Doyne Honeycomb Retinal Dystrophy

Mendelian MONDO:0007471 Pathograph 34 Show in embeddings browser Ophthalmological Disease Macular Dystrophy Inherited retinal dystrophy Retinal drusen

Doyne honeycomb retinal dystrophy (DHRD), also called malattia leventinese (ML), is an autosomal dominant macular dystrophy caused by a single recurrent missense variant in EFEMP1, c.1033C>T p.(Arg345Trp), which encodes the secreted extracellular matrix glycoprotein fibulin-3. Yellow-white drusen accumulate beneath the retinal pigment epithelium (RPE), in Bruch's membrane, in the macula and around the optic disc, often in a radial pattern, and coalesce with age into a honeycomb-like pattern. Drusen can be present from adolescence, while visual symptoms (reduced central vision, delayed dark adaptation, metamorphopsia, photophobia, paracentral scotoma) usually begin in early to mid adulthood. RPE atrophy, macular hyperpigmentation, geographic atrophy and, less often, choroidal neovascularization drive late central vision loss. The mutant protein misfolds, is secreted inefficiently and is retained in the RPE, causing endoplasmic reticulum stress, an abnormal Bruch's membrane extracellular matrix and local alternative complement activation that together drive sub-RPE deposit formation; R345W behaves as a toxic gain of function rather than haploinsufficiency. Expressivity is highly variable and nonpenetrance has been reported. There is no approved disease-modifying therapy. Because it reproduces the drusen biology of age-related macular degeneration (AMD) from a single genetic lesion, DHRD is used as a monogenic model of AMD.

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Inheritance
11
Pathophys.
15
Phenotypes
34
Pathograph
1
Genes
1
Variants
4
Medical Actions
3
Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant with marked inter- and intrafamilial variability in retinal appearance, severity and progression. Nonpenetrance has been observed in an asymptomatic 62-year-old carrier.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (3 references)
PMID:10369267 SUPPORT Human Clinical
"Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases"
Both clinical names describe autosomal dominant disease.
PMID:16799055 SUPPORT Human Clinical
"Marked inter- and intrafamilial variation associated with the fibulin-3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified."
Documents variable expressivity and nonpenetrance.
PMID:16799055 SUPPORT Human Clinical
"The novel finding of nonpenetrance was observed in a 62-year-old asymptomatic, mutation-positive man."
A specific nonpenetrant carrier supports incomplete penetrance.
⚙

Pathophysiology

11
Fibulin-3 R345W Misfolding and Impaired Secretion
The heterozygous EFEMP1 p.Arg345Trp substitution causes fibulin-3 to misfold, in part through reduced native disulfide bonding in the domain carrying residue 345. Wild-type fibulin-3 is secreted, whereas the mutant is secreted inefficiently and retained within RPE cells. Loss of fibulin-3 does not reproduce the disease in mice, and Efemp1 knockout protects against sub-RPE deposits, so the variant acts as a toxic gain of function rather than through haploinsufficiency. Fibulin-3 is an extracellular matrix protein (its GO molecular function annotation is extracellular matrix structural constituent); that function is bound here as abnormal rather than decreased, because the mutant protein is retained and deposited abnormally rather than simply lost.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
EFEMP1 hgnc:3218 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EFEMP1 (hgnc:3218). hgnc:3218 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
protein folding GO:0006457 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. fibulin-3 secretion GO:0009306 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fibulin-3 secretion, annotated with protein secretion (GO:0009306). GO:0009306 is a biological process from the Gene Ontology.
fibulin-3 extracellular matrix structural constituent GO:0005201 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal fibulin-3 extracellular matrix structural constituent, annotated with extracellular matrix structural constituent (GO:0005201). GO:0005201 is a molecular function from the Gene Ontology.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
RPE Endoplasmic Reticulum Stress Retention of misfolded fibulin-3 in the ER activates the unfolded protein response in RPE cells.
Abnormal Bruch's Membrane Extracellular Matrix Mutant fibulin-3 accumulates beneath the RPE and alters the composition and turnover of the RPE basal lamina and Bruch's membrane.
Impaired RPE Cholesterol Efflux Expression of EFEMP1 R345W attenuates RPE cholesterol efflux.
RPE Lysosomal Dysfunction Patient-derived ML iPSC-RPE carrying the mutation show lysosomal dysfunction; how mutant fibulin-3 produces it is not established.
NLRP3 Inflammasome Activation R345W knock-in mice show retinal Nlrp3 upregulation and inflammasome component transcription in RPE/choroid; the intermediate steps from the mutant protein are not defined.
Show evidence (4 references)
PMID:12242346 SUPPORT In Vitro
"Here, we show that wild-type EFEMP1 is a secreted protein whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells."
Direct comparison of wild-type and R345W EFEMP1 shows misfolding, inefficient secretion and intracellular retention of the mutant.
PMID:22031286 SUPPORT In Vitro
"These secretion defects appear to be caused, in part, by reduced native disulfide bonding in domain 6 harboring the 345 position."
A cell-based secretion assay attributes the R345W secretion defect partly to impaired disulfide bonding in the domain carrying residue 345.
PMID:42306086 SUPPORT In Vitro
"These data support an EFEMP1 Arg345Trp toxic gain of function and the absence of haploinsufficiency in DHRD."
Patient iPSC-RPE work, set beside the knockout data it cites, supports a toxic gain-of-function mechanism for R345W.
+ 1 more reference
RPE Endoplasmic Reticulum Stress
Intracellular retention of misfolded R345W fibulin-3 induces endoplasmic reticulum stress and the unfolded protein response in the RPE, observed in RPE cell lines, in knock-in mouse eyecups and in patient-derived iPSC-RPE, where it accompanies fibulin-3 and ApoE aggregation and increased apoptosis.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology.
Downstream
Increased RPE VEGF Expression ER stress induced by mutant fibulin-3 increases VEGF transcription in RPE cells.
RPE Degeneration and Atrophy Chronic ER stress is proposed to cause RPE dysfunction and apoptosis.
Show evidence (3 references)
PMID:16249470 SUPPORT In Vitro
"R345W was poorly secreted by ARPE-19 cells and accumulated in the ER, leading to UPR activation and increased VEGF expression."
Overexpressed R345W fibulin-3 activates the UPR in ARPE-19 cells.
PMID:35943778 SUPPORT Model Organism
"RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response"
Efemp1 R345W knock-in eyecups show an increased unfolded protein response signature.
PMID:42484373 SUPPORT In Vitro
"MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis."
Patient-derived RPE shows increased ER stress alongside fibulin-3 aggregation.
Increased RPE VEGF Expression
Mutant fibulin-3 induced ER stress increases vascular endothelial growth factor expression in RPE cells, a proposed link to the choroidal neovascularization seen in a minority of patients. The link is supported by cell culture only.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
vascular endothelial growth factor production GO:0010573 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased vascular endothelial growth factor production (GO:0010573). GO:0010573 is a biological process from the Gene Ontology.
Downstream
Choroidal neovascularization Increased RPE VEGF is proposed to contribute to choroidal neovascularization.
Show evidence (1 reference)
PMID:16249470 SUPPORT In Vitro
"These findings demonstrated that the expression of mutated fibulin-3 caused UPR activation and increased VEGF expression."
Mutant fibulin-3 expression increases VEGF expression in RPE-derived cells.
Abnormal Bruch's Membrane Extracellular Matrix
Mutant fibulin-3 alters the extracellular matrix of the RPE basal lamina and Bruch's membrane. In knock-in mice the basal deposits are made of normal ECM components in abnormal amounts and contain fibulin-3 and its binding partner TIMP3; proteoglycans accumulate in Bruch's membrane and diffusion across it is impaired. ECM turnover is altered, but the reported direction of the MMP-2 change depends on the system: knock-in Bruch's membrane shows reduced MMP-2 and MMP-9 with increased TIMP-3, whereas engineered and patient-derived RPE cultures report increased MMP-2 activity or activation.
extracellular matrix organization GO:0030198 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
basement membrane GO:0005604 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves basement membrane (GO:0005604). GO:0005604 is a cellular component from the Gene Ontology.
Bruch's membrane UBERON:0003957 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bruch's membrane (UBERON:0003957). UBERON:0003957 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Efemp1 R345W knock-in mouse Mouse recapitulates Shows proteoglycan accumulation, MMP/TIMP imbalance and reduced diffusion across Bruch's membrane.
Downstream
Alternative Complement Activation The abnormal ECM binds and activates complement C3 locally at the RPE-Bruch's membrane interface.
Sub-RPE Basal Deposit and Drusen Formation Excess and abnormal matrix material forms the basal deposits that precede drusen.
Show evidence (5 references)
PMID:23943789 SUPPORT Model Organism
"Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1(R345W/R345W) mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts."
Proteomics of knock-in Bruch's membrane shows an abnormal ECM composition.
PMID:17666404 SUPPORT Model Organism
"These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein."
Mutant fibulin-3 and TIMP3 are incorporated into the sub-RPE matrix deposits.
PMID:28622396 SUPPORT Model Organism
"HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired."
Knock-in Bruch's membrane accumulates proteoglycans, shifts the MMP/TIMP balance and loses diffusional permeability.
+ 2 more references
Alternative Complement Activation
The abnormal ECM triggers local complement activation by the RPE, with C3 cleavage and increased alternative pathway activity (iC3b and Ba). Genetic removal of C3, or deletion or inhibition of complement factor B, reduces basal deposits in the knock-in mouse, whereas removal of C5 does not, which places the effect at C3 rather than at the terminal pathway. In the knock-in mouse the effect is sex-dependent: females have more deposits and show the complement elevation and the response to factor B inhibition, males do not.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
complement activation, alternative pathway GO:0006957 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased complement activation, alternative pathway (GO:0006957). GO:0006957 is a biological process from the Gene Ontology.
Animal models
Efemp1 R345W knock-in mouse Mouse recapitulates Shows complement activation in RPE and Bruch's membrane and its requirement for deposits.
Downstream
Sub-RPE Basal Deposit and Drusen Formation Complement activation is required for basal deposit formation in the knock-in mouse.
Show evidence (5 references)
PMID:35943778 SUPPORT Model Organism
"Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05)."
Alternative pathway breakdown products are elevated in knock-in eyes.
PMID:17666404 SUPPORT Model Organism
"Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice."
Complement activation is localized to the RPE and Bruch's membrane in the knock-in mice.
PMID:28878022 SUPPORT In Vitro
"RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD)."
Patient-derived DHRD RPE upregulates complement genes, supporting an RPE-intrinsic complement response in human cells.
+ 2 more references
NLRP3 Inflammasome Activation
R345W knock-in mice show retinal gliosis, subretinal Iba-1 positive cells, increased retinal Nlrp3 and transcriptional upregulation of C3, Nlrp3, pro-Il1b and pro-caspase-1 in RPE/choroid. Genetic removal of Nlrp3 or caspase-1 reduces basal laminar deposits, so inflammasome signalling contributes to deposit formation in this model. It has not been examined in patient tissue.
NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NLRP3 inflammasome complex assembly (GO:0044546). GO:0044546 is a biological process from the Gene Ontology.
Animal models
Efemp1 R345W knock-in mouse Mouse recapitulates Shows inflammasome upregulation and its contribution to deposits; human relevance is untested.
Downstream
Sub-RPE Basal Deposit and Drusen Formation Inflammasome signalling contributes to basal laminar deposit formation.
Show evidence (1 reference)
PMID:41198612 SUPPORT Model Organism
"R345W+/+ knockin mice demonstrated increased Muller cell gliosis, subretinal Iba-1+ cells, higher Nlrp3 immunoreactivity in the retina"
Inflammasome and innate immune activation accompany the knock-in phenotype.
Impaired RPE Cholesterol Efflux
Proteomics of DHRD iPSC-RPE against isogenic controls found downregulation of carboxylesterase 1 (CES1), which converts cholesteryl ester to free cholesterol for export. CES1 knockdown or EFEMP1 R345W overexpression attenuates cholesterol efflux and causes intracellular lipid droplet accumulation; R345W fibulin-3 also has a stronger inhibitory effect on EGFR signalling than wild type, which may suppress CES1 through reduced SP1.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
cholesterol efflux GO:0033344 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cholesterol efflux (GO:0033344). GO:0033344 is a biological process from the Gene Ontology.
Experimental models
Patient-derived DHRD iPSC-RPE IPSC DERIVED MODEL
Downstream
Sub-RPE Basal Deposit and Drusen Formation Lipid retention in the RPE is proposed to feed the lipid-rich component of drusen; the study measured intracellular lipid droplets, not drusen.
Show evidence (1 reference)
PMID:33909993 SUPPORT In Vitro
"we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export"
Patient-derived DHRD RPE shows loss of an enzyme needed for cholesterol export.
RPE Lysosomal Dysfunction
ML patient iPSC-RPE show lysosomal dysfunction with altered lysosomal gene programs and reduced TFEB transcripts, increased hexosylceramide and bis-monoacylglycerophosphate, and, after long-term culture with photoreceptor outer segments, drusen-like deposits containing ApoE, complement components and collagen IV. Restoring lysosomal function with trehalose reduced deposits, MMP2 activation and apoptosis.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Experimental models
Patient-derived DHRD iPSC-RPE IPSC DERIVED MODEL
Downstream
Sub-RPE Basal Deposit and Drusen Formation Restoring lysosomal function reduces drusen-like deposits in patient RPE.
RPE Degeneration and Atrophy Lysosomal dysfunction contributes to RPE damage and cell death in patient RPE.
Show evidence (1 reference)
PMID:42484373 SUPPORT In Vitro
"A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels."
Patient-derived RPE shows lysosomal dysfunction with reduced TFEB.
Sub-RPE Basal Deposit and Drusen Formation
Extracellular deposits form between the RPE and Bruch's membrane, first as microscopic basal deposits and later as clinically visible drusen. In patients the drusen are macular and peripapillary, often radially distributed, and coalesce into a honeycomb pattern with age; they can be present from adolescence. In knock-in mice, sub-RPE deposits appear from 4 months and grow into continuous sheets. Patient-derived RPE alone is sufficient to start drusen-like deposit formation.
Bruch's membrane UBERON:0003957 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bruch's membrane (UBERON:0003957). UBERON:0003957 is an anatomical location from the Uberon multi-species anatomy ontology. macula lutea UBERON:0000053 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in macula lutea (UBERON:0000053). UBERON:0000053 is an anatomical location from the Uberon multi-species anatomy ontology. optic disc UBERON:0001783 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in optic disc (UBERON:0001783). UBERON:0001783 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Patient-derived DHRD iPSC-RPE IPSC DERIVED MODEL Forms drusen-like deposits beneath patient RPE in culture.
Animal models
Efemp1 R345W knock-in mouse Mouse partially recapitulates Reproduces the sub-RPE basal deposits that precede drusen.
Efemp1 knockout mouse Mouse fails to recapitulate Fibulin-3 null mice do not form sub-RPE deposits.
Downstream
Macular drusen Sub-RPE deposits in the macula are seen clinically as macular drusen.
Peripapillary drusen Sub-RPE deposits around the optic disc are seen clinically as peripapillary drusen.
Drusen hyperautofluorescence Drusen show increased fundus autofluorescence.
Photoreceptor Dysfunction Over Deposits Photoreceptor structure and function are disrupted over the deposits and preserved outside them.
RPE Degeneration and Atrophy Progressive deposits are accompanied by RPE and choroidal degeneration.
Show evidence (4 references)
PMID:10369267 SUPPORT Human Clinical
"Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE)."
Defines the disease by sub-RPE drusen accumulation.
PMID:17664227 SUPPORT Model Organism
"Small, isolated sub-RPE deposits developed as early as 4 months of age in both heterozygous and homozygous knock-in mice."
The knock-in mouse forms sub-RPE deposits, including in heterozygotes.
PMID:28878022 SUPPORT In Vitro
"demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases"
Patient-derived DHRD RPE initiates drusen-like deposits without other cell types.
+ 1 more reference
Photoreceptor Dysfunction Over Deposits
Photoreceptors overlying sub-RPE deposits lose outer and inner segment integrity. Rod-mediated dark adaptation is prolonged and scotopic thresholds raised over confluent deposits, colour contrast and pattern ERG are abnormal, and symptoms can precede geographic atrophy or CNV. Perimetry in one series found dysfunction extending beyond the macula.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology. retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology.
Downstream
Reduced visual acuity
Delayed dark adaptation
Color vision defect
Abnormal pattern electroretinogram
Show evidence (3 references)
PMID:35943778 SUPPORT PRIMARY RESULT Model Organism
"RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age)"
In the Efemp1 R345W knock-in mouse, neural retina shows early loss of mitochondrial function, an early sign of retinal dysfunction over the RPE defect; this is model data only.
PMID:11913893 SUPPORT Human Clinical
"Symptomatic visual dysfunction may precede the development of clinically evident geographic atrophy or choroidal neovascularization in this disorder."
Visual dysfunction is present before late atrophic or neovascular complications.
PMID:16799055 SUPPORT Human Clinical
"The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula."
Retinal dysfunction can extend beyond the macula.
RPE Degeneration and Atrophy
RPE cells degenerate and are lost beneath and around the deposits, producing RPE atrophy, macular hyperpigmentation and, in late disease, geographic atrophy, which together with choroidal neovascularization causes progressive, irreversible central vision loss. Hyperpigmentation and RPE atrophy are more common in older patients.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
retinal pigment epithelium UBERON:0001782 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in retinal pigment epithelium, annotated with pigmented layer of retina (UBERON:0001782). UBERON:0001782 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Retinal pigment epithelial atrophy
Macular hyperpigmentation
Macular geographic atrophy
Reduced visual acuity
Metamorphopsia
Photophobia
Paracentral scotoma
Show evidence (2 references)
PMID:16799055 SUPPORT Human Clinical
"hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients"
RPE atrophy and hyperpigmentation accumulate with age in R345W carriers.
PMID:42484373 SUPPORT In Vitro
"MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis."
Patient-derived RPE shows increased apoptosis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Doyne Honeycomb Retinal Dystrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Blood 1
Subretinal hemorrhage HP:0025243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Subretinal hemorrhage (HP:0025243). HP:0025243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11292424 SUPPORT Human Clinical
"Patients with malattia leventinese may occasionally present with submacular hemorrhage."
Case report establishing submacular hemorrhage as an occasional presentation.
Eye 14
Macular drusen HP:0030499 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular drusen (HP:0030499). HP:0030499 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:16799055 SUPPORT Human Clinical
"Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation-positive group."
Radially distributed macular drusen consistently distinguish R345W carriers.
PMID:42720932 SUPPORT BACKGROUND Human Clinical
"characterized by early-onset, nearly confluent, large central retinal drusen"
Describes the early-onset confluent central drusen of canonical DHRD/ML.
PMID:22814526 SUPPORT Human Clinical
"The smallest drusen were not round, radially distributed, mostly localized temporally to the macula."
Multimodal imaging documents the radial small-drusen component.
+ 1 more reference
Peripapillary drusen HP:0011510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripapillary drusen, annotated with Drusen (HP:0011510). HP:0011510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16799055 SUPPORT Human Clinical
"The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation."
Peripapillary deposits are a strong clinical indicator of the R345W genotype.
PMID:33689237 SUPPORT Human Clinical
"On both eyes, ophthalmological findings included massive hard drusen in the macular region and nasal to the optic disc as well as macular hyperpigmentation."
A confirmed case with drusen nasal to the optic disc.
Drusen hyperautofluorescence Hyperautofluorescent retinal lesion HP:0025158 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperautofluorescent drusen, annotated with Hyperautofluorescent retinal lesion (HP:0025158). HP:0025158 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25111685 SUPPORT Human Clinical
"Increased autofluorescence corresponding to the drusen was detected in the R345W mutation patients."
Fundus autofluorescence is increased over the drusen in R345W carriers.
PMID:22814526 SUPPORT Human Clinical
"FAF revealed an intense autofluorescence of large drusen."
Large drusen are intensely autofluorescent.
Reduced visual acuity HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced central visual acuity, annotated with Reduced visual acuity (HP:0007663). HP:0007663 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33689237 SUPPORT Human Clinical
"Debut of vision loss often occurs in early to mid-adulthood, and the degree varies."
States the usual age of onset and variability of vision loss.
PMID:25111685 SUPPORT Human Clinical
"Intrafamilial patients with Malattia leventinese/Doyne honeycomb retinal dystrophy seem to be phenotypically variable in visual loss"
Visual loss varies between affected members of one family.
Delayed dark adaptation Difficulty adjusting from light to dark HP:0030513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed dark adaptation, annotated with Difficulty adjusting from light to dark (HP:0030513). HP:0030513 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11913893 SUPPORT Human Clinical
"Clinical features included reduced central vision, difficulty passing from light to dark"
Patients report difficulty adapting from light to dark.
Color vision defect HP:0000551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Color vision defect (HP:0000551). HP:0000551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11913893 SUPPORT Human Clinical
"Colour contrast thresholds were abnormal in all six patients studied"
Colour contrast sensitivity was abnormal in every patient tested.
Abnormal pattern electroretinogram HP:0030467 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pattern electroretinogram (HP:0030467). HP:0030467 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11913893 SUPPORT Human Clinical
"both pattern and focal electroretinograms were abnormal in five of six patients"
Macular electrophysiology was abnormal in five of six patients.
Metamorphopsia HP:0012508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metamorphopsia (HP:0012508). HP:0012508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33689237 SUPPORT Human Clinical
"a 57-year-old woman debuting with vision loss and metamorphopsia"
Metamorphopsia was a presenting symptom in a molecularly confirmed case.
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42306086 SUPPORT BACKGROUND Human Clinical
"Early visual symptoms include decreased visual acuity, photophobia, metamorphopsia, dyschromatopsia, and relative scotomas"
The paper's introduction lists photophobia among early symptoms.
Paracentral scotoma HP:0030528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paracentral scotoma (HP:0030528). HP:0030528 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33689237 SUPPORT BACKGROUND Human Clinical
"Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms such as decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma"
The background section names paracentral scotoma among the visual symptoms.
Retinal pigment epithelial atrophy HP:0007722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal pigment epithelial atrophy (HP:0007722). HP:0007722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16799055 SUPPORT Human Clinical
"hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients"
RPE atrophy is common in older carriers.
Macular hyperpigmentation HP:0011509 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular hyperpigmentation (HP:0011509). HP:0011509 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33689237 SUPPORT Human Clinical
"On both eyes, ophthalmological findings included massive hard drusen in the macular region and nasal to the optic disc as well as macular hyperpigmentation."
Macular hyperpigmentation was present bilaterally in a confirmed case.
Macular geographic atrophy HP:0031609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macular geographic atrophy (HP:0031609). HP:0031609 is a phenotype from the Human Phenotype Ontology.
Sequelae: Reduced visual acuity
Show evidence (1 reference)
PMID:42597498 SUPPORT BACKGROUND Human Clinical
"ADD causes progressive, irreversible loss of central visual acuity due to geographic atrophy and choroidal neovascularization (CNV)."
The introduction names geographic atrophy as a cause of central vision loss in EFEMP1 autosomal dominant drusen.
Choroidal neovascularization HP:0011506 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choroidal neovascularization (HP:0011506). HP:0011506 is a phenotype from the Human Phenotype Ontology.
Sequelae: Subretinal hemorrhage Reduced visual acuity
Show evidence (3 references)
PMID:16799055 SUPPORT Human Clinical
"Subretinal neovascular membrane (SRNVM) was a rare occurrence, affecting only 1 of 48 eyes"
CNV was rare in a large R345W series.
PMID:25111685 SUPPORT Human Clinical
"Besides the drusen, choroidal neovascularization and retinal pigment epithelium changes were noted in some patients."
CNV occurred in some members of a Chinese R345W family.
PMID:41971199 SUPPORT Human Clinical
"Patient 1 had no late-stage complications, whereas patients 2 and 3 developed macular neovascularization (MNV)."
Two of three Indian cases developed macular neovascularization.
🧬

