title: The heart in Fabry's disease.
abstract: Fabry's disease (FD) is a rare X-linked recessive genetic disorder that leads to premature mortality as a result of renal, cardiovascular, or cerebrovascular complications. FD is caused by a deficiency of α-galactosidase A (alpha-Gal A), due to mutations in the GLA gene. There is an inability to catabolize lipids which results in cellular accumulation of its most abundant substrate, globotriaosylceramide (Gb3), and other neutral glycosphingolipids in vascular endothelium and other tissues throughout the body. This progressive glycosphingolipid accumulation leads to life-threatening clinical sequelae in renal, cardiac, and cerebrovascular systems. In males who carry the mutation (1/40,000), severe multisystem disease develops in childhood or adolescence. Hemizygous male patients have no detectable alpha-Gal activity in tests on plasma and leukocytes confirming the diagnosis. Stroke, seizures, cardiac disorders (conduction disturbances, valve disease, heart failure), and kidney disorders (proteinuria and chronic renal failure) develop in the third or fourth decade of life. Heterozygous FD is less well studied. Women who are heterozygous for the GLA gene can transmit the disease to their sons but may be free of symptoms. They may have moderate or severe disease related to uneven chromosome X inactivation with development of symptoms usually about 15 to 20 years later than males. Due to random X-chromosomal inactivation, enzymatic detection in carriers is often inconclusive with most affected females having normal levels of alpha-Gal A. Late-onset variants with predominant neurological, cardiac, or renal manifestations have been described. Until recently, FD management was symptomatic, but this has changed dramatically with the availability of enzyme replacement therapy (ERT) since 2001. They have been reported to improve clinical symptoms and quality of life. However, limited and controversial data on their efficacy in cardiac involvement have been published with reports of cardiac damage already present in older patients with FD despite use of ERT. There has been a growing awareness that the first signs and symptoms of FD may develop in childhood. Interest is now focused on whether ERT can slow or prevent the onset of these disease manifestations with earlier diagnosis and treatment. This review highlights the cardiac damage in FD and results of ERT use on cardiac disease and function.
authors.affiliation: Royal Brompton Hospital, Cry Centre for Cardiac Pathology, Sydney St, London SW36NP, United Kingdom. m.sheppard@rbht.nhs.uk
authors.forename: Mary N
authors.initials: MN
authors.lastname: Sheppard
mesh_terms: D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D009206:Myocardium / Q000473:pathology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D000519:alpha-Galactosidase / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D000519:alpha-Galactosidase