Abstract
To assess the progression of Stargardt (STGD) disease over nine years in two branches of a large consanguineous Tunisian family. Initially, different phenotypes were observed with clinical intra- and interfamilial variations. At presentation, four different retinal phenotypes were observed. In phenotype 1, bull's eye maculopathy and slight alteration of photopic responses in full-field electroretinography were observed in the youngest child. In phenotype 2, macular atrophy and yellow white were observed in two brothers. In phenotype 3, diffuse macular, peripapillary, and peripheral RPE atrophy and hyperfluorescent dots were observed in two sisters. In phenotype 4, Stargardt disease-fundus flavimaculatus phenotype was observed in two cousins with later age of onset. After a progression of 9 years, all seven patients displayed the same phenotype 3 with advanced stage STGD and diffuse atrophy. WES and MLPA identified two ABCA4 mutations M1: c.[(?_4635)_(5714+?)dup; (?_6148)_(6479_+?) del] and M2: c.[2041C>T], p.[R681∗]. In one branch, the three affected patients had M1/M1 causal mutations and in the other branch the two affected patients had M1/M2 causal mutations. After 9-year follow-up, all patients showed the same phenotypic evolution, confirming the progressive nature of the disease. Genetic variations in the two branches made no difference to similar end-stage disease.
Highlights
The ATP-binding cassette transporter ABCA4, known as ABCR, is a member of the ATP-binding cassette transporter gene subfamily A [1]
Patients III3 and III6 with Stargardt disease (STGD)-FFM phenotype 2, associating macular atrophy, yellow-white dots, hyperfluorescent atrophic spots, and silent choroid, developed diffuse macular, peripapillary, and retinal pigment epithelium (RPE) atrophy extending beyond the vascular arcades
Primary STGD phenotype 3 III1 and III2 patients with diffuse macular, peripapillary, and peripheral RPE atrophy and hyperfluorescent dots progressed to severe cone-rod dystrophy (CRD), with extensive areas of atrophy, pigment clumping, and migration throughout the posterior pole involving the peripheral retina
Summary
The ATP-binding cassette transporter ABCA4, known as ABCR, is a member of the ATP-binding cassette transporter gene subfamily A [1]. ABCA4 is important in the visual cycle, as a retinoid transporter of the toxic all-trans retinal out of the disc for recycling by the retinal pigment epithelium (RPE) [4]. Without this function, an accumulation of toxic all-transretinal derivatives in rods and cones may cause an apoptosis of the supporting retinal pigment epithelium cells and, degeneration of photoreceptors [5, 6]. Mutations in ABCA4 gene are known to cause Stargardt disease (STGD) which is the most frequent macular dystrophy [7] and typically presents with central macular atrophy and yellow-white dots at the posterior pole, primarily at the level of the RPE. Additional diseases were linked to mutations in ABCA4 including fundus flavimaculatus, l ll Journal of Ophthalmology lll
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