Malattia Leventinese

Malattia Leventinese, also known as 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 characterized by the buildup of small, yellowish deposits called "drusen" under the retina. These deposits often form a distinct radial or "honeycomb" pattern. While the drusen usually start forming in early adulthood, most people do not notice any vision problems until they reach their 30s, 40s, or 50s. As the condition progresses, the drusen can grow and merge, leading to damage in the macula, the central part of the retina responsible for sharp, detailed vision. Patients may begin to experience blurry vision, distorted vision (where straight lines look wavy), or blind spots in their central vision. In some cases, abnormal blood vessels can grow under the retina (a complication similar to "wet" macular degeneration), which can cause sudden and severe vision loss if not treated promptly. Currently, there is no cure for Malattia Leventinese, but regular eye exams are crucial. Eye doctors monitor the condition closely to catch any abnormal blood vessel growth early, which can be treated with eye injections to help preserve vision. Because this is a genetic condition passed down through families, genetic testing and counseling are recommended for patients and their relatives to understand the risks and inheritance patterns.

Condition category: Macular Dystrophy

Prevalence: Less than 100 reported cases

Inheritance patterns: Autosomal Dominant

Age of onset: Second to fourth decade of life

Clinical overview: Malattia Leventinese (MLVT), also known as Doyne Honeycomb Retinal Dystrophy (DHRD) or familial dominant drusen, is a rare, inherited macular dystrophy characterized by the early onset of drusenoid deposits in the macula and peripapillary region. Historically described as two separate entities based on the geographic origins of the affected families (Switzerland and England), they are now recognized as the same clinical entity caused by a common genetic mutation. The condition is classified as a macular dystrophy and shares significant phenotypic overlap with age-related macular degeneration (AMD), making it an important model for understanding drusenogenesis. Clinically, the hallmark of the disease is the bilateral, progressive accumulation of yellow-white deposits (drusen) beneath the retinal pigment epithelium (RPE) within Bruch's membrane. These drusen typically appear in early adulthood and often arrange in a characteristic radial or "honeycomb" pattern. A distinguishing feature from typical AMD is the frequent presence of drusen extending nasal to the optic disc. As the disease advances, the drusen coalesce, leading to RPE dysfunction, pigmentary changes, and eventually geographic atrophy. While patients often remain asymptomatic for decades despite significant fundus changes, progressive central vision loss typically manifests in the fourth to fifth decades of life. The clinical course can be complicated by the development of secondary choroidal neovascularization (CNV), which can cause rapid and severe visual decline. Diagnosis is based on the characteristic clinical findings, multimodal imaging (including OCT and FAF), and is confirmed by molecular genetic testing identifying a mutation in the EFEMP1 gene. Management is currently supportive, focusing on monitoring for and treating CNV complications.

Patient and family guide: Malattia Leventinese, also known as 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 characterized by the buildup of small, yellowish deposits called "drusen" under the retina. These deposits often form a distinct radial or "honeycomb" pattern. While the drusen usually start forming in early adulthood, most people do not notice any vision problems until they reach their 30s, 40s, or 50s. As the condition progresses, the drusen can grow and merge, leading to damage in the macula, the central part of the retina responsible for sharp, detailed vision. Patients may begin to experience blurry vision, distorted vision (where straight lines look wavy), or blind spots in their central vision. In some cases, abnormal blood vessels can grow under the retina (a complication similar to "wet" macular degeneration), which can cause sudden and severe vision loss if not treated promptly. Currently, there is no cure for Malattia Leventinese, but regular eye exams are crucial. Eye doctors monitor the condition closely to catch any abnormal blood vessel growth early, which can be treated with eye injections to help preserve vision. Because this is a genetic condition passed down through families, genetic testing and counseling are recommended for patients and their relatives to understand the risks and inheritance patterns.

Symptoms and clinical features: Patients with Malattia Leventinese are typically asymptomatic during the early stages of the disease, even when drusen are clinically visible in the second or third decade of life. Symptoms usually have an insidious onset in the fourth or fifth decade. Early symptoms include mild blurry vision, difficulty adapting to the dark (nyctalopia), and photopsias (flashes of light). As the disease progresses, patients often experience metamorphopsia (distortion of straight lines), dyschromatopsia (impaired color vision), and paracentral scotomas (blind spots near the center of vision). In advanced stages, typically in the sixth decade and beyond, significant central vision loss occurs due to geographic atrophy. If complicated by choroidal neovascularization (CNV), patients may experience a sudden, rapid, and severe decline in central vision. The severity and progression of symptoms can vary significantly between individuals, even within the same family.

