In-Depth Review

Ocular Features in Alport Syndrome: Pathogenesis andClinical Significance

Judy Savige,*†‡ Shivanand Sheth,§| Anita Leys,¶ Anjali Nicholson,| Heather G. Mack,** and Deb Colville*§

AbstractAlport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocularabnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result inabsenceof the collagen IVa3a4a5network fromthebasementmembranesof the cornea, lens capsule, and retinaandare associatedwith corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically,these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmiccomplications of posterior polymorphous corneal dystrophy, giantmacular hole, andmaculopathy all produce visualloss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnosti-cally, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy stronglysuggest the diagnosis ofAlport syndromeand are associatedwith renal failure before the age of 30 years, inmaleswithX-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in themother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a femalemeans that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomographyare widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful inthe diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It alsodetects complications, such as macular hole, for which new treatments are emerging.

Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.10581014

IntroductionAlport syndrome is characterized by hematuria, pro-gressive renal failure, hearing loss, and ocular abnormal-ities affecting the cornea, lens, and retina (1,2). Cornealscarring, temporal retinal thinning, giant macular hole,and maculopathy are recently described features that ex-tend the ophthalmic phenotype (Figures 1–3) (3–7).

Alport syndrome affects at least one in 10,000 in-dividuals, and the diagnosis is important because ofthe risk of disease in other family members; also, earlytreatment with angiotensin-converting enzyme inhib-itors delays the onset of end stage renal failure (8,9).

Inheritance of Alport syndrome is X-linked in nearly allfamilies (85%), and mutations affect the COL4A5 gene,which codes for the collagen IV a5-chain (10,11). The di-agnosis of X-linked Alport syndrome is often overlooked,especially in women, who are affected three times as of-ten as men. Inheritance in the other 15% of Alportfamilies is autosomal recessive with homozygous or com-pound heterozygous mutations in trans in the COL4A3or COL4A4 gene, which corresponds to the collagen IVa3- or a4-chain (12,13). The occurrence of an autosomaldominant form of Alport syndrome is controversial.Thin basement membrane nephropathy representsthe carrier state for autosomal recessive Alport syndrome,and affected individuals have a heterozygous COL4A3or COL4A4 mutation (13,14) but no ocular or otherextrarenal abnormalities (15).

The characteristic ocular features of Alport syn-drome are corneal opacities, anterior lenticonus and

cataract, central perimacular and peripheral coalesc-ing fleck retinopathies, and temporal retinal thinning.Rarely, posterior polymorphous corneal dystrophy, amacular hole, or a maculopathy impairs vision. Lenti-conus, corneal dystrophy, central and peripheral fleckretinopathies, temporal retinal thinning, and giantmacular hole are all highly suspicious for the diagnosisof Alport syndrome.

Biochemistry of Collagen Type IVCollagen IV is the most abundant protein found in

basement membranes and is responsible for the mem-brane’s strength and integrity. It also contributes tomany biologic functions through its interactions withother proteins and cells (16).Collagen IV occurs as three heterotrimers (a1a1a2,

a3a4a5, and a5a5a6) that form distinct networks(17). Individual chains have an intermediate collag-enous sequence with glycine as every third aminoacid, because it is the only residue small enough tofit inside the collagen helix. The collagen IV a1a1a2network predominates in embryonic membranesand the adult vasculature. It is replaced by thea3a4a5 network in the adult glomerulus (glomerularbasement membrane), cochlea (stria vascularis), cor-nea (Descemet’s and Bowman’s membranes) (18),lens capsule, and retina (inner limiting membraneand Bruch’s membrane) (19), and by the a5a5a6 net-work in the skin (17).

