare subtype showing a concentric ring pattern.

Others

Stargardt-like dystrophy: Fundus findings similar to Stargardt disease, but with autosomal dominant inheritance.

Fundus pulverulentus: Fine powdery pigment changes in the macula.

Q Does pattern dystrophy lead to blindness?

A

In many cases, vision is preserved for a relatively long time. However, if CNV (choroidal neovascularization) or geographic atrophy develops, vision loss progresses. Regular follow-up is important. For details, see “Standard treatment” section.

2. Main symptoms and clinical findings

Subjective symptoms

Symptoms are relatively mild and progress slowly.

• Metamorphopsia (distortion): One of the earliest complaints. Caused by photoreceptor damage due to RPE dysfunction.
• Mild visual acuity loss: Visual acuity is often preserved in the early stage. It can rapidly decline with CNV or atrophy.
• Central scotoma: Appears when RPE damage in the fovea progresses.
• Color vision abnormality: May occur due to decreased macular function.
• Night vision impairment: Reported in some subtypes.

Clinical Findings

The staging of AOFVD is classified into 4 stages. ¹⁾ The characteristics of each stage are described below.

Stage	Name	Main Findings
1	Previtelliform	FAF hyperautofluorescent spots, OCT normal to mild changes
2	Vitelliform	Gray-yellow round homogeneous lesion, marked FAF hyperautofluorescence
Stage 3	Pseudohypopyon stage	Liquefaction and layering of yolk-like material
Stage 4	Atrophic stage	RPE and photoreceptor atrophy, geographic atrophy

In unilateral AOFVD, an association with pachychoroid-related conditions accompanied by thickened choroid (SCT 355–669 μm) has been reported. ²⁾

Q Can the lesion appear in only one eye?

A

It is usually bilateral, but unilateral AOFVD has also been reported. Unilateral cases suggest an association with pachychoroid (choroidal thickening), and differentiation from Best disease is particularly important. ²⁾

3. Causes and Risk Factors

Pattern dystrophy is primarily a hereditary disease, but the causative genes are diverse, and sporadic cases are not uncommon.

The main causative genes are listed below.

• PRPH2 (peripherin/RDS): The most frequent causative gene. Mutations are identified in 2–18% of cases. ¹⁾ It encodes a structural protein of the photoreceptor outer segment disc membrane.
• BEST1 (bestrophin 1): Also called the VMD2 gene. It is also the causative gene for Best disease (vitelliform macular dystrophy) and may present with a phenotype similar to AOFVD. ¹⁾
• IMPG1 and IMPG2: They encode interphotoreceptor matrix proteoglycans. They present with a phenotype similar to PRPH2 mutations. ¹⁾
• Other genes/phenocopies: AOFVD-like phenotypes can result from multiple genetic abnormalities. Differentiation from Best disease and Stargardt disease is important. ¹⁾

Since PRPH2 mutations are identified in only 2–18% of all cases, the causative gene remains unidentified in many cases. ¹⁾

Genetics and family impact

Pattern dystrophy is often autosomal dominant, with a 50% chance of inheritance from parent to child. If you have family members with similar symptoms, please consider consulting an ophthalmologist and genetic counseling. Regular fundus examinations enable early detection.

4. Diagnosis and examination methods

The diagnosis of pattern dystrophy is made by combining characteristic fundus findings with various ancillary tests. Differentiation from age-related macular degeneration and Best disease is the most important issue.

Main examination methods

• Fundus autofluorescence (FAF): Lipofuscin accumulation sites show hyperfluorescence, allowing assessment of lesion extent and activity. It plays a central role in diagnosis. ¹⁾
• Fluorescein angiography (FA): Useful for detecting CNV and assessing activity. The condition is confirmed by patterns of transmission and blocking fluorescence in the lesion. ¹⁾
• Indocyanine green angiography (ICGA): Used to evaluate choroidal vessels and assess association with pachychoroid. ¹⁾
• Optical coherence tomography (OCT): Evaluates cross-sectional structure of retinal layers. Confirms layer separation of vitelliform material, RPE atrophy, and photoreceptor layer changes. ¹⁾
• OCT angiography (OCTA): Enables detection of CNV without contrast agent. CNV is assessed by the presence or absence of flow signal. ¹⁾
• Electroretinography (ERG): In pattern dystrophy, it remains normal or mildly abnormal.
• Electrooculography (EOG): Best disease shows marked reduction (Arden ratio <1.5), but AOFVD is usually normal. ^{1, 2)} This difference is the most important distinguishing point from Best disease.

Special examinations

Multispectral imaging (MSI) is useful for evaluating lesions in AOFVD. It can assess the RPE and photoreceptors in detail in the 550–850 nm wavelength band and is excellent for identifying areas of RPE destruction with nodular hyperreflectivity. ⁴⁾

Differential Diagnosis

Differential diagnosis of pattern dystrophy is important, as misdiagnosis can significantly affect treatment strategy.

Disease	Key differentiating features	EOG
Best disease (VMD2)	Young onset, prominent vitelliform lesions	Markedly reduced
Exudative age-related macular degeneration	Advanced age, drusen	Normal
Stargardt disease	ABCA4-related, often young onset	Normal to reduced

Q How is pattern dystrophy different from age-related macular degeneration (AMD)?

A

The grayish-yellow vitelliform lesions of AOFVD resemble drusen in age-related macular degeneration, so they are easily confused, especially in elderly-onset cases. Normal EOG, family history, and characteristic patterned hyperautofluorescence on FAF are features of AOFVD. ^{1, 2)}

5. Standard Treatment

Currently, there is no curative treatment for pattern dystrophy. The main goals of treatment are to manage complications (CNV, geographic atrophy) and maintain visual function.

