Autosomal Dominant Drusen: A Review

  • Post author:Haseeb N. Akhtar, Ayesha Salejee, Hassan A. Mirza
  • DOIDOI:10.48089/jfo7688280
  • Reader Impact Rating Impact Rating: 8.73 / 10 from 41 reader votes.

Haseeb N. Akhtar,*1 Ayesha Salejee,*1 Hassan A. Mirza1

*Joint first authors

1University College London, London, UK

Introduction

Autosomal Dominant Drusen (ADD), also known as Doyne Honeycomb Retinal Dystrophy, Malattia Leventinese and Familial Dominant Drusen is an inherited retinal disease characterised by early-onset drusen deposits in the macula and peripapillary region. First described in 1899, ADD is caused by pathogenic variants in the EFEMP1 gene, which encodes fibulin-3, an integral extracellular matrix protein (1,2). The aforementioned variant leads to a disruption in protein secretion; consequently, there is drusen accumulation beneath the retinal pigment epithelium (RPE) and within Bruch’s membrane (3,4). Unlike age-related macular degeneration (AMD), ADD manifests earlier, often within the first four decades of life, with a distinct radial drusen pattern and a significant risk of choroidal neovascularisation (CNV) (5,6). As such, early diagnosis is crucial in order to initiate treatment against CNV.

Epidemiology

Like other causes of inherited retinal disease, ADD is rare, with prevalence remaining uncertain due to both underdiagnosis and phenotypic overlap with AMD (7). A 2024 natural history study of 44 genetically confirmed patients reported a female predominance (77% female), though the significance of this gender preponderance remains unclear (8). In the same study, the mean age of symptom onset was 40.1 years, though 32% of the aforementioned cohort were asymptomatic at time of diagnosis (8). It is worth bearing in mind that whilst cases are often autosomal dominant in terms of inheritance pattern, sporadic cases from de novo mutations have also been described (9). Globally, there is no clear geographic clustering in terms of the ethnicity of cases (10).

Pathophysiology

As described previously, drusen accumulation within Bruch’s membrane can result in RPE atrophy and subsequent photoreceptor degeneration (11.) Secondary CNV, observed in approximately a third of patients in recent studies, is thought to arise due to chronic inflammation and vascular endothelial growth factor (VEGF) upregulation (8,12).

Clinical Features 

ADD often presents with progressive central vision loss, often preceded by metamorphopsia (8). Key findings are detailed below:

  • Drusen: yellow-white deposits radiating from the optic disc or macula, visible on fundoscopy.
  • Retinal Imaging: Spectral-domain optical coherence tomography (SD-OCT) reveals drusenoid pigment epithelial detachments (PEDs), outer retinal thinning and hyper-transmission defects indicative of RPE atrophy (8).
  • CNV: Develops in 27% of eyes, with a mean onset age of 48.4 years; it is associated with poor visual outcomes (mean best corrected visual acuity: 0.96 logMAR vs. 0.44 logMAR in non-CNV eyes) (8).

Diagnosis

ADD should be considered in patients with bilateral, symmetric drusen and a positive family history of macular degeneration. Key diagnostic steps are detailed below:

  1. Genetic Testing: Identification of the EFEMP1 p.R345W variant confirms the diagnosis (13). Documenting a pedigree chart in the medical records is also useful.
  2. Multimodal Imaging:
    1. SD-OCT: classifies the disease into four groups based on pigment epithelial detachment (PED) morphology and RPE integrity (8).
    1. Fundus Autofluorescence (FAF): hyperautofluorescent drusen with central hypoautofluorescence in advanced atrophy (8).

Management

For the treatment of CNV, intravitreal anti-VEGF agents (e.g. bevacizumab, ranibizumab) are first-line; although fewer injections are required in comparison to neovascular AMD (8,14). Regular monitoring with multimodal imaging (SD-OCT and FAF) are integral steps in order to detect the presence of CNV or to monitor atrophy progression. Supportive measures such as referral to the low vision clinic can help in providing visual rehabilitation services, e.g. magnifiers, lighting adjustments and contrast-enhancing aids. Gene therapies targeting the EFEMP1 gene and suprachoroidal therapeutic delivery remain under investigation (15,16).

Conclusion

ADD is a progressive retinal dystrophy which carries significant visual morbidity secondary to CNV. Early genetic diagnosis enables genetic counselling and proactive monitoring for the aforementioned sight-threatening complications. Future therapies targeting fibulin-3 accumulation may help to augment disease progression; intravitreal anti-VEGF remains the mainstay treatment for CNV. ADD is an important differential diagnosis to consider in younger patients with drusen, particularly those with a family history and bilateral deposits.

