Characterization of the peripheral retinopathy in X-linked and autosomal recessive Alport syndrome.
ABSTRACT Alport syndrome is an inherited disease resulting in kidney failure, hearing loss and ocular abnormalities. Alport syndrome is however often unrecognized, and the aim of this study was to characterize the associated but rarely described peripheral retinopathy and determine whether its demonstration was diagnostically helpful.
Index cases were diagnosed with Alport syndrome on renal biopsy in themselves or a family member. Inheritance and affected status were determined using microsatellite markers at the COL4A5 and COL4A3/COL4A4 loci, respectively. Participants' eyes were dilated, and examined with direct and indirect ophthalmoscopy, and slit lamp biomicroscopy by an expert ophthalmologist who was unaware of the patients' disease status.
Ten males and nine females with X-linked Alport syndrome and seven with autosomal recessive disease were studied. Of the 26 patients, 16 had central retinopathy (62%), and 19 patients had peripheral retinopathy (74%). The peripheral changes occurred in both males and females with X-linked and autosomal recessive Alport syndrome, and were more common when renal failure, hearing loss, lenticonus and the central changes were present, but were also noted in 3 X-linked carriers with normal renal function.
The peripheral retinopathy occurs in X-linked and autosomal recessive Alport syndrome even when the central retinopathy is absent. Careful retinal examination and photography that includes the periphery is a safe and inexpensive method that may help in the diagnosis of Alport syndrome especially in carriers of X-linked disease.
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ABSTRACT: Autosomal recessive Alport syndrome (ARAS) is a rare hereditary disease caused by homozygous or compound heterozygous mutations in either the COL4A3 or COL4A4 genes. Failure to diagnose ARAS cases is common, even if detailed clinical and pathological examinations are carried out. As the mutation detection rate for ARAS is unsatisfactory, we sought to develop more reliable diagnostic methods and provide a better description of the clinicopathological characteristics of this disorder. A retrospective analysis of 30 genetically diagnosed patients with ARAS in 24 pedigrees was conducted. The mutation detection strategy comprised three steps: (1) genomic DNA analysis using polymerase chain reaction (PCR) and direct sequencing; (2) mRNA analysis using reverse transcription (RT)-PCR to detect RNA processing abnormalities; (3) semi-quantitative PCR using capillary electrophoresis to detect large heterozygous deletions. Using the three-step analysis, we identified homozygous or compound heterozygous mutations in all patients. Interestingly, 20 % of our ARAS patients showed normal expression of α5 in kidney tissue. The median age of developing end-stage renal disease was 21 years. The strategy described in this study improves the diagnosis for ARAS families. Although immunohistochemical analysis of α5 can provide diagnostic information, normal distribution does not exclude the diagnosis of ARAS.Pediatric Nephrology 03/2014; · 2.88 Impact Factor
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ABSTRACT: Female subjects with X-linked Alport syndrome have a single COL4A5 mutation, germ cell mosaicism in affected tissues and typically develop renal failure later or less often than male subjects. Women with two mutations are exceedingly rare, and usually have consanguineous parents or uniparental disomy. We describe here a 20-year-old woman who inherited two different COL4A5 variants, one from her father (c.2677G>C) and one from her mother (c.384 +1 G>A). The index case had normal renal function, proteinuria and no clinically detectable hearing loss, or ocular abnormalities. Her father and paternal uncle developed end-stage renal disease at 37 and 28 years respectively, together with hearing loss, but not lenticonus or central retinopathy. Her mother had mildly impaired renal function, proteinuria, hearing loss, but no ocular abnormalities. Her maternal grandfather and 22-year-old brother, both with this mutation, developed renal failure by 28 years with hearing loss, or had proteinuria and hearing loss respectively. The index case has clinical features consistent with germ cell mosaicism of two COL45A mutations associated with adult-onset renal failure, but no ocular abnormalities. Her risk of renal failure is high, but the rate of progression to end-stage disease depends on the underlying mutations, and disease modification with renin-angiotensin blockade.Pediatric Nephrology 12/2013; · 2.88 Impact Factor
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ABSTRACT: Background Alport syndrome is a progressive inherited glomerulonephritis leading to renal failure, hearing loss and ocular changes. Purpose To report the seventh case of giant macular hole in a patient with Alport syndrome, review the literature, and propose a pathophysiological mechanism. Methods The case of a man with a giant macular hole of the right eye is described with visual acuity, fundus photographs and spectral domain ocular coherence tomography. Results A 56-year-old man with Alport syndrome and giant macular hole (2291 μm × 2265 μm) in his right eye, reducing the visual acuity to 20/200, complained of progressive visual loss in his contralateral eye. Fundus examination of the left eye revealed a circular perimacular atrophy. Conclusion Giant macular holes are one possible retinal complication of Alport syndrome. Their pathogenesis differs from idiopathic macular holes and may result from the combination of collagen type IV abnormalities in the basement membranes of both Bruch's membrane and the internal limiting membrane, along with anomalous vitreo-retinal adhesion.Journal francais d'ophtalmologie 10/2012; 35(8):573–579. · 0.51 Impact Factor
Characterization of the peripheral retinopathy in X-linked and
autosomal recessive Alport syndrome
Elizabeth A. Shaw1, Deb Colville2, Yan Yan Wang1, Ke Wei Zhang1, Hayat Dagher1, Rob Fassett3,
Robyn Guymer2and Judy Savige1
1Department of Medicine, The University of Melbourne, Austin Health/Northern Health, The Northern Hospital,
Epping, VIC 3076,2Centre for Eye Research Australia (CERA), The University of Melbourne, East Melbourne,
VIC 3002 and3Launceston General Hospital, Launceston, TAS 7250, Australia
Background. Alport syndrome is an inherited disease
resulting in kidney failure, hearing loss and ocular
abnormalities. Alport syndrome is however often
unrecognized, and the aim of this study was to
peripheral retinopathy and determine whether its
demonstration was diagnostically helpful.
