Familial Drusen

Familial Drusen, also known as Malattia Leventinese or Doyne honeycomb retinal dystrophy, is a rare, inherited eye condition that affects the retina, the light-sensitive tissue at the back of the eye. It is caused by a specific change (mutation) in a gene called EFEMP1, which is passed down through families. This condition causes small, yellow deposits called drusen to build up under the retina. These deposits often form a distinct radiating or "honeycomb" pattern. In the early stages, usually during a person's 20s or 30s, these drusen may be present without causing any noticeable vision problems. However, as the person gets older, typically in their 40s or 50s, the drusen can increase in size and number. This buildup can start to interfere with the normal function of the retina, leading to symptoms such as blurry or distorted vision, difficulty seeing in low light, and trouble with tasks that require fine detail, like reading or recognizing faces. While there is currently no cure for Familial Drusen, regular eye exams are crucial for monitoring the condition. In some cases, abnormal blood vessels may grow under the retina (a complication similar to "wet" macular degeneration), which can cause sudden vision loss. If this happens, treatments are available to help manage it and preserve vision. Although central vision may decline over time, peripheral (side) vision usually remains unaffected, allowing most people to maintain their independence.

Condition category: Macular Dystrophy

Prevalence: Rare

Inheritance patterns: Autosomal Dominant, Autosomal Recessive

Age of onset: Second to third decade of life

Clinical overview: Note: Familial Drusen overlaps clinically with Dominant Drusen and Malattia Leventinese (Doyne Honeycomb Retinal Dystrophy). When caused by EFEMP1 mutations, these are considered the same entity. See also the Dominant Drusen and Malattia Leventinese entries. Familial Drusen, also known as Malattia Leventinese (MLVT) or Doyne honeycomb retinal dystrophy (DHRD), is a rare, inherited macular dystrophy characterized by the early onset of drusenoid deposits in the retina. These deposits, which are accumulations of extracellular material, typically appear between the retinal pigment epithelium (RPE) and Bruch's membrane. The condition is inherited in an autosomal dominant pattern and is caused by a specific mutation in the EFEMP1 gene. It is classified under OMIM #126600 and Orphanet #75376. Clinically, the disease is distinguished by the presence of multiple, small, radially elongated drusen that often form a "honeycomb" pattern in the macula and peripapillary region. A unique feature is the frequent involvement of the area nasal to the optic disc. While patients may develop these signs in their second or third decade of life, they often remain asymptomatic until their fourth or fifth decade. As the disease progresses, the drusen can become confluent, leading to RPE atrophy and subsequent visual impairment. The clinical significance of Familial Drusen lies not only in its impact on patients' vision but also in its phenotypic similarities to age-related macular degeneration (AMD). The drusen formation, potential for geographic atrophy, and risk of choroidal neovascularization (CNV) in Familial Drusen closely mirror the pathological processes seen in AMD. Consequently, studying the molecular mechanisms underlying Familial Drusen, particularly the role of the EFEMP1 protein, provides valuable insights into the pathogenesis of AMD and may help identify potential therapeutic targets for both conditions.

Patient and family guide: Familial Drusen, also known as Malattia Leventinese or Doyne honeycomb retinal dystrophy, is a rare, inherited eye condition that affects the retina, the light-sensitive tissue at the back of the eye. It is caused by a specific change (mutation) in a gene called EFEMP1, which is passed down through families. This condition causes small, yellow deposits called drusen to build up under the retina. These deposits often form a distinct radiating or "honeycomb" pattern. In the early stages, usually during a person's 20s or 30s, these drusen may be present without causing any noticeable vision problems. However, as the person gets older, typically in their 40s or 50s, the drusen can increase in size and number. This buildup can start to interfere with the normal function of the retina, leading to symptoms such as blurry or distorted vision, difficulty seeing in low light, and trouble with tasks that require fine detail, like reading or recognizing faces. While there is currently no cure for Familial Drusen, regular eye exams are crucial for monitoring the condition. In some cases, abnormal blood vessels may grow under the retina (a complication similar to "wet" macular degeneration), which can cause sudden vision loss. If this happens, treatments are available to help manage it and preserve vision. Although central vision may decline over time, peripheral (side) vision usually remains unaffected, allowing most people to maintain their independence.