*Department ofMedicine, TheUniversity ofMelbourne, RoyalMelbourne Hospital,Parkville, Victoria,Australia; †TheUniversity ofMelbourneDepartment ofMedicine, NorthernHealth, Epping,Victoria, Australia;‡Department ofNephrology, RoyalMelbourne Hospital,Parkville, Victoria,Australia;§Department ofOphthalmology, RoyalChildren’s Hospital,Parkville, Victoria,Australia; |Departmentof Ophthalmology, BaiYamunabai LaxmanNair CharitableHospital, Mumbai,India; ¶Department ofOphthalmology,UniversitaireZiekenhuizen,Leuven, Belgium; and**Department ofOphthalmology, TheUniversity ofMelbourne, EastMelbourne, Victoria,Australia

Correspondence:Prof. Judy Savige, TheUniversity ofMelbourne,Department ofMedicine (MelbourneHealth), RoyalMelbourne Hospital,Parkville, VIC 3050,Australia. Email:jasavige@unimelb.edu.au

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. Published on February 3, 2015 as doi: 10.2215/CJN.10581014CJASN ePress

Collagen MutationsIn total, .1200 unique variants have been described in X-

linked Alport syndrome (www.LOVD.nl). They are mis-sense (40%), nonsense mutations and complex changesthat result in a downstream nonsense change (40%), andsplice site mutations (10%) (20). Missense mutations typi-cally produce misfolded proteins that are retained withinthe endoplasmic reticulum and destroyed by the unfoldedprotein response (21). Nonsense mutations, such as for otherinherited collagen diseases, probably result in nonsense-mediated decay, where most of the corresponding mRNAis degraded (21). Both missense and nonsense COL4 muta-tions have a positive-negative effect, causing the loss of notonly the corresponding collagen chain but also, those withwhich it normally forms the a3a4a5 heterotrimer.The loss of the collagen IV a3a4a5 network and the persis-

tence of the immature a1a1a2 network produce abnormalmembranes and the clinical features characteristic of Alportsyndrome. The a1a1a2 network is less structurally soundwith fewer intra- and interheterotrimer cross-links (22,23) andmore proteolytic cleavage sites than the a3a4a5 network (16).It is also more susceptible to biomechanical strain (24), which isexaggerated by the overproduction of ectopic laminin chains(25), and induces matrix metalloproteinase activity (26–28).

Genotype-Phenotype CorrelationsIn X-linked Alport syndrome, the clinical phenotype de-

pends on both the location of the mutation and the nature ofthe substituting residue (29–32) (Figure 1). Missense mutationsnear the carboxy terminus, large rearrangements, insertionsand deletions, and nonsense mutations typically result inearly-onset renal failure (before the age of 30 years), hearingloss, lenticonus, and retinopathy (29–31). Single-nucleotidesubstitutions that replace glycine with more highly chargedor larger residues (arginine, aspartic, or glutamic acid) alsoproduce a more severe phenotype (32). Missense mutationsnear the amino terminus usually result in mild disease. Agenotype-phenotype correlation is less obvious in femaleswith X-linked Alport syndrome because of the effects ofLyonization (33), but the same rules for phenotype severityappear to apply for autosomal recessive and X-linked in-heritance (34).

Cornea: Recurrent Corneal Ulcers, Corneal Clouding,and Posterior Polymorphous Corneal DystrophyCorneal disease is recognized infrequently in Alport syn-

drome. Erosions (3,35) result from an abnormal Bowman’s

membrane in the corneal subepithelium (Figure 2A) and pos-terior polymorphous corneal dystrophy from an abnormalDescemet’s membrane in the subendothelium (Figure 2,B–D). The affected membranes lack the collagen IV a3a4a5network, are weak, and adhere poorly to the epithelium, en-dothelium, and underlying stroma (36).Superficial corneal erosions occur in ,10% of patients

(3,35) but are intermittent and hence, seem to be less com-mon. Their onset may precede the diagnosis of Alport syn-drome and is often in the late teenage years. They typicallyoccur in individuals with early-onset renal failure and ex-trarenal features. Sometimes, corneal erosions are found indifferent members of the same family, but they do notappear to be associated with specific mutations.Erosions are accompanied by episodes of unilateral or

bilateral ocular pain occurring spontaneously at night orfirst thing in the morning, with watering, photophobia,and blurred vision (Figure 2A). Symptoms last 2–5 daysand recur (35). Precipitants include working at a computerscreen and irritation from the wind or contact lenses. Onexamination, the eye is red, and there are opacities andvesicles anteriorly at the epithelium on slit-lamp examina-tion (37). Most episodes resolve with supportive measures,such as an eye pad, topical antibiotics, and pain relief, butsometimes, they result in corneal clouding and scars.Posterior polymorphous corneal dystrophy is rare andmore

serious than the corneal erosions (Figure 2, B–D) (3,5,38).Again, patients may be asymptomatic, or complain of recur-rent episodes of grittiness, watering, and photophobia. Thediagnosis is made when multiple clusters of vesicles (“dough-nuts”) or bands (“snail tracks”) are demonstrated at the poste-rior corneal surface on slit-lamp biomicroscopy or with specularmicroscopy, in vivo confocal microscopy, or high-resolutionanterior segment optical coherence tomography (OCT; OCT

Figure 1. | Collagen IV molecule—location and nature of mutationscausing X-linked Alport syndrome.

