Renal manifestations in Fabry disease and therapeutic options Roser Torra 1 1 Nephrology Department, Inherited Renal Disorders, Fundacio´ Puigvert, Barcelona, Spain Fabry disease is an X-linked lysosomal storage disorder that affects both sexes. Progressive cellular accumulation of glycolipids starts early in life and, if untreated, eventually leads to organ failure and premature death. The Fabry nephropathy is characterized by initial proteinuria in the second to third decades of life, and development of structural changes including glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Progressive kidney failure develops at a comparable rate as in diabetic nephropathy. First signs of kidney damage may arise in childhood, prior to first signs of overt renal dysfunction underscoring the key importance of early recognition and diagnosis. Globotriaosylceramide (GL-3) deposition is probably the initiating factor of the disease pathology and, with enzyme replacement therapy (ERT), clearance can be achieved in several cell types. However, some late-stage effects are not reversible. As there is growing evidence that renal outcomes are more directly related to the degree of fibrosis and scarring, preventing the development of these irreversible changes by early initiation of ERT may have the greatest impact on renal outcomes. Proteinuria should be rigorously monitored and aggressively treated with antiproteinuric therapy. This review describes the renal clinical features and histological changes, and outline options for therapeutic intervention that offer the best hope for patients affected by this life-threatening disorder. Kidney International (2008) 74 (Suppl 111), S29–S32; doi:10.1038/ki.2008.522 KEYWORDS: Fabry; treatment; agalsidase; proteinuria; renal pathology; renal outcome Fabry disease is because of an X-linked inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal enzyme a-galactosidase A (a-Gal A). 1 Glycosphingolipids, particularly globotriaosylceramide (GL-3), progressively accumulate in a variety of cells and tissues throughout the body, leading to a wide spectrum of clinical manifestations. In hemizygous males who have the classic form of the disease, progressive damage to the somatosensory and autonomous nervous systems results in early (childhood) manifestations often including neuropathic pain, hypohidrosis, and gastrointestinal symptoms. Angio- keratomas, ocular opacities, and chronic fatigue are other common early features. With age, progressive GL-3 accumu- lation in (endothelial) cells of the microvasculature leads to ischemic tissue damage. Serious renal, cardiovascular, and cerebrovascular manifestations include proteinuria, renal failure, cardiomyopathy, arrhythmia, transient ischemic attacks, and early stroke. If untreated, these complications lead to early death of affected males in the fourth or fifth decade of life. 1 A limited number of studies have investigated the incidence of lysosomal storage disorders. The reported prevalence of Fabry disease is 1:40,000–1:117,000 (United States and Australia, respectively). 2,3 However, these numbers probably underestimate the real prevalence of the disease as many patients go undiagnosed because of the lack of prompt recognition of early Fabry symptoms. FABRY’S DISEASE IN FEMALES Historically, Fabry disease has been referred to as an X-linked recessive disorder, but the term ‘recessive’ may be misleading, as it implies that carriers of the a-Gal A gene mutations are not affected. Current knowledge confirms that a major percentage of female heterozygotes will suffer from signi- ficant morbidity and premature mortality, 4 and most will at least develop histological evidence of GL-3 storage. 5 X-chromosome inactivation (lyonization) may partly account for the disease presentation in females. 6 X-inactivation is maintained in all descendent cells rendering tissues and organs with cells with either normal or deficient a-Gal A production. The phenomenon of ‘skewing’ with one cell type being dominant could potentially lead to variable cell proportions between females, as well as between tissues (personal unpublished data). Faster deterioration in Fabry http://www.kidney-international.org review & 2008 International Society of Nephrology Correspondence: Roser Torra, Inherited Renal Disorders, Nephrology Department, Fundacio´Puigvert, Cartagena 340-350, Barcelona 08025, Spain. E-mail: [email protected] Kidney International (2008) 74 (Suppl 111), S29–S32 S29
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