Enzyme replacement therapy for Fabry disease, an inherited nephropathy.
Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified "renal variants" who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, "cardiac variants" who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant alpha-Gal A replacement for this inherited nephropathy.
Desnick
R J
RJ
Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York, NY 10029, USA. rjdesnick@mssm.edu
Banikazemi
M
M
Wasserstein
M
M
D000328:Adult; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D000795:Fabry Disease / Q000150:complications / Q000473:pathology / Q000628:therapy*; D006028:Glycosphingolipids / Q000032:analysis; D006801:Humans; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D006435:Renal Dialysis; D014281:Trihexosylceramides / Q000032:analysis; D014960:X Chromosome; D000519:alpha-Galactosidase / Q000627:therapeutic use*
D006028:Glycosphingolipids; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase