Genotype-Phenotype Correlations in Vitelliform Macular Dystrophy

Abstract

Purpose: : To determine the phenotypic variability in vitelliform macular dystrophy (VMD) patients with VMD2 mutations.

Methods: : VMD patients with VMD2 mutations, were evaluated prospectively regarding age, age at onset, best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), fluorescein angiography (FA), optical coherence tomography (OCT), electro-oculography (EOG).

Results: : Forty-two eyes of 21 patients (9 male, 12 female) were included in the study. We identified 8 different VMD2 mutations (8 heterozygous [1 novel], and 1 homozygous), in 9 unrelated families. Patients presented with various stages of the disease, form absence of clinically detectable lesions / previtelliform lesions to end-stage lesions (ie, patient FG04 [exon 7 Ala243Val] / patient CT02 [exon 7 Ile264The], and patient CT01 [exon 4 Arg92Cys] or patient CT09 [exon 2 arg25trp], respectively). Mean age was 26.43±20.66 years. Age at onset varied between 2 and 67 years (median= 17). BCVA ranged between 20/20 and 20/200 (median, 20/40). Even with the same mutation, the age at onset and the disease progression (stage of the disease, and visual function) was highly variable interfamilially and intrafamilially. In VMD and multifocal VMD patients with VMD2 mutations, early stage lesions had accumulation of yellowish material within the macula, and within and/or outside the macular area, respectively. This material was highly autofluorescent and appeared as hyper-reflective dome-shaped lesion located between the hypo-reflective outer nuclear layer and the hyper-reflective retinal pigment epithelium (RPE) layer. Later stages were characterized by partial/complete resorption of the yellowish material, which was replaced by a fluid component showing no increased fluorescence on FAF and reflectivity on OCT examination. Late lesions were characterized by partial/complete atrophy or fibrosis within the area previously occupied by the yellowish material. FA showed both masking effects, due to accumulation of material, and transmission defects due to resorption of material, with a suggestion of late leakage. The electro-oculogram showed an abnormal light peak to dark trough ratio in all affected eyes. Mean BCVA impairment showed a statistically significant correlation to an advanced stage of the disease (P < .001).

Conclusions: : The type of VMD2 mutations were not correlated with the severity of the phenotype in the VMD patients determined.

Keywords: retinal degenerations: hereditary • genetics • imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound)