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ocular features aid the diagnosis of Alport syndromeJudy Savige and Deb Colville

Abstract | Alport syndrome is a common cause of inherited kidney failure but often goes unrecognized. Most affected families show an Xlinked pattern of inheritance where affected males develop renal failure and hearing loss, and often lenticonus and retinopathy. Lenticonus is evident on both ophthalmoscopy and slitlamp examination but retinal abnormalities are more obvious on imaging. such abnormalities include a perimacular dotandfleck retinopathy and a peripheral fleck retinopathy, which might occur independently of each other; a dull macular reflex or lozenge, when the perimacular flecks are confluent; and, rarely, a macular hole caused by retinal thinning. imaging of the central and peripheral retina including redfree views is a rapid, noninvasive and inexpensive test that might aid the diagnosis of Alport syndrome, particularly in male individuals with earlyonset renal failure. the assistance of an interested ophthalmologist is invaluable in the diagnosis of Alport syndrome.

savige, J. & colville, D. Nat. Rev. Nephrol. 5, 356360 (2009); doi:10.1038/nrneph.2009.65

IntroductionInherited renal disease is responsible for 50% of cases of kidney failure in children and 20% of cases in adults.1 Alport syndrome affects one in 5,00010,000 individuals and is the most common inherited cause of renal failure after nephron ophthisis and reflux nephropathy in children, and after polycystic kidney disease in adults. Alport syndrome often goes unrecognized, however, which means that many affected indivi duals are neither treated appropriately nor provided with genetic counseling, and also means that their family members are not screened for the disease.

Diagnosis of Alport syndromeAlport syndrome is characterized clinically by renal failure, hearing loss, lenticonus (conical anterior protrusion of the lens) and by a central and peripheral retinopathy.24 About 85% of affected individuals have Xlinked disease5 with mutations in the COL4A5 gene;6 most other indivi duals with Alport syndrome have autosomalrecessive inheritance where mutations affect the COL4A3 and COL4A4 genes.7 Each of these mutations results in a defective or

absent 345 type IV collagen network in basement membranes of the glomerulus, cochlea, lens capsule and retina,811 which explains the clinical features of Alport syndrome. These membranes become lamellated or thinned.1214

Male patients with the severe form of Xlinked disease develop renal failure before the age of 30 years. They usually have hematuria in infancy, hearing loss by the age of 6 years, retinopathy in the teenage years, and lenticonus by the time endstage renal failure has developed.15,16 Hearing loss occurs in nearly all male patients with severe disease, lenticonus in up to 50% of these individuals, and retinopathy in 70%. Nearly 30% of female patients with mutations that cause severe Xlinked disease in male patients develop renal impairment by about 60 years of age.17,18 Among female patients with severe Xlinked disease, hearing loss (when it occurs) is usually present by the age of 50, lenticonus is uncommon, but central or peripheral retino pathy is found in about 30% of individuals at 40 years of age. In male patients in whom renal failure occurs after the age of 30 years, or not at all, hearing loss is common, but ocular features are often absent.15,16 The phenotype of female family members of such individuals is also mild. Clinical features in male patients and female

patients with autosomalrecessive disease resemble those seen in male patients with severe Xlinked disease.19

Clinically, a diagnosis of Alport syndrome is suspected in an individual who has hematuria or renal failure together with a family history of renal failure or Alport syndrome. The family history is often difficult to elicit, however, especially in families where few males are present, or where the affected males are too young to demonstrate clinical disease, or have atypical features. A family history is also absent in the 15% of Xlinked Alport syndrome cases with de novo mutations. The presence of hearing loss in a male patient who has hematuria or renal failure suggests the diagnosis of Alport syndrome, and audiometry can confirm the bilateral, hightone, sensorineural deafness that is typical in individuals with this syndrome. Hearing loss occurs in many inherited diseases that cause renal failure but Alport syndrome is the most common of these conditions. In children, hearing loss is often mistakenly attributed to middleear infections, and in adults, to industrial deafness or antibiotic use.

Unlike hearing loss, lenticonus and retinopathy are pathognomonic features of Alport syndrome.20,21 The demonstration of these features is helpful diagnostically,22,23 but the less well recognized association of the retinal lozenge or dull macular reflex, and that of peripheral retinopathy, with Alport syndrome,2426 are also useful.