Symptoms and clinical features: The clinical presentation of Familial Drusen (Malattia Leventinese) evolves over several decades, with symptoms correlating with the progressive accumulation of drusen and subsequent retinal changes. In the early stages, typically during the second and third decades of life, patients are almost always asymptomatic. The condition is often discovered incidentally during a routine fundus examination, which reveals the characteristic small, radially elongated drusen in the macula and peripapillary area. Despite the presence of these deposits, visual acuity remains normal, and patients do not report any visual disturbances. As the disease progresses into the intermediate stages, usually in the fourth and fifth decades, patients begin to experience mild to moderate visual symptoms. The drusen become larger, more numerous, and start to coalesce. Patients may notice a gradual decrease in central visual acuity, making tasks like reading fine print more difficult. Metamorphopsia, or distortion of straight lines, is a common complaint due to the physical elevation of the retina by the underlying drusen. Additionally, patients may report paracentral scotomas (small blind spots near the center of vision) and difficulties with dark adaptation or seeing in low-light conditions. In the advanced stages, typically occurring in the sixth decade and beyond, the visual impairment becomes more pronounced. The confluent drusen can lead to geographic atrophy of the retinal pigment epithelium (RPE) and overlying photoreceptors, resulting in significant central vision loss. A critical complication at this stage is the development of choroidal neovascular membranes (CNVM), which can cause sudden, severe vision loss due to subretinal hemorrhage and fluid accumulation. If a CNVM develops and scars, it can lead to a dense central scotoma. However, it is important to note that even in advanced disease, the peripheral retina is usually spared, allowing patients to retain their peripheral vision and navigational abilities.

Molecular pathology: The molecular pathology of Familial Drusen (Malattia Leventinese) is driven by a specific missense mutation (R345W) in the EFEMP1 gene, which encodes the EGF-containing fibulin-like extracellular matrix protein 1. EFEMP1 is a secreted glycoprotein that is widely expressed in various tissues, including the eye, where it is normally found in the extracellular matrix. While its exact physiological function is not fully understood, it is believed to play a role in maintaining the structural integrity and function of the extracellular matrix. The R345W mutation leads to the production of an abnormal EFEMP1 protein that is prone to misfolding and aggregation. This mutated protein accumulates abnormally within the cells, particularly in the retinal pigment epithelium (RPE), and is subsequently secreted and deposited in the extracellular space between the RPE and Bruch's membrane. These deposits form the characteristic drusen seen clinically. The accumulation of mutated EFEMP1 is thought to disrupt the normal turnover of extracellular matrix components and impair the function of the RPE. Downstream cellular effects of this abnormal protein accumulation include alterations in RPE cell ultrastructure and function. Studies have shown that the mutated EFEMP1 may have a hyper-inhibitory effect on certain signaling pathways, such as EGFR signaling, leading to the suppression of enzymes like carboxyl esterase 1 (CES1). This suppression impairs the RPE's ability to mediate cholesterol efflux, contributing to the lipid accumulation characteristic of drusen. Furthermore, the presence of these abnormal deposits and the resulting cellular stress can trigger localized inflammation and complement activation, further exacerbating RPE dysfunction and contributing to the progressive retinal degeneration and potential development of choroidal neovascularization.

Genetics: Familial Drusen, also known as Malattia Leventinese or Doyne honeycomb retinal dystrophy, is inherited in an autosomal dominant pattern. This means that a single copy of the mutated gene, inherited from either parent, is sufficient to cause the disorder. Consequently, an affected individual has a 50% chance of passing the mutated gene to each of their children. The condition exhibits high penetrance, meaning most individuals who inherit the mutation will eventually develop clinical signs of the disease, although the age of onset and severity can vary significantly even within the same family. The disease is caused by a specific mutation in the EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) gene, located on chromosome 2p16.1. The hallmark genetic alteration is a single missense mutation, specifically an arginine-to-tryptophan substitution at position 345 (Arg345Trp or R345W) in exon 10 of the EFEMP1 gene. This specific mutation was identified as the underlying cause for both the Doyne honeycomb retinal dystrophy and Malattia Leventinese phenotypes, confirming they are the same clinical entity. While the R345W mutation in EFEMP1 is the primary known cause, the phenotypic expression can be variable. Some patients may present with early, severe visual impairment and extensive drusen, while others may remain relatively asymptomatic until later in life. This variable expressivity suggests that other genetic or environmental factors may influence the disease course, although specific modifier genes have not been definitively established. Genetic testing for the EFEMP1 R345W mutation is the standard for confirming the diagnosis and providing accurate genetic counseling.

