ACTA OPHTHALMOLOGICA VOL. 591981
XXV MEETING OF NORDIC OPHTHALMOLOGISTS
Oulu, Finland 10- 13 June 1981

Department of0phthalmology1 (Head: Erkki Tuovinen),
Department of Pathology2 (Head: Yrjo Callan),
Department of Clinical Chemistry 3 (Head: llkka P enttilii),
Department of Dermatology 4 (H ead: Maija H orsmanheimo),
University of Kuopio, Kuopio, Finland

FABRY'S DISEASE AND CORNEA VERTICILLATA
A report of 3 cases
BY
KAIJA TUPPURAINEN 1 , YRJO COLLAN2 ,
TAPIO RANTANEN 3 and ANTERO HOLLMEN4

Fabry's disease is a rare fami lial disorder of glycolipid metabolism which is
caused by a deficiency of a lysosomal enzyme a-galactosidase. A Finnish family
is described in which cornea verticillata was found in the father and 2
daughters. In all cases, there were symptoms suggesting Fabry's disease: febrile
episodes the origin of which was not clear, limb pains and, in the case of the
father, 20 years of proteinuria with elevated ESR, and hemiplegia and aphasia
following a cerebral thrombosis at the age of 43. The diagnosis was confirmed
by demonstration of an a-galactosidase deficit in the serum and urine of all
patients. Deficiency of th is enzyme leads to abnormally high urinary tri- and
dihexosyl ceramide levels, and this was observed in the father and the elder
daughter. At the age of 12, the daughter had loss of vision in her right eye as a
result of occlusion of the central retinal artery. Electron microscopic (EM)
examination of the father's dermal angioma suggested Fabry's disease. Computerized cranial tomography of the father revealed not only the cerebrovascular condition but also a disease affecting the white matter of the brain.
Key words: familial disorder of glycolipid metabolism - deficiency of lysosomal

enzyme a-galactosidase - corneal opacities - clinical symptoms - X-linked
recessive disorder.

More than 80 years ago, Fabry & Anderson ( 1898) reported independently a skin
disease today best known as Fabry's disease (synonyms: Angiokeratoma corporis
diffusum, Glycolipid lipidosis, Di- and trihexosyl ceramide lipidosis, Fabry-

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Fig. 1.

Cornea verticillata. (Case 3, right eye).

Anderson disease, Hereditary dystopic lipidosis, Ruiter-Pompen-Wyers syndrome).
Later, Ruiter & Pompen (1939) observed cardiac, vascular and renal alterations in
addition to dermal findings, in 3 brothers. The finding of cornea verticillata, or
whorl-like corneal opacities, which is almost universal in Fabry's disease, was first
described by Fleischer (1910), but it was only in 1925 that Weicksel recognized
cornea verticillata as a symptom of Fabry's disease (Franceschetti 1968). According
to the definition given by Duke-Elder (1964), cornea verticillata is a rare condition
characterized by brownish or grey, S-shaped opaque stripes at the level of
Bowman's membrane. The stripes are arranged in a whorled pattern and join
beneath the central point of the cornea (Fig. 1).
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43*

Aetiology, symptoms and inheritance of the disease

Fabry's disease is caused by a deficiency of a lysosomal enzyme, a-galactosidase
(Brady et al. 1967), resulting in accumulation of glycosphingolipids, known as tria nd dihexosyl ceramides, in tissues and tissue fluids, p articularly of the cardiovascular system. The symptoms manifested are skin and mucous membra ne angieke ratomas, cardiovascular disease, re nal changes and ocular findings, not necessarily affecting vision.
Families with cornea verticillata have been studied by Lutz (1930), Vogels (1931),
Gruber (1946) and Denden (1963, 1966). In the publications concerned it was
assumed that inheritance was via an autosomal dominant gene. Franceschetti ( 1968)
continued the genetic research begun by Gruber ( 1946) and succeeded in demonstrating an X-linked, incompletely recessive model of inheritance. This concept was
corroborated when Franceschetti & De nden ( 1968) again investigated the cornea
verticillata family described by Denden (1963, 1966), and found several members
with Fabry's disease (Franceschetti 1968)
Homozygous men display severe symptoms of the disease, whereas heterozygous
women are asymptomatic carriers or exhibit mild symptoms. Cornea verticillata
may be the only outward sign of the disease in such cases.
Diagnosis, differential diagnosis and treatment

