Fabry Disease (?-Galactosidase A Deficiency): An X-linked Nephropathy

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Fabry disease is an X-linked recessive inborn error of glycosphingolipid catabolism caused by the deficient activity of the lysosomal enzyme, ?-galactosidase A (?-Gal A). This enzymatic defect results in the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids with terminal ?-galactosyl moieties in the lysosomes of endothelial, epithelial, perithelial, and smooth muscle cells throughout the body. In classically affected males, who have essentially no ?-Gal A activity, clinical manifestations result predominantly from the progressive lysosomal deposition of GL-3 in the vascular endothelium. Onset usually occurs in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, and the characteristic corneal and lenticular opacities. Episodic crises of agonizing, burning pain in the distal extremities most often begin in childhood or early adolescence and signal clinical onset of the disease. These crises typically last from minutes to several days and usually are triggered by exercise, fatigue, emotional stress, or rapid changes in temperature and humidity. The early acroparesthesias that occur in children presumably result from glycosphingolipid deposition in the microvasculature that supplies blood to the peripheral nerve cells. The endothelial glycosphingolipid accumulation narrows the vascular lumen and vessel spasms or frank infarction cause the excruciating pain. Angiokeratomas appear as clusters of individual punctate, dark red to blue-black angiectases in the superficial layers of the skin, and are often one of the earliest manifestations of the disease. Most classically affected males develop cardiovascular and/or cerebrovascular disease in middle age. The progressive vascular involvement is a major cause of morbidity and mortality, particularly after treatment of the renal insufficiency by chronic dialysis or transplantation.

Original languageEnglish
Title of host publicationGenetic Diseases of the Kidney
PublisherElsevier Inc.
Number of pages20
ISBN (Print)9780124498518
StatePublished - 2009


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