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Dominant Drusen: for professionals


Overview

PrevalenceLess than 100 reported cases
InheritanceAutosomal dominant
Genes involved (OMIM No.)EFEMP1 (#126600)
SymptomsBilateral progressive central vision loss starting in the 4th to 5th decade of life
Central scotomas
Nyctalopia
Metamorphopsia
Ocular FeaturesMacular and peripapillary drusen
Choroidal neovascularisation
Macula atrophy
Key investigationsFundus autofluorescence
Fundus fluorescein angiography (if CNV suspected)
OCT
SD-OCT
OCT-A
Visual field testing
Electroretinography
Molecular diagnosisWhole genome sequencing with retinal panel
ManagementOcular
Regular ophthalmic monitoring
Anti-VEGF injections if CNV detected

Systemic
Smoking cessation
Supportive measures with genetic counsellor
Therapies under ResearchNatural history studies

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Clinical phenotype

Dominant drusen, also known as Malattia Leventinese or Doyne Honeycomb Retinal Dystrophy (DHRD), is a hereditary eye condition that predominantly affects the retinal pigment epithelium (RPE) and can lead to significant visual impairment1.

Presenting features

Ocular:

  • Asymptomatic onset: patients are often asymptomatic initially, with symptoms typically manifesting in the 4th or 5th decade of life2.
  • Visual disturbances: insidious onset of visual disturbances such as blurry vision, photopsias, scotomas, metamorphopsias, and dyschromatopsias.
  • Central vision Impairment: in advanced disease stages, central vision is affected, with visual acuities often deteriorating to around 20/200.
  • Secondary CNV: secondary choroidal neovascularisation (CNV) may occur, further complicating the disease course.

Fundus appearance

  • Early-onset drusen: macular and peripapillary drusen develop between the Bruch membrane and RPE, initially presenting as small accumulations and progressing to further deposits oriented radially, forming a characteristic honeycomb pattern.
  • Nasal drusen: drusen present nasally to the optic disc are a typical feature.
  • Pigmentary changes: Pigmentary changes are common as the disease progresses.
  • Advanced disease features: More advanced and later-onset disease stages present with central vision loss, CNV and scarring, and later geographic atrophy3.

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Genetics

Gene: EFEMP1

  • OMIM No.: #126600
  • Inheritance Pattern: Autosomal dominant
  • Function and pathogenic variant: The EFEMP1 gene4,5 encodes fibulin-3, a critical protein involved in maintaining tissue integrity, particularly in the eye and cardiovascular system. Fibulin-3 plays a key role in organising the extracellular matrix, providing structural support, and regulating cell signalling pathways. In Dominant Drusen, a hotspot mutation in codon R345W of EFEMP1 disrupts the normal function of fibulin-3, leading to structural abnormalities in tissues and dysregulation of cellular processes.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Ophthalmic examination:
    • Comprehensive assessment of visual acuity, intraocular pressure, and anterior and posterior segment examination.
  2. Fundoscopy:
    • Drusen deposition: examination reveals characteristic drusen deposition between the Bruch membrane and the RPE, typically in the macular and peripapillary regions6.
    • Pigmentary changes: presence of pigmentary changes, such as mottling or clumping, may be observed, indicating disease progression.
    • CNV detection: fundoscopic signs of CNV include subretinal haemorrhage, serous retinal detachment, or fibrovascular scarring.
  3. Fundus autofluorescence (FAF):
    • Drusen deposition: Hyper-autofluorescence corresponds to areas of drusen deposition, aiding in their detection and monitoring.
    • Macular atrophy: Hypo-autofluorescence may indicate areas of macular atrophy, reflecting loss of RPE and photoreceptor cells.
  4. Fluorescein angiography (FA):
    • CNV detection: Fluorescein angiography assists in the detection and characterisation of CNV, revealing hyperfluorescent lesions corresponding to leakage sites7,8.
  5. Optical coherence tomography (OCT):
    • Drusen characteristics: OCT imaging demonstrates hyperreflective deposits with elevation between the RPE and Bruch’s membrane.9
    • Retinal thickness: assess for macular oedema or atrophy.
  6. Spectral domain OCT (SD-OCT):
    • Drusen deposits: hyperreflective deposits with elevation between the RPE and Bruch’s membrane.10
    • Ellipsoid zone integrity: diffuse loss of the ellipsoid zone as well as outer and inner segment disruption.
  7. OCT-Angiography (OCT-A):
    • Secondary CNV: non-invasive visualisation of CNV, aiding in the diagnosis and monitoring.
  8. Electroretinogram (ERG):
    • ERG: may show low-normal scotopic and photopic responses and B-wave amplitudes. In severe disease these become sub-normal.11
  9. Genetic testing: identify pathogenic variant in EFEMP1 gene.