Methods. Index cases were diagnosed with Alport
syndrome on renal biopsy in themselves or a family
COL4A5 and COL4A3/COL4A4 loci, respectively.
Participants’ eyes were dilated, and examined with
direct and indirect ophthalmoscopy, and slit lamp
biomicroscopy by an expert ophthalmologist who was
unaware of the patients’ disease status.
Results. Ten males and nine females with X-linked
Alport syndrome and seven with autosomal recessive
disease were studied. Of the 26 patients, 16 had central
retinopathy (62%), and 19 patients had peripheral
retinopathy (74%). The peripheral changes occurred in
both males and females with X-linked and autosomal
recessive Alport syndrome, and were more common
when renal failure, hearing loss, lenticonus and the
central changes were present, but were also noted
in 3 X-linked carriers with normal renal function.
Conclusions. The peripheral retinopathy occurs in
X-linked and autosomal recessive Alport syndrome
even when the central retinopathy is absent. Careful
retinal examination and photography that includes the
periphery is a safe and inexpensive method that may
help in the diagnosis of Alport syndrome especially in
carriers of X-linked disease.
the markers at
Keywords: Alport syndrome; collagen type IV;
glomerular basement membrane; retinopathy
Alport syndrome is an inherited kidney disease that
affects one in 50,000 live births . It is characterized
by haematuria, progressive renal failure, hearing loss,
ocular abnormalities and a lamellated glomerular
membrane with an abnormal collagen composition
[2–4]. Inheritance is X-linked in 80% of the patients
and autosomal recessive in most of the others , when
mutations affect the type IV collagen genes, COL4A5,
and COL4A3 and COL4A4, respectively [6,7].
The most common ocular abnormalities in Alport
syndrome are anterior lenticonus and a central or
whitish-yellow dots and flecks and spares the macula
[8–13]. The central retinopathy is pathognomonic for
Alport syndrome, and occurs in 40–70% males and
10% females with X-linked inheritance, and 70%
individuals with autosomal recessive disease [11,12].
There is no retinal involvement in the rare autosomal
dominant disease. The central retinopathy is often
accompanied by hearing loss and lenticonus, and is
usually present by the time renal impairment is first
noted but progresses until at least middle age.
The retinopathy is usually evident on ophthalmoscopy
but is best documented photographically. Vision is
normal and no treatment is necessary. The variation in
reported frequencies of retinal changes is probably
failure (which is more common in patients with the
retinopathy or who are hospital-based anyway) and
how carefully their eyes are examined. A mid-
peripheral or peripheral retinopathy is recognized
less frequently .
The aim of this study was to characterize the
peripheral retinopathy in X-linked and autosomal
Correspondence and offprint requests to: Prof. Judy Savige, The
University of Melbourne, Department of Medicine, The Northern
Hospital, Epping VIC 3076, Australia.
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recessive Alport syndrome, to examine its relationship
to the central retinopathy and other clinical features,
and to determine whether inclusion of the periphery
increased the sensitivity of the retinal examination for
the diagnosis of Alport syndrome.
Patients and methods
Diagnosis of Alport syndrome
Index cases were diagnosed with Alport syndrome when they
had haematuria or kidney failure together with a lamellated
glomerular basement membrane in a renal biopsy from
themselves or a family member. In addition, all family
members were invited to participate in the study whether or
not they were known to be affected.