Figure 2. | Corneal abnormalities. (A) Mild scarring caused by re-current corneal erosions shown on slit-lamp examination in a manwith X-linkedAlport syndrome (arrow), renal failure, and perimacularretinopathy. The patient’s mother is also affected with renal diseaseand similar corneal changes. (B) Posterior polymorphous cornealdystrophy (arrow) with diffuse and vesicular lesions posteriorly at the levelofDescemet’smembraneon slit-lampexamination in amanwithX-linkedAlport syndrome, renal failure, lens replacement for lenticonus, and peri-macular retinopathy. (C) A slit-lamp view of posterior polymorphouscorneal dystrophy showing the characteristic doughnut-like vesicles pos-teriorly (arrow). (D) Specularmicroscopyof the corneal endothelium in thepatient in C showing that the doughnut-like lesions are vesicles with thickdark borders around clusters of endothelial cells (arrow).

2 Clinical Journal of the American Society of Nephrology

is a little like ultrasound but uses the reflection of light ratherthan sound from surfaces in the eye to demarcate differentlayers) (39). The vesicles result from vacuolar degenerationof dying cells or multilayered epithelial cell protuberances fromDescemet’s membrane (40–42). Treatment is usually symp-tomatic; sometimes, the dystrophy progresses, and cornealtransplantation is required.Corneal erosions are distinguished from posterior poly-

morphous corneal dystrophy by causing gritty eyes ratherthan visual loss, being more prevalent, and their locationin the anterior cornea.

Lens: Anterior Lenticonus and CataractsThe demonstration of lenticonus is diagnostic for Alport

syndrome (Figure 3). Anterior lenticonus is present in 50%of men, but not women, with X-linked disease, where it isassociated with early-onset renal failure and perimacular ret-inopathy. In contrast, lenticonus is common in both men andwomen with autosomal recessive inheritance, and therefore,women with Alport syndrome and lenticonus are likely tohave recessive disease (43,44).Lenticonus results from the conical protrusion of the lens

anteriorly through the thinnest and weakest part of thecapsule (Figure 3B) (45). The absence of the a3a4a5 net-work from the capsule means that it develops partial splitsthat may rupture (Figure 3C). Cataracts develop fromhealing of small spontaneous ruptures (46). Lenticonusceases to progress after cataract formation (47). Posteriorlenticonus also occurs but is less common (48).Lenticonus is often first seen in early middle age after the

onset of renal failure. Patients have progressive difficulty infocusing because of their abnormal lens shape. The diagnosisis made when there is an oil droplet sign on direct ophthal-moscopy or slit-lamp examination (Figure 3A). Lenticonusworsens until visual symptoms require treatment, andmost patients eventually require surgery. Treatment for

both symptomatic lenticonus and cataract is lens removaland intraocular lens implantation (49). Lenticonus does notrecur after lens replacement.

Retina: Central Fleck Retinopathy and PeripheralCoalescing RetinopathyCommon retinal abnormalities include central or peri-

macular fleck retinopathy and peripheral coalescing fleckretinopathy. They also include manifestations of temporalthinning (4), such as loss of the foveal reflex, a lozenge,disturbances of foveal pigmentation (50), including a bull’seye or vitelliform maculopathy (7), and lamellar and giantmacular hole (6,51) (Figure 4, Table 1).Central fleck retinopathy is present in 60% of men and at

least 15% of women with X-linked Alport syndrome and50% of individuals with recessive disease (Figure 4, A–C)(52). It is more common with early-onset renal failure andlenticonus. Nearly all individuals with the central retinopa-thy also have a peripheral retinopathy, but the converse isnot true (53). The central retinopathy varies from scatteredwhitish-yellow dots and flecks to a dense, almost confluentannulus around the region of temporal retinal thinning. Thefleck retinopathy is associated with an abnormal inner lim-iting membrane (54).The clear demarcation of the central retinopathy from the

