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Clinical science
Retinal findings in patients with Alport Syndrome: expanding the clinical spectrum
  1. A A Fawzi1,
  2. N G Lee1,
  3. D Eliott1,
  4. J Song2,
  5. J M Stewart3
  1. 1
    Department of Ophthalmology, Doheny Retina Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  2. 2
    Department of Ophthalmology, Children’s Hospital of Los Angeles, Los Angeles, California, USA
  3. 3
    Department of Ophthalmology, University of California, San Francisco, San Francisco, California, USA
  1. Correspondence to Dr J M Stewart, University of California, San Francisco, 10 Koret Way, K301, San Francisco, CA 94143-0730, USA; stewartj{at}


Aims: To describe previously unreported retinal findings in patients with Alport Syndrome (AS), as well as review the range of ophthalmic manifestations.

Methods: Retrospective review of clinical records of patients with AS.

Results: Nine patients with AS were identified, of whom three had no eye findings, four showed classic features of AS, and two had new findings, bull’s eye and vitelliform maculopathy. The genetic mutation responsible for the disease in the patient with vitelliform subretinal deposits was identified.

Conclusions: Patients with AS can present with a variety of ophthalmic manifestations. Bull’s eye maculopathy and vitelliform deposits can be features of AS. The mechanism of these new macular findings remains unknown. Possible pathophysiological overlap with other maculopathies including age-related macular degeneration is discussed.

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Alport Syndrome (AS) is a genetically and clinically heterogeneous disorder characterised by ocular abnormalities, haemorrhagic nephritis, progressive renal failure and sensorineural hearing loss. These clinical findings have been recently attributed to a disorder of basement membrane type IV collagen.1 More specifically, the alpha-5 chain of type IV collagen has been shown to be responsible for the basement membrane defects in X linked AS, whereas the alpha-3 and alpha-4 chains were implicated in the less common autosomal recessive and autosomal dominant variants.2 3 4 5 Absence of all three chains in the glomerular basement membrane was noted in patients with autosomal as well as X linked AS, suggesting an obligatory association between them in the triple helical protein.2 AS is pathologically diagnosed on renal biopsy based on abnormalities in the glomerular capillary basement membranes.6 Similarly, the sensorineural hearing loss is also thought to result from structural lesions of the capillary basement membrane of the stria vascularis.

A wide range of ocular manifestations have been described in the setting of AS including corneal posterior polymorphous dystrophy and anterior lenticonus as well as changes in the internal limiting membrane of the retina and macular holes.7 8 9 10 The classic ocular features include a central or perimacular dot and fleck retinopathy, which occurs in 85% of affected adult males, and anterior lenticonus, which is present in 25%.11 The retinopathy classically manifests as whitish-yellow dots or flecks.12 Also seen, though less well described, are peripheral or mid-peripheral flecks in the retina, which may occasionally be the only manifestation in X linked carriers.12 13 It was once thought that the manifestations of retinopathy were limited to the inner retina as a result of mutations in genes coding for type IV collagen, which is the main component of the internal limiting membrane. It is now accepted that type IV collagen is also found in abundance in the Bruch membrane.13 14 15 Time-domain optical coherence tomography (OCT) in AS has shown thinning of the temporal macula in one patient.16

In this study, we expand the spectrum of retinal findings in AS to include bull’s eye maculopathy and vitelliform macular detachment, which, to the best of our knowledge, have not been reported previously in this setting. Fundus autofluorescence and high-resolution OCT findings in these patients are presented. Additionally, we have reviewed our clinical database for all patients with AS and will discuss their findings in this paper.


Adult patients with AS were retrospectively identified from the authors’ clinical practices or the Children’s Hospital of Los Angeles database. They had either a confirmed history of haematuria or kidney failure requiring dialysis or renal transplant. All patients received confirmation of the diagnosis by renal biopsy. Institutional Review Board approval was obtained for this study in concordance with the applicable rules at the respective institutions.


Table 1 summarises the patients’ demographics and clinical findings. In the next section, we will highlight the clinical findings with a special focus on their ocular manifestations.

Table 1

Demographic and clinical findings in patients with Alport Syndrome

No ophthalmological findings

Three patients with renal biopsy-proven AS were identified from the database of Children’s Hospital of Los Angeles, who did not have any ocular findings (patients 1–3, table 1).

Classic retinal findings

Four adults with AS were identified with classic ocular findings (patients 4–7, table 1). Of those patients, one patient had peripheral flecks (patient 4), one patient had central flecks only (patient 5), and two patients had a combination of central and peripheral flecks (patients 6–7).

Novel retinal findings

Two adults were followed in the retina practices of two of the authors (AAF and JMS) for unusual retinal findings.

Case examples

A 19-year-old Latin-American man (patient 8, table 1) presented with a history of blurred vision and progressive decrease in night vision. In addition, he complained of worsening photophobia. He had early-onset disease, having been diagnosed as having AS 8 years earlier, and was on haemodialysis, awaiting his third renal transplant. He had lost his prior transplants due to development of antiglomerular basement membrane antibodies. He was noted to have sensorineural hearing loss and used hearing aids. His family history was significant for a mother with AS who passed away due to renal failure. Genotyping had not been performed, but his clinical course, family history and the history of anti-GBM-related renal transplant rejection were highly suggestive of X linked AS.

His ophthalmological exam was notable for visual acuities of 20/40 OD and 20/50 OS, posterior corneal opacities, and anterior lenticonus in both eyes. His fundus exam was significant for a perifoveal pigmentary macular lesion, as well as macular flecks in the right eye (fig 1A). The left eye did not show the pigmentary maculopathy (fig 1B) but showed extensive yellow flecks in the macula. On fluorescein angiography, there was perifoveal staining in the macula of the right eye in a bull’s eye pattern (fig 1D). The left eye showed subtle window defects (fig 1D). Fundus autofluorescence showed foveal and perifoveal flecks of hyperautofluorescence in the right eye and an unremarkable left eye (fig 2A,B). High-resolution OCT of the right eye showed subfoveal thickening of the retinal pigment epithelium (RPE)/Bruch membrane layer, overlying thinning of the outer segment of the photoreceptors, and decreased thickness of the temporal outer plexiform, outer nuclear and ganglion cell layers (fig 2C). OCT of the left eye showed more subtle thinning of the retinal layers but no clear evidence of RPE/Bruch membrane deposits (fig 2D).

Figure 1

(A, B) Colour fundus photographs, patient 8. The right eye photos show a bull’s eye pattern, with central hyperpigmentation surrounded by alternating circular hypo- and hyperpigmentation. Fine perimacular fleck deposits are seen in both eyes. (C, D) Fluorescein angiograms highlighting the bull’s eye pattern in the right eye, and subtle retinal pigment epithelium mottling in the left.

Figure 2

(A, B) Autofluorescence of patient 8. The right eye shows mottled hyperautofluorescence surrounding the centre. The left eye is unremarkable. (C–F) Infrared and corresponding Fourier domain optical coherence tomography images of the right and left eyes. Right eye shows deposition of hyper-reflective material in the region of retinal pigment epithelium/Bruch membrane subfoveally. Both eyes show thinning of the inner retina in the temporal fovea, with relative preservation of the outer retina.

A 56-year-old Caucasian man (patient 9, table 1) with a case of X linked AS and who had a history of hearing loss and late-onset kidney disease underwent a renal transplant in 1998. He presented with a gradual decrease in vision in the left eye along with problems with night vision in both eyes. He noticed metamorphopsia on the Amsler grid in the right eye. His visual acuities were 20/20 OD and 20/25 OS. He had no abnormalities on anterior segment exam; however, he did have macular vitelliform lesions in both eyes with peripheral retinal flecks (fig 3A–C). His fluorescein angiogram showed leakage into the macular vitelliform detachment in the left eye (fig 3D) with a corresponding area of retinal elevation and hyper-reflective subretinal deposits best seen on OCT (left eye greater than right).

Figure 3

(A, B) Fundus photographs of patient 9 at initial presentation. Vitelliform lesions are seen in the macula, left eye greater than right eye. (C) Peripheral retinal flecks. (D) Fluorescein angiogram showing leakage in the vitelliform lesion.

The patient presented 1 year later with slightly worse vision OS. Visual acuity was 20/25+1 OD and 20/40−1 OS. Examination showed an increase in the size of the vitelliform detachment in both eyes, left greater than right. Fundus autofluorescence imaging showed increased autofluorescence corresponding to the macular vitelliform lesions (figs 4A, 5A,B). High-resolution OCT of the right eye showed thickening and hyper-reflective deposits within the outer retina, with hyporeflective spaces separating the thickened Bruch membrane from the thickened RPE and photoreceptor outer segments (fig 4B). This separation was less defined in the left eye, where the hyper-reflective deposits were more prominent, and appeared to extend within the outer retina, with focal photoreceptor disruption (fig 5C,D).

Figure 4

Images of right eye, patient 9, 10 months after presentation. (A) Autofluorescence photograph of macula showing hyperautofluorescent material. (B) Optical coherence tomography showing material deposited underneath the photoreceptors (arrowhead). There is a thin hyporeflective space separating this material from subfoveal drusenoid hyper-reflective material within the retinal pigment epithelium/Bruch membrane (asterisk).

Figure 5

Images of left eye, patient 9. (A, B) Autofluorescence photographs of the macula 4 months apart showing progression. (C, D) Infrared image of the macula. An optical coherence tomography (OCT) scan through the fovea shows hyper-reflective material deposited underneath the photoreceptors. (E, F) Infrared image of the macula. An OCT scan through inferior macula shows dense hyper-reflective material obliterating the retinal pigment epithelium/Bruch membrane.

