Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy

Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy

From Mount Sinai School of Medicine, New York, New York; National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; University of Minnesota, Minneapolis, Minnesota; Unité de Génétique Clinique, Hôpital Européen Georges Pompidou, Paris, France; Children's Hospital Medical Center, Cincinnati, Ohio; University of California, San Francisco, San Francisco, California; and Cedars-Sinai Medical Center, Los Angeles, California.

Abstract

Fabry disease (α-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 α-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.

Article and Author Information

Grant Support: By a grant from the National Institutes of Health (5 R37 DK34045) and the Genzyme Corporation, Cambridge, Massachusetts.
Acknowledgment: The authors thank Lisa Underhill for author interviews and writing assistance.
Potential Financial Conflicts of Interest: Consultancies: R.J. Desnick (Genzyme Corp.), R. Brady (Genzyme Corp., Transkaryotic Therapies, Inc.), J. Barranger (Genzyme Corp.), D.P. Germain (Genzyme Corp., Transkaryotic Therapies, Inc.), G. Grabowski (Genzyme Corp., Transkaryotic Therapies, Inc.), S. Packman (Genzyme Corp., Transkaryotic Therapies, Inc.), W.R. Wilcox (Genzyme Corp.); Honoraria: J.A. Barranger (Genzyme Corp.), A.J. Collins (Genzyme Corp.), D.P. Germain (Genzyme Corp., Transkaryotic Therapies, Inc.), G. Grabowski (Genzyme Corp., Transkaryotic Therapies, Inc., Profound); W.R. Wilcox (Genzyme Corp.); Stock ownership or options (other than mutual funds): R.O. Brady (Genzyme Corp.); Grants received: R.J. Desnick (Genzyme Corp.), J.A. Barranger (Genzyme Corp.), A.J. Collins (Genzyme Corp.), G. Grabowski (Genzyme Corp.), W.R. Wilcox (Genzyme Corp.); Grants pending: J.A. Barranger (Genzyme Corp.), W.R. Wilcox (Genzyme Corp.); Patents pending: R.J. Desnick (patents from Mt. Sinai Medical Center licensed to Genzyme Corp.), J.A. Barranger (Genzyme Corp.); Royalties: J.A. Barranger (Genzyme Corp.).
Requests for Single Reprints: Robert J. Desnick, PhD, MD, Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, NY 10029; e-mail: rjd.fabry{at}mssn.edu.
Current Author Addresses: Dr. Desnick: Department of Human Genetics, Box 1498, Mount Sinai School of Medicine, Fifth Avenue at 100th Street, New York, NY 10029.
Dr. Brady: National Institute of Neurological Disorders and Stroke, Building 10, Room 3D04, National Institutes of Health, 10 Center CR MSC 1260, Bethesda, MD 20892-1260.
Dr. Barranger: Department of Human Genetics, University of Pittsburgh Medical Center, Pittsburgh, PA 15261.
Dr. Collins: University of Minnesota, 914 S. 8th Street, Suite D206, Minneapolis, MN 55404.
Dr. Germain: Unité de Génétique Clinique, Hôpital Européen Georges Pompidou, Paris, France.
Dr. Goldman: Mount Sinai Medical Center–Cardiology, One Gustave Levy Place, New York, NY 10029.
Dr. Grabowski: Director Human Genetics, Children's Hospital Medical Center, Elland and Bethesda Avenues, Cincinnati, OH 45229-2899.
Dr. Packman: Division of Medical Genetics, Department of Pediatrics, Room U-585k, University of California, San Francisco, 533 Parnassus Avenue, San Francisco, CA 94143-0748.
Dr. Wilcox: Cedars-Sinai Medical Center, Division of Medical Genetics, SSB-3, 8700 Beverly Boulevard, Los Angeles, CA 90048.