What Is Honeycomb Retinal Dystrophy?

Honeycomb retinal dystrophy is a rare inherited eye disease in which yellowish-white waste deposits called drusen slowly build up beneath the retina, eventually threatening central vision. The condition is caused by a single mutation in a gene called EFEMP1, and because it follows an autosomal dominant inheritance pattern, a person needs only one copy of the faulty gene to develop the disease. It shares enough features with the far more common age-related macular degeneration (AMD) that researchers study it as a kind of genetic model for understanding how drusen damage the eye in both conditions.

Names for the Same Disease

You will encounter several names in the medical literature, all describing the same condition. “Doyne honeycomb retinal dystrophy” (DHRD) comes from Robert Doyne, an English ophthalmologist who described a family with the disease in the early 1900s. “Malattia Leventinese” (ML) refers to a cluster of cases identified in the Leventina valley of Switzerland. For decades, researchers debated whether these were two separate diseases. Genetic testing settled the question: both are caused by the exact same mutation in the same gene, making them one disease with two historical names.¹ You may also see the term “autosomal dominant radial drusen” (ADRD), which describes the distinctive radiating pattern of the deposits.

How It Affects Vision

The disease tends to be slow-moving. Most people with the mutation develop visible drusen well before they notice any change in their eyesight. In a long-term study following dozens of patients, the average age when symptoms first appeared was around 40, though some individuals noticed problems as early as their mid-twenties and others not until their early fifties.² A number of patients in that study remained asymptomatic throughout the entire follow-up period, meaning they carried the mutation and had drusen on examination but never reported visual complaints.

When symptoms do appear, the most common are a drop in central sharpness and a sense that straight lines look wavy or distorted. In the same study, about 70% of symptomatic patients reported reduced vision and roughly half reported distortion.² Over a mean follow-up of about eight years, best-corrected visual acuity in both eyes worsened significantly. That said, the decline is generally gradual, and many patients retain functional reading vision for years or even decades.

Another early complaint is trouble adjusting when moving from a bright room into darkness. Studies have found that people with the EFEMP1 mutation can have measurable problems with dark adaptation even before obvious geographic atrophy or other advanced complications develop.³ If you have the condition, you might notice this as a delay in seeing clearly after walking into a dim restaurant or a movie theater.

The Genetic Cause

Honeycomb retinal dystrophy traces to a single point mutation in the EFEMP1 gene, which encodes a protein called fibulin-3. The mutation, known as R345W (Arg345Trp), swaps one amino acid for another at position 345 of the protein chain. Researchers who identified the mutation tested hundreds of control individuals and hundreds of patients with ordinary AMD and found the change in none of them, confirming it as specific to this dystrophy.⁴ Within affected families, the mutation tracks perfectly with disease: family members who carry it develop drusen, and those who do not carry it are unaffected.⁵

The gene was mapped to chromosome 2p16 before the specific mutation was pinpointed.⁶ Because the disease is autosomal dominant, each child of an affected parent has a 50% chance of inheriting the mutation. No carriers have been documented without at least some drusen on careful examination, which means penetrance appears to be very high, though the severity and timing of vision loss vary widely even within the same family.

What Happens Inside the Eye

Fibulin-3, the protein produced by EFEMP1, is a component of the extracellular matrix, the scaffolding that holds cells in place and regulates their communication. In the eye, fibulin-3 is produced by several cell types including retinal pigment epithelium (RPE) cells, the layer of cells that sits just behind the light-sensing photoreceptors. RPE cells perform critical housekeeping for the retina: recycling visual pigments, absorbing stray light, and clearing metabolic waste.

When the R345W mutation is present, the altered fibulin-3 protein misfolds. Cells detect the misfolded protein and mount a stress response. In mouse models carrying the equivalent mutation, this stress response is detectable even in young animals and becomes more pronounced with age.⁷ The stressed RPE cells appear to function less efficiently, with lower expression of genes essential for the visual cycle.

Meanwhile, the mutant protein forms extracellular aggregates, and the entire matrix produced by RPE cells becomes abnormal. Studies comparing the matrix laid down by cells with the R345W mutation to that of normal cells found it thicker, more disorganized, and enriched in proteins like fibronectin and collagen that are also prominent in the deposits seen in AMD.⁸ The abnormal matrix also triggers the complement system, part of the immune system that flags damaged tissue for cleanup. In the retina, chronic complement activation probably contributes to the progressive damage.⁹

In knock-in mice carrying the mutation, small isolated deposits beneath the RPE appeared as early as four months of age. Over time these deposits grew and eventually merged into continuous sheets.¹⁰ That timeline mirrors what clinicians see in people: a few scattered drusen in young adults that multiply and coalesce over decades.