Fa bry's disease can be diagnosed by establishing a reduced a-galactosidase level in
plasma, serum, leucocytes, tears or skin fibroblasts. Alternatively, an increased
trihexosyl ceramide level in the urine, plasma or skin fibroblasts can be demonstrated (Desnick et al. 1978).
As regards differential diagnosis when cornea verticillata is present, chloroquine
and the cardiac drug known as amiodarone may cause problems. Francois (1969)
d escribed corneal opacities due to amiodarone in 6 cases, with clearing of the
corneas after discontinuation of the drug. Similar opacities can also occur in
patients on chloroquine, after 4 to 6 months of a daily dosage of 300 to 600 mg;
these opacities also disappear after discontinuation of the drug.
Treatment of Fabry's disease is symptomatic. Pain can be alleviated with oral
cortisone or a combination of diphenylhyd antoin and carbamazepine. Research
into therapy based on substitution of the deficie nt e nzyme is not yet comple te
(Desnick et al ( 1978).

Patients and Methods
Case 1

A male teacher aged 47, K.A. , became ill at the age of 28, showing symptoms of fever and
proteinuria, with a raised ESR. A search has been made for somatic disease ever since the
patie nt reached the age of 32. Lupus erythematosus (LE) and sarcoidosis were considered.
T he patient has been continually on cortisone therapy since reaching the age o f 38. At 43, he

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developed right-sided hemiplegia and aphasia as well as hemianopsia of the right side. These
were considered to be due to cerebral thrombosis. At the time, liver biopsy led to suspicions of
sarcoidosis, but no specific changes were detected on dermal and renal biopsy. At the age of
46 another cerebral thrombosis occurred. A year later, the patient was re-examined, since
cornea verticillata had been detected in his 2 daughters. Subepithelial nasal corneal opacities
were detected in both eyes of the patient. Apart from hemianopsia, ocular findings were
normal.

Case2
A 20-year-old woman, A.M.A. (daughter of K.A.), who had, even as a child, suffered from
limb pains. At the age of 12, the patient suffered loss of vision in the right eye through
occlusion of the central retinal artery. Bilateral cornea verticillata was detected. At this stage,
a search was made for somatic disease, but no diagnosis was reached. Six months later, the
patient developed left-sided facial paresis which resolved completely within two weeks on
medication with cortisone.
In the summer of 1980, the patient was re-examined in the Eye Clinic of Kuopio University
Central Hospital, when findings were normal apart from blindness of the right eye and
cornea verticillata.

Case3
A 16-year-old woman, T.A. (daughter of K.A.), consulted an ophthalmologist in the spring of
1980 because she wanted new spectacles. Cornea verticillata was seen in both eyes (Fig. 1).
The ocular findings were otherwise normal, but in the twilight adaptation test vision was
impaired. At the age of 7 the patient had suffered from a febrile episode of unknown origin
for 2 weeks.

Table 1.

a-galactosidase levels in serum and urine in patients and in controls
a-galactosidase,
serum

!J.mOI/h/1
urine

Subject
K.A., patient 1, 47, male
A.M.A. , patient 2, 20, female
T.A., patient 3, 16, female
Mean± so

2.8
6.1
4.2
4.37 ± 1.34

11.7
16.9
18.2
15.57 ± 2.85

Controls
T.R., 35, male
M.K., 50, male
A. L., 21, female
R.L., 25, female
Mean ± so; controls

9.1
12.0
8.9
13.1
10.775 ± 1.82

23.1
19.9
45.1
33.8
30.48 ± 9.89

The results show distinctly d ifferent values for the father and his daughters as a group, and
the controls. When tested with the t-test the serum values show statistically significant
difference at 1% level whereas the results on urine are not statistically significant.

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Table2.
Urinary excretion of trihexosyl ceramide

!lmol/24 h
K.A., patient 1, 47, male
A.M.A., patient 2, 20, female

0.2-0.5

Normal value in males
Normal value in females

0.007-0.028 1
0.009-0.038 1

Patients with Fabry's disease
Carriers of Fabry's disease

0.24-4.912
0.13-0.982

I

1 Kousa et al 1976. 2 Desnick et al. 1971. Dihexosyl ceramide was clearly

identifiable in urine samples from both patients.

Serum and urine a-galactosidase levels were determined in all patients (Desnick et a!.
1973). In addition, di- and trihexosyl ceramides were determined in the 24 h urines of the
father and the elder daughter (Des nick et al. 1977).
Three cavernous angiomas were found on the father's skin, 2 of which were studied using
light microscope and one by electron microscopy.

Results
The level of a-galactosidase was reduced in both serum and urine in all subjects as
compared with controls (Table 1). Results of statistical analysis are given in Table I.
An abnormally high level of trihexosyl ceramide was determined in the 24 h urines
of the father and the elder daughter. In addition, a dihexosyl ceramide component
could be identified in both urines, which supports the diagnosis of Fabry's disease
(Table 2).
On biopsy of the father's skin lesion an angioma was detected with granules in the
endothelial cells which could be stained yellow with Sudan IV. These were visible
only in frozen sections. In sections in paraffin wax they could no longer be
demonstrated. Similar granules were also detected in the cellular cytoplasm of the
small arteriole walls, particularly in the muscle layer. The granules were pale and
small (approximately 0.!1 J.Lm ac.ross), so that it was difficult to detect them with this
stain at low magnifications (100-400 x). Electron microscopic examination revealed myelin-like dark intralysosomal accumulations, in which the lamellar structure characteristic of material of lipid origin was detected in the endothelial cells of
the vessels in the angioma (Figs. 2-3)

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Fig. 2.
Left: low power micrograph of one of the angiomas found in case 1. There is no abnormality
in the epidermis, but superficial parts of the dermis show a collection of distinctly dilated
blood capillaries - a small cavernous haemangioma. PAS-haematoxylin stain. Magnification
I 10 X. Right: electron micrograph of the capillary endothelium in a haemangioma similar to
the one shown on the left. Note dark myelin-like bodies in the cytoplasm of the endothelial
cells. Magnification 12 000 x.

Discussion
Some 500 patients with Fabry's disease have been described in the literature
throughout the world (Franceschetti 1976). Earlier, in Finland, Kousa et al (1976)
reported 2 cases, a 24-year-old man and a 28-year-old woman, but cornea
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verticillata was not detected in either on ophthalmological examination, which
would suggest that this corneal alteration has not previously been seen in Finnish
patients. Sher et al. ( 1979) published a report of a study of a group of 37
homozygous men and 25 heterozygous women. Loss of vision in one eye was stated
to have resulted in 2 men from central retinal arterial occlusion. One of the 2
patients was aged 16. In one of our patients (a heterozygous female carrier) loss of
vision had occurred for the same reason at the age of 12.
Relatively few studies h ave been carried out on patients with Fabry's disease using
electron microscopy. In one case, Malmqvist et a!. ( 1971) detected inclusions made
up of a myelin-like substance in the epithelial and endothelial cells of the kidney,

Fig.3.
High power electro n micrograph of a couple of the dark bodies shown in Fig. 2 right. Note
the intralysosomal location of the bodies - unit membrane distinctly surrounds the bodies.
The bodies show lamellation suggesting lipid nature. Magnification 175 000 x.

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duodenum and striated muscle. The authors considered that the substance was
trihexoside, which accumulates in lysosomes.
Weingeist & Blodi (I 971) studied the cornea, conjunctiva and choroid of a
71-year-old female carrier electron microscopically. It was noted that the corneal
epithelial basal membrane had doubled in places, while amorphous material had
accumulated at the corresponding site beneath the basal membrane. This
amorphous material was assumed to be sphingolipid. The authors presented a
hypothesis on the basis of which such accumulations manifest as cornea verticillata.
The electron microscopic examination of the dermal angioma of our patient (a
47-year-old male) revealed myelin-like intralysosomal accumulations in the endothelial cells of angiomatous blood vessels. This material was morphologically very
similar to that described by Malmqvist et al. (1971), and was probably accumulated
trihexoside.
In all our patients, diagnosis was confirmed by determining the a-galactosidase
levels in both serum and urine. In addition, increased tri- and dihexosyl ceramide
levels were detected in the urine of 2 patients (a father and his elder daughter).

Acknowledgment
Our best thanks to Pentti Mikkonen for the photograph and to Heikki Rauvala for the
analysis of tri- and d ihexosyl ceramides.

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Author's address:
Kaija Tuppu rainen, University Eye Hospital, 70210 Kuopio 21, Finland.

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