Early-onset drusen in Malattia Leventinese with EFEMP1 mutation differ from drusen in age-related macular...

To study the clinical, genetic, and phenotypic aspects of Malattia Leventinese (ML)/Doyne honeycomb retinal dystrophy (DHRD) and to differentiate it from age-related macular degeneration (AMD).

Three cases of ML/DHRD from the Indian population were evaluated, including fundus examination, fundus autofluorescence (FAF), and swept-source optical coherence tomography (SSOCT). Genetic investigations involved screening for an inherited retinal gene panel using the Illumina MiSeq platform for one case. Pedigree charting, blood collection, DNA extraction, and variant annotation were performed, followed by pathogenicity assessment of the identified variants using multiple bioinformatics tools.

All cases exhibited early-onset central vision loss and small, radially distributed drusen, consistent with ML/DHRD. Genetic analysis done in patient one revealed a heterozygous, autosomal dominant, pathogenic mutation (c.1033C>T p.ARG345Trp) in the EFEMP1 gene, confirming the ML diagnosis. Patient 1 had no late-stage complications, whereas patients 2 and 3 developed macular neovascularization (MNV). OCT showed gross thickening of the retinal pigment epithelium with hyperreflectivity, along with outer retinal tubulations (ORT) and interlaminar bridges, indicating outer retinal degeneration.

Malattia Leventinese is a rare autosomal dominant macular dystrophy caused by a single EFEMP1 missense mutation (R345W), leading to early-onset radial or honeycomb drusen and central vision loss in the third decade. In this series, all patients showed typical radial drusen, with macular neovascularization in two cases, and demonstrated interlaminar bridges and ORTs on OCT. The mutant EFEMP1 protein misfolds and accumulates abnormally between the RPE and Bruch's membrane, accelerating drusen formation. Some phenotypic variability, including intrafamilial differences, likely reflects additional genetic or environmental modifiers. The presence of the R345W mutation, age at onset, and drusen distribution pattern are crucial for differentiating ML/DHRD from AMD.

The identified pathogenic EFEMP1 mutation (R345W) established a molecular link to ML/DHRD. Typical phenotypic patterns and drusen characteristics can differentiate ML/DHRD from AMD.