Fabry disease is caused by a deficiency of α-galactosidase A, which leads to the accumulation of ceramide trihexoside in the renal and cardiovascular systems. Generalized gangliosidosis is characterized by deficiencies of β-galactosidases and the resultant accumulation of ganglioside GM1 in the central nervous system and of keratan sulfate in somatic tissues. It has been linked to 3p12–p13. Tay-Sachs disease is related to the generalized gangliosidoses but results from β-hexosaminidase A deficiency, which causes accumulation of ganglioside GM2.
In the sphingolipidoses, the cornea exhibits distinctive changes consisting of whorl-like lines (cornea verticillata) in the basal layers of the epithelium that appear to converge at the inferior central corneal epithelium (Fig 8-2).
Figure 8-2 Slit-lamp photograph from a patient with Fabry disease, showing cornea verticillata in the basal layers of the epithelium.
(Courtesy of Stephen E. Orlin, MD.)
Periorbital edema occurs in 25% of cases, posterior spokelike cataracts in 50%, and conjunctival aneurysms in 60%. Other ocular signs include papilledema, retinal or macular edema, optic atrophy, and retinal vascular dilation. The corneal changes resemble those noted in patients after long-term oral chloroquine or amiodarone therapy.
Hemizygous males with Fabry disease are more seriously affected than heterozygous females and show the typical corneal changes. A heterozygous female patient with Fabry disease will show the same corneal changes. Fabry disease is also characterized by renal failure, peripheral neuropathy with painful dysesthesias in the lower extremities, and skin lesions (angiokeratomas). The skin lesions are small, round, vascular eruptions that later become hyperkeratotic. They consist of an accumulation of sphingolipid within the vascular endothelium.
The clinical phenotype of multiple sulfatase deficiency combines features of metachromatic leukodystrophy and MPS. Affected children have subtle diffuse corneal opacities, macular changes, optic atrophy, and progressive psychomotor retardation. They die in the first decade of life.
The ocular findings in Tay-Sachs disease primarily involve the retina; however, the corneal endothelial cells can appear distended and filled with single membrane–bound vacuoles.
In patients with Fabry disease, levels of α-galactosidase A are markedly decreased in urine and plasma. The conjunctival biopsy result may be positive before cornea verticillata are apparent. Prenatal diagnosis can be performed with chorionic villus sampling. Gene sequencing may help in diagnosing Fabry disease in suspected female carriers, as enzyme levels may be close to normal in heterozygotes.
If a female patient is found to be an asymptomatic heterozygous carrier of Fabry disease, genetic counseling should be considered. Enzyme replacement with infusion of α-galactosidase A is a therapeutic option, but long-term benefit has not been proven. Corneal deposits have been cleared with enzyme replacement therapy. The addition of agents that help stabilize native enzymes may improve the efficacy of enzyme replacement therapy.
Fledelius HC, Sandfeld L, Rasmussen ÅK, Madsen CV, Feldt-Rasmussen U. Ophthalmic experience over 10 years in an observational nationwide Danish cohort of Fabry patients with access to enzyme replacement. Acta Ophthalmol. 2015;93(3):258–264.
Samiy N. Ocular features of Fabry disease: diagnosis of a treatable life-threatening disorder. Surv Ophthalmol. 2008;53(4):416–423.