Doyne Honeycomb Retinal Dystrophy

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Doyne Honeycomb Retinal Dystrophy, also known as Malattia Leventinese or Familial Dominant Drusen, all refer to the same genetic inherited retinal dystrophy characterized by an autosomal dominant mutation in the EFEMP1 gene in which patients develop early onset macular and peripapillary drusen that are often oriented radially, initially described as a "Honeycomb" pattern by Doyne in 1899.

Disease Entity

Doyne Honeycomb Retinal Dystrophy (DHRD) or Malattia Leventinese (MLVT) or Dominant Drusen can be coded under the header H35.5 for Hereditary Retinal Dystrophy.

  • H35.50 - Unspecified hereditary retinal dystrophy
  • H35.51 - Vitreoretinal dystrophy
  • H35.52 - Pigmentary retinal dystrophy
  • H35.53 - Other dystrophies primarily involving the sensory retina
  • H35.54 - Dystrophies primarily involving the retinal pigment epithelium

Disease and History

Doyne Honeycomb Retinal Dystrophy (DHRD) was first described phenotypically by Doyne in 1899 in four sisters in England[1]. He found that each had an early onset retinal dystrophy with closely grouped white lesions in the macula and disc area which he termed "Honeycomb" pattern. Vogt in 1925 then described a similar phenotypic picture in a cluster of likely related individuals in the Leventine Valley of Switzerland, thus spawning the name Malattia Leventinese (MLVT) [2]. There had been suspicion for a period of time that the two separately described entities likely referenced the same disease given their similarities, and in 1996 both DHRD and MLVT were mapped to abnormalities in chromosome 2, first by Heon in patients with MLVT[3], then by Gregory shortly after for patients with DHRD[4]. Even in light of this discovery in 1996, it was still thought that the two diseases may represent separate entities.

However in 1999, Stone et al.[5] identified a single mutation in the EFEMP1 gene on chromosome 2 in both families with DHRD and MLVT, confirming that the two represented slight phenotypic variances of the same disease, and thus why we now consider them to be the same clinical entity.

Risk Factors

Since Doyne Honeycomb Retinal Dystrophy results from an autosomal dominant mutation in the EFEMP1 gene, having an affected family member is the only identifiable risk factor

Pathophysiology and Genetics

Doyne Honeycomb Retinal Dystrophy is characterized by an autosomal dominant mutation in the EFEMP1 gene, specifically a single missense Arg345Trp mutation

EFEMP1 stands for EGF-containing fibrillin-like extracellular matrix protein 1, and the gene coding for it lies on chromosome 2p16

Normally, EFEMP1 is widely expressed in the extracellular matrix, however, its exact function is unknown.

Fu et al. 2007 proved the EFEMP1 mutation to be pathological by showing EFEMP1 R345W knockin mice develop deposits between Bruch's membrane and RPE. They stated that the deposits may contain increased amounts of mutated EFEMP1 proteins as well as TIMP3 protein, and that this may lead to basal deposit formation. Their research also showed that R345W knockin mice demonstrated evidence of alterations in RPE cell ultrastructure, and that basal deposits and alterations in RPE cell ultrastructure were associated with increased with increased levels of C3 compliment activation[6].

Doyne Honeycomb dystrophy represents a unique heritable macular retinal dystrophy, in which the drusen that form and sequelae including geographic atrophy and choroidal neovascularization closely represent age-related macular degeneration, thus making EFEMP1 an important protein in the study of AMD parthenogenesis, modeling, and therapeutic studies.

Diagnosis

Diagnosis of Doyne Honeycomb Retinal Dystrophy is made clinically, and must be confirmed with genetic testing to prove a EFEMP1 mutation.

History and Symptoms

Patients may be asymptomatic early in the course of disease, most not experiencing symptoms until the 4th and 5th decade of life. Patients may describe an initial insidious onset of visual disturbances such as blurry vision, photopsias, scotomas, metamorphopsias, and dyschromatopsias. In advanced stages, in the 7th and 8th decades of life, central vision is involved, and visual acuity can be worse than 20/200. Large differences in severity and progression can be seen between eyes of the same patient [7][8], as well between patients in the same family[8], with more advanced central vision loss depending on presence or absence of choroidal neovascular membranes (CNVM) and geographic atrophy.

Physical examination

The disease is typically characterized by early-onset drusenoid deposits involving the posterior pole and the peripapillary area. The deposits are characteristically described as multiple "radially elongated" or "honeycomb pattern" small drusen in early stages, but can become indistinguishable from deposits in advanced AMD in later stages as they become larger and more confluent. Pigmentary changes often occur as the disease progresses . CNVM can form, with subsequent scarring, and in advanced stages geographic atrophy can occur in the areas of confluent drusen.

