Abetalipoproteinemia with angioid streaks, choroidal neovascularization, atrophy, and extracellular deposits revealed by multimodal retinal imaging

Abstract

Purpose: Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas.

Methods: We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD).

Results: Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments.

Conclusion: We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.

Keywords: Retina; abetalipoproteinemia; age-related macular degeneration; angioid streaks; autofluorescence; optical coherence tomography.

Figure 1.. Case 1. Angioid streaks and retinopathy in abetalipoproteinemia, through multimodal imaging.

A-B. Ultra-widefield pseudocolor fundus photography (California, Optos Inc, Marlborough, MA) showing extensive peripapillary chorioretinal atrophy with macular involvement, along with bilateral annular areas of retinal pallor extending anteriorly from the posterior atrophy to the mid-periphery corresponding to sub-retinal pigment epithelial (RPE) deposits (the boundaries are indicated by orange arrowheads). A small area of hyperpigmentation is evident at the fovea. Angioid streaks originating from the optic discs are visible and marked by white arrowheads. C-D. Ultra-widefield fundus autofluorescence (California, Optos Inc, Marlborough, MA) showing the extent of the RPE atrophy through a large area of hypoautofluorescence, which is encircled by an area of hyperautofluorescence. Angioid streaks, highlighted by white arrowheads, appear hypoautofluorescent. The green lines indicate the location of the cross-sectional spectral domain optical coherence tomography (SD-OCT) images displayed on panel E and F. E-F. SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) B-scans showing foveal atrophy of the outer retina with inactive subretinal fibrosis, splitting of the RPE-BL-Bruch membrane complex, and a thickened and interrupted Bruch membrane (purple arrowheads).

Figure 2.. Case 1. Angioid streaks, choroidal neovascularization, and atrophy in macular area of left eye.

A. Confocal color fundus photography (EIDON, Centervue Padova, Italy) showing peripapillary chorioretinal atrophy with macular involvement and hyperpigmented area at the fovea. Angioid streaks originating from the optic disc and radiating outward are highlighted by white arrowheads. The boundaries of the annular area of retinal palor suggesting sub-retinal pigment epithelial deposits are indicated by orange arrowheads. The green square and lines indicate the areas imaged via en face optical coherence tomography angiography (OCTA) in panels D and E and cross-sectional high-resolution OCT (high-res OCT) in panels B (top green line) and C (bottom green line), respectively. B-C. High-res OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) B-scans showing disruptions in the highly reflective and thickened Bruch membrane (purple arrowheads) consistent with calcification, with RPE atrophy and subretinal fibrosis. No exudation was detected. The inset shows a magnified view of the region within the red box. D. En face OCTA (6×6mm, PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA) showing a relatively spared superficial and deep retinal vascular network (segmentation shown in panel F). The asterisk marks the fovea. E. En face OCTA (6×6mm, PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA) segmented at the level of the RPE-Bruch membrane complex (segmentation shown in panel G) indicating choroidal neovascularization (CNV) through observed flow signals. Parafoveal CNV are indicated by red arrowheads. The asterisk marks the fovea. F. OCTA (PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA) B-scan showing the segmentation used in the en face OCTA in panel D. Multiple areas of subretinal fibrosis with observable flow signals (represented as red pixels) are noted (examples are indicated by red arrowheads). G. OCTA (PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA) B-scan showing the segmentation used in the en face OCTA in panel E. Multiple areas of pigment epithelial detachment with observable flow signals (represented as red pixels) are noted (examples are indicated by red arrowheads).

Figure 3.. Case 1. Peripheral sub-retinal pigment epithelial (RPE) deposits in the patient’s left eye.

