perspectives

opinion

ocular features aid the diagnosis

of Alport syndrome
Judy 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

Introduction

Inherited renal disease is responsible for

50% of cases of kidney failure in children
and 20% of cases in adults. 1 Alport syn
drome affects one in 5,00010,000 indivi
duals and is the most common inherited
cause of renal failure after nephronophthisis
and reflux nephropathy in children, and
after polycystic kidney disease in adults.
Alport syndrome often goes unrecognized,
however, which means that many affected
individuals 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 syndrome

Alport syndrome is characterized clinically

by renal failure, hearing loss, lenticonus
(conical anterior protrusion of the lens)
and by a central and peripheral retino
pathy.24 About 85% of affected individuals
have Xlinked disease5 with mutations in
the COL4A5 gene;6 most other individuals
with Alport syndrome have autosomal
recessive inheritance where mutations affect
the COL4A3 and COL4A4 genes.7 Each of
these mutations results in a defective or
Competing interests
the authors declare no competing interests.

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 syn
drome. 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 retinopathy 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

356 | JUNE 2009 | volUmE 5

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 hema
turia 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 muta
tions. 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 dis
eases that cause renal failure but Alport
syndrome is the most common of these
conditions. In children, hearing loss is often
mistakenly attributed to middleear infec
tions, 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
confirmation of the diagnosis. In adult
male patients with Xlinked disease, the
renal biopsy typically demonstrates a
lamellated glomerular basement mem
brane (GBM); in boys and female patients,
the GBM is thinned with segmental lamella
tion. Thinning of the GBM, however, also
occurs in thin basement membrane nephro
pathya 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
patients with Xlinked dis eas e 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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perspectives
a

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.

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 epidermal membrane of a
skin biopsy is character istic of Xlinked
Alport syndrome and distinguishes it from
autosomalrecessive disease.27 The immuno
histochemical 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 stan
dard technique for diagnosis of Alport
syndrome and also confirm the mode of
inheritance. In Xlinked disease, the loca
tion and nature of the mutation correlates
with disease severity.1517 large deletions,
rearrangements and nonsense muta
tions 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, perimacular
dotandfleck retinopathy, peripheral
confluent retinopathy, 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

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 55year
old 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.

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.

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 ero
sions and posterior polymorphous corneal

NATUrE rEVIEws | nephrology

dystrophy also occur in Alport syndrome

but are uncommon.34,35 Clinically, Alport
syndrome must be differentiated 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

VolUME 5 | JUNE 2009 | 357

2009 Macmillan Publishers Limited. All rights reserved

perspectives
a

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.

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, lenti
conus 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 cata
ract. lenticonus is usually accompanied by
central or peripheral retinopathy, and con
tinues to deteriorate in adult life. It eventu
ally results in the need for lens replacement,
commonly in the fourth or fifth decade of
life, and does not recur.
Central retinopathy occurs in approxi
mately 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
autosomalrecessive Alport syndrome.15
The central retinopathy ranges from a few
scattered, bilateral, symmetrical, whitish
yellow dots and flecks in the temporal
macula to a perimacular annulus of densely
packed dots. The retinopathy is evident on
ophthalmoscopy 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

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.

common in indivi duals who also have

renal failure, hearing loss and lenticonus.20
Central retinopathy does not occur in girls
with Xlinked disease and the demon
stration 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 syn
drome, the dots and flecks produce an
abnormal tapetallike sheen at the fovea
on ophthalmo scopy and retinal photo
graphy. 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 syn
drome is evident as patchy, asymmetrical,
confluent depigmented areas more than
two opticdisc diameters from the foveola
on ophthalmoscopy and retinal photo
graphy (Figure 6). In Xlinked disease the

358 | JUNE 2009 | volUmE 5

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 late
onset 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.

peripheral retinopathy is present in about

70% of male and 30% of female patients,
and is even more common in individuals
with autosomalrecessive disease. 26 The
peripheral retinopathy might be obvious on
careful ophthalmoscopy but photography 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
retinopathy often occurs together with

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2009 Macmillan Publishers Limited. All rights reserved

perspectives
central retinopathy 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 necessary. Although periph
eral 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 recommendations

These ocular features could aid the diag

nosis 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 examination
and photography. The central and periph
eral retino pathies are often obvious on
ophthalmoscopy, but retinal photography
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 retino
pathy might be visible on central views
but usually requires 79 peripheral photo
graphs, 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 varia
tion than is the distinctive central retino
pathy 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.

9.

Conclusions

12.

retinal examination and photography of

the central and peripheral retina, including
redfree views, is a rapid, noninvasive, inex
pensive 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 syn
drome in male patients with earlyonset
renal failure. The demonstration of a florid
retinopathy in a young female patient sug
gests, but is not conclusive of, autosomal
recessive 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
jasavige@unimelb.edu.au
1.

2.

3.

4.

5.
6.

7.

8.

Grunfeld, J. p. congenital/inherited kidney

diseases: how to identify them early and how to
manage them. Clin. Exp. Nephrol. 9, 192194
(2005).
Gubler, M. et al. Alports syndrome: a report of
58 cases and a review of the literature. Am. J.
Med. 70, 493505 (1981).
Arnott, e. J., crawfurd, M. D. A. & toghill, p. J.
Anterior lenticonus and Alports syndrome. Br. J.
Ophthalmol. 50, 390403 (1966).
polak, B. c. p. & Hogewind, B. L. Macular lesions
in Alports disease. Am. J. Ophthalmol. 84,
532535 (1977).
Feingold, J. et al. Genetic heterogeneity of Alport
syndrome. Kidney Int. 27, 672677 (1985).
Barker, D. F. et al. identification of mutations in
the COL4A5 collagen gene in Alport syndrome.
Science 248, 12241227 (1990).
Mochizuki, t. et al. identification of mutations in
the 3(iv) and 4(iv) collagen gene in
autosomal recessive Alport syndrome. Nat.
Genet. 8, 7781 (1994).
Yoshioka, K. et al. type iv collagen 5 chain:
normal distribution and abnormalities in
Xlinked Alport syndrome revealed by
monoclonal antibody. Am. J. Pathol. 44,
986996 (1994).

NATUrE rEVIEws | nephrology

10.

11.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Zehnder, A. F. et al. Distribution of type iv

collagen in the cochlea in Alport syndrome.
Arch. Otolaryngol. Head Neck Surg. 131,
10071013 (2005).
Ohkubo, s. et al. immunohistochemical and
molecular genetic evidence for type iv collagen
5 chain abnormalities in the anterior
lenticonus associated with Alport syndrome.
Arch. Ophthalmol. 121, 846850 (2003).
chen, L., Miyamura, N., Ninomiya, Y. &
Handa, J. t. Distribution of the collagen iv
isoforms in human Bruchs membrane. Br. J.
Ophthalmol. 87, 212215 (2003).
rumpelt, H. J., Langer, K. H., scharer, K.,
straub, e. & thoenes, W. split and extremely
thin glomerular basement membranes in
hereditary nephritis (Alports syndrome).
Virchows Arch. A Path. Anat. Histol. 364,
225233 (1974).
Arnold, W. Uberlegungen zur pathogenese des
cochleorenalen syndroms. Acta Otolaryngol.
89, 330341 (1980).
streeten, B. W., robinson, M. r., Wallace, r. &
Jones, B. D. Lens capsule abnormalities in
Alports syndrome. Arch. Ophthalmol. 105,
16931697 (1987).
colville, D. et al. Ocular manifestations of
autosomal recessive Alport syndrome.
Ophthalmic Genet. 18, 119128 (1997).
Jais, J. p. et al. Xlinked Alport syndrome:
natural history in 195 families and genotype
phenotype correlations in males. J. Am. Soc.
Nephrol. 11, 649657 (2000).
Gross, O., Netzer, K.O., Lambrecht, r.,
seibold, s. & Weber, M. Metaanalysis of
genotypephenotype correlation in Xlinked
Alport syndrome: impact on clinical
counselling. Nephrol. Dial. Transplant. 17,
12181227 (2002).
Jais, J. p. et al. Xlinked Alport syndrome:
natural history and genotypephenotype
correlations in girls and women belonging to
195 families: a european community Alport
syndrome concerted Action study. J. Am. Soc.
Nephrol. 14, 26032610 (2003).
Dagher, H. et al. A comparison of the clinical,
histopathological and ultrastructural
phenotypes in carriers of Xlinked and
autosomal recessive Alports syndrome. Am. J.
Kidney Dis. 38, 12171228 (2001).
colville, D. & savige, J. A. Alport syndrome.
A review of the ocular manifestations.
Ophthalmic Genet. 18, 161173 (1997).
Govan, J. A. Ocular manifestations of Alports
syndrome: a hereditary disorder of basement
membranes? Br. J. Ophthalmol. 67, 493503
(1983).
colville, D., Dagher, H., Miach, p. & savige, J.
Ocular clues to the nature of disease causing
endstage renal failure. Nephrol. Dial.
Transplant. 15, 429432 (2000).
Zhang, K. W. et al. the use of ocular
abnormalities to diagnose Xlinked Alport
syndrome in children. Pediatr. Nephrol. 23,
12451250 (2008).
cervantescoste, G., Fuentespaez, G.,
Yeshurun, i. & Jimenezsierra, J. M. tapetallike
sheen associated with fleck retinopathy in
Alport syndrome. Retina 23, 245247 (2003).
colville, D., Wang, Y. Y., tan, r. & savige, J. the
retinal lozenge or dull macular reflex in
Alport syndrome is associated with a severe
retinopathy and early onset renal failure. Br. J.
Ophthalmol. [doi:10.1136/bjo.2008.142869]
(2008).

VolUME 5 | JUNE 2009 | 359

2009 Macmillan Publishers Limited. All rights reserved

perspectives
26. shaw, e. A. et al. characterization of the
peripheral retinopathy in Xlinked and
autosomal recessive Alport syndrome. Nephrol.
Dial. Transplant. 22, 104108 (2007).
27. Kashtan, c. e., Fish, A. J., Kleppel, M.,
Yoshioka, K. & Michael, A. F. Nephritogenic
antigen determinants in epidermal and renal
basement membranes of kindreds with Alport
type familial nephritis. J. Clin. Invest. 78,
10351044 (1986).
28. tazonvega, B. et al. Genetic testing for Xlinked
Alport syndrome by direct sequencing of
COL4A5 hair root cDNA samples. Am. J. Kidney
Dis. 50, 257269 (2007).
29. rahman, W. & Banerjee, s. Giant macular hole
in Alport syndrome. Can. J. Ophthalmol. 42,
314315 (2007).
30. Mete, U. O. et al. Alports syndrome with
bilateral macular hole. Acta Ophthalmol. Scand.
74, 7780 (1996).

31. shaikh, s., Garretson, B. & Willliams, G. A.

vitreoretinal degeneration complicated by
retinal detachment in Alport syndrome. Retina
23, 119120 (2003).
32. Usui, t. et al. symmetrical reduced retinal
thickness in a patient with Alport syndrome.
Retina 24, 977979 (2004).
33. Gehrs, K. M., pollock, s. c. & Zilkha, G. clinical
features and pathogenesis of Alport
retinopathy. Retina 15, 305311 (1995).
34. teekhasaenee, c. et al. posterior polymorphous
dystrophy and Alport syndrome. Ophthalmology
98, 12071215 (1991).
35. rhys, c., snyers, B. & pirson, Y. recurrent
corneal erosion associated with Alports
syndrome. Kidney Int. 52, 208211 (1997).
36. colville, D., savige, J. A., Branley, p. & Wilson, D.
Ocular abnormalities in thin basement
membrane disease. Br. J. Ophthalmol. 81,
373377 (1997).

360 | JUNE 2009 | volUmE 5

37. colville, D., Guymer, r., sinclair, r. A. &

savige, J. A. visual impairment caused by
retinal abnormalities in mesangiocapillary
(membranoproliferative) glomerulonephritis
type ii (dense deposit disease). Am. J. Kidney
Dis. 42, e2e5 (2003).
38. Mullins, r. F., Aptsiauri, N. & Hageman, G. s.
structure and composition of drusen
associated with glomerulonephritis:
implications for the role of complement
activation in drusen biogenesis. Eye 15,
390395 (2001).

Acknowledgments
Our 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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