Doyne Honeycomb fundus photo - Courtesy of Dr. Marc Mathias
Notice the radially elongated drusen temporally that is characteristic of DHRD - Courtesy of Dr. Marc Mathias

Imaging

Spectral domain optical coherence tomography (SD-OCT) imaging can reveal focal dome-shaped, saw-tooth, or diffuse hyperreflective deposits with elevation between the RPE and Bruch's membrane, usually becoming more confluent over time[9]. Early in disease, the outer retina (photoreceptors) may remain intact, but later stages can show variable or diffuse ellipsoid zone loss and outer segment disruption. OCT can also reveal hypo-reflective fluid from a corresponding neovascular membrane. Diffuse retinal atrophy can be seen in later stages.

OCT of the same patient, showing drusenoid deposits between the RPE and Bruch's, with areas of overlying outer retinal atrophy. Courtesy of Dr. Marc Mathias

Fundus autofluorescence (FAF) can reveal hypo or hyper-autofluorescence of drusen, with one study showing larger drusen were more typically hyper-autofluorescent [9]. This increased autofluorescence associated with drusen in DHRD (and in other genetic drusen forming maculopathies) seems to be in contrast to typical drusen of AMD, where there is generally little correspondence between distribution of drusen and FAF[9][10]. Central areas may be hypo-autofluorescent due to central geographic atrophy and loss or dysfunction of RPE.

Fluoroscein angiography (FA) can reveal presence of CNVM with leakage, and large drusen are typically hyper-fluorescent in late stages[9]. Variable hypo or hyperfluorescence can be seen in areas of pigmentary changes, atrophy, and scarring.

Genetic Testing

Patients with suspected DHRD or any early onset maculopathy should be considered for genetic testing, which can confirm mutation of the EFEMP1 gene. There are several commercially available genetic tests for inherited retinal diseases and dystrophies. A list of these tests can be found via the NCBI genetic testing registry below.

https://www.ncbi.nlm.nih.gov/gtr/conditions/C0854723/

Differential diagnosis

Differential diagnosis of any patient with early-onset drusen should include any of the hereditary maculopathies and pattern dystrophies:

  • Stargardt Disease
  • Autosomal Dominant Stargardt-Like Macular Dystrophy
  • North Carolina Macular Dystrophy
  • Sorsby Fundus Dystrophy
  • Best Disease
  • Pattern Dystrophies
  • Age-related Macular Degeneration (if presenting at more advanced age)

Management

Currently, there is no genetic or targeted therapies to correct the underlying EFEMP1 genetic mutation in DHRD.

Typically, patients with DHRD are managed conservatively with observation, unless a CNVM develops.

CNVM in DHRD is typically treated with a series of intravitreal anti-VEGF injections[11].

One case report showed functional improvement using sub threshold retinal laser in a patient with DHRD [12].

Patients with a confirmed EFEMP1 mutation should have their children screened for involvement.

Follow up

We recommend annual follow up with OCT imaging in patients without CNVM.

Prognosis

Prognosis is variable, not only between patients but also between the eyes of the same patient. Central visual acuity can be excellent, but generally worsens with age, with vision less than 20/200 in the 7th and 8th decades of life not being uncommon in some cases.

Additional Resources

Online Mendelian Inheritence in Man https://www.omim.org/entry/126600

References

  1. Doyne, R.W. Peculiar condition of choroiditis occurring in several members of the same family. Trans. Ophthalmol. Soc. UK 19, 71 –71 (1899).
  2. Vogt, A. in Handbuch der gesammten Augenheilkunde. Untersuchungsmethoden (eds Graefe, A. & Saemisch, T.) 1–118 (Verlag von Wilhelm Engelman, Berlin, 1925).
  3. Héon, Elise, et al. "Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16-21." Archives of ophthalmology 114.2 (1996): 193-198.
  4. Gregory, Cheryl Y., et al. "The gene responsible for autosomal dominant Doyne's honeycomb retinal dystrophy (DHRD) maps to chromosome 2p16." Human molecular genetics 5.7 (1996): 1055-1059.
  5. Stone, Edwin M., et al. "A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy." Nature genetics 22.2 (1999): 199-202.
  6. Fu, Li, et al. "The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice." Human molecular genetics 16.20 (2007): 2411-2422.
  7. ZECH, JEAN-CHRISTOPHE, et al. "Macular dystrophy of malattia leventinese. A 25 year follow up." British journal of ophthalmology 83.10 (1999): 1194-1194.
  8. 8.0 8.1 Michaelides, Michel, et al. "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction." Investigative ophthalmology & visual science 47.7 (2006): 3085-3097.
  9. 9.0 9.1 9.2 9.3 Querques, Giuseppe, et al. "Multimodal morphological and functional characterization of Malattia Leventinese." Graefe's Archive for Clinical and Experimental Ophthalmology 251.3 (2013): 705-714.
  10. Michaelides, Michel, et al. "Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction." Investigative ophthalmology & visual science 47.7 (2006): 3085-3097.
  11. Sohn, Elliott H., 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." Archives of ophthalmology 129.12 (2011): 1626-1628.
  12. https://link.springer.com/article/10.1186/s13256-018-1935-1