Originally described as a dermatologic curiosity by Fabry in 1898 and independently by Anderson in the same year, Fabry disease is now recognized as an inborn error of glycosphingolipid metabolism resulting from the defective activity of the lysosomal enzyme, alpha-galactosidase A (see Desnick and Sweeley for a comprehensive review). The enzymatic defect, transmitted by an X-linked recessive gene, leads to the accumulation of neutral glycosphingolipids with terminal alpha-galactosyl residues in the plasma and in the lysosomes of endothelial, perithelial, and smooth muscle cells of the cardiovascular-renal system and, to a lesser extent, in reticuloendothelial, myocardial, and connective tissue cells. Epithelial cells in the kidney, cornea, and other tissues contain the lysosomal depositions, as do the ganglia and perineural cells of the autonomic nervous system. The major accumulated substrate is globotriaosylceramide [galactosyl-(alpha 1----4)-galactosyl-(beta 1----4)-glucosyl-(beta 1----1')-ceramide]; another substrate, galabiosylceramide [galactosyl-(alpha 1----4)-galactosyl-(beta 1----1')-ceramide] is deposited primarily in renal lysosomes. The clinical manifestations of Fabry disease are the sequelae of the anatomical and physiologic alterations produced by progressive glycosphingolipid deposition. Clinical onset of the disease in hemizygous males usually occurs during childhood or adolescence, with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of the vascular cutaneous lesions (angiokeratoma), hypohidrosis, and the characteristic corneal dystrophy. With increasing age, the major morbid symptoms of the disease result from the progressive infiltration of glycosphingolipid in the cardiovascular-renal system. Death usually occurs from renal, cardiac, or cerebral complications of the vascular disease. Prior to the availability of treatment by renal transplantation or dialysis, the average age at death for affected males was about 40 years. Heterozygous females, who may exhibit the disease in an attenuated form, are most likely to have only corneal opacities. Previously, the diagnosis of affected hemizygous males and heterozygous females was based on clinical findings and the levels of alpha-galactosidase A activity in easily obtained sources, e.g., plasma and isolated lymphocytes or granulocytes. Because the gene encoding alpha-galactosidase A undergoes random X-inactivation, the expressed level of enzymatic activity in females heterozygous for the disease gene may vary significantly, thereby making accurate carrier detection difficult.(ABSTRACT TRUNCATED AT 400 WORDS)