Diagnostic evaluation: Diagnosis of Familial Drusen (Malattia Leventinese) is primarily clinical, supported by multimodal imaging and confirmed by genetic testing. Fundoscopy reveals characteristic early-onset drusenoid deposits at the posterior pole, peripapillary area, center of the macula, and along vascular arcades. These deposits often form a radially elongated or "honeycomb" pattern in early stages. As the disease progresses, the drusen may become larger and confluent, indistinguishable from those seen in advanced age-related macular degeneration (AMD). Involvement nasal to the optic disc is a typical and distinguishing feature. Spectral domain optical coherence tomography (SD-OCT) is crucial for evaluating the structural changes in the retina. It typically shows focal dome-shaped, saw-tooth, or diffuse hyperreflective deposits with elevation between the retinal pigment epithelium (RPE) and Bruch's membrane. Over time, these deposits become more confluent. In later stages, OCT may reveal variable or diffuse ellipsoid zone loss, outer and inner segment disruption, and diffuse retinal atrophy. It is also essential for detecting hyporeflective subretinal fluid indicative of a choroidal neovascular membrane (CNVM). Electrophysiological testing, such as full-field electroretinography (ffERG) and multifocal ERG (mfERG), can be used to assess retinal function, though findings may be normal in early stages. As the disease advances, mfERG may show reduced central responses corresponding to areas of macular atrophy. Genetic testing is the definitive diagnostic tool, confirming the presence of a pathogenic variant in the EFEMP1 gene, specifically the R345W mutation. The differential diagnosis includes other early-onset macular dystrophies such as Stargardt disease, Sorsby fundus dystrophy, North Carolina macular dystrophy, Best disease, and pattern dystrophies.

Differential diagnosis: Differential diagnosis of familial drusen (Malattia Leventinese) includes: (1) Age-related macular degeneration — later onset, no autosomal dominant inheritance, no radial pattern. (2) Doyne honeycomb retinal dystrophy — same condition (allelic with EFEMP1 mutations). (3) Sorsby fundus dystrophy — subretinal deposits with early CNV, TIMP3 mutations. (4) North Carolina macular dystrophy — nonprogressive, congenital, PRDM13 mutations. (5) Membranoproliferative glomerulonephritis type II — drusen-like deposits with renal disease, complement dysregulation. (6) Cuticular drusen — numerous small uniform drusen, stars-in-the-sky pattern on FA.

Natural history: The natural history of Familial Drusen (Malattia Leventinese) is characterized by a progressive accumulation of drusenoid deposits and a gradual decline in visual function. The onset of clinical signs, specifically the appearance of drusen, typically occurs in the second or third decade of life, although it can occasionally be seen earlier. Initially, patients are usually asymptomatic, and the drusen may be discovered incidentally during a routine eye examination. As the disease progresses into the fourth and fifth decades, patients often begin to experience visual symptoms. The drusen become more numerous, larger, and confluent, leading to alterations in the overlying retinal pigment epithelium (RPE) and photoreceptors. Symptoms at this intermediate stage may include mild to moderate decreased visual acuity, metamorphopsia (distortion of vision), paracentral scotomas, and difficulties with dark adaptation. The rate of progression can vary significantly among individuals, even within the same family. In the advanced stages, typically occurring in the sixth decade and beyond, patients may experience more severe central vision loss. This is often due to the development of geographic atrophy, where areas of the RPE and photoreceptors degenerate completely. Additionally, a significant prognostic factor is the potential development of choroidal neovascular membranes (CNVM), which can cause sudden and severe vision loss due to fluid leakage and scarring in the macula. Despite these complications, peripheral vision is generally preserved throughout the patient's life.

