Alport Syndrome (AS) is a genetic condition caused by mutations in Collagen IV, specifically in the COL4A3, COL4A4, and COL4A5 genes. Collagen IV is expressed within basement membranes as three different heterotrimers: α1α1α2, α3α4α5, α5α5α6.1 The α3α4α5 heterotrimer is present in the adult glomerulus, cochlea, cornea, lens capsule, and retina,2 whereas the α5α5α6 isoform is highly expressed in vascular connective tissue.3 Anterior segment ocular manifestations of AS include recurrent corneal erosions,2 posterior polymorphous corneal dystrophy, anterior lenticonus, and anterior polar cataracts.4,5 Posteriorly, collagen IV mutations disrupt Bruch's membrane and the internal limiting membrane (ILM), leading to peripheral retinopathy and an abnormal macular reflex. Macular cysts and retinal thinning have also been reported.6
Swept-source optical coherence tomography (SS-OCT) allows for wider field fundus imaging, whereas OCT angiography (OCTA) allows for visualization of the retinal and choroidal microvasculature. In this report, we used SS-OCT and SS-OCTA to investigate the choriocapillaris in AS. We found choriocapillaris flow impairment, which has not been reported previously and may contribute to the overlying retinopathy.
A 57-year old woman presented to the Bascom Palmer Eye Institute complaining of decreased vision. Past medical history was significant for hypertension, end-stage renal disease diagnosed at age 13, and deafness diagnosed at age 10. The patient had been diagnosed previously with AS by renal biopsy at the age of 15, although the specific mutation could not be identified upon review of medical records. Past surgical history was significant for renal transplant at age 25, parathyroidectomy at age 27, and cataract surgery in the right and left eyes at ages 47 and 48, respectively. Notably, medical records indicated that the patient was diagnosed with anterior polar cataracts prior to cataract extraction. Her medications included oral prednisone, apixaban (Eliquis; Bristol-Myers Squibb, New York, NY), aspirin, allopurinol, and amlodipine-benazepril (Lotrel; Novartis, Basel, Switzerland). Family history was negative for AS; however, the patient reported that two members of her family had suffered from renal failure at a young age.
Best-corrected visual acuity (BCVA) on presentation was 20/40 in the right eye and 20/25 in the left eye. Intraocular pressure and pupillary exam were unremarkable. Anterior segment examination was normal aside from pseudophakia in both eyes. Posterior examination showed a patchy pigmentary retinopathy (Figures 1A and 1B). Fundus autofluorescence demonstrated diffuse patchy hyperautofluorescence (Figures 1C and 1D). Spectral-domain OCT (SD-OCT) demonstrated inner retinal loss adjacent to the fovea, most prominently seen temporal to the maculae (Figures 2A and 2B).
Widefield fundus photos of (A) the right eye and (B) the left eye showing patchy pigmentary changes (artifact noted in superotemporal quadrant.) Fundus autofluorescence (C) of the right eye and (D) of the left eye showing patchy hyperautofluorescence corresponding to the areas of pigmentary changes.
Spectral-domain optical coherence tomography of (A) the right eye and (B) the left eye. Significant inner retinal thinning is observed in a “staircase”-like pattern, mostly in the temporal macula. No cysts are seen, and the outer retinal structures appear preserved.
The structure and flow images from SS-OCTA showed significant abnormalities. Total retinal thickness was decreased, and there was enlargement of the foveal avascular zone compared with age-matched controls (Figure 3). The inner retina had diffuse cystic changes within the inner atrophic retina along the arcades (Figure 4). SS-OCTA of the inner choroid demonstrated an increase in the number of patchy flow voids within the choriocapillaris (Figure 5).
Swept-source optical coherence tomography angiography of the right eye. En face images of (A) total retinal vasculature flow, (B) total retinal thickness map, and (C) cross-sectional structural B-scans from this patient demonstrate a significant loss of the central macula microvasculature and retinal thinning. (D–F) Images from an age-matched control are provided for reference; en face images of (D) total retinal vasculature flow, (E) total retinal thickness map, and (F) cross-sectional structural B-scans of the central macula.
Swept-source optical coherence tomography along the superior arcade in the right eye. (A) Cross-sectional structural B-scan, along with (B) a B-scan with segmentation of the inner retina, demonstrate the inner retinal cysts (arrows). (C) Superficial retinal structure map demonstrates cystic changes within the central macula and along the arcades with abnormal thinning temporally. The black line represents the axis of the cross-sectional B-scan.
Swept-source optical coherence tomography angiography of the choriocapillaris (CC) of the right eye. En face images of (A) CC flow, (B) CC structure, and (C) corresponding cross-sectional B-scans of this patient demonstrate reduced CC flow with an increase in the number and area of flow voids. (D–F) Images from an age-matched control are provided for reference; en face images of (D) CC flow, (E) CC structure, and (F) corresponding cross-sectional B-scans.
Various ophthalmic findings in AS have been previously reported. Central fleck retinopathy has been noted in 60% of men and 15% of women with X-linked disease,7 whereas peripheral fleck retinopathy has been noted in 94% of X-linked males and individuals with AS.8 Both fundus findings are thought to be sequelae of an abnormal ILM. A thin temporal macula and a dull macular reflex have also been noted. These changes are likely due to thinning of the ILM and nerve fiber layer.9 A prior case described a unique “stair-case” pattern of subfoveal retinal thinning on OCT.6 A similar stair-case pattern with temporal macular thinning on OCT imaging was seen in our case, as well. Inner retinal cysts have also been discussed previously, and these changes were thought to result from defective Collagen IV in Bruch's membrane causing retinal pigment epithelial dysfunction and aberrant fluid shifts into the inner retina. It is also possible that collagen mutations may have a direct effect on the breakdown of the ILM.9
Two unique findings in this particular case were the presence of inner retinal cysts along the arcades as seen in Figure 4, as well as the SS-OCTA findings of decreased microvascular density within the choriocapillaris layer. The presence of inner retinal cysts suggests a unifying potential mechanism for the peripheral and central changes noted on funduscopic exam. One theory is that the collagen IV mutations likely induce an unstable ILM and may be associated with Müller cell dysfunction. This instability may subsequently lead to the collapse of inner retina and inner retinal thinning, which may progress over time. The enlargement of the foveal avascular zone noted on SS-OCTA may be a sequela of this process or a direct effect of the collagen mutations on the microvasculature.
Although this chronic pathologic process may be ongoing within the inner retina, the increase in the number and area of the choriocapillaris flow voids observed on SS-OCTA imaging is noteworthy. Although the exact mutation in our patient was unknown, we suspect a COL4A5 mutation given this effect on the vasculature. Interestingly, the outer retina did not appear atrophic given the choriocapillaris loss, although the pigmentary changes observed on fundus photos could suggested altered retinal pigment epithelial function. In addition, the choriocapillaris flow voids could explain the decreased BCVA in this pseudophakic patient with no other clear explanations for vision loss.
In summary, this is the first report of SS-OCTA imaging of a patient with AS. In addition to diffuse inner retinal cysts, we found an enlarged foveal avascular zone with a decreased microvascular density within the central macula and an increase in the number and area of central macular choriocapillaris flow voids. These findings suggest a unifying pathogenesis that could explain the abnormalities in both the retina and choriocapillaris due to collagen mutations in AS.
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