Participants were asked about a hearing loss or previous
abnormal audiometry, and each provided a urine specimen
which was examined by phase contrast microscopy for
glomerular haematuria , as well as a peripheral blood
sample for estimation of serum creatinine and for DNA
In each family, the mode of inheritance and disease status
were confirmed by the correlation of haematuria or renal
failure with haplotypes at the COL4A5 and COL4A3/
COL4A4 loci . DNA was extracted from blood or
Haplotypes were constructed after PCR amplification of
microsatellite markers at COL4A5 (DXS1120, DXS 1105,
2B6, 2B20 and DXS456) and at COL4A3/COL4A4 (D2S351,
CA11, COL4A4/HaeIII, D2S401 and PAX3). Linkage
studies in many of these families have been described
All participants were examined by an ophthalmologist with
an interest in Alport syndrome (DC) who was not aware of
the patients’ disease status. Participants were asked about
any abnormalities of night vision, colour vision, visual fields,
or a change in spectacle strength. They were then examined
for the ‘oil-droplet sign’ of anterior lenticonus using a hand-
held refractoscope. Their eyes were dilated with tropicamide
1%, and their optic fundi examined for central and
peripheral retinal abnormalities by direct ophthalmoscopy,
slit lamp biomicroscopy with a 78D lens (in most cases), and
by indirect ophthalmoscopy with a 20D lens. The peripheral
retina was defined as being beyond the perifovea and thus
about 3mm or 2 optic disc diameters from the foveola .
Retinal photography including at least eight retinal views
was performed with a digital or Zeiss film camera in 22 cases.
Three individuals had ‘red-free’ retinal photographs which
filter out the background colour and better demonstrates
This study had the approval of the Austin Hospital
Human Research Ethics Committee and all participants
provided signed informed consent.
In this study, 26 individuals from 12 families (80%)
with X-linked and 3 families (20%) with autosomal
recessive disease were examined (Table 1, Figure 1).
Fourteen who had been examined for the central
retinopathy were recalled for these examinations, and
eight individuals were from six families who had not
been studied previously.
X-linked Alport syndrome
Ten males from ten different families (median age 34
years, range 11–54) were examined. Three (30%) had
not reached end-stage renal failure, and seven (70%)
were on dialysis or had undergone transplantation.
Nine had a hearing loss (90%), seven (70%) had
lenticonus (or had a lens replacement) and eight (80%)
had the typical central dot and fleck retinopathy.
Nine (90%) also had a peripheral retinopathy. For
example, an 11-year-old male with normal renal
function and a hearing loss had both the central and
peripheral retinopathy. A 40-year-old male with renal
failure, hearing loss and lenticonus, had the peripheral
retinopathy but no central changes. In contrast, a
38-year-old male with normal renal function and
Nine females from nine families (median age 41
years, range 8–68) were studied. (Both males and
females were studied in 7 families). All had haematuria,
one (11%) had kidney failure, two (22%) had a hearing
loss, none had lenticonus and one had the central
retinopathy (11%). Three had the peripheral retino-
pathy (33%). One woman (11%) had both central and
peripheral retinal changes, and two (22%) had only the
peripheral retinopathy. One of these was the mother of
an affected 27-year-old male who had both the central
and peripheral retinopathy, and the other was the
mother of the 38-year-old affected male who had no
Autosomal recessive Alport syndrome
Seven individuals (six males and one female, median
age 32 years, range 26–47) from three different families
were examined. Six (86%) already had end-stage
kidney failure, five of these had undergone transplan-
tation, and all seven (100%) had a hearing loss,
anterior lenticonus and the central retinopathy. All
seven (100%) had the peripheral retinopathy.
Unaffected family members
None of the 21 unaffected family members (no
haematuria, normal renal function, absence of disease
haplotype) had lenticonus, or the central or peripheral
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Table 1. Peripheral retinopathy and other clinical features in patients with X-linked and autosomal recessive Alport syndrome
Renal status Age at renal
M, male; F, female; H, haematuria; P, proteinuria; RF, renal failure; N/A, not applicable; Y, yes; N, no.
aThe three patients in whom the peripheral retinopathy occurred without the central retinopathy.
Fig. 1. (A) Central retinopathy demonstrating perimacular dots and flecks. (B) Typical peripheral retinopathy showing confluent white areas.
(C) Peripheral retinopathy showing fine dots and flecks in the mid-periphery and periphery but not centrally. This is from a female carrier of
X-linked Alport syndrome. (D) Red-free photograph of same patient as in 1c showing fine white stippling in the mid-periphery consistent with
Peripheral retinopathy in Alport syndrome 3 of 5
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Peripheral Alport retinopathy (Figure 1)
A mid-peripheral or peripheral retinopathy was very
common in the males with X-linked Alport syndrome
and individuals with autosomal recessive disease
(16/17, 94%) who were examined in this study.