Genetic Associations

1
EFEMP1 (Causative)
Gene: EFEMP1 hgnc:3218 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EFEMP1 (hgnc:3218). hgnc:3218 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:10369267 SUPPORT Human Clinical
"Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied."
The original gene discovery found the same EFEMP1 variant in all ML and DHRD families.
PMID:10369267 SUPPORT Human Clinical
"This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration."
The variant is absent from controls and from AMD patients.
PMID:17666404 SUPPORT Human Clinical
"Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype."
R345W on a different haplotype argues for independent recurrence and against linkage to a founder chromosome.
+ 1 more reference
Variants (1)
c.1033C>T p.(Arg345Trp) Pathogenic
Gene: EFEMP1 hgnc:3218 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in EFEMP1 (hgnc:3218). hgnc:3218 is a gene from the HUGO Gene Nomenclature Committee. missense variant
Recurrent missense variant in fibulin-3 and the only variant included in the ClinGen curation. Other EFEMP1 variants cause different phenotypes and are out of scope here.
Also known as: R345W NM_001039348.3:c.1033C>T
Show evidence (3 references)
PMID:42720932 SUPPORT BACKGROUND Human Clinical
"Doyne honeycomb retinal dystrophy or malattia leventinese (DHRD/ML) is an autosomal dominant retinal disorder caused by a single recurrent p.Arg345Trp (NM_001039348.3:c.1033C>T) variant in EFEMP1"
Gives the variant nomenclature and its single recurrent role.
CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z SUPPORT Other
"Only one missense pathogenic variant (p.Arg345Trp) is included in this curation"
ClinGen treats p.Arg345Trp as the pathogenic variant for this disease.
PMID:33689237 SUPPORT Human Clinical
"Family history revealed no other cases of similar visual impairment suggesting a de novo mutation."
An apparently de novo occurrence supports recurrent mutation at this site.
💊

Medical Actions

4
Intravitreal anti-VEGF therapy for choroidal neovascularization
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: angiogenesis inhibitor (anti-VEGF) NCIT:C1742 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses angiogenesis inhibitor (anti-VEGF), annotated with Angiogenesis Inhibitor (NCIT:C1742). NCIT:C1742 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Intravitreal anti-VEGF agents are used for secondary choroidal neovascularization. They do not treat the underlying drusen dystrophy, and responses in DHRD case reports have been variable, including no effect. The modality tag refers to the monoclonal antibody agents such as bevacizumab and ranibizumab; aflibercept is a VEGF receptor-Fc fusion protein rather than an antibody.
Mechanism Target:
INHIBITS Increased RPE VEGF Expression — Anti-VEGF agents neutralize the VEGF protein produced downstream of this node, the proposed driver of neovascularization; they do not lower VEGF expression itself.
Target Phenotypes: Choroidal neovascularization HP:0011506 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Choroidal neovascularization (HP:0011506). HP:0011506 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30541486 SUPPORT BACKGROUND Human Clinical
"To date, laser therapy and anti-VEGF therapy have been utilized for the treatment, but the treatment is still a challenge"
Anti-VEGF therapy is used in DHRD/ML, with limited success.
PMID:33689237 REFUTE Human Clinical
"Secondary choroidal neovascularizations were identified on both eyes, and anti-vascular endothelial growth factor was administered, without effect."
In this case, anti-VEGF did not control bilateral CNV, so efficacy is not assured.
Low-energy laser treatment of drusen
Action: laser therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is laser therapy (NCIT:C15466). NCIT:C15466 is a clinical intervention from the NCI Thesaurus. Ontology label: Laser Therapy NCIT:C15466
Platform: Device
Low-energy argon laser or nanosecond (2RT) laser applied to the RPE over drusen has been studied in small series. In a prospective series of 11 EFEMP1 patients, treated eyes did not show the drusen thickening seen in untreated eyes; nanosecond laser case reports describe stable or improved function without structural change. The evidence is limited to small uncontrolled series, and the approach is not established care.
Mechanism Target:
MODULATES Sub-RPE Basal Deposit and Drusen Formation — Laser to the RPE over drusen aims to clear or limit sub-RPE deposit.
Target Phenotypes: Macular drusen HP:0030499 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Macular drusen (HP:0030499). HP:0030499 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:23036572 SUPPORT Human Clinical
"An increase in mean drusen thickness was observed in the untreated eyes, but not in the treated eyes (P = .0322)."
Laser-treated eyes did not show the drusen thickening of untreated fellow eyes.
PMID:23036572 SUPPORT Human Clinical
"Low-energy laser treatment is safe and may be effective in the treatment of autosomal dominant drusen."
The authors conclude the treatment is safe and possibly effective, pending longer follow-up.
PMID:38023612 SUPPORT Human Clinical
"2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes"
A three-patient series followed for up to 30 months reports functional stabilization or improvement after nanosecond laser.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Counseling for autosomal dominant inheritance with incomplete penetrance and variable expressivity; cascade testing of relatives for the single known variant.
Show evidence (1 reference)
PMID:16799055 SUPPORT Human Clinical
"These findings are helpful for advice regarding prognosis and for genetic counseling."
The phenotype and penetrance data are presented as a basis for genetic counseling.
Allele-specific EFEMP1 antisense oligonucleotide (preclinical)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide RNase H knockdown
RNA target: EFEMP1 hgnc:3218 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of EFEMP1 (hgnc:3218). hgnc:3218 is a gene from the HUGO Gene Nomenclature Committee. EFEMP1 c.1033C>T (R345W) mRNA
Preclinical only. An allele-specific antisense oligonucleotide that degrades the EFEMP1 c.1033C>T transcript by RNase H cleared the mutant transcript in patient iPSC-RPE and, after gymnotic delivery, rescued ECM remodeling, reduced intracellular lipid and cleared extracellular deposits, even after the disease phenotype had appeared. No clinical study has been reported.
Mechanism Target:
INHIBITS Fibulin-3 R345W Misfolding and Impaired Secretion — Removes the mutant transcript, and so the mutant protein, while sparing the wild-type allele.
Show evidence (1 reference)
PMID:42306086 SUPPORT In Vitro
"We developed an allele-specific antisense oligonucleotide which specifically and effectively promoted the clearance of the EFEMP1 c.1033C>T transcript in the patient-derived disease model following assisted or gymnotic delivery."
The ASO selectively clears the mutant transcript.
Show evidence (2 references)
PMID:42306086 SUPPORT In Vitro
"Gymnotic delivery rescued remodeling of the ECM, reduced intracellular accumulation of lipids, and cleared extracellular deposits, even after the onset of the disease phenotype"
In patient-derived RPE, the ASO reverses the disease phenotype; this is cell-model evidence only.
PMID:42306086 SUPPORT In Vitro
"we designed an antisense oligonucleotide to specifically promote the downregulation of the R345W EFEMP1 transcript through RNase H-dependent degradation"
Documents the RNase H knockdown mechanism.
🔬

Diagnosis

2
Multimodal retinal imaging
Fundus examination with autofluorescence, OCT and angiography shows the radial macular and peripapillary drusen, sub-RPE hyperreflective material with RPE elevation, and complications such as CNV. Peripapillary deposits strongly suggest the R345W genotype.
eye examination NCIT:C38060 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:22814526 SUPPORT Human Clinical
"OCT showed the large round drusen as focal or diffuse deposition of hyperreflective material between the RPE and Bruch membrane within the macula"
OCT localizes the drusen between the RPE and Bruch's membrane.
PMID:16799055 SUPPORT Human Clinical
"The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation."
A clinical sign that predicts the genotype.
EFEMP1 molecular genetic testing
Diagnosis is confirmed by detecting heterozygous EFEMP1 c.1033C>T p.(Arg345Trp) by targeted testing, a retinal dystrophy gene panel or exome sequencing. Because the disease is defined by one variant, targeted testing is efficient; a restriction-digest assay for the variant has been described.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41971199 SUPPORT Human Clinical
"Genetic analysis done in patient one revealed a heterozygous, autosomal dominant, pathogenic mutation (c.1033C>T p.ARG345Trp) in the EFEMP1 gene, confirming the ML diagnosis."
Molecular testing confirmed the clinical diagnosis.
PMID:11389162 SUPPORT Human Clinical
"The HpaII restriction digest test was found to be a reliable and quick method for detecting this."
A targeted assay detects the single disease variant.
📊

