Choroideremia: Analysis of the Retina from a Female Symptomatic Carrier

Abstract

Purpose To define the retinal pathology in a 91 year-old affected matriarch of a three-generation choroideremia family with multiple manifesting carriers. Methods Tissue from three different retinal areas was processed for immunohistochemistry. The macular area was processed for transmission electron microscopy. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin and cone opsins. The affected donor eyes were compared to a postmortem matched normal eye. Results The retina displayed areas of severe degeneration, with no photoreceptor outer segments, photoreceptor nuclear atrophy, and atrophy of the inner retina. Other retinal areas were near to normal. The RPE was severely degenerated, with thinning, pigment clumping and sub-epithelial debris deposition in all the areas examined. The choroid displayed depigmentation. Labeling with cone opsin antibodies revealed that cones were drastically affected: blue opsin was almost completely absent, while red/green opsins were distributed along the entire plasma membrane of the cell. Rhodopsin was also distributed along the entire rod plasma membrane. Ultrastructural analysis of the affected macula revealed the absence of RPE apical microvilli and basal infoldings. Instead, RPE’s basal surface and choroid displayed the presence of banded fibers composed of clumps of wide-spacing collagen. Bruch’s membrane was filled with vesicular structures, some smooth and others with bristle-like projections. Conclusions The histological data suggests that the clinical manifestation in this donor is related to degenerative changes in the retina, RPE and choroid.

High-Resolution Adaptive Optics Retinal Imaging of Cellular Structure in Choroideremia

“…For this we carried out a multimodality imaging study on a large number of affected individuals and carriers. Similar to other studies, 2,5,[8][9][10]35 this study presented data to indicate the RPE is a primary site of degeneration for choroideremia. This is evident by aligning and comparing images between relatively intact retina and the border of retinal atrophy across the various imaging modalities.…”

“…This patchy fundus appearance is explained by lyonization where, rarely, a female carrier may exhibit significant vision loss as a result of skewed X-inactivation. 4,5 Despite genetic characterization of CHM, the exact mechanism of vision loss associated with choroideremia remains unknown. In general, choroideremia leads to the degeneration of the outer retina, the RPE, and the choroid/choriocapillaris.…”

Gene Therapy for Choroideremia Using an Adeno-Associated Viral (AAV) Vector

“…In human female carriers, skewed X-inactivation across the retinal layers can leave affected clones of photoreceptors against normal pigment epithelial cells, and histological postmortem specimens suggest that photoreceptors degenerate independently of the RPE (Flannery et al 1990;Syed et al 2001;Bonilha et al 2008). There is also evidence from optical coherence tomography scans of male choroideremia patients that the photoreceptor layer thins in advance of degeneration of the RPE (Jacobson et al 2006b).…”

“…In contrast, X-inactivation very early during development can result in large areas of retina affected by choroideremia caused by clonal expansion of cells expressing only the defective CHM gene (the "good" copy on the other X chromosome having been silenced). These rare, severe cases can lead to blindness in female carriers (Bonilha et al 2008).…”

Vi-2 : Apport De l'ÉLECTROPHYSIOLOGIE Chez l'ADULTE : Exemples

“…L'évolution chez les conductrices se fait vers l'atrophie de plages disséminées de neurorétine, de l'épithélium pigmentaire et de la choriocapillaire correspondante, d'autres plages restant normales [Bonilha et al, 2008]. Figure VI-71.…”