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Diagnosis

Ascertain if there is a history of macular degeneration with early onset and the need for anti-VEGF injections. Sequencing of the EFEMP1 gene serves as a confirmatory tool.

Differential Diagnoses

Differential diagnoses include AMD, Early onset drusen, Sorsby syndrome, Pattern dystrophy, Stargardt disease

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Management

Ocular

  1. Regular ophthalmology monitoring: monitor disease progression and identify complications promptly.
  2. CNV management: early detection and management of secondary CNV with anti-VEGF injections, photodynamic therapy, or thermal laser therapy. Prompt diagnosis and intervention are crucial to preserve vision and minimise permanent damage. Patients should therefore be safety-netted to come in if their vision starts to worsen.12
  3. Drusen clearance: Some studies have shown low energy argon laser treatment helped clear drusen deposits and this led to improved visual acuity and retinal sensitivity.13
  4. Genetics: Referral to ocular genetics service or clinical genetics for whole-genome sequencing.

Systemic

  1. Multidisciplinary Support: Referral to appropriate services for nutritional support, physical and occupational therapy.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic Counsellors (GCs) and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They inform patients of the diagnosis in a private room and provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Current research

Current research on dominant drusen focuses on understanding its genetic and molecular basis, improving diagnostics, and developing therapies. Key areas include identifying genetic mutations, particularly in complement pathways and lipid metabolism, and enhancing imaging techniques like OCT and fundus autofluorescence for early detection and monitoring. Additionally, efforts are underway to create targeted therapies to modulate the complement system and address lipid dysregulation, aiming to prevent drusen progression and associated macular degeneration.

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Further information and support

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References

  1. Michaelides M, Jenkins SA, Brantley MA, et al. Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction. Invest Ophthalmol Vis Sci. 2006;47:3085-97.
  2. Zech JC, et al. Macular dystrophy of malattia leventinese. A 25 year follow up. Br J Ophthalmol. 1999;83(10):1194.
  3. Zhang T, Xie X, Cao G, et al. Malattia leventinese/Doyne honeycomb retinal dystrophy in a Chinese family with mutation of the EFEMP1 gene. Retina. 2014;34(12):2462-71.
  4. Marmorstein LY, McLaughlin PJ, Peachey NS, et al. 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. Hum Mol Genet. 2007;16:2423-32. doi:10.1093/hmg/ddm199.
  5. Fu L, et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet. 2007;16(20):2411-22.
  6. Evans K, et al. Assessment of the phenotypic range seen in Doyne honeycomb retinal dystrophy. Arch Ophthalmol. 1997;115:904-10. doi:10.1001/archopht.1997.01100160074012.
  7. Serra R, Coscas F, Messaoudi N, et al. Choroidal neovascularization in Malattia Leventinese diagnosed using optical coherence tomography angiography. Am J Ophthalmol. 2017;176:108-17. doi:10.1016/j.ajo.2016.12.027.
  8. Souied EH, Leveziel N, Querques G, et al. Indocyanine green angiography features of Malattia leventinese. Br J Ophthalmol. 2006;90(3):296-300.
  9. Souied EH, Leveziel N, Letien V, et al. Optical coherent tomography features of malattia leventinese. Am J Ophthalmol. 2006;141:404-7. doi:10.1016/j.ajo.2005.09.001.
  10. Gerth C, Zawadzki RJ, Werner JS, et al. Retinal microstructure in patients with EFEMP1 retinal dystrophy evaluated by Fourier domain OCT. Eye (Lond). 2009;23:480-3. doi:10.1038/eye.2008.251.
  11. Scarpatetti A, Forni S, Niemeyer G. Die Netzhautfunktion bei Malattia leventinese (dominant drusen) [The function of the retina in malattia leventinese (dominant drusen) (author’s transl)]. Klin Monbl Augenheilkd. 1978 Apr;172(4):590-7. German.
  12. Sohn EH, et al. Responsiveness of Choroidal Neovascular Membranes in Patients With R345W Mutation in Fibulin 3 (Doyne Honeycomb Retinal Dystrophy) to Anti–Vascular Endothelial Growth Factor Therapy. Arch Ophthalmol. 2011;129(12):1626-8.
  13. Stanton JB, Marmorstein AD, Zhang Y, et al. Deletion of EFEMP1 is protective against the development of Sub-RPE deposits in mouse eyes. Invest Ophthalmol Vis Sci. 2017;58:1455-61. doi:10.1167/iovs.16-20955.

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Updated on June 5, 2024
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