Enzyme Replacement in Fabry Disease: The Essence Is in the Kidney

Fabry disease is an X-linked, single-gene defect caused by a deficiency of lysosomal α-galactosidase A resulting in failure to catabolize α-D-galactosyl glycolipid moieties, mostly globotriaosylceramide (1). It is a panethnic disorder with an estimated incidence of 1 in 117 000 live births in males, but recent neonatal screening suggested an incidence of up to 1 in 3100 live births (2). Female heterozygotes often express delayed heterogeneous signs and symptoms ranging from no disease expression to full-blown disease as seen in hemizygous men (3).

Fabry disease has been classified as a lysosomal storage disorder because of the conspicuous presence of membranous inclusions in lysosomes of most types of cells and tissues. However, its salient characteristic, the systemic increase in glycolipids, is better considered as a risk factor for developing organ damage whose manifestations are relatively common in the general population. These include a painful small-fiber peripheral neuropathy (4), cerebrovascular stroke (5), progressive renal failure (6), and manifold cardiac abnormalities (7). This view of Fabry disease leads directly to the preferred therapeutic approach, which is to prevent the progressive and irreversible deterioration of major organ systems.

In the past 15 years, enzyme replacement therapy (ERT) has been successfully used in Gaucher disease and, more recently, in other lysosomal disorders, including Fabry disease. There are currently 2 preparations of α-galactosidase A for ERT—agalsidase alfa (Replagal, Shire Human Genetic Therapies, Cambridge, Massachusetts) (8) and agalsidase beta (Fabrazymel, Genzyme Corp., Cambridge, Massachusetts) (9). Both preparations are used in most countries, but the U.S. Food and Drug Administration (FDA) approved only agalsidase beta. They approved it on an expedited basis because of a demonstration that it markedly reduced the number of lysosomal inclusions in renal vascular endothelial cells (9) and on the condition that a later study of agalsidase …