Clinical and Experimental Ophthalmology

2005;

33

: 164–168

Original Article

_____________________________________

Original Article

Ophthalmological manifestations of Fabry disease: a survey of patients at the Royal Melbourne Fabry Disease Treatment Centre

Thanh T Nguyen

MB BS

, Trevor Gin

FRANZCO

, Kathy Nicholls

FRACP

, Michael Low

BMedSci

, Jason Galanos

MB BS

and Andrew Crawford

FRANZCO

Royal Melbourne Hospital, Melbourne, Victoria, Australia

A

BSTRACT

Background:

Fabry disease is a rare X-linked inborn errorof glycosphingolipid metabolism. The aim of this studywas to document the ophthalmological manifestations ofpatients attending the Royal Melbourne Hospital Fabrydisease treatment centre.

Methods:

Patients at the treatment centre had full ophthal-mological examination performed. This included bestcorrected visual acuity, ocular motility examination andexamination of the adnexae. Patients also underwent slit-lamp examination looking for the presence of features ofFabry disease, particularly examining the bulbar conjunctiva,cornea, lens and fundus.

Results:

Thirty-four hemizygous male and 32 heterozygousfemale patients were recruited. The mean age of thehemizygous male patients was 37.7 years (range 18–57 years).The mean age of the heterozygous female patients was34.6 years (range 1–78 years). Visual acuity was not affected.97.1% of the hemizygotes and 78.1% of the heterozygoteshad vascular abnormalities of the bulbar conjunctiva.Cornea verticillata was noted in 94.1% of the hemizygotesand 71.9% of the heterozygotes. 41.2% of the hemizygotesand 9.4% of the heterozygotes had anterior cataractformation. Posterior lens opacities were observed in 11.8%of the hemizygotes and none of the heterozygotes. Retinalvascular tortuosity was observed in 76.5% of the hemi-zygotes and 18.8% of the heterozygotes.

Conclusion:

Conjunctival vascular tortuosity was the mostcommon manifestation in this series. Conjunctival andretinal vessel tortuosity, and corneal verticillata are frequentlyobserved in Fabry disease. The incidence of lenticularchanges is not consistently reported, but in this series andmany others, it is much less common than that of corneal,conjunctival and retinal changes.

Key words:

cataract, conjunctiva, cornea, Fabry disease,retinal vessels.

I

NTRODUCTION

Anderson–Fabry disease (angiokeratoma corporis diffusumuniversale), or as it is more commonly known, Fabry disease,is named after the two medical practitioners, Fabry fromGermany and Anderson from England, who first describedangiokeratoma at the end of the nineteenth century. It is arare disorder, with estimates of prevalence ranging from 1 in40 000 to 1 in 60 000 males.

1

Fabry disease is an X-linked inborn error of glyco-sphingolipid metabolism due to the deficient activity of

α

-galactosidase A, a lysosomal enzyme. This results in theaccumulation of galacto-conjugates such as globotriosylce-ramide (also called ceramide trihexoside or Gb3) in mostbody cell types throughout the body. More than 200 muta-tions of the

GLA

gene, encoding for

α

-galactosidase A, havebeen reported to date.

1

Affected males are hemizygotesfor the

GLA

gene and generally have no detectable

α

-galactosidase A enzymatic activity.

2

The clinical features include acroparaesthesia, cutaneousangiokeratomas, hypohidrosis, ocular anomalies and end-organ disease (renal failure and ischaemic complicationsinvolving the myocardium and brain). Most affected patientspresent with severe peripheral pain in childhood or adoles-cence and frequently progress to multiorgan failure by thefourth or fifth decades.

2,3

Patients suffer from strokes, deaf-ness, renal failure, eye abnormalities and psychologicalproblems.

4

Female carriers may also become sympto-matic.

1,2,5–7

The onset and progression of serious manifesta-tions are highly variable but the median survival is 50 yearsfor hemizygous male patients and 70 years for obligatefemale patients.

8

Until a few years ago, medical management for Fabrypatients was symptomatic using analgesics, renal and vascularprotection with angiotensin-converting enzyme inhibitor,

�

Correspondence:

Dr Thanh T Nguyen, Western General Hospital, Gordon Street, Footscray, Vic. 3011, Australia. Email: bittet@yahoo.com

Ocular manifestations of Fabry disease 165

statins and folic acid. Subsequent to gene cloning andrecombinant enzyme synthesis, trials in mouse models andhuman trials, two competing enzyme preparations areavailable. Both offer very promising results. The twoenzyme formulations currently available are agalsidase alfa(Replagal, Transkaryotic Therapies, Cambridge, MA, USA)produced from modified human fibroblast cell lines andagalsidase beta (Fabrazyme, Genzyme, Cambridge, MA,USA) produced from Chinese hamster ovary cell lines.

1,8

Both have been approved by the European Community,Australia and Canada, and Fabrazyme is approved in the US.In Australia, the enzymes are currently provided by thepharmaceutical companies under Compassionate Use and aspart of ongoing research programs. From July 2004, theenzymes will be funded by the Australian Government. Inour experience, the patients tolerate the enzyme well.Improvements noted include a decrease in pain, increasedperspiration and stabilization of renal function. At present,patients are having fortnightly infusions.

Ocular findings have become one of the hallmarks ofFabry disease, and in some patients have provided a pathwayto diagnosis. The ocular changes usually do not interferewith visual acuity and no correlation with the diseaseseverity has been established.

Conjunctival changes consist of dilatation and tortuosityof the vessels, calibre irregularity and aneurysm formation.Fundal changes are similar in nature, and can be exacerbatedby coexisting renal disease and systemic hypertension.

Cornea verticillata, a whorl-like opacity, is considered tobe the most characteristic and usual ocular findings.

5,9

Thesecorneal changes are also considered a marker of carrierstatus in the heterozygous females.

9,10

Lenticular changes include the anterior subcapsularcataract and the posterior ‘Fabry’ cataract, which wasdescribed by Spaeth and Frost in 1965

11

and consists of adeposition of fine granular material on or near the posteriorlens capsule.

Large series outlining the ocular manifestations inpatients with Fabry disease have been reported from centresof ongoing research into Fabry disease in the USA andEurope. In this report, we present the ocular findings ofpatients attending our Fabry Treatment Centre at the RoyalMelbourne Hospital. This cohort of patients will be reviewedto ascertain any therapeutic effect of enzyme replacementtherapies on ocular changes.

M

ETHOD

Subjects

Participants were recruited from the Fabry Disease Treat-ment Centre at the Royal Melbourne Hospital. The patientswere initially referred to the Department of Ophthalmologyby the treating physicians as part of an extensive clinicalevaluation. Patients were previously diagnosed for Fabrydisease by

α

-galactosidase assay and/or molecular analysis.

12

Thirty-four hemizygous male and 32 heterozygous femalepatients were recruited. Participants gave informed consentto the study approved by our institutional Human Researchand Ethics Committee. Four hemizygotes and 11 hetero-zygotes who attended the clinic did not participate.

Ophthalmological evaluation

Twenty-seven of the 34 hemizygotes and 31 of the 32heterozygotes were reviewed by a single examiner (AC).The other eight patients were reviewed by other ophthal-mologists in the ophthalmology outpatient clinic.

The following objective data were recorded: visualacuity, ocular motility examination including the presenceof diplopia, pupillary reactivity to light and accommoda-tion, visual fields on confrontation testing, presence of peri-orbital swelling, intraocular pressure, and the presence oftypical features of Fabry disease in the bulbar conjunctiva(aneurysmal vessels), cornea (verticillata), lens (anteriorand posterior opacification), and fundus (vessel tortuosityand retinal vascular occlusion).

A grading system was developed to record the presenceof typical features in those sites. The bulbar conjunctiva andthe cornea were each divided into four quadrants and scoresof 0.5, 1, 2 or 3 were assigned to each quadrant according tothe presence of the typical features in subtle, mild, moderateor severe degree. The lens and the fundi were each treatedas a single region and a score of 0.5,1, 2 or 3 was given toeach eye according to the presence and degree of severity ofthe changes.

To ensure uniformity and thorough examination for allpossible Fabry ocular anomalies, the examiners wereprovided with a checklist containing details of the typicalfeatures of Fabry disease.

R

ESULTS

Demographics

Twenty of the male patients who participated are currentlyundergoing fortnightly enzyme replacement therapy. How-ever, most patients had their eyes examined prior to com-mencement of enzyme replacement therapy. Only five ofour male patients had their eyes examined for the first timeduring the course of their therapy: two patients were in theirfirst year, two in their second and one in his third year ofenzyme replacement therapy. The hemizygotes ranged inage from 18 to 57 years, with an average of 37.7 years. Theheterozygotes’ age range was 1–78 years with an averageof 34.6 years. Four of the heterozygotes were less than10 years old. All patients were asymptomatic.

There was no reported diplopia. Pupillary reactivity tolight and accommodation were normal. No abnormality wasdetected on confrontation testing. The intraocular pressurewas not found to be elevated. Only three male patients werenoted to have periorbital oedema.

166 Nguyen

et al

.

Visual acuity

Amongst the hemizygotes, 57 eyes (83.8%) had a bestcorrected visual acuity of 6/6 or better and two eyes (2.9%)had acuity of 6/12. Amongst the heterozygotes, 56 eyes(87.5%) had a corrected acuity of 6/6 or better, and onlytwo (3.1%) had 6/12 or less.

Conjunctiva

In the hemizygous population, the vascular abnormalitiesof the bulbar conjunctiva were found in 33 of the 34patients (97.1%). These patients had bilateral changes.Severe changes were seen in four patients, moderatechanges in 18, and mild or subtle changes in 11. Theabnormalities consisted of tortuosity or microaneurysms ofthe conjunctival vessels (Fig. 1). The changes were absentin one 52-year-old patient. Interestingly, 18 patients werenoted to have more changes in the inferior quadrants andeight of these had no vascular abnormalities noted in thesuperior quadrants.

In the heterozygotes, 25 of the 32 patients (78.1%) hadvascular changes. Mild or subtle changes were noted in 20patients. No severe changes were found. Again, inferiorquadrants changes were more marked than the superiorquadrants in 21 patients, with 15 having no abnormalitiesfound in the superior quadrants. The changes were uni-lateral in five patients.

Cornea

Thirty-two hemizygotes (94.1%) were noted to havecorneal verticillata (Fig. 2). Four patients had moderatechanges, 23 had mild changes, and five had subtle changesonly. Two patients aged 36 and 32 years did not have anycorneal changes observed. Again, in 31 patients, the changeswere more marked in the inferior quadrants, with 16 havingno changes superiorly.

In the heterozygotes, corneal changes were observed in23 patients (71.9%). Seven patients had moderate changesobserved, 11 had mild changes, and five had subtle changes.No changes were seen in the superior quadrants in 12patients.

Retina

Retinal vessel tortuosity was observed in 26 hemizygotes(76.5%) (Fig. 3). Of these, 13 had moderate changes, 12had mild changes and one had subtle changes. In the heter-ozygotes, only six patients (18.8%) had vessel tortuosity, ofwhom three had subtle changes only and three had mildchanges.

No changes consistent with a current or past history ofretinal vascular occlusions were observed.

One 47-year-old patient was noted to have mild degreeof disc oedema. Two patients, aged 37 and 48, were observedto have mildly pale discs bilaterally. These three hemi-zygote patients had normal visual acuity (6/6 or better).