foveola is consistent with involvement of the inner limitingmembrane/nerve fiber layer. This is not a true membranebut rather, results from fusion of the Muller cell end platesand incorporates the collagen IV a3a4a5 network. The cen-tral retinopathy probably represents an abnormality ofthese end plates. Thinning of the inner limiting membrane/nerve fiber layer may interfere with the nutrition of theoverlying cells, removal of debris, and maintenance of thewatertight barrier.Visual acuity is essentially normal, although formal testing

of retinal function shows minor abnormalities. The centralretinopathy is best seen with color photographs and redfreeimages centered on the macula. Specialized tests of retinalfunction, such as electroretinogram and electrooculogram, arenormal or nearly normal. The central retinopathy becomesmore prominent with time. No treatment is required.The peripheral fleck retinopathy is the most common

retinal abnormality, occurring in most men and 25% ofwomen with X-linked Alport syndrome and most indi-viduals with recessive disease (Figure 4, D–F) (53). Theperipheral retinopathy is characterized by asymmetricpatches of confluent flecks (54). The fleck location in rela-tion to the blood vessels and appearance on OCT suggestthat they result mainly from an abnormality at the level ofthe retinal pigment epithelium/Bruch’s membrane. Thefinding of a peripheral retinopathy is a very helpful pointerto the diagnosis of Alport syndrome, especially in womenwith X-linked disease (53).The peripheral retinopathy is associated with early-onset

renal failure, lenticonus, and central retinopathy but alsooccurs in women with X-linked disease who have normalrenal function (53). It is probably more common than thecentral retinopathy because of the periphery’s larger sur-face area.Visual acuity is, again, normal. The peripheral retinop-

athy is best seen on ophthalmic examination or with retinal

Figure 3. | Lens abnormalities. (A) Lenticonus appearance on slit-lampexamination showing an anterior dimple or oil droplet (arrow) in amanwith X-linked Alport syndrome, renal impairment, and posterior poly-morphous corneal dystrophy. The oil droplet is also obvious on directophthalmoscopy. (B) Anterior segment view showing the anteriorbulging of the lens (arrows) with a Scheimpflug camera (Pentacam) inthe patient from A. (C) Electron microscopy of an anterior lens capsuleobtained at surgery showing the thinned capsule (arrow) and verticaltears (upper panel) compared with normal (arrow in lower panel). Theabnormal lens was from a man with X-linked Alport syndrome, renalfailure, lenticonus, and retinopathy.

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Ocular Features in Alport Syndrome, Savige et al. 3

photographs that extend beyond the standard views intothe periphery and with redfree retinal images. Again, tests ofretinal function are normal (54). No treatment is required.

Temporal Retinal Thinning, Dull Macular Reflex,Lozenge, Foveopathy, and Macular HoleTemporal retinal thinning is very common in men and

women with X-linked Alport syndrome, and with recessivedisease (Figure 4, G–J) (4,55). The lozenge (56), dull mac-ular reflex (56,57), foveopathy, and lamellar and macularholes all affect the temporal retina (Figure 4, K–O) (6,51)and reflect retinal thinning of both the inner limiting mem-brane and Bruch’s membrane (4,19,44).Temporal thinning is apparent on retinal color photography

as the dull macular reflex or lozenge with a larger, more ovalshape rather than the normal round foveal reflex. Thinning

is confirmedwith retinal thickness measurements in the,5thpercentile on OCT (55). Although thinning is common inall forms of Alport syndrome and less sensitive diagnos-tically than a peripheral retinopathy, its demonstration ismore objective. Thinning occurs with retinal ischemia butotherwise, not in non-Alport renal failure. Tests of retinalfunction are normal when there is thinning only. Vision isnot affected.

FoveopathyHypopigmentation occurs in Alport syndrome but is

typically overlooked (58). It is often present together withperimacular flecks or other ocular features. Vision and vi-sual fields are not usually affected. Occasionally, severeforms, such as a bull’s eye or vitelliform retinopathy, arefound (7).