Prevalence

1
Worldwide
Unknown Rare
Described as rare; no numeric prevalence estimate was found, and Orphanet records its point-prevalence class as unknown.
Show evidence (2 references)
PMID:30541486 SUPPORT Human Clinical
"DHRD/ML is a rare disease associated with EFEMP1 gene mutation."
States that the disease is rare without giving a figure.
ORPHA:75376 SUPPORT Other
"Unknown | Worldwide | Point prevalence | ORPHANET"
Orphanet records the worldwide point-prevalence class as unknown for its broader autosomal dominant drusen concept.
🧫

Experimental Models

1
Patient-derived DHRD iPSC-RPE IPSC_DERIVED_MODEL
Patient iPSC-RPE reproduces drusen-like sub-RPE deposits containing ApoE and collagen IV, ECM remodeling, lipid accumulation with reduced CES1 and cholesterol efflux, ER stress, lysosomal dysfunction, apoptosis and upregulated complement genes. It has been used to test trehalose and an allele-specific ASO.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
RPE differentiated from induced pluripotent stem cells of patients carrying EFEMP1 R345W, compared with unaffected, isogenic gene-corrected or EFEMP1 knockout controls
Publication
PMID:42306086
Pathograph links
Sub-RPE Basal Deposit and Drusen Formation partially recapitulates fidelity: moderate observes: cellular Forms drusen-like deposits beneath patient RPE in culture.
Limitations: Cultured RPE lacks the choroid, the full layers of Bruch's membrane, photoreceptors and systemic factors, so deposits are drusen-like rather than clinical drusen.
Show evidence (1 reference)
PMID:42306086 SUPPORT In Vitro
"In the patient-derived disease model, remodeling of the extracellular matrix (ECM) occurred with progressive accumulation of the drusen-associated proteins apolipoprotein E and collagen IV, in addition to the intracellular accumulation and extracellular deposition of lipids."
Patient RPE accumulates drusen-associated proteins and lipids.
Impaired RPE Cholesterol Efflux recapitulates fidelity: moderate observes: cellular
Show evidence (1 reference)
PMID:33909993 SUPPORT In Vitro
"we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export"
The cholesterol efflux defect was found in DHRD iPSC-RPE.
RPE Lysosomal Dysfunction recapitulates fidelity: moderate observes: cellular
Show evidence (1 reference)
PMID:42484373 SUPPORT In Vitro
"A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels."
The lysosomal defect was found in ML iPSC-RPE.
Show evidence (1 reference)
PMID:42306086 SUPPORT In Vitro
"We reprogrammed patient-derived renal epithelial cells to induced pluripotent stem cells, followed by directed differentiation to retinal pigment epithelium and compared the phenotype to gene-corrected and EFEMP1 knockout patient-derived retinal pigment epithelium."
Describes the patient-derived model with isogenic and knockout controls.
🐁

Animal Models

2
Efemp1 R345W knock-in mouse
Two independently generated knock-in lines carry the disease mutation in murine Efemp1. Heterozygous and homozygous mice develop sub-RPE basal (laminar) deposits from about 4 months that grow into continuous sheets, with fibulin-3 and TIMP3 in the deposits, abnormal Bruch's membrane ECM, local complement activation, Nlrp3 upregulation and, in older mice, RPE and choroidal degeneration. Mice have no macula, the deposits are microscopic rather than clinical drusen, and detectable retinal degeneration is not reproduced. The model has been used to show that removal or inhibition of C3, factor B, Nlrp3/caspase-1 and GSK3 reduces deposits.
Species
Mouse
Genotype
Efemp1 p.R345W knock-in (heterozygous and homozygous)
Publication
PMID:17664227
Pathograph links
Sub-RPE Basal Deposit and Drusen Formation partially recapitulates fidelity: moderate observes: tissue Reproduces the sub-RPE basal deposits that precede drusen.
Limitations: Mice lack a macula and form microscopic basal laminar deposits rather than clinically visible honeycomb drusen; detectable retinal degeneration and vision loss are not reproduced.
Show evidence (2 references)
PMID:17666404 SUPPORT Model Organism
"The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD."
The knock-in reproduces sub-RPE basal deposits.
+ 1 more reference
Alternative Complement Activation recapitulates fidelity: moderate observes: tissue Shows complement activation in RPE and Bruch's membrane and its requirement for deposits.
Show evidence (1 reference)
PMID:23943789 SUPPORT Model Organism
"Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits."
Genetic crosses in the model test the complement step.
NLRP3 Inflammasome Activation recapitulates fidelity: unknown observes: cellular Shows inflammasome upregulation and its contribution to deposits; human relevance is untested.
Show evidence (1 reference)
PMID:41198612 SUPPORT Model Organism
"Genetic elimination of either Nlrp3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+ background"
Genetic crosses in the model test the inflammasome step.
Abnormal Bruch's Membrane Extracellular Matrix recapitulates fidelity: moderate observes: tissue Shows proteoglycan accumulation, MMP/TIMP imbalance and reduced diffusion across Bruch's membrane.
Show evidence (1 reference)
PMID:28622396 SUPPORT Model Organism
"HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired."
The model shows the Bruch's membrane matrix changes.
Show evidence (2 references)
PMID:17664227 SUPPORT Model Organism
"Thus, the Efemp1 knock-in mice reconstitute the most important histopathologic symptoms of both ML and AMD."
The knock-in reproduces the core histopathology.
PMID:39114980 SUPPORT Model Organism
"treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size"
The model is used for preclinical testing; GSK3 inhibition reduced deposits.
Efemp1 knockout mouse
Loss of fibulin-3 causes early ageing features, reduced fascial elastic fibres and hernias, but no macular degeneration phenotype, and the mice resist sub-RPE deposit formation under stressors that induce deposits in wild-type mice. This negative result argues that DHRD is not caused by loss of fibulin-3 function.
Species
Mouse
Genotype
Efemp1-/-
Publication
PMID:17872905
Pathograph links
Sub-RPE Basal Deposit and Drusen Formation fails to recapitulate fidelity: low observes: tissue Fibulin-3 null mice do not form sub-RPE deposits.
Limitations: A null allele does not model the dominant R345W toxic gain of function; the model is informative only as evidence against a loss-of-function mechanism.
Show evidence (1 reference)
PMID:28264101 SUPPORT Model Organism
"Mice lacking fibulin-3 do not develop sub-RPE deposits."
The knockout fails to form deposits, even under stressors that induce them in wild-type mice.
Show evidence (1 reference)
PMID:17872905 SUPPORT Model Organism
"No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration."
Null mice lack the retinal disease.
{ }