How It Looks on Examination

The “honeycomb” in the name comes from the way the drusen are arranged. On a standard eye exam, the deposits tend to concentrate in three areas: the macula (the center of your visual field), around the edge of the optic nerve head, and along the major retinal blood vessels. The pattern is strikingly symmetrical between the two eyes, and the drusen often radiate outward from the macula in a spoke-like arrangement.¹¹ When drusen are densely packed in the macula, they can form the honeycomb-like mosaic that gives the condition its name.

Modern imaging has made diagnosis much more precise. Optical coherence tomography (OCT), which takes cross-sectional images of the retina, shows dome-shaped deposits sitting beneath the RPE layer.¹² Fundus autofluorescence, another non-invasive imaging tool, shows increased brightness in the areas corresponding to drusen.¹³ Fluorescein angiography, which uses a dye injected into the bloodstream, reveals the drusen as bright spots that glow under filtered light.³ Together, these tools let an ophthalmologist build a detailed map of where deposits sit and how the surrounding retina is responding.

Genetic testing for the EFEMP1 R345W mutation can confirm the diagnosis definitively, which matters because the drusen in honeycomb retinal dystrophy can look superficially similar to age-related drusen. The younger age at presentation, bilateral symmetry, radiating distribution, and strong peripapillary involvement are the clinical clues that prompt a clinician to order genetic testing rather than assuming garden-variety AMD.

How It Differs from Age-Related Macular Degeneration

The resemblance between honeycomb retinal dystrophy and AMD is more than cosmetic. Both involve drusen accumulating beneath the RPE at the level of Bruch’s membrane, both can progress to geographic atrophy or abnormal blood vessel growth, and the drusen in both conditions share many of the same molecular components.¹⁴ That overlap is exactly why researchers prize the condition as a model: AMD involves dozens of genetic and environmental risk factors, making it hard to isolate any single mechanism, whereas honeycomb retinal dystrophy has a clear, single-gene cause that nonetheless produces a strikingly similar disease.

Under the microscope, however, the drusen are not identical. The most distinctive feature of honeycomb dystrophy drusen is a laminated, onion-like structure with alternating layers, a pattern not seen in typical age-related drusen. The dystrophy drusen also show especially strong staining for collagen type IV.¹⁴ These structural differences suggest that while the downstream consequences overlap, the initial process of deposit formation differs between the two conditions.

Age is the other obvious differentiator. AMD rarely produces significant drusen before the sixth or seventh decade. Honeycomb retinal dystrophy can produce visible deposits in adolescence, and the drusen pattern described earlier, especially the radial arrangement and peripapillary involvement, are unusual in AMD.¹⁵ A 35-year-old with bilateral, symmetrical radial drusen clustered around the optic nerve head is a very different clinical picture from a 72-year-old with scattered soft drusen in the central macula.

Complications That Threaten Sight

The slow accumulation of drusen is not itself the main danger. The real threats come when the disease advances to one of two complications: geographic atrophy, in which patches of RPE cells die and the overlying photoreceptors follow, or choroidal neovascularization (CNV), in which abnormal new blood vessels grow from beneath the retina into the sub-RPE space. These new vessels are fragile and leak fluid or blood, causing rapid and sometimes severe vision loss.¹⁶

CNV in honeycomb retinal dystrophy is uncommon but well documented. When it does develop, the decline can be abrupt. In one reported case, vision in the affected eye dropped from 20/20 to 20/250 in a matter of months. The good news is that early intervention appears to help: in two published cases treated with intravitreal injections of bevacizumab (a drug that blocks the growth signal driving the abnormal vessels), vision improved substantially. One patient’s acuity recovered all the way to 20/20 after a course of seven injections over two years, whereas an untreated eye in another patient remained at poor acuity six years later.¹⁷

Not every case responds as dramatically. In another patient with EFEMP1-related CNV who received multiple bevacizumab injections, subretinal fluid improved but visual acuity continued to decline and the CNV area remained largely unchanged on imaging.¹⁸ The discrepancy probably reflects how much underlying retinal damage has already occurred by the time treatment begins, which reinforces the clinical argument for treating CNV early when it appears.

Current Management and Monitoring

There is no treatment that slows or reverses the drusen buildup itself. Management today centers on regular monitoring and prompt treatment of complications. Patients are typically followed with periodic OCT and fundus imaging so that any new fluid, hemorrhage, or atrophy is caught early. An Amsler grid, a simple paper chart with a grid of straight lines, is a useful home monitoring tool: if straight lines start appearing wavy or a dark spot appears, that can signal CNV developing and warrants urgent evaluation.

Anti-VEGF injections (bevacizumab, ranibizumab, aflibercept) remain the first-line treatment when CNV does develop, following the same logic that has transformed wet AMD care. The cases described above suggest that vision can sometimes be recovered if treatment begins promptly.¹⁷ For geographic atrophy, options are more limited, though new complement-targeted therapies approved for AMD-related atrophy are generating interest for potential off-label or trial use in this condition as well.