Figure 4. | Retinal abnormalities. (A) Central or perimacular fleck retinopathy sparing the foveola and located principally in the temporal retina(arrow) in a man with X-linked Alport syndrome, renal failure, and lenticonus. (B and C) Perimacular fleck retinopathy in a woman with X-linked Alport syndrome, renal impairment, and hearing loss (arrows). The flecks are pronounced in the temporal retina. They are more obviousand can be distinguished from the normal retinal sheen on the redfree image (arrows). (D and E) Peripheral coalescing fleck retinopathy ina womanwith X-linked Alport syndrome, normal renal function, and hearing loss. The flecks are.2 disc diameters from the foveola andmoreobvious on the redfree image (arrows). (F) Peripheral retinopathywith widespread evenly distributed retinal flecks (arrows) in an ultrawide fieldscan (Optos camera) in a man with X-linked disease. The lozenge and central fleck retinopathy are not obvious in this view. (G) Pigmentdisturbance with bull’s eyemaculopathy. There is a ring of hypopigmentation with central hyperpigmentation in awomanwith X-linked Alportsyndrome, renal impairment, and peripheral retinopathy (arrow). (H) Lozenge from temporal extension of the normal round foveolar reflex(arrow) caused by retinal thinning in a man with X-linked Alport syndrome, renal failure, hearing loss, lenticonus, and perimacular fleckretinopathy. (I) Temporal retinal thinning seen on a cross-section of the retina from a man with X-linked Alport syndrome, renal failure, andhearing loss. (J) Temporal thinning confirmed in the patient from I indicating that the temporal thickness is in the,5th percentile (red). (K–N)Retinal shadow suggesting (K) macular hole in a womanwith autosomal recessive Alport syndrome, hearing loss, and lenticonus. (L) The holesare more obvious on a black and white image of the macula and temporal retina. (M) The lamellar holes are confirmed with three well de-marcated areas of thinning seen on optimal coherence tomography (OCT) (,200-mm thick). (N) These correspond to three areas of lamellarthinning on OCT. (O) Full-thickness giant macular hole in a woman with Alport syndrome and renal failure.

4 Clinical Journal of the American Society of Nephrology

Lamellar and Giant Macular HolesLamellar or partial-thickness macular holes are uncom-

mon in men with X-linked Alport syndrome and men andwomen with recessive disease (55). Full-thickness holesare even less common. Macular holes occur at a youngerage and are larger (giant holes) than the spontaneousholes in patients who do not have Alport syndrome. Holesmay be bilateral, asymmetric, or unilateral. They start withmultiple small defects (59) hollowed out from the surfaceof the inner limiting membrane (6) due to acceleratedpassage of fluid through the defective Bruch’s mem-brane, and followed by fusion of the microcysts, whenthe abnormal membrane breaks down (51). Thus, full-thickness macular holes arise from collagen IV abnor-malities in Bruch’s membrane and the internal limitingmembrane together with anomalous vitreoretinal trac-tion, retinal detachment (60), and anterior lens capsulerupture (61).Patients with macular holes have difficulty with cen-

tral vision and metamorphopsia (where straight lines aredistorted). Holes sometimes only become evident whenthere is no improvement in vision after surgery forlenticonus. Lamellar holes are not necessarily seen onretinal photographs, and OCT is required for theirdemonstration. They may be confused with a retinallozenge. Holes in Alport syndrome respond less well tosurgical closure and often result in a permanent loss ofvision.

Clinical Usefulness of Ophthalmic FeaturesThe ocular features of Alport syndrome are explained by

distribution of the collagen IV a3a4a5 network in base-ment membranes of the eye, mutations that result in theloss of this network, basement membrane thinning, lamel-lation and rarefaction, and the intraocular mechanicalstresses.Most of the ocular features in Alport syndrome do not

affect vision but are useful diagnostically, and in some cases,they suggest the likelihood of early-onset renal failure andthe mode of inheritance.Some ocular features (lenticonus and central and pe-

ripheral retinopathy) are common in Alport syndrome, andtheir presence confirms the diagnosis (Table 2). Retinaltemporal thinning is very common and suggests Alportsyndrome in an individual with hematuria or renal failure.Posterior polymorphous corneal dystrophy and macularhole are rare but also suggest this diagnosis. Ocular fea-tures are less sensitive but more specific than hearing lossin Alport syndrome, because hearing loss occurs with otherinherited renal diseases and in dialysis patients.In addition, ocular features may help distinguish between