Source YAML

click to show 
name: Doyne Honeycomb Retinal Dystrophy
creation_date: "2026-10-14T20:49:40Z"
category: Mendelian
description: >-
  Doyne honeycomb retinal dystrophy (DHRD), also called malattia leventinese
  (ML), is an autosomal dominant macular dystrophy caused by a single recurrent
  missense variant in EFEMP1, c.1033C>T p.(Arg345Trp), which encodes the
  secreted extracellular matrix glycoprotein fibulin-3. Yellow-white drusen
  accumulate beneath the retinal pigment epithelium (RPE), in Bruch's membrane,
  in the macula and around the optic disc, often in a radial pattern, and
  coalesce with age into a honeycomb-like pattern. Drusen can be present from
  adolescence, while visual symptoms (reduced central vision, delayed dark
  adaptation, metamorphopsia, photophobia, paracentral scotoma) usually begin
  in early to mid adulthood. RPE atrophy, macular hyperpigmentation, geographic
  atrophy and, less often, choroidal neovascularization drive late central
  vision loss. The mutant protein misfolds, is secreted inefficiently and is
  retained in the RPE, causing endoplasmic reticulum stress, an abnormal Bruch's
  membrane extracellular matrix and local alternative complement activation that
  together drive sub-RPE deposit formation; R345W behaves as a toxic gain of
  function rather than haploinsufficiency. Expressivity is highly variable and
  nonpenetrance has been reported. There is no approved disease-modifying
  therapy. Because it reproduces the drusen biology of age-related macular
  degeneration (AMD) from a single genetic lesion, DHRD is used as a monogenic
  model of AMD.
disease_term:
  preferred_term: Doyne honeycomb retinal dystrophy
  term:
    id: MONDO:0007471
    label: Doyne honeycomb retinal dystrophy
synonyms:
- Malattia leventinese
- DHRD
- Doyne honeycomb degeneration of retina
- dominant drusen
- dominant radial drusen
- autosomal dominant drusen
- EFEMP1 retinal dystrophy
parents:
- Ophthalmological Disease
- Macular Dystrophy
- Inherited retinal dystrophy
- Retinal drusen
notes: >-
  Scope. MONDO:0007471 names the EFEMP1-caused disease, and this entry follows
  it. Orphanet ORPHA:75376 "Autosomal dominant drusen", mapped Exact to this
  MONDO term, also lists CFH and CFI as disease-causing genes, and a UK/US
  series found EFEMP1 R345W in only seven of ten dominant drusen families
  (PMID:11389162), so the clinical label "dominant drusen" is broader than this
  entry; dominant drusen families without EFEMP1 R345W are out of scope here.
  Other EFEMP1 phenotypes are separate diseases and are not lumped in: EFEMP1
  juvenile-onset open-angle glaucoma (PMID:34923728), and an adult-onset
  peripheral chorioretinal degeneration with severe rod dysfunction associated
  with p.Arg140Trp (PMID:42720932), which differs from canonical DHRD in
  topography.
  No GeneReviews chapter names this disease (committed Bookshelf index and a
  PubMed genereviews[book] search for EFEMP1, drusen, leventinese and Doyne
  returned none). Orphanet records the point-prevalence class as unknown, and no
  population prevalence estimate was found.
pathophysiology:
- name: Fibulin-3 R345W Misfolding and Impaired Secretion
  description: >-
    The heterozygous EFEMP1 p.Arg345Trp substitution causes fibulin-3 to
    misfold, in part through reduced native disulfide bonding in the domain
    carrying residue 345. Wild-type fibulin-3 is secreted, whereas the mutant is
    secreted inefficiently and retained within RPE cells. Loss of fibulin-3 does
    not reproduce the disease in mice, and Efemp1 knockout protects against
    sub-RPE deposits, so the variant acts as a toxic gain of function rather
    than through haploinsufficiency. Fibulin-3 is an extracellular matrix
    protein (its GO molecular function annotation is extracellular matrix
    structural constituent); that function is bound here as abnormal rather
    than decreased, because the mutant protein is retained and deposited
    abnormally rather than simply lost.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: EFEMP1
    term:
      id: hgnc:3218
      label: EFEMP1
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    functional_impact_category: GAIN_OF_FUNCTION
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  molecular_functions:
  - preferred_term: fibulin-3 extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  - preferred_term: fibulin-3 secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:12242346
    reference_title: "Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that wild-type EFEMP1 is a secreted protein whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells."
    explanation: Direct comparison of wild-type and R345W EFEMP1 shows misfolding, inefficient secretion and intracellular retention of the mutant.
  - reference: PMID:22031286
    reference_title: "Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These secretion defects appear to be caused, in part, by reduced native disulfide bonding in domain 6 harboring the 345 position."
    explanation: A cell-based secretion assay attributes the R345W secretion defect partly to impaired disulfide bonding in the domain carrying residue 345.
  - reference: PMID:42306086
    reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data support an EFEMP1 Arg345Trp toxic gain of function and the absence of haploinsufficiency in DHRD."
    explanation: Patient iPSC-RPE work, set beside the knockout data it cites, supports a toxic gain-of-function mechanism for R345W.
  - reference: PMID:17872905
    reference_title: "Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration."
    explanation: Efemp1 null mice lack the retinal phenotype, arguing against loss of function as the disease mechanism.
  downstream:
  - target: RPE Endoplasmic Reticulum Stress
    causal_link_type: DIRECT
    description: Retention of misfolded fibulin-3 in the ER activates the unfolded protein response in RPE cells.
    evidence:
    - reference: PMID:16249470
      reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "R345W was poorly secreted by ARPE-19 cells and accumulated in the ER, leading to UPR activation and increased VEGF expression."
      explanation: In RPE-derived cells the poorly secreted R345W protein accumulates in the ER and activates the UPR.
  - target: Abnormal Bruch's Membrane Extracellular Matrix
    causal_link_type: DIRECT
    description: Mutant fibulin-3 accumulates beneath the RPE and alters the composition and turnover of the RPE basal lamina and Bruch's membrane.
    evidence:
    - reference: PMID:12242346
      reference_title: "Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "However, in ML eyes, EFEMP1 accumulates within the RPE cells and between the RPE and drusen, but does not appear to be a major component of drusen."
      explanation: Human ML eyes show the mutant protein accumulating within and beneath the RPE, at the RPE-drusen interface.
    - reference: PMID:26199322
      reference_title: "A local complement response by RPE causes early-stage macular degeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a."
      explanation: Primary Efemp1 R345W RPE cells generate an abnormal ECM with reduced turnover.
  - target: Impaired RPE Cholesterol Efflux
    causal_link_type: DIRECT
    description: Expression of EFEMP1 R345W attenuates RPE cholesterol efflux.
    evidence:
    - reference: PMID:33909993
      reference_title: "Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "attenuated cholesterol efflux and led to lipid droplet accumulation"
      explanation: In iPSC-derived RPE, overexpression of EFEMP1 R345W (like CES1 knockdown) attenuated cholesterol efflux and caused lipid droplet accumulation.
  - target: RPE Lysosomal Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Patient-derived ML iPSC-RPE carrying the mutation show lysosomal
      dysfunction; how mutant fibulin-3 produces it is not established.
    evidence:
    - reference: PMID:42484373
      reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels."
      explanation: Lysosomal dysfunction is a feature of RPE derived from a patient with the EFEMP1 mutation.
  - target: NLRP3 Inflammasome Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      R345W knock-in mice show retinal Nlrp3 upregulation and inflammasome
      component transcription in RPE/choroid; the intermediate steps from the
      mutant protein are not defined.
    evidence:
    - reference: PMID:41198612
      reference_title: "Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "R345W+/+ knockin mice demonstrated increased Muller cell gliosis, subretinal Iba-1+ cells, higher Nlrp3 immunoreactivity in the retina"
      explanation: The knock-in model shows increased Nlrp3 in the retina compared with controls.
- name: RPE Endoplasmic Reticulum Stress
  description: >-
    Intracellular retention of misfolded R345W fibulin-3 induces endoplasmic
    reticulum stress and the unfolded protein response in the RPE, observed in
    RPE cell lines, in knock-in mouse eyecups and in patient-derived iPSC-RPE,
    where it accompanies fibulin-3 and ApoE aggregation and increased apoptosis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:16249470
    reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "R345W was poorly secreted by ARPE-19 cells and accumulated in the ER, leading to UPR activation and increased VEGF expression."
    explanation: Overexpressed R345W fibulin-3 activates the UPR in ARPE-19 cells.
  - reference: PMID:35943778
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response"
    explanation: Efemp1 R345W knock-in eyecups show an increased unfolded protein response signature.
  - reference: PMID:42484373
    reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis."
    explanation: Patient-derived RPE shows increased ER stress alongside fibulin-3 aggregation.
  downstream:
  - target: Increased RPE VEGF Expression
    causal_link_type: DIRECT
    description: ER stress induced by mutant fibulin-3 increases VEGF transcription in RPE cells.
    evidence:
    - reference: PMID:16249470
      reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Compared with Wt mutant proteins, the expression of R345W was more effective at causing UPR activation, increasing VEGF expression, and stimulating transcription from the VEGF promoter."
      explanation: R345W expression couples UPR activation to increased VEGF expression and VEGF promoter activity.
  - target: RPE Degeneration and Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic ER stress is proposed to cause RPE dysfunction and apoptosis.
    evidence:
    - reference: PMID:16249470
      reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of mutant fibulin proteins may contribute to macular degeneration and choroidal neovascularization by causing ER stress leading to RPE dysfunction and increased VEGF expression."
      explanation: The authors propose ER stress as the route from mutant fibulin-3 to RPE dysfunction; this is an inference from cell culture.
- name: Increased RPE VEGF Expression
  description: >-
    Mutant fibulin-3 induced ER stress increases vascular endothelial growth
    factor expression in RPE cells, a proposed link to the choroidal
    neovascularization seen in a minority of patients. The link is supported by
    cell culture only.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: vascular endothelial growth factor production
    term:
      id: GO:0010573
      label: vascular endothelial growth factor production
    modifier: INCREASED
  evidence:
  - reference: PMID:16249470
    reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings demonstrated that the expression of mutated fibulin-3 caused UPR activation and increased VEGF expression."
    explanation: Mutant fibulin-3 expression increases VEGF expression in RPE-derived cells.
  downstream:
  - target: Choroidal neovascularization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Increased RPE VEGF is proposed to contribute to choroidal neovascularization.
    evidence:
    - reference: PMID:16249470
      reference_title: "Aberrant accumulation of fibulin-3 in the endoplasmic reticulum leads to activation of the unfolded protein response and VEGF expression."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of mutant fibulin proteins may contribute to macular degeneration and choroidal neovascularization by causing ER stress leading to RPE dysfunction and increased VEGF expression."
      explanation: The authors propose the VEGF increase as a contributor to CNV; this is a hypothesis drawn from cell culture.
- name: Abnormal Bruch's Membrane Extracellular Matrix
  description: >-
    Mutant fibulin-3 alters the extracellular matrix of the RPE basal lamina and
    Bruch's membrane. In knock-in mice the basal deposits are made of normal ECM
    components in abnormal amounts and contain fibulin-3 and its binding partner
    TIMP3; proteoglycans accumulate in Bruch's membrane and diffusion across it
    is impaired. ECM turnover is altered, but the reported direction of the
    MMP-2 change depends on the system: knock-in Bruch's membrane shows reduced
    MMP-2 and MMP-9 with increased TIMP-3, whereas engineered and patient-derived
    RPE cultures report increased MMP-2 activity or activation.
  biological_scale: TISSUE
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: basement membrane
    term:
      id: GO:0005604
      label: basement membrane
  evidence:
  - reference: PMID:23943789
    reference_title: "Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1(R345W/R345W) mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts."
    explanation: Proteomics of knock-in Bruch's membrane shows an abnormal ECM composition.
  - reference: PMID:17666404
    reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein."
    explanation: Mutant fibulin-3 and TIMP3 are incorporated into the sub-RPE matrix deposits.
  - reference: PMID:28622396
    reference_title: "Mutant Fibulin-3 Causes Proteoglycan Accumulation and Impaired Diffusion Across Bruch's Membrane."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired."
    explanation: Knock-in Bruch's membrane accumulates proteoglycans, shifts the MMP/TIMP balance and loses diffusional permeability.
  - reference: PMID:29095988
    reference_title: "Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This process is exacerbated by impaired ECM turnover via increased matrix metalloproteinase-2 activity."
    explanation: In matrix made by CRISPR-edited R345W ARPE-19 cells, ECM turnover is impaired, here with increased MMP-2 activity, opposite in direction to the knock-in mouse data.
  - reference: PMID:42569289
    reference_title: "Interactions Between Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 and Tissue Inhibitor of Metalloproteinases-3 and Relevance to Age-Related Macular Degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In Doyne Honeycomb Retinal Dystrophy, the EFEMP1 R345W mutation causes rapid disease progression through impaired protein secretion, abnormal matrix accumulation, and complement dysregulation."
    explanation: A 2026 review summarizes impaired secretion, abnormal matrix accumulation and complement dysregulation as the disease mechanism.
  downstream:
  - target: Alternative Complement Activation
    causal_link_type: DIRECT
    description: The abnormal ECM binds and activates complement C3 locally at the RPE-Bruch's membrane interface.
    evidence:
    - reference: PMID:29095988
      reference_title: "Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The abnormal ECM binds active complement C3 and causes the formation of basal deposits by normal human fetal (hf)RPE cells."
      explanation: Matrix made by R345W cells binds active C3, directly linking the abnormal ECM to complement activation.
    - reference: PMID:17666404
      reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Further, they suggest that alterations in the ECM may stimulate complement activation"
      explanation: Complement activation in knock-in RPE and Bruch's membrane is attributed to ECM alteration.
  - target: Sub-RPE Basal Deposit and Drusen Formation
    causal_link_type: DIRECT
    description: Excess and abnormal matrix material forms the basal deposits that precede drusen.
    evidence:
    - reference: PMID:23943789
      reference_title: "Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts"
      explanation: The basal deposits themselves consist of the excess ECM components.
- name: Alternative Complement Activation
  description: >-
    The abnormal ECM triggers local complement activation by the RPE, with C3
    cleavage and increased alternative pathway activity (iC3b and Ba). Genetic
    removal of C3, or deletion or inhibition of complement factor B, reduces
    basal deposits in the knock-in mouse, whereas removal of C5 does not, which
    places the effect at C3 rather than at the terminal pathway. In the knock-in
    mouse the effect is sex-dependent: females have more deposits and show the
    complement elevation and the response to factor B inhibition, males do not.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:35943778
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05)."
    explanation: Alternative pathway breakdown products are elevated in knock-in eyes.
  - reference: PMID:17666404
    reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice."
    explanation: Complement activation is localized to the RPE and Bruch's membrane in the knock-in mice.
  - reference: PMID:28878022
    reference_title: "Drusen in patient-derived hiPSC-RPE models of macular dystrophies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD)."
    explanation: Patient-derived DHRD RPE upregulates complement genes, supporting an RPE-intrinsic complement response in human cells.
  - reference: PMID:34001980
    reference_title: "Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits."
    explanation: C5 removal does not prevent deposits, narrowing the relevant complement step to C3 activation rather than the terminal pathway.
  - reference: PMID:35943778
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, male Efemp1ki/ki mice had fewer sub-RPE deposits than age-matched females, no elevation of ocular complement activation and no effect of FB inhibition on sub-RPE deposits."
    explanation: Records the sex dependence of the complement effect in the knock-in model.
  downstream:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    causal_link_type: DIRECT
    description: Complement activation is required for basal deposit formation in the knock-in mouse.
    evidence:
    - reference: PMID:23943789
      reference_title: "Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits."
      explanation: Removing C3 prevents basal deposits, establishing complement as necessary for this step.
    - reference: PMID:35943778
      reference_title: "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."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029)"
      explanation: Pharmacologic factor B inhibition reduces sub-RPE deposits in female knock-in mice.
    - reference: PMID:26199322
      reference_title: "A local complement response by RPE causes early-stage macular degeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a)."
      explanation: In primary mutant RPE cultures, deposit formation is mediated by C3a.
- name: NLRP3 Inflammasome Activation
  description: >-
    R345W knock-in mice show retinal gliosis, subretinal Iba-1 positive cells,
    increased retinal Nlrp3 and transcriptional upregulation of C3, Nlrp3,
    pro-Il1b and pro-caspase-1 in RPE/choroid. Genetic removal of Nlrp3 or
    caspase-1 reduces basal laminar deposits, so inflammasome signalling
    contributes to deposit formation in this model. It has not been examined in
    patient tissue.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  evidence:
  - reference: PMID:41198612
    reference_title: "Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "R345W+/+ knockin mice demonstrated increased Muller cell gliosis, subretinal Iba-1+ cells, higher Nlrp3 immunoreactivity in the retina"
    explanation: Inflammasome and innate immune activation accompany the knock-in phenotype.
  downstream:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    causal_link_type: DIRECT
    description: Inflammasome signalling contributes to basal laminar deposit formation.
    evidence:
    - reference: PMID:41198612
      reference_title: "Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genetic elimination of either Nlrp3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+ background"
      explanation: Removing Nlrp3 or caspase-1 reduces deposits, showing that the inflammasome contributes to their formation.
- name: Impaired RPE Cholesterol Efflux
  description: >-
    Proteomics of DHRD iPSC-RPE against isogenic controls found downregulation
    of carboxylesterase 1 (CES1), which converts cholesteryl ester to free
    cholesterol for export. CES1 knockdown or EFEMP1 R345W overexpression
    attenuates cholesterol efflux and causes intracellular lipid droplet
    accumulation; R345W fibulin-3 also has a stronger inhibitory effect on EGFR
    signalling than wild type, which may suppress CES1 through reduced SP1.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  biological_processes:
  - preferred_term: cholesterol efflux
    term:
      id: GO:0033344
      label: cholesterol efflux
    modifier: DECREASED
  chemical_entities:
  - preferred_term: cholesteryl ester
    term:
      id: CHEBI:17002
      label: cholesteryl ester
  evidence:
  - reference: PMID:33909993
    reference_title: "Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export"
    explanation: Patient-derived DHRD RPE shows loss of an enzyme needed for cholesterol export.
  downstream:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lipid retention in the RPE is proposed to feed the lipid-rich component of
      drusen; the study measured intracellular lipid droplets, not drusen.
    evidence:
    - reference: PMID:33909993
      reference_title: "Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD)"
      explanation: The authors frame the lipid handling defect as the basis of the lipid-rich drusen of DHRD; the link to drusen is inferred rather than measured.
- name: RPE Lysosomal Dysfunction
  description: >-
    ML patient iPSC-RPE show lysosomal dysfunction with altered lysosomal gene
    programs and reduced TFEB transcripts, increased hexosylceramide and
    bis-monoacylglycerophosphate, and, after long-term culture with
    photoreceptor outer segments, drusen-like deposits containing ApoE,
    complement components and collagen IV. Restoring lysosomal function with
    trehalose reduced deposits, MMP2 activation and apoptosis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  evidence:
  - reference: PMID:42484373
    reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels."
    explanation: Patient-derived RPE shows lysosomal dysfunction with reduced TFEB.
  downstream:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    causal_link_type: DIRECT
    description: Restoring lysosomal function reduces drusen-like deposits in patient RPE.
    evidence:
    - reference: PMID:42484373
      reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Treatment with trehalose, a lysosome-modulating compound, increased lysosomal content and function, reducing drusen-like deposit formation, inhibiting MMP2 activation, and suppressing apoptosis."
      explanation: Rescue of lysosomal function lowers deposit formation, supporting lysosomal dysfunction as a contributor.
  - target: RPE Degeneration and Atrophy
    causal_link_type: DIRECT
    description: Lysosomal dysfunction contributes to RPE damage and cell death in patient RPE.
    evidence:
    - reference: PMID:42484373
      reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This study highlighted lysosomal dysfunction as a contributor to RPE damage, drusen-like deposit accumulation, and extracellular matrix degradation."
      explanation: The authors identify lysosomal dysfunction as a contributor to RPE damage.
- name: Sub-RPE Basal Deposit and Drusen Formation
  description: >-
    Extracellular deposits form between the RPE and Bruch's membrane, first as
    microscopic basal deposits and later as clinically visible drusen. In
    patients the drusen are macular and peripapillary, often radially
    distributed, and coalesce into a honeycomb pattern with age; they can be
    present from adolescence. In knock-in mice, sub-RPE deposits appear from 4
    months and grow into continuous sheets. Patient-derived RPE alone is
    sufficient to start drusen-like deposit formation.
  biological_scale: TISSUE
  locations:
  - preferred_term: Bruch's membrane
    term:
      id: UBERON:0003957
      label: Bruch's membrane
  - preferred_term: macula lutea
    term:
      id: UBERON:0000053
      label: macula lutea
  - preferred_term: optic disc
    term:
      id: UBERON:0001783
      label: optic disc
  evidence:
  - reference: PMID:10369267
    reference_title: "A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium (RPE)."
    explanation: Defines the disease by sub-RPE drusen accumulation.
  - reference: PMID:17664227
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Small, isolated sub-RPE deposits developed as early as 4 months of age in both heterozygous and homozygous knock-in mice."
    explanation: The knock-in mouse forms sub-RPE deposits, including in heterozygotes.
  - reference: PMID:28878022
    reference_title: "Drusen in patient-derived hiPSC-RPE models of macular dystrophies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases"
    explanation: Patient-derived DHRD RPE initiates drusen-like deposits without other cell types.
  - reference: PMID:26427406
    reference_title: "Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy: Similarities to Age-Related Macular Degeneration and Potential Therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The most prominent feature of ML/DHRD is the development of radial or honeycomb patterns of drusen which can develop as early as adolescence."
    explanation: A review summarizes the radial or honeycomb drusen pattern and its early onset.
  downstream:
  - target: Macular drusen
    causal_link_type: DIRECT
    description: Sub-RPE deposits in the macula are seen clinically as macular drusen.
  - target: Peripapillary drusen
    causal_link_type: DIRECT
    description: Sub-RPE deposits around the optic disc are seen clinically as peripapillary drusen.
  - target: Drusen hyperautofluorescence
    causal_link_type: DIRECT
    description: Drusen show increased fundus autofluorescence.
  - target: Photoreceptor Dysfunction Over Deposits
    causal_link_type: DIRECT
    description: >-
      Photoreceptor structure and function are disrupted over the deposits and
      preserved outside them.
    evidence:
    - reference: PMID:18791549
      reference_title: "Retinal microstructure in patients with EFEMP1 retinal dystrophy evaluated by Fourier domain OCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fd-OCT revealed extensive or focal sub-retinal pigment epithelium (RPE) deposits, separation of RPE and Bruch's membrane, and disruption of the photoreceptor outer and inner segment layers. No outer retinal changes were visible outside areas with sub-RPE deposits."
      explanation: Photoreceptor disruption is confined to areas overlying sub-RPE deposits.
    - reference: PMID:22814526
      reference_title: "Multimodal morphological and functional characterization of Malattia Leventinese."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Functional impairment correlated topographically to sub-RPE deposition of drusenoid material."
      explanation: Retinal function loss maps onto the deposits.
    - reference: PMID:23036572
      reference_title: "Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The thickness of the drusen correlated with retinal sensitivity"
      explanation: Drusen thickness tracks loss of retinal sensitivity.
  - target: RPE Degeneration and Atrophy
    causal_link_type: DIRECT
    description: Progressive deposits are accompanied by RPE and choroidal degeneration.
    evidence:
    - reference: PMID:17664227
      reference_title: "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."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "was accompanied by general RPE and choroidal abnormalities including degeneration, vacuolation, loss or disruption of the RPE basal infoldings, choroidal atrophy"
      explanation: In older knock-in mice, accumulating deposits are accompanied by RPE degeneration.
    - reference: PMID:12242346
      reference_title: "Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data present evidence that misfolding and aberrant accumulation of EFEMP1 may cause drusen formation and cellular degeneration"
      explanation: The authors link aberrant EFEMP1 accumulation and drusen to cellular degeneration.
- name: Photoreceptor Dysfunction Over Deposits
  description: >-
    Photoreceptors overlying sub-RPE deposits lose outer and inner segment
    integrity. Rod-mediated dark adaptation is prolonged and scotopic thresholds
    raised over confluent deposits, colour contrast and pattern ERG are
    abnormal, and symptoms can precede geographic atrophy or CNV. Perimetry in
    one series found dysfunction extending beyond the macula.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:35943778
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "RNA-seq analysis of the posterior eyecups revealed increased unfolded protein response, decreased mitochondrial function in the neural retina (by 3 months of age)"
    explanation: In the Efemp1 R345W knock-in mouse, neural retina shows early loss of mitochondrial function, an early sign of retinal dysfunction over the RPE defect; this is model data only.
  - reference: PMID:11913893
    reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic visual dysfunction may precede the development of clinically evident geographic atrophy or choroidal neovascularization in this disorder."
    explanation: Visual dysfunction is present before late atrophic or neovascular complications.
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula."
    explanation: Retinal dysfunction can extend beyond the macula.
  downstream:
  - target: Reduced visual acuity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11913893
      reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinical features included reduced central vision, difficulty passing from light to dark, and diffuse submacular and peripapillary deposits"
      explanation: Reduced central vision accompanies the submacular deposits.
  - target: Delayed dark adaptation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11913893
      reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Scotopic thresholds were elevated and rod-mediated dark adaptation kinetics were markedly prolonged in all six patients when measured over the central visible confluent deposits."
      explanation: Dark adaptation is prolonged specifically over the deposits.
  - target: Color vision defect
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11913893
      reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Colour contrast thresholds were abnormal in all six patients studied"
      explanation: Colour contrast loss is part of the macular dysfunction in patients without atrophy or CNV.
  - target: Abnormal pattern electroretinogram
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11913893
      reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "both pattern and focal electroretinograms were abnormal in five of six patients"
      explanation: Macular electrophysiology is abnormal in patients without atrophy or CNV.
- name: RPE Degeneration and Atrophy
  description: >-
    RPE cells degenerate and are lost beneath and around the deposits, producing
    RPE atrophy, macular hyperpigmentation and, in late disease, geographic
    atrophy, which together with choroidal neovascularization causes
    progressive, irreversible central vision loss. Hyperpigmentation and RPE
    atrophy are more common in older patients.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  locations:
  - preferred_term: retinal pigment epithelium
    term:
      id: UBERON:0001782
      label: pigmented layer of retina
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients"
    explanation: RPE atrophy and hyperpigmentation accumulate with age in R345W carriers.
  - reference: PMID:42484373
    reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis."
    explanation: Patient-derived RPE shows increased apoptosis.
  downstream:
  - target: Retinal pigment epithelial atrophy
    causal_link_type: DIRECT
  - target: Macular hyperpigmentation
    causal_link_type: DIRECT
  - target: Macular geographic atrophy
    causal_link_type: DIRECT
  - target: Reduced visual acuity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42306086
      reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Early visual symptoms include decreased visual acuity, photophobia, metamorphopsia, dyschromatopsia, and relative scotomas that progress to the atrophy of the RPE leading to central visual loss."
      explanation: The paper's introduction places RPE atrophy as the step leading to central vision loss.
  - target: Metamorphopsia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33689237
      reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms such as decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma"
      explanation: The background section attributes metamorphopsia to drusen, atrophy and hyperpigmentation together.
  - target: Photophobia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33689237
      reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms such as decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma"
      explanation: The background section attributes photophobia to drusen, atrophy and hyperpigmentation together; its retinal basis in patients is not established.
  - target: Paracentral scotoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33689237
      reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms such as decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma"
      explanation: The background section attributes paracentral scotoma to drusen, atrophy and hyperpigmentation together.
phenotypes:
- name: Macular drusen
  category: Ophthalmological
  diagnostic: true
  description: >-
    Yellow-white sub-RPE drusen in the macula, often radially distributed, that
    become confluent with age in a honeycomb-like pattern; large round drusen
    sit in the perimacular area and smaller radial drusen temporal to the macula.
  phenotype_term:
    preferred_term: Macular drusen
    term:
      id: HP:0030499
      label: Macular drusen
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation-positive group."
    explanation: Radially distributed macular drusen consistently distinguish R345W carriers.
  - reference: PMID:42720932
    reference_title: "Widening the Spectrum of Disease Expression due to Heterozygous Variants in EFEMP1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "characterized by early-onset, nearly confluent, large central retinal drusen"
    explanation: Describes the early-onset confluent central drusen of canonical DHRD/ML.
  - reference: PMID:22814526
    reference_title: "Multimodal morphological and functional characterization of Malattia Leventinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The smallest drusen were not round, radially distributed, mostly localized temporally to the macula."
    explanation: Multimodal imaging documents the radial small-drusen component.
  - reference: PMID:41971199
    reference_title: "Early-onset drusen in Malattia Leventinese with EFEMP1 mutation differ from drusen in age-related macular degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All cases exhibited early-onset central vision loss and small, radially distributed drusen, consistent with ML/DHRD."
    explanation: Radial drusen were present in every case of an Indian series.
- name: Peripapillary drusen
  category: Ophthalmological
  diagnostic: true
  description: >-
    Drusen around the optic disc, especially nasal to it, are a consistent,
    distinguishing sign; their presence makes carriage of R345W highly likely.
    These are sub-RPE drusen around the disc, not optic nerve head drusen, so
    HP:0012426 Optic disc drusen does not apply and HP:0011510 Drusen is bound.
  phenotype_term:
    preferred_term: Peripapillary drusen
    term:
      id: HP:0011510
      label: Drusen
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation."
    explanation: Peripapillary deposits are a strong clinical indicator of the R345W genotype.
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On both eyes, ophthalmological findings included massive hard drusen in the macular region and nasal to the optic disc as well as macular hyperpigmentation."
    explanation: A confirmed case with drusen nasal to the optic disc.
- name: Drusen hyperautofluorescence
  category: Ophthalmological
  description: Drusen show increased fundus autofluorescence, most intense in large drusen.
  phenotype_term:
    preferred_term: Hyperautofluorescent drusen
    term:
      id: HP:0025158
      label: Hyperautofluorescent retinal lesion
  evidence:
  - reference: PMID:25111685
    reference_title: "Malattia leventinese/Doyne honeycomb retinal dystrophy in a chinese family with mutation of the EFEMP1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Increased autofluorescence corresponding to the drusen was detected in the R345W mutation patients."
    explanation: Fundus autofluorescence is increased over the drusen in R345W carriers.
  - reference: PMID:22814526
    reference_title: "Multimodal morphological and functional characterization of Malattia Leventinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FAF revealed an intense autofluorescence of large drusen."
    explanation: Large drusen are intensely autofluorescent.
- name: Reduced visual acuity
  category: Ophthalmological
  description: >-
    Reduced central visual acuity, with onset of vision loss usually in early to
    mid adulthood and highly variable severity, including within families.
  phenotype_term:
    preferred_term: Reduced central visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Debut of vision loss often occurs in early to mid-adulthood, and the degree varies."
    explanation: States the usual age of onset and variability of vision loss.
  - reference: PMID:25111685
    reference_title: "Malattia leventinese/Doyne honeycomb retinal dystrophy in a chinese family with mutation of the EFEMP1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intrafamilial patients with Malattia leventinese/Doyne honeycomb retinal dystrophy seem to be phenotypically variable in visual loss"
    explanation: Visual loss varies between affected members of one family.
- name: Delayed dark adaptation
  category: Ophthalmological
  description: >-
    Difficulty passing from light to dark, with markedly prolonged rod-mediated
    dark adaptation and raised scotopic thresholds over confluent macular
    deposits.
  phenotype_term:
    preferred_term: Delayed dark adaptation
    term:
      id: HP:0030513
      label: Difficulty adjusting from light to dark
  evidence:
  - reference: PMID:11913893
    reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features included reduced central vision, difficulty passing from light to dark"
    explanation: Patients report difficulty adapting from light to dark.
- name: Color vision defect
  category: Ophthalmological
  description: Abnormal colour contrast thresholds (dyschromatopsia).
  phenotype_term:
    preferred_term: Color vision defect
    term:
      id: HP:0000551
      label: Color vision defect
  evidence:
  - reference: PMID:11913893
    reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colour contrast thresholds were abnormal in all six patients studied"
    explanation: Colour contrast sensitivity was abnormal in every patient tested.
- name: Abnormal pattern electroretinogram
  category: Ophthalmological
  description: Pattern and focal electroretinograms are abnormal, while the full-field scotopic ERG can be normal.
  phenotype_term:
    preferred_term: Abnormal pattern electroretinogram
    term:
      id: HP:0030467
      label: Abnormal pattern electroretinogram
  evidence:
  - reference: PMID:11913893
    reference_title: "Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both pattern and focal electroretinograms were abnormal in five of six patients"
    explanation: Macular electrophysiology was abnormal in five of six patients.
- name: Metamorphopsia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Metamorphopsia
    term:
      id: HP:0012508
      label: Metamorphopsia
  evidence:
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 57-year-old woman debuting with vision loss and metamorphopsia"
    explanation: Metamorphopsia was a presenting symptom in a molecularly confirmed case.
- name: Photophobia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:42306086
    reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Early visual symptoms include decreased visual acuity, photophobia, metamorphopsia, dyschromatopsia, and relative scotomas"
    explanation: The paper's introduction lists photophobia among early symptoms.
- name: Paracentral scotoma
  category: Ophthalmological
  phenotype_term:
    preferred_term: Paracentral scotoma
    term:
      id: HP:0030528
      label: Paracentral scotoma
  evidence:
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms such as decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma"
    explanation: The background section names paracentral scotoma among the visual symptoms.
- name: Retinal pigment epithelial atrophy
  category: Ophthalmological
  description: RPE atrophy, more common in older patients.
  phenotype_term:
    preferred_term: Retinal pigment epithelial atrophy
    term:
      id: HP:0007722
      label: Retinal pigment epithelial atrophy
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients"
    explanation: RPE atrophy is common in older carriers.
- name: Macular hyperpigmentation
  category: Ophthalmological
  phenotype_term:
    preferred_term: Macular hyperpigmentation
    term:
      id: HP:0011509
      label: Macular hyperpigmentation
  evidence:
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On both eyes, ophthalmological findings included massive hard drusen in the macular region and nasal to the optic disc as well as macular hyperpigmentation."
    explanation: Macular hyperpigmentation was present bilaterally in a confirmed case.
- name: Macular geographic atrophy
  category: Ophthalmological
  description: Geographic atrophy in late disease, a main cause of irreversible central vision loss.
  phenotype_term:
    preferred_term: Macular geographic atrophy
    term:
      id: HP:0031609
      label: Macular geographic atrophy
  evidence:
  - reference: PMID:42597498
    reference_title: "Development of an antisense oligonucleotide targeting EFEMP1 in models relevant to macular degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "ADD causes progressive, irreversible loss of central visual acuity due to geographic atrophy and choroidal neovascularization (CNV)."
    explanation: The introduction names geographic atrophy as a cause of central vision loss in EFEMP1 autosomal dominant drusen.
  sequelae:
  - target: Reduced visual acuity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42597498
      reference_title: "Development of an antisense oligonucleotide targeting EFEMP1 in models relevant to macular degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "ADD causes progressive, irreversible loss of central visual acuity due to geographic atrophy and choroidal neovascularization (CNV)."
      explanation: Geographic atrophy leads to loss of central visual acuity.
- name: Choroidal neovascularization
  category: Ophthalmological
  description: >-
    Secondary choroidal (macular) neovascularization occurs in a minority of
    patients and worsens the prognosis; one series found a subretinal
    neovascular membrane in only 1 of 48 eyes, while other families and case
    series report it more often. Response to anti-VEGF treatment has been
    variable.
  phenotype_term:
    preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subretinal neovascular membrane (SRNVM) was a rare occurrence, affecting only 1 of 48 eyes"
    explanation: CNV was rare in a large R345W series.
  - reference: PMID:25111685
    reference_title: "Malattia leventinese/Doyne honeycomb retinal dystrophy in a chinese family with mutation of the EFEMP1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Besides the drusen, choroidal neovascularization and retinal pigment epithelium changes were noted in some patients."
    explanation: CNV occurred in some members of a Chinese R345W family.
  - reference: PMID:41971199
    reference_title: "Early-onset drusen in Malattia Leventinese with EFEMP1 mutation differ from drusen in age-related macular degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 1 had no late-stage complications, whereas patients 2 and 3 developed macular neovascularization (MNV)."
    explanation: Two of three Indian cases developed macular neovascularization.
  sequelae:
  - target: Subretinal hemorrhage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11292424
      reference_title: "Malattia leventinese presenting with subretinal neovascular membrane and hemorrhage."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Funduscopic evaluation revealed a subretinal hemorrhage involving the center of the foveal in the left eye that was interpreted as secondary to a neovascular membrane on fluorescein angiography."
      explanation: The hemorrhage was attributed to a neovascular membrane.
  - target: Reduced visual acuity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42597498
      reference_title: "Development of an antisense oligonucleotide targeting EFEMP1 in models relevant to macular degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "ADD causes progressive, irreversible loss of central visual acuity due to geographic atrophy and choroidal neovascularization (CNV)."
      explanation: CNV leads to loss of central visual acuity.
- name: Subretinal hemorrhage
  category: Ophthalmological
  description: Submacular hemorrhage from a neovascular membrane, an occasional presentation.
  phenotype_term:
    preferred_term: Subretinal hemorrhage
    term:
      id: HP:0025243
      label: Subretinal hemorrhage
  evidence:
  - reference: PMID:11292424
    reference_title: "Malattia leventinese presenting with subretinal neovascular membrane and hemorrhage."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with malattia leventinese may occasionally present with submacular hemorrhage."
    explanation: Case report establishing submacular hemorrhage as an occasional presentation.
genetic:
- name: EFEMP1
  gene_term:
    preferred_term: EFEMP1
    term:
      id: hgnc:3218
      label: EFEMP1
  relationship_type: CAUSATIVE
  association: Causative
  variant_origin: GERMLINE
  features: >-
    A single recurrent heterozygous missense variant, c.1033C>T p.(Arg345Trp)
    (R345W) in exon 10, accounts for molecularly confirmed DHRD/ML. It was
    absent from 477 controls and 494 AMD patients in the original study. The
    variant occurs on more than one haplotype, and an apparently de novo case
    has been reported, consistent with recurrent mutation rather than a single
    founder. R345W acts as a toxic gain of function.
  evidence:
  - reference: PMID:10369267
    reference_title: "A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we use a combination of positional and candidate gene methods to identify a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 (for EGF-containing fibrillin-like extracellular matrix protein 1) in all families studied."
    explanation: The original gene discovery found the same EFEMP1 variant in all ML and DHRD families.
  - reference: PMID:10369267
    reference_title: "A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration."
    explanation: The variant is absent from controls and from AMD patients.
  - reference: PMID:17666404
    reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype."
    explanation: R345W on a different haplotype argues for independent recurrence and against linkage to a founder chromosome.
  - reference: PMID:17666404
    reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results confirm that the R345W mutation in EFEMP1 is pathogenic."
    explanation: The knock-in mouse phenotype confirms pathogenicity.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z
    evidence:
    - reference: CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z
      reference_title: "EFEMP1 / Doyne honeycomb retinal dystrophy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "EFEMP1 | HGNC:3218 | Doyne honeycomb retinal dystrophy | MONDO:0007471 | AD | Definitive"
      explanation: The ClinGen Retina GCEP classifies EFEMP1 in DHRD as Definitive for autosomal dominant inheritance.
  variants:
  - name: c.1033C>T p.(Arg345Trp)
    synonyms:
    - R345W
    - NM_001039348.3:c.1033C>T
    description: >-
      Recurrent missense variant in fibulin-3 and the only variant included in
      the ClinGen curation. Other EFEMP1 variants cause different phenotypes and
      are out of scope here.
    gene:
      preferred_term: EFEMP1
      term:
        id: hgnc:3218
        label: EFEMP1
    clinical_significance: PATHOGENIC
    type: missense_variant
    evidence:
    - reference: PMID:42720932
      reference_title: "Widening the Spectrum of Disease Expression due to Heterozygous Variants in EFEMP1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Doyne honeycomb retinal dystrophy or malattia leventinese (DHRD/ML) is an autosomal dominant retinal disorder caused by a single recurrent p.Arg345Trp (NM_001039348.3:c.1033C>T) variant in EFEMP1"
      explanation: Gives the variant nomenclature and its single recurrent role.
    - reference: CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z
      reference_title: "EFEMP1 / Doyne honeycomb retinal dystrophy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Only one missense pathogenic variant (p.Arg345Trp) is included in this curation"
      explanation: ClinGen treats p.Arg345Trp as the pathogenic variant for this disease.
    - reference: PMID:33689237
      reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Family history revealed no other cases of similar visual impairment suggesting a de novo mutation."
      explanation: An apparently de novo occurrence supports recurrent mutation at this site.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Autosomal dominant with marked inter- and intrafamilial variability in
    retinal appearance, severity and progression. Nonpenetrance has been
    observed in an asymptomatic 62-year-old carrier.
  evidence:
  - reference: PMID:10369267
    reference_title: "A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malattia Leventinese (ML) and Doyne honeycomb retinal dystrophy (DHRD) refer to two autosomal dominant diseases"
    explanation: Both clinical names describe autosomal dominant disease.
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked inter- and intrafamilial variation associated with the fibulin-3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified."
    explanation: Documents variable expressivity and nonpenetrance.
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The novel finding of nonpenetrance was observed in a 62-year-old asymptomatic, mutation-positive man."
    explanation: A specific nonpenetrant carrier supports incomplete penetrance.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Described as rare; no numeric prevalence estimate was found, and Orphanet
    records its point-prevalence class as unknown.
  evidence:
  - reference: PMID:30541486
    reference_title: "Doyne honeycomb retinal dystrophy/malattia leventinese induced by EFEMP1 mutation in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DHRD/ML is a rare disease associated with EFEMP1 gene mutation."
    explanation: States that the disease is rare without giving a figure.
  - reference: ORPHA:75376
    reference_title: "Autosomal dominant drusen"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records the worldwide point-prevalence class as unknown for its broader autosomal dominant drusen concept.
diagnosis:
- name: Multimodal retinal imaging
  description: >-
    Fundus examination with autofluorescence, OCT and angiography shows the
    radial macular and peripapillary drusen, sub-RPE hyperreflective material
    with RPE elevation, and complications such as CNV. Peripapillary deposits
    strongly suggest the R345W genotype.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:22814526
    reference_title: "Multimodal morphological and functional characterization of Malattia Leventinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OCT showed the large round drusen as focal or diffuse deposition of hyperreflective material between the RPE and Bruch membrane within the macula"
    explanation: OCT localizes the drusen between the RPE and Bruch's membrane.
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation."
    explanation: A clinical sign that predicts the genotype.
- name: EFEMP1 molecular genetic testing
  description: >-
    Diagnosis is confirmed by detecting heterozygous EFEMP1 c.1033C>T
    p.(Arg345Trp) by targeted testing, a retinal dystrophy gene panel or exome
    sequencing. Because the disease is defined by one variant, targeted testing
    is efficient; a restriction-digest assay for the variant has been described.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41971199
    reference_title: "Early-onset drusen in Malattia Leventinese with EFEMP1 mutation differ from drusen in age-related macular degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis done in patient one revealed a heterozygous, autosomal dominant, pathogenic mutation (c.1033C>T p.ARG345Trp) in the EFEMP1 gene, confirming the ML diagnosis."
    explanation: Molecular testing confirmed the clinical diagnosis.
  - reference: PMID:11389162
    reference_title: "Molecular genetic heterogeneity in autosomal dominant drusen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HpaII restriction digest test was found to be a reliable and quick method for detecting this."
    explanation: A targeted assay detects the single disease variant.
treatments:
- name: Intravitreal anti-VEGF therapy for choroidal neovascularization
  description: >-
    Intravitreal anti-VEGF agents are used for secondary choroidal
    neovascularization. They do not treat the underlying drusen dystrophy, and
    responses in DHRD case reports have been variable, including no effect.
    The modality tag refers to the monoclonal antibody agents such as
    bevacizumab and ranibizumab; aflibercept is a VEGF receptor-Fc fusion
    protein rather than an antibody.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiogenesis inhibitor (anti-VEGF)
      term:
        id: NCIT:C1742
        label: Angiogenesis Inhibitor
  target_phenotypes:
  - preferred_term: Choroidal neovascularization
    term:
      id: HP:0011506
      label: Choroidal neovascularization
  target_mechanisms:
  - target: Increased RPE VEGF Expression
    treatment_effect: INHIBITS
    description: >-
      Anti-VEGF agents neutralize the VEGF protein produced downstream of this
      node, the proposed driver of neovascularization; they do not lower VEGF
      expression itself.
  evidence:
  - reference: PMID:30541486
    reference_title: "Doyne honeycomb retinal dystrophy/malattia leventinese induced by EFEMP1 mutation in a Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "To date, laser therapy and anti-VEGF therapy have been utilized for the treatment, but the treatment is still a challenge"
    explanation: Anti-VEGF therapy is used in DHRD/ML, with limited success.
  - reference: PMID:33689237
    reference_title: "First reported case of Doyne honeycomb retinal dystrophy (Malattia Leventinese/autosomal dominant drusen) in Scandinavia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary choroidal neovascularizations were identified on both eyes, and anti-vascular endothelial growth factor was administered, without effect."
    explanation: In this case, anti-VEGF did not control bilateral CNV, so efficacy is not assured.
- name: Low-energy laser treatment of drusen
  description: >-
    Low-energy argon laser or nanosecond (2RT) laser applied to the RPE over
    drusen has been studied in small series. In a prospective series of 11
    EFEMP1 patients, treated eyes did not show the drusen thickening seen in
    untreated eyes; nanosecond laser case reports describe stable or improved
    function without structural change. The evidence is limited to small
    uncontrolled series, and the approach is not established care.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: laser therapy
    term:
      id: NCIT:C15466
      label: Laser Therapy
  target_phenotypes:
  - preferred_term: Macular drusen
    term:
      id: HP:0030499
      label: Macular drusen
  target_mechanisms:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    treatment_effect: MODULATES
    description: Laser to the RPE over drusen aims to clear or limit sub-RPE deposit.
  evidence:
  - reference: PMID:23036572
    reference_title: "Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An increase in mean drusen thickness was observed in the untreated eyes, but not in the treated eyes (P = .0322)."
    explanation: Laser-treated eyes did not show the drusen thickening of untreated fellow eyes.
  - reference: PMID:23036572
    reference_title: "Laser clearance of drusen deposit in patients with autosomal dominant drusen (p.Arg345Trp in EFEMP1)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low-energy laser treatment is safe and may be effective in the treatment of autosomal dominant drusen."
    explanation: The authors conclude the treatment is safe and possibly effective, pending longer follow-up.
  - reference: PMID:38023612
    reference_title: "Long-Term Structural and Functional Assessment of Doyne Honeycomb Retinal Dystrophy following Nanosecond 2RT Laser Treatment: A Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes"
    explanation: A three-patient series followed for up to 30 months reports functional stabilization or improvement after nanosecond laser.
- name: Genetic counseling
  description: >-
    Counseling for autosomal dominant inheritance with incomplete penetrance and
    variable expressivity; cascade testing of relatives for the single known
    variant.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:16799055
    reference_title: "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings are helpful for advice regarding prognosis and for genetic counseling."
    explanation: The phenotype and penetrance data are presented as a basis for genetic counseling.
- name: Allele-specific EFEMP1 antisense oligonucleotide (preclinical)
  description: >-
    Preclinical only. An allele-specific antisense oligonucleotide that degrades
    the EFEMP1 c.1033C>T transcript by RNase H cleared the mutant transcript in
    patient iPSC-RPE and, after gymnotic delivery, rescued ECM remodeling,
    reduced intracellular lipid and cleared extracellular deposits, even after
    the disease phenotype had appeared. No clinical study has been reported.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: EFEMP1
      term:
        id: hgnc:3218
        label: EFEMP1
    target_transcript: EFEMP1 c.1033C>T (R345W) mRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Fibulin-3 R345W Misfolding and Impaired Secretion
    treatment_effect: INHIBITS
    description: Removes the mutant transcript, and so the mutant protein, while sparing the wild-type allele.
    evidence:
    - reference: PMID:42306086
      reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We developed an allele-specific antisense oligonucleotide which specifically and effectively promoted the clearance of the EFEMP1 c.1033C>T transcript in the patient-derived disease model following assisted or gymnotic delivery."
      explanation: The ASO selectively clears the mutant transcript.
  evidence:
  - reference: PMID:42306086
    reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gymnotic delivery rescued remodeling of the ECM, reduced intracellular accumulation of lipids, and cleared extracellular deposits, even after the onset of the disease phenotype"
    explanation: In patient-derived RPE, the ASO reverses the disease phenotype; this is cell-model evidence only.
  - reference: PMID:42306086
    reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we designed an antisense oligonucleotide to specifically promote the downregulation of the R345W EFEMP1 transcript through RNase H-dependent degradation"
    explanation: Documents the RNase H knockdown mechanism.
animal_models:
- name: Efemp1 R345W knock-in mouse
  species: Mouse
  genotype: Efemp1 p.R345W knock-in (heterozygous and homozygous)
  description: >-
    Two independently generated knock-in lines carry the disease mutation in
    murine Efemp1. Heterozygous and homozygous mice develop sub-RPE basal
    (laminar) deposits from about 4 months that grow into continuous sheets,
    with fibulin-3 and TIMP3 in the deposits, abnormal Bruch's membrane ECM,
    local complement activation, Nlrp3 upregulation and, in older mice, RPE and
    choroidal degeneration. Mice have no macula, the deposits are microscopic
    rather than clinical drusen, and detectable retinal degeneration is not
    reproduced. The model has been used to show that removal or inhibition of
    C3, factor B, Nlrp3/caspase-1 and GSK3 reduces deposits.
  publication: PMID:17664227
  modeled_mechanisms:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Reproduces the sub-RPE basal deposits that precede drusen.
    limitations: >-
      Mice lack a macula and form microscopic basal laminar deposits rather than
      clinically visible honeycomb drusen; detectable retinal degeneration and
      vision loss are not reproduced.
    evidence:
    - reference: PMID:17666404
      reference_title: "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD."
      explanation: The knock-in reproduces sub-RPE basal deposits.
    - reference: PMID:31095679
      reference_title: "The Efemp1R345W Macular Dystrophy Mutation Causes Amplified Circadian and Photophobic Responses to Light in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mice, Efemp1R345W does not cause detectable degeneration but small subretinal deposits do accumulate."
      explanation: Records the limitation that the model forms deposits without detectable degeneration.
  - target: Alternative Complement Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Shows complement activation in RPE and Bruch's membrane and its requirement for deposits.
    evidence:
    - reference: PMID:23943789
      reference_title: "Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits."
      explanation: Genetic crosses in the model test the complement step.
  - target: NLRP3 Inflammasome Activation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: Shows inflammasome upregulation and its contribution to deposits; human relevance is untested.
    evidence:
    - reference: PMID:41198612
      reference_title: "Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genetic elimination of either Nlrp3 or Casp1 significantly reduced both the size and coverage of BLamDs in the R345W+/+ background"
      explanation: Genetic crosses in the model test the inflammasome step.
  - target: Abnormal Bruch's Membrane Extracellular Matrix
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Shows proteoglycan accumulation, MMP/TIMP imbalance and reduced diffusion across Bruch's membrane.
    evidence:
    - reference: PMID:28622396
      reference_title: "Mutant Fibulin-3 Causes Proteoglycan Accumulation and Impaired Diffusion Across Bruch's Membrane."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired."
      explanation: The model shows the Bruch's membrane matrix changes.
  evidence:
  - reference: PMID:17664227
    reference_title: "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."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, the Efemp1 knock-in mice reconstitute the most important histopathologic symptoms of both ML and AMD."
    explanation: The knock-in reproduces the core histopathology.
  - reference: PMID:39114980
    reference_title: "GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size"
    explanation: The model is used for preclinical testing; GSK3 inhibition reduced deposits.
- name: Efemp1 knockout mouse
  species: Mouse
  genotype: Efemp1-/-
  description: >-
    Loss of fibulin-3 causes early ageing features, reduced fascial elastic
    fibres and hernias, but no macular degeneration phenotype, and the mice
    resist sub-RPE deposit formation under stressors that induce deposits in
    wild-type mice. This negative result argues that DHRD is not caused by loss
    of fibulin-3 function.
  publication: PMID:17872905
  modeled_mechanisms:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: Fibulin-3 null mice do not form sub-RPE deposits.
    limitations: >-
      A null allele does not model the dominant R345W toxic gain of function;
      the model is informative only as evidence against a loss-of-function
      mechanism.
    evidence:
    - reference: PMID:28264101
      reference_title: "Deletion of Efemp1 Is Protective Against the Development of Sub-RPE Deposits in Mouse Eyes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice lacking fibulin-3 do not develop sub-RPE deposits."
      explanation: The knockout fails to form deposits, even under stressors that induce them in wild-type mice.
  evidence:
  - reference: PMID:17872905
    reference_title: "Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "No apparent macular degeneration associated defects were found in Efemp1(-/-) mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration."
    explanation: Null mice lack the retinal disease.
experimental_models:
- name: Patient-derived DHRD iPSC-RPE
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  cell_source: >-
    RPE differentiated from induced pluripotent stem cells of patients carrying
    EFEMP1 R345W, compared with unaffected, isogenic gene-corrected or EFEMP1
    knockout controls
  publication: PMID:42306086
  description: >-
    Patient iPSC-RPE reproduces drusen-like sub-RPE deposits containing ApoE
    and collagen IV, ECM remodeling, lipid accumulation with reduced CES1 and
    cholesterol efflux, ER stress, lysosomal dysfunction, apoptosis and
    upregulated complement genes. It has been used to test trehalose and an
    allele-specific ASO.
  modeled_mechanisms:
  - target: Sub-RPE Basal Deposit and Drusen Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Forms drusen-like deposits beneath patient RPE in culture.
    limitations: >-
      Cultured RPE lacks the choroid, the full layers of Bruch's membrane,
      photoreceptors and systemic factors, so deposits are drusen-like rather
      than clinical drusen.
    evidence:
    - reference: PMID:42306086
      reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "In the patient-derived disease model, remodeling of the extracellular matrix (ECM) occurred with progressive accumulation of the drusen-associated proteins apolipoprotein E and collagen IV, in addition to the intracellular accumulation and extracellular deposition of lipids."
      explanation: Patient RPE accumulates drusen-associated proteins and lipids.
  - target: Impaired RPE Cholesterol Efflux
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    evidence:
    - reference: PMID:33909993
      reference_title: "Impaired cholesterol efflux in retinal pigment epithelium of individuals with juvenile macular degeneration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export"
      explanation: The cholesterol efflux defect was found in DHRD iPSC-RPE.
  - target: RPE Lysosomal Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    evidence:
    - reference: PMID:42484373
      reference_title: "Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels."
      explanation: The lysosomal defect was found in ML iPSC-RPE.
  evidence:
  - reference: PMID:42306086
    reference_title: "Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We reprogrammed patient-derived renal epithelial cells to induced pluripotent stem cells, followed by directed differentiation to retinal pigment epithelium and compared the phenotype to gene-corrected and EFEMP1 knockout patient-derived retinal pigment epithelium."
    explanation: Describes the patient-derived model with isogenic and knockout controls.
references:
- reference: CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z
  title: EFEMP1 / Doyne honeycomb retinal dystrophy (Definitive)
📚

References & Deep Research

References

1
CGGV:assertion_2859008e-eeb1-4af4-8a6e-1bf5372bb3ab-2021-08-05T160000.000Z
EFEMP1 / Doyne honeycomb retinal dystrophy (Definitive)
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Doyne_Honeycomb_Retinal_Dystrophy · 2026-10-14T21:43:30Z · View source

New entry for Doyne honeycomb retinal dystrophy / malattia leventinese (MONDO:0007471), scoped to the EFEMP1 c.1033C>T p.(Arg345Trp) disease that MONDO and ClinGen (Definitive, AD) describe. The stub stubs/Doyne_Honeycomb_Retinal_Dystrophy.yaml is deleted. Content: 11 pathophysiology nodes forming one causal graph from fibulin-3 misfolding and impaired secretion through RPE ER stress, VEGF induction, abnormal Bruch's membrane ECM, alternative complement activation, NLRP3 inflammasome activation, impaired RPE cholesterol efflux and lysosomal dysfunction, to sub-RPE deposit and drusen formation, photoreceptor dysfunction over deposits, and RPE degeneration. 15 HPO-bound phenotypes, all causally connected. Genetic record with the R345W variant, ClinGen validity assertion, autosomal dominant inheritance with incomplete penetrance and variable expressivity, two diagnosis rows, four treatments (anti-VEGF for CNV, low-energy laser, genetic counseling, a preclinical allele-specific ASO), the Efemp1 R345W knock-in and Efemp1 knockout mouse models (the knockout as a FAILS_TO_RECAPITULATE link), and a patient iPSC-RPE experimental model. 126 snippets from 37 PubMed records plus the ClinGen and Orphanet records, all verified against the cache. Deep research: research/Doyne_Honeycomb_Retinal_Dystrophy-deep-research-openscientist.md. Reference validation: 16/16 references resolved, 0 off topic. Term validation flagged six mislabelled CURIEs (for example UBERON:0002423 given for macula, HP:0011506 given for macular drusen); none of the report's term suggestions were used, and all bindings were looked up independently. just preflight-dr returned WARN only because the abbreviation RPE (retinal pigment epithelium) was counted as a gene symbol; the report names EFEMP1 30 times and cites OMIM 126600, matching MONDO. Report citations not used: PMID:39464028 (bioRxiv preprint of the published PMID:41198612, which is cited instead), PMID:17659362 (general AMD review, not specific to this disease), and PMID:32911658 (review whose gain-of-function point is covered by primary data). Scope decisions recorded in notes: Orphanet ORPHA:75376 is a broader autosomal dominant drusen concept that includes CFH and CFI; EFEMP1 juvenile open-angle glaucoma and the p.Arg140Trp peripheral chorioretinal degeneration are separate diseases. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). A ClinicalTrials.gov search found no disease-specific trial; NCT03011541 (a broad stem cell study) was not included. Orphanet phenotype frequencies were not used because they describe the broader Orphanet concept.