Management and treatment research: ### Current Management and Monitoring There is currently no cure for familial drusen, also called Malattia Leventinese or Doyne honeycomb retinal dystrophy. The condition is most often associated with changes in the **EFEMP1** gene. Care focuses on monitoring the retina, preserving useful vision, and identifying complications early. - Regular follow-up with a retina specialist may include dilated eye examinations, visual-acuity testing, and **optical coherence tomography (OCT)**. OCT is a noninvasive scan that provides detailed images of retinal layers and can detect fluid or other changes. - Monitoring central vision at home with an **Amsler grid** may be recommended. New wavy or distorted lines, a dark or missing area in central vision, or a sudden change in vision should be reported promptly. - Low-vision rehabilitation can help with reading, mobility, work, and daily activities when central vision is affected. Options may include magnifiers, electronic reading devices, glare-control lenses, improved lighting, and training in adaptive strategies. - Supplements used for age-related macular degeneration (AMD), including AREDS or AREDS2 formulations, have not been shown to slow EFEMP1-related familial drusen. A retina specialist can help determine whether they are appropriate for an individual’s overall eye health. ### Treatment of Retinal Complications Some people with familial drusen develop **macular neovascularization**, in which abnormal blood vessels grow beneath or within the retina. These vessels can leak fluid or blood and may cause relatively rapid changes in central vision. When macular neovascularization occurs, treatment commonly involves injections into the eye of medicines that block **vascular endothelial growth factor (VEGF)**, a signal that promotes abnormal blood-vessel growth. Anti-VEGF medicines, such as bevacizumab, ranibizumab, and aflibercept, may be used to treat this complication. Vision testing and OCT imaging help guide treatment timing and monitor response. ### Approved Therapies There are no therapies approved specifically to treat the underlying genetic cause of familial drusen or to remove drusen caused by EFEMP1-related disease. Anti-VEGF medicines are established treatments for macular neovascularization. They treat this potentially vision-threatening complication when it occurs, rather than the inherited condition itself. ### Investigational Therapies There are currently no disease-specific treatment candidates listed for familial drusen. In particular, no registered gene therapy, cell therapy, or medication study is currently listed as targeting **EFEMP1**-related familial drusen. Research into the genetic and biological processes involved in drusen formation may support future treatment development. At present, potential disease-modifying approaches remain experimental. ### Clinical Trial Participation No recruiting clinical trials specifically for familial drusen are currently listed. - **NCT01115387**: *GARM II: A Study on the Genetics of Age-related Maculopathy* is active but not recruiting. This is a genetics study, not a treatment trial. - **NCT07409389**: *Repeated Low-Level Red-Light Therapy in Dry Age-Related Macular Degeneration* is not yet recruiting. Familial drusen is distinct from AMD, and eligibility would need to be confirmed with the study team. - **NCT07135245**: *Improved Treatment and Monitoring of Alzheimer's Disease* is not yet recruiting and is not a familial drusen treatment study. People interested in research participation can discuss genetic testing, registries, and referral to an inherited retinal disease specialist with their retina provider.

Outlook: The prognosis for visual outcomes in Familial Drusen (Malattia Leventinese) is generally favorable in the early decades of life, but central vision often declines as the disease progresses. Most patients maintain good visual acuity and remain asymptomatic until their fourth or fifth decade. However, as drusen become confluent and geographic atrophy develops, patients typically experience a gradual decrease in central vision, metamorphopsia, and reading difficulties. The most significant factor negatively affecting prognosis is the development of choroidal neovascularization (CNV), which can lead to sudden, severe central vision loss if left untreated. Despite the progressive loss of central vision in advanced stages, peripheral vision is typically spared, allowing patients to maintain mobility and independence. Quality of life considerations primarily revolve around adapting to central vision impairment. Patients may require low vision aids, such as magnifiers and enhanced lighting, to assist with daily activities like reading and recognizing faces. Regular monitoring by an ophthalmologist is essential for early detection and treatment of complications like CNV, which can help preserve visual function and maintain a better quality of life for as long as possible.

Epidemiology: Familial Drusen (Malattia Leventinese) is a rare inherited retinal dystrophy, with an exact prevalence that remains unknown but is estimated to be approximately 1 in 5,000 individuals. The condition was initially described in two distinct populations: a family in Oxford, England (Doyne honeycomb retinal dystrophy) and a cluster of individuals in the Leventine Valley of Switzerland (Malattia Leventinese). While originally thought to be separate entities, they are now recognized as the same disease caused by the same genetic mutation. The condition affects both males and females equally, consistent with its autosomal dominant inheritance pattern. Due to its rarity, large-scale epidemiological studies are limited, but cases have been reported globally across various ethnic groups.

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