History of Fabry Disease

In 1898, two physicians – Johann Fabry in Germany, and William Anderson in England – independently published articles in dermatology journals describing patients with what is now known as Fabry disease ^{[1, 2]} . During the ensuing 100 years, many important advances have been made in understanding the pathogenesis and the genetic basis of the disorder. In 1947, the disease was first postulated to be a generalized storage disorder because of the abnormal vacuoles found in virtually all cells of affected individuals^[3]. In 1963, the material that accumulates in the cells of Fabry patients was identified as neutral glycosphingolipids, of which the predominant lipid is GL-3^[4] Shortly thereafter, the cause of the disease was found to be a deficiency of the enzyme required for this glycosphingolipid catabolism – ceramide trihexosidase (a galactosidase) ^[5]. In 1970, Kint, a Belgian biochemist, reported the anomeric configuration of the terminal galactoside linkage to be alpha (α-galactosidase or α-GAL). ^[6]

These discoveries made it possible to diagnose the disease by measuring the activity of α-GAL in leukocytes, plasma or serum, tears, biopsied tissues, or cultured skin fibroblasts of affected patients.

In the late 1980s, the full-length cDNA was isolated and the entire gene sequence for α-GAL was determined^[7]. The identification of numerous mutations in Fabry kindreds has made it possible to identify carrier females definitively through mutation or genetic linkage analysis. The precise identification of the molecular defect in Fabry disease, plus the availability of new molecular genetic techniques, have fueled research on several disease specific therapeutic strategies currently at various stages of development.

References

1. Anderson W. A case of “Angeio-keratoma.” Brit J Dermatol 1898;10:113-7.

2. Fabry J. Ein Beitrag Zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa hemorrhagica Hebrae). Arch Dermatol Syphilis 1898; 43:187-200.

3. Pompen AWM, Ruiter M, Wyers HJG. Angiokeratoma corporis diffusum (universale) Fabry, as a sign of an unknown internal disease: two autopsy reports. Acta Med Scand 1947; 128:234-55

4. Brady RO, Gal AE, Bradley RM, Martensson E, Warshaw AL, Laster L. Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 296:1163-7

5. Sweeley CC, Klionsky B. Fabry’s disease: classification as sphingolipidosis and partial characterization of a novel glycolipid. J Biol Chem 1963; 238:3148-50

6. Kint JA. Fabry's disease: alpha-galactosidase deficiency. Science 1970; 167(922):1268-9.

7. Bishop DF, Calhoun DH, Bernstein HS, Hanzopoulos P, Quinn M, Desnick RJ. Human α-galactosidase A: Nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci U S A 1986; 83:4859-63.