OpenScientist ▸
Doyne Honeycomb Retinal Dystrophy (DHRD) / Malattia Leventinese — Comprehensive Disease Report
openscientist-autonomous 15 citations 2026-10-14T21:03:52.930929

Doyne Honeycomb Retinal Dystrophy (DHRD) / Malattia Leventinese — Comprehensive Disease Report

Disease: Doyne Honeycomb Retinal Dystrophy (DHRD) Synonym: Malattia Leventinese (ML); Autosomal dominant radial drusen; Autosomal dominant drusen MONDO: MONDO:0007471 · OMIM: #126600 · Gene: EFEMP1 (fibulin-3) at 2p16.1 · Inheritance: Autosomal dominant · Category: Mendelian

Evidence source note: This report synthesizes aggregated disease-level resources (OMIM, Orphanet, ClinVar, UniProt) and primary literature (PubMed). It is not derived from individual patient EHR data. Evidence types are flagged as human clinical, model organism (mouse), in vitro (iPSC-RPE/cell), or review. DHRD is rare, so much of the clinical literature consists of case series and single families; mechanistic depth comes from mouse and iPSC models.

Summary

Doyne Honeycomb Retinal Dystrophy (DHRD) and Malattia Leventinese (ML) are the same autosomal dominant macular dystrophy, caused by a single recurrent missense mutation in EFEMP1: c.1033C>T, p.Arg345Trp (R345W), which alters the secreted extracellular-matrix glycoprotein fibulin-3. This degree of genetic homogeneity is remarkable: essentially every molecularly confirmed case worldwide carries this one variant, which was mapped to chromosome 2p16-21 and found absent in 477 controls and 494 age-related macular degeneration (AMD) patients, establishing both specificity and the monogenic nature of the disease (PMID: 10369267).

Mechanistically, mutant fibulin-3 misfolds and is retained intracellularly within retinal pigment epithelium (RPE) cells rather than being efficiently secreted (PMID: 12242346). This triggers endoplasmic-reticulum (ER) stress, aberrant extracellular-matrix accumulation, and a downstream cascade of alternative-pathway complement activation, NLRP3-inflammasome inflammation, and impaired RPE cholesterol efflux and lysosomal function. The clinical consequence is the early-adult-onset accumulation of radial / honeycomb sub-RPE drusen between the RPE and Bruch's membrane, producing progressive, bilateral central vision loss, sometimes complicated by secondary choroidal neovascularization (CNV).

There is no approved disease-modifying therapy; management is supportive (low-vision aids, monitoring, genetic counseling), with intravitreal anti-VEGF reserved for neovascular complications (variable, sometimes absent response). However, the well-defined causal chain has yielded multiple preclinically validated therapeutic strategies — GSK3 inhibition, complement factor B inhibition, NLRP3/caspase-1 inhibition, and lysosome modulation (trehalose) — tested in the Efemp1 R345W knock-in mouse and patient-derived iPSC-RPE. Because DHRD reproduces the drusen biology of AMD from a single clean genetic lesion, it is widely regarded as a monogenic surrogate model for AMD.

Key Findings

F001 — A single recurrent EFEMP1 R345W mutation causes DHRD/ML

A single heterozygous missense variant — EFEMP1 c.1033C>T, p.Arg345Trp (R345W) — has been identified as the cause in essentially all molecularly confirmed cases of DHRD/ML, inherited in an autosomal dominant pattern. EFEMP1 encodes the secreted ECM glycoprotein fibulin-3 (F3). Recent case reports from previously unreported populations (the first Scandinavian case, PMID: 33689237; Indian cases, PMID: 41971199) continue to confirm R345W as the sole recurrent pathogenic variant.

"A single variant in EFEMP1: c.1033C>T (R345W) has been identified as the cause in all cases." — PMID: 33689237

"Malattia Leventinese is a rare autosomal dominant macular dystrophy caused by a single" — PMID: 41971199

F002 — Mutant fibulin-3 misfolds and is retained intracellularly, driving sub-RPE drusen

Marmorstein et al. (PMID: 12242346) showed that wild-type EFEMP1 is a secreted protein whereas mutant EFEMP1 (R345W) is misfolded, secreted inefficiently, and retained within cells. In ML eyes, EFEMP1 accumulates within RPE cells and between the RPE and drusen; notably, EFEMP1 is not a major component of the drusen itself. In AMD eyes, EFEMP1 accumulates beneath the RPE overlying drusen. Patient-derived iPSC-RPE models from ML patients show fibulin-3 and ApoE aggregation, increased ER stress, and enhanced apoptosis (PMID: 42484373).

"wild-type EFEMP1 is a secreted protein whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells" — PMID: 12242346

"MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis" — PMID: 42484373

F003 — Alternative-pathway complement and NLRP3 inflammasome drive sub-RPE deposits

In Efemp1 R345W/R345W knock-in mice, aged eyes showed an ~2-fold elevation of complement breakdown products iC3b and Ba (P<0.05); deletion of complement factor B (Cfb) partially normalized dysregulated pathways, and an oral factor B inhibitor reduced sub-RPE deposits by 65% (P=0.029) (PMID: 35943778). Genetic removal of Nlrp3 and its downstream effector caspase-1 (Casp1) protected against R345W Efemp1-induced basal laminar deposit formation (PMID: 39464028; PMID: 41198612). RNA-seq of knock-in eyecups showed an increased unfolded-protein response, decreased neural-retina mitochondrial function by 3 months, and increased inflammatory pathways by 17 months.

"oral dosing of a small molecule FB inhibitor from 10 to 12 months of age reduced sub-RPE deposits by 65% (P = 0.029)" — PMID: 35943778

"Complement activation was increased in aged Efemp1ki/ki eyes with an approximately 2-fold elevation of complement breakdown products iC3b and Ba (P < 0.05)" — PMID: 35943778

"we directly tested the role of Nlrp3 and its downstream effector, caspase 1 (Casp1) in mediating early AMD-like pathology" — PMID: 39464028

F004 — DHRD/ML maps to 2p16-21; R345W absent in controls and AMD cohorts (specificity)

Stone et al. (1999, PMID: 10369267) mapped both ML and DHRD loci to chromosome 2p16-21 and identified a single non-conservative Arg345Trp mutation in EFEMP1 in all families studied. The change was absent in 477 control individuals and in 494 AMD patients, establishing disease specificity and distinguishing DHRD/ML genetically from common AMD.

"a single non-conservative mutation (Arg345Trp) in the gene EFEMP1 ... in all families studied. This change was not present in 477 control individuals or in 494 patients with age-related macular degeneration" — PMID: 10369267

F005 — Phenotype: early-onset radial/honeycomb sub-RPE drusen with variable expressivity, CNV, central vision loss

Clinical reports consistently describe early-onset (typically 2nd–4th decade) yellow-white drusen beneath the RPE, often radially distributed around the macula and nasal to the optic disc, which coalesce into a honeycomb pattern. Drusen show increased fundus autofluorescence. Complications include RPE changes and secondary CNV. Marked intra- and inter-familial phenotypic variability in visual loss and imaging findings occurs despite the identical genotype (PMID: 25111685; PMID: 33689237; PMID: 41971199).

"Intrafamilial patients with Malattia leventinese/Doyne honeycomb retinal dystrophy seem to be phenotypically variable in visual loss, ophthalmoscopic findings, autofluorescence imaging, and optical coherence tomography changes" — PMID: 25111685

"All cases exhibited early-onset central vision loss and small, radially distributed drusen, consistent with ML/DHRD" — PMID: 41971199

F006 — No approved disease-modifying therapy; supportive care with emerging preclinical targets

No approved therapy halts DHRD/ML progression; care is supportive (low-vision aids, monitoring, genetic counseling). Secondary CNV is treated with intravitreal anti-VEGF, though responses are variable and sometimes absent (PMID: 33689237). Nanosecond 2RT laser has been piloted and may stabilize some functional parameters without structural change (PMID: 38023612). Preclinical disease-modifying strategies target the causal pathway: GSK3 inhibition (CHIR99021) reduced R345W-associated basal laminar deposits (PMID: 39114980); an oral complement factor B inhibitor reduced sub-RPE deposits by 65% (PMID: 35943778); NLRP3/caspase-1 ablation prevented deposits (PMID: 39464028); and the lysosome modulator trehalose reduced drusen-like deposits in patient iPSC-RPE (PMID: 42484373).

"treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice" — PMID: 39114980

"2RT treatment in DHRD may improve or stabilize some retinal function parameters without significant structural changes" — PMID: 38023612

"Secondary choroidal neovascularizations were identified on both eyes, and anti-vascular endothelial growth factor was administered, without effect" — PMID: 33689237

F007 — Disease models: Efemp1 R345W knock-in mouse and patient iPSC-RPE recapitulate sub-RPE/basal laminar deposits

The principal in vivo model is the Efemp1 p.R345W knock-in mouse (Efemp1ki/ki; R345W+/+), which develops microscopic basal laminar deposits (BLamDs) — an early feature of DHRD/ML and AMD — alongside increased unfolded-protein response, decreased neural-retina mitochondrial function by 3 months, increased inflammatory/complement pathways by 17 months, and a sex difference (females > males). A HiBiT luminescent tag knocked into the endogenous F3 locus enables high-throughput fibulin-3 detection for drug screening (PMID: 39114980). In vitro, patient-derived iPSC-RPE recapitulate fibulin-3/ApoE aggregation, ER stress, apoptosis, and (with photoreceptor outer-segment feeding) drusen-like deposits containing ApoE, complement, and collagen IV (PMID: 42484373); isogenic DHRD iPSC-RPE revealed impaired cholesterol efflux via CES1 downregulation (PMID: 33909993).

"Aged Efemp1 R345W/R345W knock-in mice (Efemp1ki/ki) develop microscopic deposits on the basal side of retinal pigment epithelial cells (RPE), an early feature in DHRD/ML and AMD" — PMID: 35943778

"Long-term culture with photoreceptor outer segments led to drusen-like deposits containing ApoE, complement components, and collagen IV accumulation" — PMID: 42484373

F008 — Lipid/cholesterol dysregulation and lysosomal dysfunction are downstream RPE pathologies

DHRD iPSC-RPE exhibit abnormal intracellular lipid-droplet accumulation and pericellular lipid-rich deposits, driven by downregulation of carboxylesterase 1 (CES1) — impairing conversion of cholesteryl ester to free cholesterol and thus cholesterol efflux (PMID: 33909993). CES1 knockdown or EFEMP1 overexpression reproduced lipid accumulation. Independently, ML iPSC-RPE show lysosomal dysfunction with reduced TFEB transcripts and altered lysosomal gene programs, plus increased hexosylceramide and bis(monoacylglycero)phosphate; trehalose restored lysosomal function and reduced drusen-like deposits, MMP2 activation, and apoptosis (PMID: 42484373).

"we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export" — PMID: 33909993

"A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels" — PMID: 42484373

F009 — Diagnosis rests on multimodal retinal imaging plus EFEMP1 genetic confirmation

Multimodal imaging defines the diagnostic signature: large round drusen in the perimacular area and around the optic disc, and small non-round, radially distributed drusen temporal to the macula. Fundus autofluorescence (FAF) shows intense autofluorescence of large drusen; on fluorescein (FA)/indocyanine green (ICGA) angiography, large round drusen become hyperfluorescent late while small radial drusen decrease fluorescence; OCT shows hyperreflective material between RPE and Bruch's membrane causing focal dome-shaped or diffuse RPE elevation (PMID: 22814526). Best-corrected visual acuity ranged 20/25 to 20/200. Definitive diagnosis is molecular: detection of heterozygous EFEMP1 c.1033C>T (p.Arg345Trp) by single-gene testing, inherited retinal disease gene panels, or exome sequencing (PMID: 41971199).

"OCT showed the large round drusen as focal or diffuse deposition of hyperreflective material between the RPE and Bruch membrane within the macula, determining focal dome-shaped or diffuse RPE elevation" — PMID: 22814526

"The smallest drusen were not round, radially distributed, mostly localized temporally to the macula" — PMID: 22814526

F010 — DHRD/ML is a monogenic surrogate model for AMD; fibulin-3 regulates Bruch's-membrane ECM and MMP/TIMP3 balance

A 2026 review frames DHRD as "a monogenic disorder that serves as a surrogate model for AMD due to similar phenotypic manifestations," focusing on interactions between EFEMP1, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases-3 (TIMP3), and complement factors, and states the EFEMP1 R345W mutation "causes rapid disease progression through impaired protein secretion, abnormal matrix accumulation, and complement dysregulation" (PMID: 42569289). In both DHRD/ML and AMD, drusen form as extracellular deposits between RPE and Bruch's membrane, and both share alternative-complement activation (factor H/factor B axis; PMID: 17659362).

"Doyne Honeycomb Retinal Dystrophy-a monogenic disorder that serves as a surrogate model for AMD due to similar phenotypic manifestations" — PMID: 42569289

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A germline heterozygous EFEMP1 c.1033C>T (p.R345W) mutation produces a single amino-acid substitution (Arg→Trp) in secreted fibulin-3. (demonstrated — PMID: 10369267)
  2. The R345W substitution causes fibulin-3 to misfold, so the protein is secreted inefficiently and retained intracellularly within the RPE. (demonstrated — PMID: 12242346)
  3. Intracellular retention leads to ER stress (unfolded-protein response) and co-aggregation with ApoE, which results in enhanced RPE apoptosis. (demonstrated in iPSC-RPE and knock-in eyecups — PMID: 42484373)
  4. Branch A — ECM dysregulation: abnormal fibulin-3 handling disturbs the MMP/TIMP3 balance and extracellular-matrix homeostasis of Bruch's membrane, promoting abnormal matrix accumulation. (mechanistic review — PMID: 42569289)
  5. Branch B — Complement: sub-RPE changes activate the alternative complement pathway (↑iC3b, ↑Ba; factor B–dependent), which drives sub-RPE deposit accumulation. (demonstrated — PMID: 35943778)
  6. Branch C — Inflammasome: NLRP3/caspase-1 activation contributes to basal laminar deposit formation. (demonstrated by genetic ablation — PMID: 39464028)
  7. Branch D — Lipid/lysosome: CES1 downregulation impairs cholesterol efflux → lipid-droplet accumulation; reduced TFEB causes lysosomal dysfunction → impaired clearance. (demonstrated in iPSC-RPE — PMID: 33909993; PMID: 42484373)
  8. Branches A–D converge to produce extracellular drusen between RPE and Bruch's membrane, in a characteristic radial/honeycomb macular and peripapillary pattern. (demonstrated — PMID: 22814526)
  9. Progressive drusen, RPE atrophy, and (in a subset) secondary choroidal neovascularization result in bilateral early-adult-onset central vision loss, metamorphopsia, and scotomas. (demonstrated — PMID: 25111685; PMID: 33689237)
EFEMP1 R345W → fibulin-3 misfolding → intracellular retention / ER stress / ApoE co-aggregation → RPE apoptosis
                              │
    ┌─────────────────┬──────────────┼─────────────────┬───────────────────┐
    ▼                 ▼               ▼                 ▼                   ▼
       ECM / MMP-TIMP3   Alternative     NLRP3 / Casp1    CES1↓ cholesterol    TFEB↓ lysosomal
       dysregulation     complement      inflammasome     efflux impaired      dysfunction
    └─────────────────┴──────────────┴─────────────────┴───────────────────┘
                              ▼
      Sub-RPE / basal-laminar DRUSEN (radial → honeycomb)
                              ▼
RPE atrophy ± secondary CNV  →  bilateral central vision loss

Upstream vs downstream: The mutation and protein misfolding (steps 1–3) are strictly upstream and shared by every patient. Complement, inflammasome, ECM, and lipid/lysosome arms (steps 4–7) are downstream, partially parallel, and therapeutically tractable. Drusen and vision loss (steps 8–9) are the terminal, clinically observed outputs.

Cell types / processes: RPE (CL:0002586, retinal pigment epithelial cell) is the primary affected cell; photoreceptors are secondarily affected. Key GO biological processes: response to endoplasmic reticulum stress (GO:0034976), complement activation, alternative pathway (GO:0006957), NLRP3 inflammasome complex assembly (GO:0044546), cholesterol efflux (GO:0033344), autophagy/lysosome organization (GO:0007040), extracellular matrix organization (GO:0030198). Anatomy: macula lutea (UBERON:0002423), RPE (UBERON:0001782), Bruch's membrane (UBERON:0004864).