Lens

Amongst the hemizygotes, 14 patients (41.2%) were observedto have anterior cataracts (Fig. 4). Of these, 10 were mild ormore, and four were subtle. In the heterozygotes only threepatients (9.4%) were observed to have anterior cataracts.One 72-year-old woman had subtle changes and twopatients, aged 78 and 60, had mild changes only.

Only four hemizygotes (11.8%) had mild posterioropacities. There were no posterior opacities observed in theheterozygotes.

Figure 1.

Conjunctival manifestations of Fabry disease. (a) ’Mild’venous vascular aneurysmal dilatation; and (b) ’moderate’ increasedvessel tortuosity.

Figure 2.

Corneal manifestations of Fabry disease. (a) ’Mild’cornea verticillata, which are opacities characterized by one ormore lines irradiating from a point near the centre of the cornea;and (b) ’moderate’ cornea verticillata.

Figure 3.

Retinal vascular manifestations of Fabry disease, show-ing an increase in the tortuosity of both retinal arteries and veins allover the retina but mainly in the posterior pole. (a) ’Mild’ retinalvessel tortuosity; and (b) ’moderate’ retinal vessel tortuosity.

Ocular manifestations of Fabry disease 167

Age

Overall, in all of the findings observed, no clear relationshipwith age was found.

D

ISCUSSION

Eye findings have become one of the hallmarks of Fabrydisease. Ocular changes are one of the earliest clinical mani-festations and usually appear in the second decade of life.

13

Many elements of the eyes can be affected but Fabry diseasedoes not directly affect visual acuity

2,9,14,15

and this was alsoobserved in our series. Also, no patient was found to haveocular motility disturbance in our series, as has previouslybeing described.

2,9

Due to the low incidence of Fabry disease, large cohortseries of ocular manifestations are few. Two previous largepublished studies were by Sher

et al.

in 1979, where findingsin 37 hemizygotes and 25 heterozygotes were presented,

9

and Orssaud

et al.

in 2003, who presented findings in 32hemizygous patients.

2

Abnormalities of the conjunctivae often occur in patientswith Fabry disease. Aneurysmal conjunctival vessels werefirst noted in 1925.

11

The most consistent findings arevenous vascular aneurysmal dilatation and increased vesseltortuosity

9,14,16,17

(Fig. 1). This abnormality is not specificfor Fabry disease and can be seen in diabetic patients.

2

Theaccumulation of glycolipid deposits in the media of smallconjunctival vessels

16

and endothelial cells

18

result in theaneurysmal or telengiectatic conjunctival vessels. Aneurysmsof the conjunctival vessels were the most common ocularchanges in our series, present in 97.1% of the hemizygotesand 78.1% of the heterozygotes. This is higher than otherpreviously reported series: 78% and 68% of hemizygotes bySher

et al.

and Orssaud

et al.

, respectively,

2,9

and 46% ofheterozygotes.

9

However, as observed in the our series, thechanges are typically more marked in the inferior bulbarconjunctiva.

Fundal changes are similar in nature and can be exacer-bated by coexisting renal disease and systemic hypertension.Fundal vascular tortuosity was first described in 1909.

11

Theretinal vascular manifestations are characterized by anincrease in the tortuosity of both retinal arteries and veins allover the retina but mainly in the posterior pole

2,9

(Fig. 3).The calibre of the retinal vessels in Fabry disease is normal,in contrast to the retinal vascular changes seen in systemichypertension, which are associated with vascular narrowing,increased light reflex, reddish-brown discoloration of thearterioles, and haemorrhages.

2

Veins are more often involved,becoming tortuous and later showing segmental dilation.

9,13,17

Arterial changes include sheathing, dilation and a corkscrewappearance, aneurysms, arteriovenous anastomoses andcentral retinal artery occlusion.

5,9,10,13,19

Non-vascular changesthat may be secondary to vasculopathy include papill-oedema and optic atrophy.