A. Ultra-widefield pseudocolor fundus photography (California, Optos Inc, Marlborough, MA) showing the extent of the sub-RPE deposits in the periphery. The red square corresponds to the location of the fundus autofluorescence (FAF) (panel B) and near-infrared reflectance (NIR) (panel C) images. The orange dashed lines indicate the boundaries of these deposits: the temporal line corresponds to the orange arrowhead shown on the optical coherence tomography (OCT) B-scan on panel E. B. Ultra-widefield FAF (California, Optos Inc, Marlborough, MA) showing the discrete hyperautofluorescence of the sub-RPE deposits. C. NIR imaging performed on a spectral domain OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) showing the hyperreflectivity of the deposits. The green square and lines indicate the areas imaged via cross-sectional high-resolution OCT (high-res OCT) in panels D (top green line) and E (bottom green line). D. High-res OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) B-scan of the retinal periphery (corresponding to the upper green line in panel C) showing a thickening and a hyporeflective split of the RPE-Bruch membrane complex. E. High-res OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) B-scan of the retinal periphery (corresponding to the lower green line in panel C) showing a highly reflective and thickened Bruch membrane consistent with calcification and a hyporeflective split of the RPE-Bruch membrane complex. Note the difference in the thickness of the RPE-Bruch membrane complex between panel D and E. The orange arrowhead indicates the temporal boundary of the sub-RPE deposits that are displayed between the two orange dashed lines on panel A.

Figure 4.. Case 2. Central atrophic scar, multiple white deposits and atrophy in abetalipoproteinemia through multimodal imaging.

A-B. Confocal color fundus photography (EIDON, Centervue Padova, Italy) showing a central atrophic scar with hyperpigmentation and multiple white deposits around the area of atrophy on the right eye. The left eye shows a normal-appearing macula with few central white deposits and a flat choroidal nevus inferior to the optic nerve. A peripapillary chorioretinal atrophy is present on both eyes. No angioid streaks are visible. The red lines indicate the location of the cross-sectional high resolution optical coherence tomography (high-res OCT) (Spectralis, Heidelberg Engineering, Heidelberg, Germany) (SD-OCT) images displayed on panel E and F. C-D. Confocal fundus autofluorescence (EIDON, Centervue Padova, Italy) showing a central area of hypoautofluorescence in the right eye and slightly decreased autofluorescence of the left macula. The peripapillary chorioretinal atrophy is well visualized through an area of hypoautofluorescence around the optic discs. The green lines indicate the location of the cross-sectional high-res OCT images displayed on panel G and H. E-F. High-res OCT B-scans centered at the optic disc of both eyes showing the highly reflective and thickened Bruch membrane consistent with calcification. The inset shows a magnified view of the region within the red box, highlighting breaks within Bruch membrane (purple arrowheads). G-H. High-res OCT B-scans centered at the fovea of both eyes, showing central macular outer retina and RPE atrophy with pigment clumping and multiple subretinal drusenoid deposits (figure G, yellow arrowhead) around the area of foveal RPE atrophy on the right eye, and a normal-appearing macula with a cluster of subfoveal cuticular drusen (figure H, yellow arrowhead) on the left eye.

Figure 5.. Case 2. Subretinal and sub-retinal pigment epithelium deposits in the left eye.

A. Confocal color fundus photography (EIDON, Centervue Padova, Italy) of the center and lower macula showing a cluster of subfoveal yellow dots and scattered white dots near the inferior temporal vascular arcade. The superior and lower green lines indicate the location of the cross-sectional high resolution optical coherence tomography (high-res OCT) (Spectralis, Heidelberg Engineering, Heidelberg, Germany) (SD-OCT) images displayed on panel B and C respectively. B. High-res OCT B-scan (corresponding to the superior green line in panel A) passing through the fovea showing subfoveal nodular drusen with bar coding and a discrete hyporeflective split of the retinal pigment epithelium-Bruch membrane complex. The inset shows a magnified view of the region within the red box. C. High-res OCT B-scan (corresponding to the inferior green line in panel A) showing the presence of multiple subretinal drusenoid deposits. The inset shows a magnified view of the region within the red box.

Figure 6.. Case 2. Absence of blue and green autofluorescence in the left eye as determined by macular pigment optical density (MPOD; obtained with two-wavelength autofluorescence).

A. MPOD of the left eye of a patient affected with abetalipoproteinemia. The blue and green autofluorescence images of the macula show no perceptible difference in the central autofluorescence, unlike a subject with normal MPOD (see panel B). This profile indicates a deficiency in MPOD related to abetalipoproteinemia. B. Normal MPOD in a healthy young male with a marked increase in optical density towards the central macular region due to high xanthophyll concentration in the central foveal bouquet.