Further clinical testing was performed. Humphrey 30–2 testing showed a reduced foveal sensitivity of 28 dB OD and 22 dB OS, and a relative central scotoma OS. This was confirmed on Goldmann perimetry. MP-1 microperimetry showed decreased sensitivity in the areas corresponding to the macular vitelliform lesions OU. The electro-oculogram was normal OU. The full-field electroretinogram showed about a 30% reduction to all stimuli in the left eye as compared with the right eye. Multifocal electroretinography showed normal amplitudes with mildly delayed timing between fixation and 5–10° eccentric to fixation OD, and severely reduced amplitude and delayed timing throughout the central 10–20° OS.

Genetic testing of the patient and his family members was performed and reported in a prior publication.17 Within the patient’s family, there were five affected males, one deceased male who was presumed to be affected, and five known or presumed female carriers. The causative mutation in the COL4A5 gene for this cohort was found to be a splice-site mutation consisting of a single base change, c.889+1 G>A.17


In this study we describe several novel retinal findings in the setting of AS, along with the corresponding findings on OCT and fundus autofluorescence. Yellow vitelliform macular lesions and bull’s eye maculopathy were encountered in two patients, associated with RPE/Bruch membrane and outer retinal deposits on OCT. These changes occurred in two males with confirmed AS and were noted at a late stage in the disease, when both patients had already undergone renal transplantation. By contrast, in 40% of cases the ocular manifestations may be the earliest sign of AS prior to the onset of renal disease.18 The ophthalmologist hence has an important role in raising the possibility of the diagnosis and promptly directing the patient or the carrier to further nephrological work-up, before the onset of end-stage renal disease.18 19

In patients with complex medical conditions such as renal failure due to AS, it may be difficult to pinpoint the cause of a particular finding such as the novel retinal features we describe. For example, patient 8 developed anti-GBM antibodies, leading to loss of his renal transplant. McCoy et al first described a unique mode of renal transplant rejection in male patients with X linked AS related to occurrence of antiglomerular basement membrane (GBM) antibodies, as their immune system is first exposed to the normal GBM in the allograft.20 These antibodies are a consequence of the absence of alpha 3, 4, 5 trimers of collagen IV in patients with AS.21 Serous retinal detachment has been described in Goodpasture (anti-GBM) Syndrome;22 it is possible that the maculopathy in our patient is a sequela of resolved detachment, although this specific finding has not been reported in Goodpasture syndrome and would not necessarily be expected to demonstrate hyperautofluorescence as our patient’s fundus did. Since this patient did not have any clinical ophthalmological records prior to the allograft rejection, we are unable to confirm whether the bull’s eye maculopathy was a primary manifestation of AS or a consequence of the autoimmune reaction.

In this study, new technology allowed us to provide greater detail about a previously reported macular finding in AS. Previously, using Stratus OCT, Usui and associates found generalised thinning of the temporal macula in patients with AS.16 On Fourier domain OCT, we were able to localise the loss of tissue to the temporal retina and found that it predominantly affected the inner retina (fig 2D,F). The mechanism of this thinning remains to be determined and is difficult to evaluate further in the absence of histopathological data.

The presence of vitelliform macular detachments in our patients with AS raises the question of pathophysiological overlap with age-related macular degeneration (AMD), in which these findings are also seen. The extent to which genetic mutations contribute to vitelliform-type detachments is unknown. Vitelliform macular detachment in the setting of small drusen is present in 20% of AMD patients.23 24 Our patient had a documented splice mutation in the COL4A5 gene and showed subretinal deposits and thickening of the Bruch membrane, similar to what might be seen in a patient with AMD. The functional implications of the COL4A5 mutation and the structure of the mutated protein have not been studied; however, it is conceivable that the mutation could lead to deposition of abnormal collagen material in the Bruch membrane and the RPE. Based on its function in the Bruch membrane, and on the clinical findings in this patient, it is possible that mutations in type IV collagens may help explain a subset of patients with vitelliform lesions in the setting of AMD.14 The relationship of the macular findings (vitelliform detachment and bull’s eye pigmentary disturbance) to the more commonly seen flecks is uncertain, but they are probably unrelated. Macular flecks in the setting of AS usually spare the central macula, while these lesions were predominantly central.

In conclusion, there are wide-ranging variations in retinal findings in patients with AS. A careful clinical examination with attention to the peripheral retinal flecks may help identify the diagnosis. The OCT finding of macular RPE/Bruch membrane deposits, which were hyperautofluorescent in two of our patients and were clinically similar to vitelliform deposits in one of these, suggests that lipofuscin and melanolipofuscin accumulation has taken place. The OCT images illustrate that the retinal pathology can be variable and may be related to the wide range of genetic mutations. In addition, the retinal findings can be asymmetrical, and central macular lesions can occur, as seen in patients 8 and 9. Further studies are warranted to identify phenotype/genotype correlations and the functional changes in the retina associated with various mutations in collagen type IV.


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Related Data


  • Funding That Man May See and Research to Prevent Blindness.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by University of Southern California.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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