Most individuals with suspected Alport syndrome undergo renal biopsy for confirma tion of the diagnosis. In adult male patients with Xlinked disease, the renal biopsy typically demonstrates a lamellated glomerular basement membrane (GBM); in boys and female patients, the GBM is thinned with segmental lamellation. Thinning of the GBM, however, also occurs in thin basement membrane nephropathya generally benign conditionand lamellation is not evident in indivi duals with Alport syndrome and endstage renal failure. Immunohistochemistry of the renal tissue is helpful: in affected male pat ients with Xl inked disease the 345(IV) collagen heterotrimer is absent from the GBM or is defective, and in female patients staining is often abnormal

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as well. In autosomalrecessive disease, the GBM is lamellated, and staining for the 345(IV) collagen heterotrimer again is often abnormal. The absence of the 5(IV) chain from the epi dermal membrane of a skin biopsy is character istic of Xlinked Alport syndrome and distinguishes it from autosomal recessive disease.27 The immunohistochemical approach, however, requires fresh tissue, is technically demanding, is less helpful in female than in male patients with Xlinked disease, and is only 80% sensitive at best.

Genetic studies represent the gold standard technique for diagnosis of Alport syndrome and also confirm the mode of inheritance. In Xlinked disease, the location and nature of the mutation correlates with disease severity.1517 large deletions, rearrangements and nonsense mutations are associated with earlyonset renal failure, hearing loss and possibly lenticonus. Genetic assays are expensive, however, and not widely available; in addition, even with direct sequencing of hair root messenger rNA, these assays are only 80% sensitive at best.28

Ocular characteristics The demonstration of ocular features is particularly helpful in the diagnosis of Alport syndrome. These abnormalities include anterior lenticonus, peri macular dotandfleck retinopathy, peripheral confluent retino pathy, and retinal lozenge or dull macular reflex, and occur in up to 70% of all patients with Alport syndrome (Figures 13).3,4,1526 Macular thinning is

probably common in Alport syndrome but thinning sufficient to cause a macular hole is rare.2932 The retinopathy affects the superficial layers of the retina and the defective 345(IV) collagen network is present in the Bruch membrane, but the precise pathology of the retinopathies is still unknown.33 recurrent corneal erosions and posterior poly morphous corneal

dystrophy also occur in Alport syndrome but are uncommon.34,35 Clinically, Alport syndrome must be differ entiated from thin basement membrane nephropathy, which is much more common but has no ocular associations.36

Anterior lenticonus occurs when the lens bulges forwards through the thinned lens capsule.3,1420 In Xlinked disease, this

Figure 1 | photograph of red reflex showing the oil droplet appearance of anterior lenticonus in a 52yearold man with autosomalrecessive Alport syndrome, renal failure, hearing loss and central retinopathy.

a b

c d

Figure 2 | retinal photographs showing central retinopathy in Alport syndrome. a | typical central perimacular dotandfleck retinopathy in a 32yearold man with Xlinked Alport syndrome, earlyonset renal failure and hearing loss, who had undergone bilateral lens replacements for lenticonus. scattered dots and flecks are present, mainly temporal to the macula. b | Florid central retinopathy in a 38yearold man with earlyonset renal failure, hearing loss and lens replacement. confluent perimacular dots and flecks that are sharply demarcated from the unaffected macula can be seen. c | central retinal view from a 55yearold woman with Xlinked Alport syndrome and recentonset renal failure, mild hearing loss but no lenticonus. No retinal dots or flecks are obvious. d | the same retinal view shown in panel c after redfree manipulation, which demonstrates multiple large dots and flecks surrounding the unaffected macula.

a b

Figure 3 | retinal photographs illustrating the dull macular reflex or lozenge that can occur in Alport syndrome. a | central retinal view in a 42yearold man with Xlinked Alport syndrome and earlyonset renal failure, hearing loss and lens replacements. the image shows the lozenge but no dots and flecks are obvious. b | the same retinal view shown in panel a after redfree manipulation. the background dots and flecks are more obvious, particularly at the margin of the unaffected macula.

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feature is present in up to 50% of male indivi duals but is uncommon in female patients; in autosomalrecessive disease, the abnormality is common in both sexes. when lenticonus occurs, it is usually evident by the time an individual develops endstage renal failure. Patients complain of glare, and worsening difficulties with vision that cannot be corrected with a stronger spectacle prescription. Although typically detected by slitlamp examination, lenticonus is also obvious on ophthalmoscopy as a dimple or oil droplet in the red reflex, so called because it moves with eye movement like an oil droplet on water (Figure 1). This feature is sometimes mistaken for a cataract. lenticonus is usually accompanied by central or peripheral retinopathy, and continues to deteriorate in adult life. It eventually results in the need for lens replacement, commonly in the fourth or fifth decade of life, and does not recur.

