Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder. Although the disease presents in childhood and culminates in cardiac, cerebrovascular, and end-stage renal disease, diagnosis is often delayed or missed. This paper reviews the key signs and symptoms of Fabry disease and provides expert recommendations for diagnosis, follow-up, medical management, and the use of enzyme replacement therapy. Recommendations are based on reviews of the literature on Fabry disease, results of recent clinical trials, and expertise of the authors, all of whom have extensive clinical experience with Fabry disease and lysosomal storage disorders and represent subspecialties involved in treatment. All males and female carriers affected with Fabry disease should be followed closely, regardless of symptoms or treatment status. Clinical trials have shown that recombinant human alpha-galactosidase A replacement therapy--the only disease-specific therapy currently available for Fabry disease--is safe and can reverse substrate storage in the lysosome, the pathophysiologic basis of the disease. Enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations should be initiated as early as possible. Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children, and patients with compromised renal function.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team.