Purpose: To investigate the effect of ABCA4 mutation status on lipofuscin-related quantitative autofluorescence (qAF) in humans and on bisretinoid accumulation in mice. Methods: Genotyped parents (n = 26; age 37–64 years) of patients with biallelic ABCA4-related retinopathy underwent in-depth retinal phenotyping including qAF imaging as a surrogate measure for RPE lipofuscin accumulation. In addition, bisretinoids as the main components of autofluorescent lipofuscin at the ocular fundus were quantified in Abca4−/−, Abca4+/−, and wild-type mice. Results: Index patients showed a retinal phenotype characteristic for ABCA4-related retinopathy, including increased qAF levels. In contrast, qAF measures in carriers of only one ABCA4 mutation were not different from age-matched controls in this sample, and there was no difference between truncating and missense mutations. Also, none of these carriers presented an abnormal phenotype on conventional imaging. One parent with ABCA4-related retinopathy and increased qAF carried an additional ABCA4 mutation, explaining the phenotype under a recessive disease model (pseudodominance). Biochemical analysis in the mouse model revealed direct downstream products (A2PE-H2, at-RALdimer-PE) of the ABCA4 substrate N-Ret-PE to be similar in wild-type and Abca4+/− mice. Both bisretinoids were 12- to 18-fold increased in Abca4−/− mice. Levels of A2E and A2PE in Abca4+/− mice were in between those measured in wild-type and Abca4−/− mice. Conclusions: This study indicates that carriers of monoallelic ABCA4 mutations are phenotypically normal. However, biochemical analysis in the Abca4-deficient mouse model suggests detectable effects of one mutation in ABCA4 on the molecular level. The findings may have implications for therapeutic approaches such as gene replacement therapy.
The purpose of this study was to investigate morphologic differences in a consecutive case series of patients suffering from adult-onset vitelliform macular dystrophy with cuticular drusen (CD) compared with another patient group with a vitelliform lesion only using high-resolution in vivo retinal imaging.Simultaneous spectral domain optical coherence tomography (870 nm, 40.000 A-scans per second) and confocal scanning laser ophthalmoscopy were performed in 6 patients (12 eyes) with adult-onset vitelliform macular dystrophy using a combined instrument (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany).Mean age was 69 years (59-82 years), and mean visual acuity was 20/80. The vitelliform lesion presented with an accumulation of yellow-gray material with increased fundus autofluorescence. Spectral domain optical coherence tomography imaging showed that the neurosensory detachment was filled with an amorphous homogenously reflective material located between the retinal pigment epithelium and neurosensory retina in the inferior part of the lesion with the superior part being optically empty. The retinal pigment epithelium basal membrane/Bruch membrane band on spectral domain optical coherence tomography showed multiple focal nodules, in analogy to histologic descriptions of CD. Longitudinal observations in a subgroup of patients showed that the vitelliform detachment collapsed with subsequent development of geographic atrophy in patients with CDs.Cuticular drusen may be an indicator for a generalized retinal pigment epithelium dysfunction. High-resolution spectral domain optical coherence tomography allows to image morphologic differences in adult-onset vitelliform macular dystrophy with and without CDs, providing further evidence that adult-onset vitelliform macular dystrophy with CDs represents a separate disease entity.
Purpose: To evaluate dark adaptation (DA) in patients with macular telangiectasia Type 2 (MacTel). Methods: After a local photobleach (4 × 4° size, 83% bleach), DA was measured using a test stimulus (2° diameter) projected at 5° eccentricity horizontal from the foveal center within the temporal parafovea. Cone plateau, rod intercept time, and rod recovery rate (S2) were calculated from the resulting DA curves. Findings were correlated with disease stages (according to Gass and Blodi), the area of ellipsoid zone loss in optical coherence tomography, and macular pigment loss (“MP-Classes 1–3”). Results: Fifty-nine eyes of 59 patients were compared with 18 eyes of 18 healthy controls. Dark adaptation was significantly impaired in patients with MacTel. Although differences were most pronounced for parameters indicating rod-mediated recovery, cone-mediated recovery was also decreased, yet to a lesser extent. Dark adaptation parameters were only weakly associated with disease stages and ellipsoid zone loss. A better association was found between rod-mediated recovery (S2 and rod intercept time) and macular pigment loss (Kendall's tau for rod intercept time: 0.69 and S2: −0.51; both P < 0.0001). Conclusion: Dark adaptation is significantly impaired in patients with MacTel. Our results indicate an association of reduced macular pigment and rod dysfunction in MacTel.
purpose. Macular telangiectasia (MacTel) type 2 typically exhibits sharply demarcated parafoveal scotomas. In an investigation of their significance for reading performance, reading acuity and speed were measured and correlated with parafoveal sensitivity and fixation stability. methods. In this prospective controlled cross-sectional observational study, 49 eyes of 26 patients with MacTel type 2 were investigated. Twenty-four eyes of 14 age-matched normal subjects served as the control. Reading acuity and reading speed (in words per minute [wpm]) were assessed by Radner charts. Retinal sensitivity was measured using fundus controlled microperimetry (MP1; Nidek Technologies). Fixation stability was quantified by the bivariate contour ellipse area (BCEA). Multiple logistic regression analysis was used to delineate outcome predictors of reading acuity and speed. results. Mean reading speed was considerably reduced in patients (to 141 wpm; control speed, 190 wpm; P < 0.001) as was reading acuity (patients, 20/63; control subjects, 20/32; P < 0.001). Mean best corrected visual acuity (BCVA) was reduced in most eyes (patients, 20/50; control subjects, 20/20; P < 0.001). Mean BCEA was not reduced compared with that in the control subjects. BCVA reduction predicted reading acuity loss (P = 0.02) and a decrease in maximum reading speed (P < 0.001). Parafoveal sensitivity loss resulted in decreased reading acuity (P = 0.03) and reading speed reduction (P < 0.001). conclusions. These findings indicate that parafoveal sensitivity loss in MacTel type 2 is associated with loss of reading performance despite stable central fixation. Reading performance appears to be a sensitive variable of functional impairment in MacTel type 2 and should therefore be considered an outcome measure in future interventional trials.
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