X-linked and autosomal recessive inheritance. Thus, a pe-ripheral retinopathy in the mother of a boy with hematuriaindicates not only the diagnosis of Alport syndrome but also,that inheritance is X-linked. Lenticonus, central retinopathy,and macular hole are rare in women with X-linked disease.Thus, a woman referred for investigation of hematuria who

Table 1. Prevalence of ocular features in X-linked and autosomal recessive Alport syndrome

Ocular FeatureX-Linked Alport Syndrome (%)

Autosomal Recessive Alport Syndrome (%)Men Women

Recurrent corneal erosions ,10 ,10 Not describedPosterior polymorphouscorneal dystrophy

Rare Rare Not described

Lenticonus 50 ,5 75 (52)Central or perimacular fleckretinopathy

70 20 75 (52)

Peripheral retinopathy 80 50 75 (52)Temporal retinal thinning 55 30 90Lamellar macular hole ,5 Not described ,5Other maculopathies ,5 ,5 Not described

Table 2. Usefulness of ocular features in diagnosis, predicting early-onset renal failure, and identifying mode of inheritance

Ocular Feature Diagnostic Severe Mutations Early-Onset RenalFailure

Distinguish AutosomalRecessive AlportSyndrome fromX-Linked Alport

Syndrome in Women

Posterior polymorphouscorneal dystrophy

Yes (38,40) Yes Yes ?

Lenticonus Yes (50) Yes Yes Yes (52)Central retinopathy Yes Yes (31) Yes (31) Yes (52)Retinal thinning Yes (55) No No NoGiant macular hole Yes (51) Yes Yes YesPeripheral retinopathy Yes (54) No (31) No No (52)

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015 Ocular Features in Alport Syndrome, Savige et al. 5

has any of these features is likely to have not only Alportsyndrome but also, autosomal recessive inheritance.Some ocular features are associated with early-onset renal

failure in X-linked Alport syndrome. Thus, lenticonus andcentral retinopathy usually indicate renal failure onset beforethe age of 30 years. Early-onset renal failure occurs moreoften with COL4A5 mutations such as large rearrangements,nonsense mutations, etc. Lenticonus and central retinopathyalso seem to be more common in autosomal recessive inher-itance caused by nonsense mutations (34).

Which Ocular Investigations Should Be Performed?Why are ocular abnormalities in Alport syndrome often

overlooked? The fleck retinopathy does not affect visionand can be subtle or even confused with a youthful retinalsheen. Ophthalmologists see manyminor retinal changes intheir routine practice, and, unless vision is abnormal, maynot report these.In assessing patients with possible Alport syndrome, it is

important to work closely with an interested ophthalmolo-gist who performs a formal ophthalmic examination withslit-lamp examination as well as retinal photography andOCT. These tests are widely available, inexpensive, noninva-sive and acceptable to patients. Corneal abnormalities are bestseen on slit-lamp examination. Lenticonus appears as abubble in the red reflex on ophthalmoscopy, although anophthalmologist will use a retinoscope. The central retinop-athy is usually evident on retinal photographs but moreobvious with redfree images. The peripheral retinopathymay be obvious on standard retinal views, but peripheralexamination may be necessary. OCT demonstrates tem-poral retinal thinning, especially in men with X-linked dis-ease and individuals with recessive inheritance.When a boy presents for investigation of Alport syn-

drome, ocular features are less likely to be present, but hismother should be examined, especially for the peripheralretinopathy.The recent “Expert Guidelines for the Management of Al-

port Syndrome and Thin Basement Membrane Nephropa-thy” recommend that Alport syndrome be diagnosed withgenetic testing (62). The finding of any of the ocular featuresof Alport syndrome, although they rarely interfere with vi-sion, provides additional evidence supporting this requestand also, in rare instances, for explaining vision impairment.

AcknowledgmentsWethank themanypatients and their clinicianswhoassistedwith

these studies and in particular, members of the Department ofOphthalmology at the Nair Hospital (Mumbai, India) and Dr. PeterCrowley and Paul Martinello of the Austin Health Department ofAnatomical Pathology (Heidelberg, Australia) for the lens electronmicrographs.

Some of this work was presented in poster format at the AnnualMeeting at Ahmedabad India, February 3–6, 2011.

DisclosuresNone.

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