Treatment for Choroidal Neovascularization (CNV)

CNV occurs in 2.1–11.7% of cases. ¹⁾ Anti-VEGF therapy (bevacizumab, ranibizumab, aflibercept, etc.) is the main treatment option for CNV.

Anti-VEGF therapy has been reported to prevent a loss of 3 or more lines of visual acuity in 87.5% of cases. ¹⁾

Photodynamic therapy (PDT) has been reported to be ineffective for CNV in pattern dystrophy. ¹⁾

In AOFVD with exudative perifoveal vascular anomalous complex (ePVAC)-like lesions, there are case reports of poor response to anti-VEGF therapy. A pachychoroid-related vascular compression hypothesis has been proposed. ³⁾

Management of Geographic Atrophy (GA)

Geographic atrophy is observed in 21.3–26.9% of cases. ¹⁾ Currently, there is no established treatment to slow its progression, and observation is the standard of care.

Visual Rehabilitation

For patients with progressive vision loss, low vision rehabilitation using magnifiers, tinted glasses, and low vision aids is beneficial.

Treatment Precautions

• PDT for pattern dystrophy has been reported to be insufficiently effective for CNV. ¹⁾
• In cases with serous retinal detachment due to mechanical compression, such as those associated with ePVAC, the efficacy of anti-VEGF therapy may be limited. ³⁾
• In the advanced stage of geographic atrophy, effective treatment options are scarce, so regular follow-up and early detection of complications are important.

6. Pathophysiology and Detailed Mechanisms

The central pathology of pattern dystrophy is abnormal accumulation of lipofuscin in the RPE.

Mechanisms of Lipofuscin Accumulation

Lipofuscin is a complex of oxidized lipids and proteins that the RPE cannot fully process during the recycling of photoreceptor outer segments. It accumulates even with normal aging, but in pattern dystrophy, excessive accumulation occurs due to genetic factors.

Effects of PRPH2 Mutations

PRPH2 (peripherin) is a membrane protein expressed at the rim of photoreceptor outer segment discs, maintaining disc structure integrity. Abnormal PRPH2 function leads to photoreceptor outer segment dysgenesis and degeneration, increasing metabolic load on the RPE and promoting lipofuscin accumulation. ¹⁾

Effects of BEST1 (Bestrophin 1) Mutations

BEST1 is a Ca²⁺-activated Cl⁻ channel expressed on the basolateral membrane of the RPE. Mutations impair RPE Ca²⁺ homeostasis, leading to abnormal outer segment phagocytosis, lipofuscin accumulation, and formation of yolk-like material. ¹⁾

Pachychoroid and Vascular Compression Hypothesis

In unilateral AOFVD cases, a thick choroid (pachychoroid) is observed, and a hypothesis has been proposed that compression of choroidal vessels impairs blood flow to the RPE and photoreceptors. ^{2, 3)} OCTA analyses have also reported abnormalities in choroidal blood flow, drawing attention to its association with the pachychoroid disease spectrum. ¹⁾

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7. Latest Research and Future Perspectives (Research Stage Reports)

For patients: Please be sure to 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 experts regarding future medical developments.

Evaluation by Multispectral Imaging (MSI)

MSI is a non-invasive technique that captures retinal images using broadband wavelengths from 550 to 850 nm. In evaluating AOFVD lesions, it can visualize RPE changes and photoreceptor damage distribution that are difficult to detect with OCT.

Yuan M et al. (2022) performed MSI on three eyes with AOFVD and identified areas of RPE disruption with nodular hyperreflectivity using infrared wavelength (850 nm) imaging. ⁴⁾ Short-wavelength (550 nm) imaging delineated the lesion extent more clearly, and comparison with FAF enabled precise mapping of RPE function loss areas.

Deep Learning-Based Staging and Automated Diagnosis

AI-based analysis of OCT and FAF images is advancing. Research is underway for automated identification, staging, and prediction of atrophy progression in AOFVD lesions, with validation expected in large cohorts. ¹⁾

Causative Gene Discovery by Whole Exome Sequencing (WES)

Many pattern dystrophy cases remain unexplained by conventional targeted gene panel testing. Comprehensive analysis is expected to advance the search for genes other than PRPH2 and phenocopies. ¹⁾ This is also expected to elucidate genotype-phenotype correlations.

Q Will gene therapy become possible in the future?

A

For cases with identified causative genes such as PRPH2 mutations, gene replacement therapy using adeno-associated virus (AAV) is being investigated at the basic research stage. However, it has not yet reached clinical application and is not established as standard treatment.

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8. References

1. Nipp GE, Rao RC, Pennesi ME, et al. Adult-onset foveomacular vitelliform dystrophy: a review. Front Ophthalmol. 2023;3:1237788.
2. Spanos E, Daoud YJ, Bhatt A, et al. Unilateral adult-onset foveomacular vitelliform dystrophy: case series and literature review. Cureus. 2024;16(8):e68214.
3. Milan S, Pastore MR, Gaggino A, Rinaldi S, Tognetto D. Exudative perifoveal vascular anomalous complex (ePVAC) resembling lesion in a patient with adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol Case Rep. 2024;36:102211. PMID: 39559550. PMCID: PMC11570888. doi:10.1016/j.ajoc.2024.102211.
4. Yuan M, Tan ZJ, Lin Z, et al. Multispectral imaging in adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol Case Rep. 2022;26:101542.