13,20

We observed retinal vasculartortuosity in 76.5% of male patients and 18.8% of femalepatients. This is comparable to Sher

et al.

(70% of malepatients and 25% female),

9

but more than that observed byOrssaud

et al

.

2

Cornea verticillata, opacities characterized by one ormore lines irradiating from a point near the centre of thecornea (Fig. 2),

13

is considered to be the most characteristicand common of the ocular findings.

5,9

The whorl-like linesare due to the accumulation of glycosphingolipids in thesubepithelial layer of the cornea at or near the level of theBowman’s membrane.

5,6,9,16,19

It was also one of the earliestocular manifestations reported. It was first described in1910,

13

but not linked to Fabry disease until many yearslater. At an early stage, the changes resemble a fine, diffuseepithelial haze, which may be seen as early as 6 months ofage.

14,21

Histological abnormalities have been reported in afoetus carrying the mutation.

22

These corneal changes arealso considered a marker of carrier status in heterozygousfemales.

9,10

Cornea verticillata are also associated with phe-nothiazines, chloroquine, indomethacin, chlorpromazine,and amiodarone.

6,9,13,14,21,23

There has been no reportedinterference with visual acuity, and no correlation withdisease severity has been established.

In our series, the incidence was found to be 94.1% inmale patients and 71.9% in female patients, and the changeswere usually inferior. Sher

et al.

reported similar findings.

9

but Orssaud

et al.

only reported 53.1% involvement.

2

Two types of lens opacities have been described: fine,whitish granular anterior capsular or subcapsular cataract(Fig. 4), first reported in 1959;

9,13

and posterior opacitiesdue to fine granular deposits that radiate from the posteriorpole of the lens along the posterior capsule.

9,13,14,17

Thislatter ‘Fabry cataract’ was first described by Spaeth and Frostin 1965.

11

In our series, anterior cataracts were observed in 41.2%of hemizygotes and only 9.4% of heterozygotes. Theobserved incidence in male patients is comparable to Sher

et al.

who noted 35% of anterior cataracts in male patients,but none in his female patients.

9

Figure 4.

Lenticular manifestations of Fabry disease, showing’moderate’ fine, whitish granular anterior capsular cataract.

168 Nguyen

et al

.

In our series, 11.8% of the hemizygous patients werenoted to have posterior opacities but none were observed inthe heterozygotes. Our observed incidence was lower thanobserved by Sher

et al.

(37% in male and 14% in femalepatients),

9

and Orssaud

et al.

(37.5% of male patients).

2

Conjunctival vascular tortuosity was the most commonmanifestation in our series. Corneal verticillata and retinalvascular changes were also frequently observed. Conjunctivaland retinal vessel tortuosities and corneal verticillata arefrequently observed in Fabry disease, and are often the mostcommon manifestations reported by many authors.

2,9,11,13,18,24,25

The incidence of lenticular changes is not consistentlyreported, but in ours and other large series, it is muchless common than of corneal, conjunctival and retinalchanges.

2,9,25

It has been suggested that the ophthalmologist is in anexcellent position to diagnose Fabry disease because the eyefindings are so conspicuous.

11

However, due to its lowincidence and mode of genetic transmission, most are diag-nosed from family tracing of the index cases. In a recentlyreported series of patients in the USA, a known familyhistory of Fabry disease contributed to the diagnosis in 46%of patients.

26

When there was no family history of thecondition, the diagnosis was made by dermatologists (28%),neurologists (23%), nephrologists (19%), rheumatologists(2%), and cardiologists (2%).

This cohort of patients will be reviewed throughout thetreatment arm of this study to ascertain any therapeuticeffect on ocular changes.

A

CKNOWLEDGEMENTS

We are grateful for the help of Elizabeth Centra andRacheal De Caneva, the Fabry Trial nurses, who were veryhelpful in coordinating patient appointments to encourageparticipation.

R

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