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Narrative Review: Fabry Disease

Joe T.R. Clarke, MD, PhD
[+] Article and Author Information

From the Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; and Centre Hospitalier Universitaire de Sherbrooke, Hôpital Fleurimont, Sherbrooke, Québec, Canada.


Potential Financial Conflicts of Interest: Honoraria: Genzyme Corp., Genzyme Canada, Transkaryotic Therapies Inc., Shire HGT; Grants received: Genzyme Corp., Genzyme Canada, Transkaryotic Therapies Inc., Shire HGT.

Requests for Single Reprints: Joe T.R. Clarke, MD, PhD, Division of Clinical & Metabolic Genetics, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; e-mail, jtrc@sickkids.ca.


Ann Intern Med. 2007;146(6):425-433. doi:10.7326/0003-4819-146-6-200703200-00007
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Fabry disease is an X-linked, hereditary, lysosomal storage disease caused by deficiency of the enzyme α-galactosidase A, which results in the accumulation of the neutral glycosphingolipid globotriaosylceramide (Gb3) in the walls of small blood vessels, nerves, dorsal root ganglia, renal glomerular and tubular epithelial cells, and cardiomyocytes. It is a complex, multisystem disorder that is characterized clinically by chronic pain and acroparesthesia, gastrointestinal disturbances, characteristic skin lesions (angiokeratomata), progressive renal impairment, cardiomyopathy, and stroke. Enzyme replacement therapy (ERT) with intravenous infusions of recombinant human α-galactosidase A consistently decreases Gb3 levels in plasma and clears lysosomal inclusions from vascular endothelial cells. The effects of ERT on other tissues are not as obvious, suggesting that treatment must be initiated early in the course of the disease to be optimally effective or that some complications of the disease are not responsive to enzymes delivered intravenously.

Figures

Grahic Jump Location
Figure 1.
Electrocardiogram showing sinus bradycardia and evidence of left ventricular hypertrophy.
Grahic Jump Location
Grahic Jump Location
Figure 2.
Histopathologic changes in the kidney.

A. Two glomeruli, 1 with marked vacuolation of glomerular epithelial cells (left) and 1 with moderately advanced sclerosis (right) (periodic acid–Schiff stain). B. Electron photomicrograph of glomerular epithelial cells showing intralysosomal concentric lamellar membranous inclusions typical of Fabry disease.

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Grahic Jump Location
Figure 3.
Axial fluid-attenuated inversion recovery magnetic resonance image (TR9002. 0/TE170.5) of the brain showing a lesion in the right posteromedial midbrain (arrow).
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Grahic Jump Location
Figure 4.
Histopathologic changes in a small cutaneous blood vessel showing vacuolation of endothelial and smooth-muscle cells (periodic acid–Schiff stain).
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Grahic Jump Location
Figure 5.
Sequence of events in the biosynthesis and trafficking of α-galactosidase A.

Nascent α-galactosidase A molecules are shown as solid circles. P = phosphorylation of mannose residues; RER = rough endoplasmic reticulum.

Grahic Jump Location

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