Molecular pathology: Malattia Leventinese is caused by mutations in the EFEMP1 gene, which encodes the protein fibulin-3 (EGF-containing fibulin-like extracellular matrix protein 1). Fibulin-3 is a widely expressed extracellular matrix protein that plays a critical role in maintaining tissue integrity, providing structural support, and regulating cell signaling pathways. In the eye, it is important for the structural organization of the extracellular matrix. The disease is almost exclusively associated with a specific hotspot missense mutation, Arg345Trp (R345W), in the EFEMP1 gene. This mutation disrupts the normal function and folding of fibulin-3. The mutant protein is thought to have secretion deficiencies, possibly due to reduced disulfide bonding, leading to its abnormal accumulation. This results in the formation of extensive deposits (drusen) between the retinal pigment epithelium (RPE) and Bruch's membrane. These deposits contain increased amounts of mutated EFEMP1 proteins as well as other components like TIMP3. The accumulation of these deposits leads to alterations in RPE cell ultrastructure, basal deposit formation, and increased complement activation. Additionally, the mutation may have a hyper-inhibitory effect on EGFR signaling, suppressing carboxyl esterase 1 (CES1), an enzyme responsible for exporting cholesterol. This decreased ability to mediate cholesterol efflux could contribute to the lipid accumulation found in the drusen, ultimately leading to RPE dysfunction, photoreceptor loss, and macular degeneration.

Genetics: Malattia Leventinese is inherited in an autosomal dominant pattern with high penetrance. It is caused by a specific mutation in the EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) gene, located on chromosome 2p16. The vast majority of cases are caused by a single recurrent missense mutation, Arg345Trp (R345W), in exon 10 of the EFEMP1 gene. Because it is an autosomal dominant condition, an affected individual has a 50% chance of passing the mutated gene to each child. While penetrance is high, expressivity can be variable, meaning the severity and progression of the disease can differ significantly even among affected members of the same family. Some individuals may remain asymptomatic for decades despite having visible drusen, while others may experience earlier and more severe vision loss. Genetic counseling is highly recommended for affected individuals and their families to discuss the risks of transmission, family planning options (including prenatal testing and preimplantation genetic diagnosis), and the importance of regular ophthalmic screening for at-risk relatives.

Diagnostic evaluation: Diagnosis of Malattia Leventinese (Doyne Honeycomb Retinal Dystrophy) is primarily clinical, supported by multimodal imaging and confirmed by genetic testing. Clinical examination typically reveals characteristic early-onset drusenoid deposits at the posterior pole, peripapillary area, and along vascular arcades, often in a radial or honeycomb pattern. Spectral-domain optical coherence tomography (SD-OCT) is crucial, demonstrating hyperreflective deposits with elevation between the retinal pigment epithelium (RPE) and Bruch's membrane. Fundus autofluorescence (FAF) typically shows hyper-autofluorescence corresponding to drusen, which contrasts with typical age-related macular degeneration. Fluorescein angiography (FA) and indocyanine green angiography (ICGA) are used to detect secondary choroidal neovascularization (CNV) and differentiate drusen types. Electroretinography (ERG) may show low-normal responses that become sub-normal in severe disease. Definitive diagnosis requires molecular genetic testing to identify the pathogenic variant (typically the R345W mutation) in the EFEMP1 gene.

Differential diagnosis: Age-related Macular Degeneration, Stargardt Disease, Autosomal Dominant Stargardt-Like Macular Dystrophy, North Carolina Macular Dystrophy, Sorsby Fundus Dystrophy, Best Disease, Pattern Dystrophies

Natural history: The natural history of Malattia Leventinese is characterized by a slowly progressive course. Drusen typically begin to accumulate in the second or third decade of life, initially presenting as small deposits in the macula and peripapillary region. During these early stages, patients are usually asymptomatic and maintain excellent visual acuity. As the disease progresses into the fourth and fifth decades, the drusen increase in size and number, often coalescing into a characteristic radial or "honeycomb" pattern. Patients may begin to experience insidious visual symptoms such as mild blurriness, metamorphopsia, and paracentral scotomas. In the later stages (sixth decade and beyond), progressive retinal pigment epithelium (RPE) atrophy and geographic atrophy occur, leading to more significant central vision loss. The clinical course can abruptly change to rapid and severe visual loss if complicated by the development of secondary choroidal neovascularization (CNV), which can lead to subretinal hemorrhage and disciform scarring.