Emerging Gene-Targeted Therapies

Because honeycomb retinal dystrophy has a single, well-characterized genetic cause, it is a natural target for precision therapies. The most promising work to date involves antisense oligonucleotides (ASOs), short synthetic fragments of genetic material designed to seek out and neutralize a specific faulty RNA message before it gets turned into protein. Researchers recently developed an ASO that selectively promotes the clearance of the mutant EFEMP1 transcript while leaving the healthy copy intact. In lab-grown RPE cells derived from a patient carrying the mutation, the ASO reduced the buildup of abnormal extracellular deposits, cleared intracellular lipid accumulation, and restored normal matrix structure, even when delivered after the disease features had already appeared.¹⁹

That last point is especially encouraging. Many genetic therapies work best when given before damage accumulates. Showing that the ASO can reverse disease features already in progress, at least in a dish, suggests a wider treatment window than researchers might have expected. One practical hurdle is that the ASO is designed specifically for the human version of the EFEMP1 sequence. There is a three-base-pair mismatch between the human and mouse versions of the gene in the region the ASO targets, which means the existing mouse models of the disease cannot be used to test the drug in living animals.²⁰ Developing a humanized animal model or moving directly to carefully designed human safety trials will be a necessary next step.

Other research directions include exploring whether blocking complement factor B, a specific piece of the complement immune pathway, can slow deposit formation. In mice carrying the EFEMP1 mutation, removing complement factor B dramatically reduced the accumulation of sub-RPE deposits.⁹ Since complement-targeting drugs are already in clinical use for other eye conditions, repurposing them could potentially move faster than a completely novel therapy.

Living with the Diagnosis

A diagnosis of honeycomb retinal dystrophy can feel alarming, but it helps to understand the typical pace of the disease. Many people retain good functional vision well into middle age and beyond, especially if they avoid CNV or catch it early. The condition does not affect peripheral vision in the way that diseases like retinitis pigmentosa do; the damage is concentrated in central vision, which affects tasks like reading and recognizing faces but leaves navigational vision intact for most people throughout life.

If you have been diagnosed, your ophthalmologist will likely recommend genetic counseling, both for family planning purposes and to alert other family members who may carry the mutation without knowing it. Since drusen can be present long before symptoms appear, identifying carriers early allows monitoring to begin before complications arise. Siblings and children of affected individuals have predictable odds of carrying the mutation, and a simple blood test can resolve the question. For families already aware of their status, the emerging ASO research offers a reason for cautious optimism that the therapeutic landscape may look very different within the next decade.

1
Nature Genetics. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy
2
PubMed Central. A Long-Term Retrospective Natural History Study of EFEMP1-Associated Autosomal Dominant Drusen – Section: Results
3
Eye. Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy) – Section: Abstract
4
PubMed. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy
5
PubMed. Dominant radial drusen and Arg345Trp EFEMP1 mutation – Section: RESULTS
6
Human Molecular Genetics. The Gene Responsible for Autosomal Dominant Doyne’s Honeycomb Retinal Dystrophy (DHRD) Maps to Chromosome 2p16 – Section: Abstract
7
Human Molecular Genetics. Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration – Section: Results
8
Human Molecular Genetics. Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway – Section: Results
9
Human Molecular Genetics. Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration – Section: Discussion
10
Oxford Academic. Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice: a model for the early pathogenic course of macular degeneration – Section: Abstract
11
PubMed Central. Utility of pattern recognition and multimodal imaging in the diagnosis and management of doyne honeycomb retinal dystrophy complicated with type one choroidal neovascular membrane – Section: Abstract
12
PubMed Central. The First Case Series of Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy in Türkiye Identified with EFEMP1 Gene Mutation – Section: Case Presentations and Genetic Evaluation
13
Retina. Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy in a Chinese Family with Mutation of the EFEMP1 Gene – Section: Results
14
PubMed Central. Comparison of Drusen and Modifying Genes in Autosomal Dominant Radial Drusen and Age-Related Macular Degeneration – Section: Results
15
PubMed. Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy: Similarities to Age-Related Macular Degeneration and Potential Therapies
16
PubMed. Doyne Honeycomb Retinal Dystrophy (Malattia Leventinese, Autosomal Dominant Drusen)
17
JAMA Ophthalmology. Responsiveness of Choroidal Neovascular Membranes in Patients With R345W Mutation in Fibulin 3 (Doyne Honeycomb Retinal Dystrophy) to Anti–Vascular Endothelial Growth Factor Therapy – Section: Comment
18
PubMed Central. Optical coherence tomography angiography of choroidal neovascularization in four inherited retinal dystrophies – Section: Results
19
Molecular Therapy: Nucleic Acids. Allele-specific antisense oligonucleotide therapy rescues disease phenotype in a patient-derived iRPE model of Doyne honeycomb retinal dystrophy – Section: Abstract
20
Molecular Therapy: Nucleic Acids. Antisense oligonucleotide therapy for Doyne honeycomb retinal dystrophy – Section: Discussion