The peripheral retinopathy occurred in 3 of the 9
X-linked Alport carriers (33%) and was more common
than the central retinopathy in female carriers of
X-linked Alport syndrome (3/9, 33%). Overall it
occurred in 19 of the 26 individuals studied (74%)
compared with the central retinopathy which was
present in 16 (62%).
mid-periphery, the periphery or both. In some cases,
the changes were localized and sparse but occasionally
affected nearly all the periphery. The mid-peripheral
retinopathy often comprised dots and flecks (like the
central changes) while the peripheral retinopathy often
comprised diffuse confluent areas of depigmentation.
The extent of involvement and the pattern varied in
different family members. Vision was not affected.
The youngest patient in whom these changes were
noted was an 11-year-old boy with X-linked Alport
syndrome. The peripheral retinopathy was more likely
to be present when the affected individual had renal
failure, hearing loss, lenticonus and the central
Of the 26 individuals examined, 22 (85%) under-
went both clinical and photographic examination of
the retina. Photography detected peripheral changes
in 19 individuals (19/22, 86%) compared with expert
the single individual in whom the peripheral retino-
pathy was overlooked clinically had poorly dilated
The ‘red-free’ photographs demonstrated the central
and peripheral retinopathy more clearly and more
extensively than did ordinary retinal photography.
This study found a mid-peripheral or peripheral
retinopathy was very common in affected individuals
and carriers with X-linked Alport syndrome and in
affected individuals with autosomal recessive disease
even when there was no central retinopathy.
Alport syndrome is often unrecognized which means
many affected individuals and their family members
who are at risk of renal failure are not screened and do
not receive genetic counselling. The diagnosis of Alport
syndrome usually depends on the demonstration of
the typical clinical features, a positive family history,
a lamellated glomerular basement membrane, abnor-
mal basement membrane collagen composition, or the
demonstration of mutations in the COL4A5, COL4A3
or COL4A4 genes. However all these methods are
problematic. The clinical features are often atypical,
and there is no family history if the disease has arisen
de novo or the family is small, comprises only females
or young boys, or the affected males have atypical
disease . In addition, some patients with Alport
syndrome have a glomerular membrane that is thinned
rather than lamellated , and appears to have
a normal composition. Although genetic testing is the
gold standard for the diagnosis of Alport syndrome
it is not widely available.
However, there are some ocular clues to this
diagnosis. The central perimacular dot and fleck
retinopathy, when present, is characteristic, and retinal
examination is particularly useful in the elderly,
where the clinician is reluctant to perform a renal
biopsy, where the biopsy has been unhelpful, and in
individuals who have already undergone transplanta-
tion. Nevertheless, the demonstration of the central
retinopathy is also relatively insensitive for Alport
syndrome especially in carriers of X-linked disease.
This study found that a peripheral retinopathy may
occur even in the absence of the central retinopathy
and suggests that including the periphery increases the
sensitivity of retinal examination for the diagnosis of
Alport disease. We acknowledge though that most
patients studied here had renal failure which makes
retinal changes more likely. In addition, the impor-
tance of fully dilating the pupils, collaborating with an
interested ophthalmologist, and using full retinal
photography and even ‘red-free’ views cannot be
overstated. Furthermore, peripheral changes must be
distinguished from other retinal disease including
fundus albipunctatus, other causes of generalized
drusen and the pigmentary retinopathies that are
usually accompanied by night blindness and progres-
sive visual loss.
The central and peripheral retinopathies appear to
have an identical pathogenesis in X-linked and
autosomal recessive Alport syndrome. Like the central
retinopathy, the peripheral retinal changes were first
noted in adolescence and worsened until at least middle
age. In the patients described here, the peripheral
retinopathy was more common when the central
retinopathy occurred, and when renal failure, lentico-
nus and the hearing loss were also present. However,
while most affected patients in our series had a more
severe phenotype with a younger age of onset of renal
failure, the peripheral retinopathy was also present in
individuals with normal renal function. The increased
likelihood of the peripheral retinopathy may reflect the
earlier age at onset of changes or the larger surface area
of the periphery compared with the central retina.
The peripheral retinal changes occurred in some
affected family members but not in others and were
thus not related to the nature of the underlying genetic
mutations. For example, in one family, a female carrier
had haematuria, normal renal function and a periph-
eral retinopathy but her 40-year-old affected son with
renal failure had no retinal abnormalities.
In conclusion, careful retinal examination and
photography are useful clinical tests that may demon-
strate the central and peripheral retinopathies diag-
nostic of Alport syndrome.
4 of 5E. A. Shaw et al.
by guest on May 31, 2013
Health and Medical Research Council of Australia and the
Australian Kidney Foundation.
This work was supported by the National
Conflict of interest statement. None declared.
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Received for publication: 10.5.06
Accepted in revised form: 27.8.06
Peripheral retinopathy in Alport syndrome 5 of 5
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