Management and treatment research: ### Current management and monitoring There is no cure or treatment proven to stop drusen formation or prevent retinal atrophy in Malattia Leventinese, also called Doyne honeycomb retinal dystrophy. Care focuses on monitoring retinal changes, treating complications promptly, and supporting vision and daily activities. Regular follow-up with a retina specialist may include: - Dilated eye examinations - Visual acuity testing and discussion of changes in central vision - Optical coherence tomography (OCT), a noninvasive scan that provides detailed images of the retina - Retinal photography and, when needed, fluorescein angiography or OCT angiography to look for abnormal blood vessels People may be advised to monitor central vision at home with an Amsler grid. New distortion, straight lines that appear wavy, a new blurry or dark spot, or a sudden decline in vision should be reported promptly. These symptoms can sometimes signal choroidal neovascularization (CNV), in which abnormal blood vessels grow beneath the retina and may leak fluid or blood. Low-vision rehabilitation can help people maintain independence when central vision is affected. Support may include magnifiers, electronic reading devices, improved lighting, occupational therapy, and orientation and mobility services. ### Treatment of choroidal neovascularization If CNV develops, treatment commonly involves injections of anti-VEGF medicine into the eye. Anti-VEGF medicines block vascular endothelial growth factor (VEGF), a signal that promotes the growth and leakage of abnormal blood vessels. Medicines that may be used include: - Bevacizumab - Ranibizumab - Aflibercept A retina specialist individualizes the injection schedule based on symptoms, OCT findings, and signs of active leakage. Anti-VEGF treatment can reduce retinal fluid and help stabilize vision; some people may also have improved visual acuity. Thermal laser treatment and photodynamic therapy are generally not first-line options when anti-VEGF treatment is appropriate. ### Approved therapies No therapies are approved specifically for Malattia Leventinese or for preventing progression of its drusen and retinal atrophy. ### Investigational therapies There are currently no condition-specific investigational treatment programs listed in the available treatment pipeline data for Malattia Leventinese. Stem-cell approaches are being studied in a range of retinal diseases. These approaches are investigational and have not been established as effective treatments for Malattia Leventinese. ### Clinical trial participation One recruiting study is listed in the available clinical-trial data: - **NCT03011541** — *Stem Cell Ophthalmology Treatment Study II*; recruiting; MD Stem Cells This study is not identified as a Malattia Leventinese-specific treatment. People considering a clinical trial should discuss eligibility, possible risks and benefits, costs, follow-up needs, and study procedures with their retina specialist and the study team.

Outlook: The visual prognosis for Malattia Leventinese is generally fair in the early to middle stages of life, as patients often maintain good central vision for decades despite the presence of extensive drusen. However, the prognosis worsens with age. By the fifth or sixth decade, progressive geographic atrophy of the macula typically leads to a slow, irreversible decline in central visual acuity, often dropping to 20/200 or worse. The prognosis becomes significantly guarded if secondary choroidal neovascularization (CNV) develops, which can cause rapid and severe central vision loss if not promptly treated. While peripheral vision is usually spared, the loss of central vision significantly impacts reading, driving, and overall quality of life in advanced stages.

Epidemiology: Malattia Leventinese is a rare inherited retinal disorder. The exact incidence and prevalence are unknown, but it is considered extremely rare, with fewer than 100 cases reported in the literature. It was initially described in families from Oxford, England (as Doyne Honeycomb Retinal Dystrophy) and the Leventine Valley of Switzerland (as Malattia Leventinese). While it can affect individuals of various ethnicities, it has been documented in European, American, Indian, and Chinese families. There is no known gender predilection. Symptoms typically manifest in the fourth or fifth decade of life, though drusen can be observed much earlier, often by the second or third decade.

Selected references: 1. Stone EM, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999. 2. Michaelides M, 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. 3. Fu L, et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet. 2007. 4. de Guimarães TAC, et al. A Long-Term Retrospective Natural History Study of EFEMP1-Associated Autosomal Dominant Drusen. Invest Ophthalmol Vis Sci. 2024. 5. Marmorstein LY, 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.