Multimodal Imaging of Dual BEST1/EFEMP1-Associated Hereditary Macular Disease

Purpose: To describe the morphological and functional features of two patients phenotypically and genotypically diagnosed with Best disease and autosomal dominant drusen (BD-ADD) using multimodal imaging. It is hypothesized that the concurrent presence of pathogenic mutations in both BEST1 and EFEMP1 genes is associated with a phenotype that may exhibit characteristic features of both diseases potentially revealing further additive effects on retinal function or structure. The data are compared with those from a patient with genetically confirmed ADD. Methods: The patients received a full ophthalmological investigation, including fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT) and polarization-sensitive optical coherence tomography (PS-OCT). Genetic analysis of DNA samples was performed by targeted whole-exome sequencing. Results: Macular SD-OCT demonstrated a thickened retinal pigment epithelium (RPE)-Bruch's membrane complex corresponding to macular drusen-like deposits in both ADD and BD-ADD cases. In contrast to isolated ADD, BD-ADD showed small hyperautofluorescent dots originating in hyperreflective photoreceptor debris at or above the RPE on FAF imaging. FAF further showed large hyperautofluorescent spots corresponding to sub-RPE drusen in both ADD and BD-ADD. The tissue-specific contrast of PS-OCT imaging allowed identification of the RPE within the macular lesion, structural changes of the subretinal material and incipient scar formation. Genetic analysis identified pathogenic mutations in both the BEST1 and the EFEMP1 gene in both BD-ADD cases. Conclusions: The characteristic morphological and functional features of both diseases are evident in the patients with the BD-ADD dual genotype. The coexistence of two independent autosomal dominant disorders provides an illustrative opportunity to inform our understanding of BEST1- and EFEMP1-mediated retinal disease.