Central retinopathy occurs in approximately 70% of adult male patients and 15% of adult female patients with severe Xlinked Alport syndrome,2,4,1623 but is evident less often in individuals with lateonset disease (Figure 2). The condition is common in both male and female patients with autosomal recessive Alport syndrome.15 The central retinopathy ranges from a few scattered, bilateral, symmetrical, whitishyellow dots and flecks in the temporal macula to a perimacular annulus of densely packed dots. The retinopathy is evident on ophthalmo scopy and retinal photographs. Even in patients in whom no retinopathy is obvious, the dots might be apparent with redfree manipulation of retinal images. The central retinopathy has been described in boys as young as 11 years23 and is most

common in indivi duals who also have renal failure, hearing loss and lenticonus.20 Central retino pathy does not occur in girls with Xlinked disease and the demonstration of a florid central retinopathy in a young woman suggests autosomalrecessive disease. Central retinopathy is not associated with visual impairment and no treatment is necessary.

In some patients with Alport syndrome, the dots and flecks produce an abnormal tapetallike sheen at the fovea on ophthalmo scopy and retinal photography.24,25 Their demarcation from the perifovea results in a dull macular reflex or lozenge that surrounds and contrasts sharply with the normal macula (Figure 3). The lozenge is associated with severe Alport syndrome with earlyonset renal failure,25 and must be distinguished from the retinal sheen that is normal in young people (Figure 4). The obvious absence of dots and flecks at the macula in Alport syndrome distinguishes the lozenge from the drusen that are seen in mesangiocapillary and other forms of glomerulonephritis (Figure 5).37,38 The location of the lozenge corresponds with the macular hole.24 Macular holes associated with Alport syndrome are larger and less amenable to surgery than those that occur spontaneously.21,22

The peripheral retinopathy in Alport syndrome is evident as patchy, asymmetrical, confluent depigmented areas more than two opticdisc diameters from the foveola on ophthalmoscopy and retinal photography (Figure 6). In Xlinked disease the

peripheral retinopathy is present in about 70% of male and 30% of female patients, and is even more common in indivi duals with autosomalrecessive disease.26 The peripheral retinopathy might be obvious on careful ophthalmoscopy but photo graphy is more sensitive. The peripheral retinopathy is sometimes evident on standard retinal photographic views centered on the fovea or optic disc but usually requires a series of 79 peripheral photographs. Again, views of the abnormalities can be improved by use of redfree manipulation. Peripheral retino pathy often occurs together with

Figure 4 | retinal photograph showing the retinal sheen that is normal in young people. the retinal sheen is not made up of dots and flecks, its appearance differs in different retinal views and it can be minimized with full dilatation of the pupils.

Figure 5 | typical retinopathy seen in mesangiocapillary glomerulonephritis type ii. in contrast with Alport retinopathy, the abnormality in mesangiocapillary glomerulonephritis comprises large, soft drusen at the macula that are present from the late teenage years onwards. the appearance of this abnormality is identical to that seen in agerelated macular degeneration, a condition that generally occurs in individuals older than 60 years.

a

b

c

Figure 6 | retinal photographs of peripheral retinopathy in Alport syndrome. a | peripheral retinopathy in a 34yearold man with earlyonset renal failure, hearing loss and lens replacements, which shows the mottled, confluent appearance of the peripheral retinopathy. b | central and peripheral retinal view in a 55yearold man with Xlinked Alport syndrome and lateonset renal failure, hearing loss, and lens replacements. No retinopathy is obvious. c | same retinal view shown in panel b after redfree manipulation. this image shows both the central and peripheral retinopathy with scattered perimacular drusen and peripheral superior mottling.

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central retino pathy but it is more common than central retino pathy, presumably because the surface area of the periphery is larger than that of the central retina.21,26 Peripheral retinopathy is first noted in adolescent male patients with Xlinked disease and is a particularly useful sign in female patients in whom Xlinked disease is suspected but who do not have central retinopathy. As with the perimacular dots and flecks, vision remains normal and no treatment is neces sary. Although peripheral retinopathy is also pathognomonic for Alport syndrome, its differentiation from normal retinal variation is more difficult than that of the central dots and flecks.

Diagnostic recommendationsThese ocular features could aid the diagnosis of patients with Alport syndrome as they occur in up to 70% of affected indivi duals and are pathognomonic for this condition.

Anterior lenticonus is usually obvious on ophthalmoscopy and, although highly specific for Alport syndrome, this feature is uncommon in the absence of central or peripheral retinopathy. In addition, anterior lenticonus can be confused with a cataract by unsuspecting clinicians.

retinal examination and photography is helpful diagnostically in male patients older than 10 years in whom Xlinked Alport syndrome is suspected. Family members who have hematuria or renal failure should also undergo retinal examina tion and photo graphy. The central and peripheral retino pathies are often obvious on ophthalmo scopy, but retinal photo graphy shows subtle abnormalities, the appearance of which is improved on redfree images. The retinal lozenge or dull macular reflex is also pathognomonic for Alport syndrome, and suggests severe disease with earlyonset renal failure. The central retinopathy should be distinguished from the normal youthful retinal sheen.

