LAUSR

In Fabry disease (FD), GLA mutations cause an enzyme deficiency, glycosphingolipid accumulation, and potentially lethal kidney, heart and central nervous system involvement [1]. Globotriaosylceramide (Gb3) is the best-characterized accumulated glycosphingolipid, but the relative increase in plasma globotriaosylsphingosine (lyso-Gb3) is larger (up to >100-fold higher than controls). Circulating lyso-Gb3 directly injures podocytes, eliciting a stress response similar to the high-glucose stress response [2–4]. Fabry nephropathy starts in childhood. In children, podocyte glycolipid deposits are larger than in endothelial cells, correlate with proteinuria and associate with podocyte injury (foot process effacement), which precedes proteinuria [5]. Pathological albuminuria is usually the first evidence of Fabry nephropathy, progressing to overt proteinuria that may reach the nephrotic range [6]. Glomerular filtration rate (GFR) decreases, leading to renal replacement therapy (RRT) at age 40 years in classical FD [6, 7]. The magnitude of proteinuria is a key determinant of nephropathy progression in treated and non-treated patients, placing podocytes at the centre of Fabry nephropathy [8, 9].