Abstract
BackgroundFabry disease. an X-linked deficiency of α-galactosidase A coded by the GLA gene, leads to intracellular globotriaosylceramide (GL-3) accumulation. Although less common than in males, chronic kidney disease, occurs in ∼15% of females. Recent studies highlight the importance of podocyte injury in Fabry nephropathy development and progression. We hypothesized that the greater the % of podocytes with active wild-type GLA gene (due to X-inactivation of the mutant copy) the less is the overall podocyte injury.MethodsKidney biopsies from 12 treatment-naive females with Fabry disease, ages 15 (8–63), median [range], years were studied by electron microscopy and compared with 4 treatment-naive male patients.ResultsIn females, 51 (13–100)% of podocytes (PC) per glomerulus had no GL-3 inclusions, this consistent with a non-Fabry podocyte phenotype (NFPC). In PC with GL-3 inclusions [Fabry podocyte phenotype (FPC)], GL-3 volume density per podocyte was virtually identical in females and males, consistent with little or no cross-correction between FPC and NFPC. %NFPC per glomerulus (%NFPC/glom) correlated with age in females (r = 0.65, p = 0.02), suggesting a survival disadvantage for FPC over time. Age-adjusted %NFPC/glom was inversely related to foot process width (FPW) (r = −0.75, p = 0.007), an indicator of PC injury. GL-3 volume density in FPC in females correlated directly with FPW.ConclusionsThese findings support important relationships between podocyte mosaicism and podocyte injury in female Fabry patients. Kidney biopsy, by providing information about podocyte mosaicism, may help to stratify females with Fabry disease for kidney disease risk and to guide treatment decisions.
Highlights
Fabry disease is a storage disease caused by deficiency of the agalactosidase A enzyme that hydrolyzes the terminal agalactosyl moieties from glycolipids and glycoproteins
This leads to the accumulation of its substrates, predominately globotriaosylceramide (GL-3) in various cell types and organs, causing a constellation of complications including skin lesions, strokes, cardiac arrhythmias and cardiomyopathy, neuropathies and renal failure. [1] agalactosidase A (aGal A) is encoded by the GLA gene located on the X chromosome locus Xq21.3-q22
Subjects and Clinical Parameters Kidney biopsies from 12 enzyme replacement therapy (ERT)-naive females with Fabry disease, age 15 (8–63) years were studied by electron microscopy for distribution of podocyte involvement by the Fabry phenotype
Summary
Fabry disease is a storage disease caused by deficiency of the agalactosidase A (aGal A) enzyme that hydrolyzes the terminal agalactosyl moieties from glycolipids and glycoproteins. This leads to the accumulation of its substrates, predominately globotriaosylceramide (GL-3) in various cell types and organs, causing a constellation of complications including skin lesions, strokes, cardiac arrhythmias and cardiomyopathy, neuropathies and renal failure. [16,17,18] We hypothesized that podocytes, due to random X-inactivation, are heterogeneously involved by Fabry disease in female patients and that this heterogeneity could influence podocyte injury. Recent studies highlight the importance of podocyte injury in Fabry nephropathy development and progression. We hypothesized that the greater the % of podocytes with active wild-type GLA gene (due to X-inactivation of the mutant copy) the less is the overall podocyte injury
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