Section-by-Section Report

1. Disease Information

DHRD is a rare, autosomal dominant, bilateral macular dystrophy characterized by early-onset sub-RPE drusen forming a honeycomb pattern. It is identical in etiology to Malattia Leventinese, originally described in families from the Leventine valley of Switzerland. Identifiers: MONDO:0007471; OMIM #126600; gene EFEMP1 (OMIM *601548); ICD-10 H35.5 (hereditary retinal dystrophy); MeSH "Retinal Dystrophies"/"Macular Degeneration" (no DHRD-specific MeSH descriptor). Synonyms: Malattia Leventinese; Doyne honeycomb degeneration/choroiditis; autosomal dominant radial drusen; autosomal dominant drusen; dominant drusen. Information is derived from aggregated disease-level resources (OMIM, Orphanet) and from individual-patient case series/cohorts in the ophthalmic literature.

2. Etiology

Causal factor: purely genetic — a single heterozygous EFEMP1 R345W mutation (F001, F004). Genetic risk: R345W is both necessary and (with autosomal dominant inheritance) sufficient; no susceptibility loci or validated modifier genes are established, though phenotypic variability implies unidentified genetic/environmental modifiers. Environmental/lifestyle risk factors, protective factors, infectious agents, and gene–environment interactions are not established for this monogenic disease. Because DHRD overlaps mechanistically with AMD, it is plausible (but unproven for DHRD) that AMD-associated environmental factors (smoking, oxidative stress) modulate expressivity.

3. Phenotypes

Phenotype Type HPO term Onset Progression Frequency
Macular/peripapillary drusen (radial → honeycomb) Clinical sign HP:0011506 (Macular drusen) 2nd–4th decade Progressive Near-universal (hallmark)
Reduced central visual acuity Symptom HP:0007663 / HP:0000572 (central scotoma) Early–mid adult Progressive, variable Common
Metamorphopsia Symptom HP:0012508 Adult Variable Common
RPE atrophy/changes Clinical sign HP:0007814 Adult Progressive Subset
Choroidal neovascularization Clinical sign HP:0030500 Adult Episodic complication Subset
Abnormal fundus autofluorescence Lab/imaging — Adult Progressive Characteristic

Severity and progression are variable even within families sharing R345W (PMID: 25111685). Quality-of-life impact: progressive central vision loss impairs reading, driving, and facial recognition; formal EQ-5D/SF-36 data specific to DHRD are not available.

4. Genetic / Molecular Information

Causal gene: EFEMP1 (HGNC:3218; fibulin-3; 2p16.1; OMIM *601548). Pathogenic variant: c.1033C>T, p.Arg345Trp (R345W) — a missense variant, classified pathogenic (ClinVar), germline, functionally acting via a dominant gain-of-toxic-function misfolding mechanism rather than simple haploinsufficiency (F002). Allele frequency: effectively absent in population databases and in 477 controls / 494 AMD cases (PMID: 10369267). Modifier genes: none validated; variable expressivity suggests their existence. Epigenetic information: none specific to DHRD. Chromosomal abnormalities: none — this is a point mutation.

5. Environmental Information

No environmental, lifestyle, or infectious contributors are established for DHRD; it is a Mendelian point-mutation disorder. Any environmental influence is limited to possible (unproven) modulation of expressivity.

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the ordered causal chain and branch diagram. In brief: R345W → fibulin-3 misfolding/intracellular retention → ER stress + ApoE aggregation + RPE apoptosis → convergent downstream arms (alternative complement, NLRP3 inflammasome, ECM/MMP-TIMP3 dysregulation, CES1-dependent cholesterol-efflux failure, TFEB-dependent lysosomal dysfunction) → sub-RPE drusen → RPE atrophy ± CNV → central vision loss. Molecular profiling (knock-in RNA-seq) shows early unfolded-protein response and mitochondrial decline, with later inflammatory/complement upregulation (PMID: 35943778). Lipidomics of ML iPSC-RPE shows increased hexosylceramide and BMP (PMID: 42484373).

7. Anatomical Structures Affected

Organ: eye — specifically the macula (UBERON:0002423) and peripapillary retina. Tissue/cell: retinal pigment epithelium (UBERON:0001782; CL:0002586) is primary; photoreceptors secondary; drusen deposit at the RPE–Bruch's membrane interface (UBERON:0004864). Subcellular: endoplasmic reticulum (GO:0005783; misfolding/retention), lysosome (GO:0005764; dysfunction), mitochondria (GO:0005739; functional decline), extracellular matrix/basal lamina. Localization: bilateral, macular + peripapillary (nasal to optic disc).

8. Temporal Development

Onset: typically 2nd–4th decade (early adult); insidious/chronic. Drusen may be detectable before symptoms. Progression: early (sparse radial drusen) → intermediate (coalescence into honeycomb) → advanced (RPE atrophy, central vision loss) → complication stage (CNV in a subset). Rate is slow but progressive and variable; disease is chronic and lifelong. Patterns: no spontaneous remission; CNV episodes are episodic. A therapeutic "critical period" for deposit prevention (before irreversible RPE/photoreceptor loss) is suggested by preclinical studies that intervene at the deposit-formation stage.

9. Inheritance and Population

Inheritance: autosomal dominant, high/near-complete but age-dependent penetrance, with variable expressivity (F005). Epidemiology: rare; precise prevalence/incidence not well quantified. Founder clustering historically noted in the Swiss Leventine valley (ML), with cases now reported worldwide (Europe, China, India, Scandinavia). No genetic anticipation (not a repeat-expansion disorder). Germline mosaicism, consanguinity, and carrier-frequency considerations are not prominent given dominant inheritance and the single recurrent allele. Sex ratio: roughly equal in humans, though the mouse model shows a female-biased deposit burden. Age distribution skews toward adult diagnosis.

10. Diagnostics

Clinical/imaging (F009): fundoscopy (radial/honeycomb drusen), OCT (hyperreflective sub-RPE material, dome-shaped RPE elevation), FAF (intense drusen autofluorescence), FA/ICGA (late hyperfluorescence of large drusen). Functional: microperimetry, Preferential Hyperacuity Perimeter, visual acuity (20/25–20/200). Genetic testing is definitive: single-gene EFEMP1 testing, inherited retinal dystrophy gene panels (e.g., Illumina MiSeq), or WES/WGS detecting heterozygous c.1033C>T. Given the single recurrent variant, targeted single-variant testing is highly efficient. Differential diagnosis: AMD (later onset, no R345W), familial/cuticular drusen, Sorsby fundus dystrophy (TIMP3), autosomal dominant drusen of other etiologies, pattern dystrophies. Screening: cascade/predictive genetic testing of at-risk relatives.

11. Outcome / Prognosis

DHRD is not life-threatening; survival and mortality are unaffected. Morbidity is visual: progressive bilateral central vision loss causing significant disability for reading/driving, with preserved peripheral vision. CNV, when it occurs, accelerates central loss. Prognostic factors: extent/confluence of drusen, RPE atrophy, development of CNV; genotype is uniform (R345W) so does not stratify prognosis. No validated molecular prognostic biomarkers specific to DHRD. Recovery potential is limited once atrophy develops.

12. Treatment

No approved disease-modifying therapy (F006). Supportive: low-vision rehabilitation, Amsler-grid self-monitoring, genetic counseling. Neovascular complications: intravitreal anti-VEGF (bevacizumab/ranibizumab/aflibercept; NCIT: Anti-VEGF Therapy) — response variable, sometimes absent (PMID: 33689237). Interventional (experimental): nanosecond 2RT laser — functional stabilization without structural change (PMID: 38023612). Preclinically validated disease-modifying candidates:

Strategy Agent Model Effect PMID
GSK3 inhibition CHIR99021 (25 mg/kg i.p., 1 mo) R345W+/+ mouse ↓ basal laminar deposit number & size 39114980
Complement factor B inhibition Oral small-molecule FB inhibitor Efemp1ki/ki mouse Sub-RPE deposits −65% (P=0.029) 35943778
NLRP3/caspase-1 inhibition Genetic ablation (Nlrp3, Casp1) R345W mouse Prevented basal laminar deposits 39464028
Lysosome modulation Trehalose ML iPSC-RPE ↓ drusen-like deposits, MMP2, apoptosis 42484373

No DHRD-specific pharmacogenomics, gene therapy, cell therapy, or RNA-based therapy has reached the clinic, though the single recurrent allele makes DHRD attractive for allele-specific gene editing/silencing. Suggested NCIT intervention terms: Anti-VEGF Therapy, Laser Therapy, Gene Therapy, Supportive Care.

13. Prevention

No primary prevention exists for a germline Mendelian disease. Secondary prevention: regular ophthalmic surveillance to detect CNV early for anti-VEGF. Genetic prevention/counseling: cascade testing of relatives, reproductive options (preimplantation genetic testing, prenatal diagnosis) given the single known variant and 50% transmission risk. Tertiary prevention: low-vision support and prompt CNV management to limit disability. No immunization or public-health/environmental interventions apply.

14. Other Species / Natural Disease

No naturally occurring R345W-driven DHRD/ML is documented in companion or wild animals (no OMIA entry for this specific disease). Orthologous gene: mouse Efemp1 (and orthologs across vertebrates) is highly conserved; the R345W knock-in demonstrates functional conservation of the mechanism. No zoonotic or cross-species transmission applies (non-infectious genetic disease).

15. Model Organisms

In vivo: the Efemp1 p.R345W knock-in mouse (Efemp1ki/ki; R345W+/+) is the principal model, recapitulating sub-RPE basal laminar deposits, unfolded-protein response, mitochondrial decline, and age-dependent complement/inflammation, with a female-biased deposit burden (F007). A HiBiT-tagged F3 locus mouse enables high-throughput fibulin-3 quantification for drug screening (PMID: 39114980). In vitro: patient-derived iPSC-RPE (and isogenic CRISPR-corrected controls) reproduce fibulin-3/ApoE aggregation, ER stress, apoptosis, CES1-dependent lipid accumulation, TFEB-linked lysosomal dysfunction, and (with outer-segment feeding) drusen-like deposits (PMID: 42484373; PMID: 33909993). Phenotype recapitulation: strong for early sub-RPE/basal-laminar deposit biology and molecular cascades. Limitations: mice do not form a true macula and develop only microscopic (not clinical honeycomb) drusen; long aging is required; iPSC-RPE lack full retinal architecture and chronic in-vivo context.

Evidence Base

PMID Title (abbrev.) Evidence type Supports
10369267 Single EFEMP1 mutation for ML and DHRD Human genetic F001, F004 (single causal variant, 2p16-21, specificity)
12242346 Aberrant EFEMP1 accumulation underlies drusen Human tissue / in vitro F002, F010 (misfolding, intracellular retention)
25111685 ML/DHRD Chinese family Human clinical F005 (variable expressivity, CNV, FAF)
22814526 Multimodal characterization of ML Human clinical/imaging F009 (OCT, FAF, FA/ICGA, radial drusen)
33689237 First Scandinavian DHRD case Human clinical F001, F005, F006 (R345W, CNV, anti-VEGF no effect)
41971199 Early-onset drusen in ML (Indian cases) Human clinical/genetic F001, F005, F009 (single variant, radial drusen, panel testing)
35943778 Complement factor B critical for sub-RPE deposits Mouse model F003, F007 (complement, knock-in model, FB inhibitor)
39464028 Nlrp3 removal protects against deposits Mouse model F003, F006 (inflammasome)
41198612 Nlrp3 removal (R345W) Mouse model F003 (NLRP3/caspase-1 in BLamDs)
39114980 GSK3 inhibition prevents AMD-like pathology Mouse model F006, F007 (CHIR99021, HiBiT model)
42484373 Restoring lysosomal function (trehalose) in ML iPSC-RPE F002, F007, F008 (aggregation, lysosome, TFEB, trehalose)
33909993 Impaired cholesterol efflux in juvenile macular degeneration iPSC-RPE F007, F008 (CES1, lipid efflux)
38023612 Nanosecond 2RT laser in DHRD Human case series F006 (interventional functional benefit)
42569289 EFEMP1–TIMP3 interactions & AMD relevance Review F010 (monogenic surrogate for AMD, MMP/TIMP3)
17659362 Molecular biology of AMD Review F010 (alternative complement in AMD)
32911658 Pathophysiological significance of fibulin-3 Review F002, F010 (fibulin-3 biology)

Limitations and Knowledge Gaps

  • Epidemiology is poorly quantified. No reliable prevalence/incidence figures for DHRD/ML exist; most data come from case series and families, not registries.
  • Mechanism of dominance is incompletely resolved. Whether R345W fibulin-3 acts purely as a gain-of-toxic-misfolding, dominant-negative, or combined mechanism is not fully settled.
  • Modifiers of expressivity are unknown. Identical genotype yields highly variable phenotype even within families; the responsible genetic/environmental modifiers are unidentified.
  • Model limitations. Mice lack a macula and form only microscopic deposits; iPSC-RPE lack intact retinal architecture — neither fully reproduces clinical honeycomb drusen or long-term CNV.
  • No human therapeutic trials of the preclinical targets. GSK3, factor B, NLRP3, and lysosome strategies are validated only in mouse/iPSC-RPE; human efficacy and safety are unknown.
  • Quality-of-life data are absent. No DHRD-specific EQ-5D/SF-36/PROMIS outcomes have been reported.
  • Causal-chain branch ordering is partly inferred. The relative timing/dominance of complement vs inflammasome vs lipid/lysosome arms is not fully established in humans.

Proposed Follow-up Experiments / Actions

  1. Natural-history registry — establish a multicenter DHRD/ML cohort with standardized multimodal imaging to quantify prevalence, progression rate, CNV incidence, and vision-loss trajectories.
  2. Modifier discovery — WGS + expression/epigenetic profiling across discordant R345W carriers (including unaffected relatives) to find genetic/environmental modifiers of expressivity.
  3. Allele-specific gene therapy — because the disease is driven by one dominant allele, develop allele-specific CRISPR editing or ASO/siRNA silencing of mutant EFEMP1, validated in R345W knock-in mice and iPSC-RPE.
  4. Translate preclinical pharmacology — advance the best-validated candidates (complement factor B inhibitor; GSK3 inhibitor; NLRP3 inhibitor; trehalose/lysosome modulators) toward IND-enabling studies and early-phase trials, using drusen volume (OCT/FAF) as a surrogate endpoint.
  5. Biomarker development — define imaging (drusen volume kinetics) and molecular (complement breakdown products, lipid species) biomarkers for trial stratification and prognosis.
  6. Improved models — generate macula-bearing or longer-lived models (e.g., non-human primate knock-in, retinal organoids with photoreceptor–RPE co-culture) to capture honeycomb-drusen and CNV phenotypes.
  7. Cross-validate with AMD — directly test whether DHRD-derived therapeutic targets (factor B, NLRP3, GSK3) translate to polygenic AMD, leveraging DHRD as a clean monogenic surrogate.

Report compiled from 10 confirmed findings across 5 investigation iterations and 18 reviewed papers. All mechanistic and clinical claims are cited to primary literature or reviews with exact PMID references; citation snippets were verified against stored abstracts during the investigation.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 16
Resolved 16
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 16
On topic 15
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 21
Resolved 20
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 12
Terms named correctly 5
Terms named as a different term 6
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • UBERON:0002423 (2 mentions) - the report calls it "macula"; UBERON calls it hepatobiliary system
  • UBERON:0004864 (2 mentions) - the report calls it "RPE–Bruch's membrane interface"; UBERON calls it vasculature of retina
  • HP:0011506 (1 mention) - the report calls it "Macular drusen"; HP calls it Choroidal neovascularization
  • HP:0012508 (1 mention) - the report calls it "Symptom"; HP calls it Metamorphopsia
  • HP:0007814 (1 mention) - the report calls it "Clinical sign"; HP calls it Retinal pigment epithelial mottling
  • HP:0030500 (1 mention) - the report calls it "Clinical sign"; HP calls it Yellow/white macular lesion

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0007040 (1 mention) - the report calls it "autophagy/lysosome organization"; GO calls it lysosome organization