References

1.        Gregory CY, Evans K, Wijesuriya SD, Kermani S, Jay MR, Plant C, et al. The gene responsible for autosomal dominant Doyne’s honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16. Hum Mol Genet. 1996;5(7).

2.        Stone EM, Lotery AJ, Munier FL, Héon E, Piguet B, Guymer RH, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. 1999 [cited 2025 Feb 2]; Available from: https://genetics.nature.com/web_specials/

3.        Hulleman JD, Kaushal S, Balch WE, Kelly JW. Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. 2011;22.

4.        Marmorstein LY, Mclaughlin PJ, Peachey NS, Sasaki T, Marmorstein AD. 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. [cited 2025 Feb 2]; Available from: https://academic.oup.com/hmg/article/16/20/2423/562454

5.        Michaelides M, Jenkins SA, Brantley MA, Andrews RM, Waseem N, Luong V, 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 [Internet]. 2006 Jul 1 [cited 2025 Feb 2];47(7):3085–97. Available from: https://www.ncbi.nlm.nih.

6.        Zech JC, Zaouche S, Mourier F, Plauchu H, Grange JD, Trepsat C. Macular dystrophy of malattia leventinese. A 25 year follow up. British Journal of Ophthalmology [Internet]. 1999 Oct 1 [cited 2025 Feb 2];83(10):1194–1194. Available from: https://bjo.bmj.com/content/83/10/1194.7

7.        Piguet B, Haimovici R, Bird AC. Dominantly inherited drusen represent more than one disorder: A historical review. Eye 1995 9:1 [Internet]. 1995 [cited 2025 Feb 2];9(1):34–41. Available from: https://www.nature.com/articles/eye19955

8.        de Guimarães TAC, Kalitzeos A, Mahroo OA, van der Spuy J, Webster AR, Michaelides M. A Long-Term Retrospective Natural History Study of EFEMP1-Associated Autosomal Dominant Drusen. Invest Ophthalmol Vis Sci. 2024;65(6).

9.        Héon E, Piguet B, Munier F, Sneed SR, Morgan CM, Forni S, et al. Linkage of Autosomal Dominant Radial Drusen (Malattia Leventinese) to Chromosome 2p16-21. Archives of Ophthalmology [Internet]. 1996 Feb 1 [cited 2025 Feb 2];114(2):193–8. Available from: https://jamanetwork.com/journals/jamaophthalmology/fullarticle/641514

10.      Rahman N, Georgiou M, Khan KN, Michaelides M. Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options. British Journal of Ophthalmology [Internet]. 2020 Apr 1 [cited 2025 Feb 2];104(4):451–60. Available from: https://bjo.bmj.com/content/104/4/451

11.      Georgiou M, Fujinami K, Vincent A, Nasser F, Khateb S, Vargas ME, et al. KCNV2-Associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints—KCNV2 Study Group Report 2. Am J Ophthalmol [Internet]. 2021 Oct 1 [cited 2025 Feb 2];230:1–11. Available from: https://www.ajo.com/article/S0002939421001173/fulltext

12.      De Guimaraes TAC, Georgiou M, Bainbridge JWB, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. British Journal of Ophthalmology [Internet]. 2021 Feb 1 [cited 2025 Feb 2];105(2):151–7. Available from: https://bjo.bmj.com/content/105/2/151

13.      Mishra A V., Vermeirsch S, Lin S, Martin-Gutierrez MP, Simcoe M, Pontikos N, et al. Sex Distributions in Non-ABCA4 Autosomal Macular Dystrophies. Invest Ophthalmol Vis Sci [Internet]. 2024 May 1 [cited 2025 Feb 2];65(5). Available from: https://pubmed.ncbi.nlm.nih.gov/38700873/

14.      Geraldo R, Filho G, Zacharias LC, Monteiro V, Preti RC, Pimentel SG. Prevalence of outer retinal tubulation in eyes with choroidal neovascularization. Int J Retin Vitr. 2016;2:6.

15.      Tayyab H, Ahmed CN, Sadiq MAA. Efficacy and safety of Suprachoroidal Triamcinolone Acetonide in cases of resistant diabetic Macular Edema. Pak J Med Sci [Internet]. 2020 Jan 1 [cited 2025 Feb 2];36(2):42. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6994882/

16.      Georgiou M, Kalitzeos A, Patterson EJ, Dubra A, Carroll J, Michaelides M. Adaptive optics imaging of inherited retinal diseases. British Journal of Ophthalmology [Internet]. 2018 Aug 1 [cited 2025 Feb 2];102(8):1028–35. Available from: https://bjo.bmj.com/content/102/8/1028

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