As mentioned above, peripheral retinopathy might be visible on central views but usually requires 79 peripheral photographs, again with redfree manipulation. Although these images are particularly helpful in female patients with suspected Xlinked disease, peripheral changes are harder to differentiate from normal variation than is the distinctive central retinopathy and usually require ophthalmological confirmation.

In general, the nonmydriatic retinal camera that is used to screen for diabetic retinopathy is suitable for the above mentioned examinations. Dilatation of the pupils might be necessary to reduce retinal sheen in younger patients, and also in individuals with lenticonus or cataract, those aged over 50 years, and for peripheral retinal views.

Conclusionsretinal examination and photography of the central and peripheral retina, including redfree views, is a rapid, noninvasive, inexpensive test for Alport syndrome that could enable a diagnosis to be made at the initial consultation. The lack of retinopathy does not, however, exclude Alport syndrome. retinal examination is a highly sensitive and specific diagnostic test for Alport syndrome in male patients with earlyonset renal failure. The demonstration of a florid retinopathy in a young female patient suggests, but is not conclusive of, autosomalrecessive inheritance. The assistance of an interested ophthalmologist is invaluable in the interpretation of ocular signs for the diagnosis of Alport syndrome. The University of Melbourne Department of Medicine (Northern Health), The Northern Hospital, Epping, Vic, Australia (J. Savige, D. Colville).

Correspondence: J. Savige, The University of Melbourne, Department of Medicine (Northern Health), The Northern Hospital, Epping, Vic 3076, Australia [email protected]

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AcknowledgmentsOur work is supported by the National Health and Medical research committee of Australia and by Kidney Health Australia. We would also like to thank the many patients and their families who have contributed to our work.

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Ocular features aid the diagnosis of Alport syndromeJudy Savige and Deb ColvilleIntroductionDiagnosis of Alport syndromeOcular characteristics Figure 1 | Photograph of red reflex showing the oil droplet appearance of anterior lenticonus in a 52-year-old man with autosomal-recessive Alport syndrome, renal failure, hearing loss and central retinopathy.Figure 2 | Retinal photographs showing central retinopathy in Alport syndrome. a | Typical central perimacular dot-and-fleck retinopathy in a 32-year-old man with Xlinked Alport syndrome, early-onset renal failure and hearing loss, who had undergone bilateral lens replacements for lenticonus. Scattered dots and flecks are present, mainly temporal to the macula. b | Florid central retinopathy in a 38-year-old man with early-onset renal failure, hearing loss and lens replacement. Confluent perimacular dots and flecks that are sharply demarcated from the unaffected macula can be seen. c | Central retinal view from a 55-year-old woman with Xlinked Alport syndrome and recent-onset renal failure, mild hearing loss but no lenticonus. No retinal dots or flecks are obvious. d | The same retinal view shown in panel c after red-free manipulation, which demonstrates multiple large dots and flecks surrounding the unaffected macula.Figure 3 | Retinal photographs illustrating the dull macular reflex or lozenge that can occur in Alport syndrome. a | Central retinal view in a 42-year-old man with Xlinked Alport syndrome and early-onset renal failure, hearing loss and lens replacements. The image shows the lozenge but no dots and flecks are obvious. b | The same retinal view shown in panel a after red-free manipulation. The background dots and flecks are more obvious, particularly at the margin of the unaffected macula. Figure 4 | Retinal photograph showing the retinal sheen that is normal in young people. The retinal sheen is not made up of dots and flecks, its appearance differs in different retinal views and it can be minimized with full dilatation of the pupils. Figure 5 | Typical retinopathy seen in mesangiocapillary glomerulonephritis typeII. In contrast with Alport retinopathy, the abnormality in mesangiocapillary glomerulonephritis comprises large, soft drusen at the macula that are present from the late teenage years onwards. The appearance of this abnormality is identical to that seen in age-related macular degeneration, a condition that generally occurs in individuals older than 60years.Figure 6 | Retinal photographs of peripheral retinopathy in Alport syndrome. a | Peripheral retinopathy in a 34-year-old man with early-onset renal failure, hearing loss and lens replacements, which shows the mottled, confluent appearance of the peripheral retinopathy. b | Central and peripheral retinal view in a 55-year-old man with Xlinked Alport syndrome and late-onset renal failure, hearing loss, and lens replacements. No retinopathy is obvious. c | Same retinal view shown in panel b after red-free manipulation. This image shows both the central and peripheral retinopathy with scattered perimacular drusen and peripheral superior mottling.Diagnostic recommendationsConclusionsAcknowledgments

ocular features aid the diagnosis of as

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