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Kidney non-tumor

Hereditary renal disease

Fabry’s disease


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 28 August 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
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● Also called alpha-galactosidase A deficiency, angiokeratoma corporis diffusum universale
● X linked (Xq22.1) recessive lysosomal storage disease which causes deficiency in lysosomal alpha-galactosidase A, which catabolizes neutral glycosphingolipids
● Deficiency causes intracellular accumulation of galabiosylceramide (ceramide trihexoside) and digalactosyl ceramide within skin, renal glomeruli, renal tubular epithelium, blood vessels, corneal epithelium, myocardium and ganglion cells

Clinical features
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● Affects 1 per 40,000
● Highly penetrant in hemizygous males with symptoms at infancy or childhood
● Later presentation in heterozygous females, who have more variable severity due to variable lyonization of X chromosome and may have normal leukocyte alpha-galactosidase A activity
● Clinical symptoms include angiokeratomas on skin of abdomen, buttocks, lips, genitalia and upper thighs
● Also hematuria and proteinuria progressing to renal failure, corneal dystrophy and recurrent shooting pains in legs
● Death due to renal, cardiac or cerebrovascular disease at age 40+ years

Diagnosis
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● Low blood or urine levels of alpha-galactosidase by enzymatic assay (may be normal in female heterozygotes)
● Elevated ceramide trihexoside in urine by thin layer chromatography
● Immunostains for ceramide trihexoside
● In women, must perform DNA mutation analysis of alpha-galactosidase A gene to exclude carrier state
● Patients may present with advanced disease identifiable only by ultrastructural studies (Ultrastruct Pathol 2010;34:307)

Case reports
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● 23 year old man with congenital agammaglobulinemia (J Korean Med Sci 2011;26:966)
● 34 year old man with atypical variant (Arch Pathol Lab Med 1996;120:86)
● 42 year old woman with persistent proteinuria (Arch Pathol Lab Med 1985;109:89)
● Cases with accumulation in heart, not kidney or liver (Hum Pathol 1990;21:1067)

Treatment
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● Recombinant human alpha-galactosidase A replacement therapy

Micro description
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Kidney:
● Enlarged and bubbly, clear vacuoles in visceral epithelium (demonstrated by trichrome stain), parietal epithelium, mesangial cells, endothelial cells, vascular smooth muscle and distal tubular cells
● Narrowing and thrombosis of arteries and arterioles
● Patchy tubular atrophy and interstitial fibrosis
● Progression to focal segmental and global glomerulosclerosis

Micro images
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Various images including EM

       
Foamy cytoplasm and inclusions


Birefringent glycosphingolipid deposits


Global sclerosis, segmental sclerosis with moderate interstitial fibrosis, diffuse foamy changes of podocyte and tubular epithelial cell cytoplasm


Reduction in inclusions after enzyme therapy


Figure 1: vacuolar change in renal tubular cells with large nodular aggregates of foam cells
Figure 2: enlarged glomeruli due to segmental vacuolar changes in visceral epithelial cells
Figure 3: strong oil-red-O staining of vacuolated cells
Figure 4: EM shows abundant whorled lamellated electron dense myelin-like bodies lined by single membranes; various images including EM


Immunofluorescence
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● Negative

Positive stains
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● PAS, Oil red O, Sudan black and Luxol fast blue (stain glycolipid and phospholipid-like material)

Electron microscopy description
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● Characteristic single membrane bound intracellular inclusions (myelin-like figures, zebra bodies), that are 0.1 to 10 microns in diameter, round and lamellated with concentric electron dense layers, found in endothelial and smooth muscle cells, myocardium, fibroblasts and glomerular epithelium; deposits reduced after enzyme therapy (Clin Nephrol 2009;71:550)
● Changes also present in urine sediment (Arch Pathol Lab Med 1981;105:361)

Electron microscopy images
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Lamellated lipid inclusions of visceral epithelial cells

       
Electron-dense laminated myelin figures


A: Numerous electron dense lamellar inclusion bodies in cytoplasm of skin fibroblasts and B/C: renal podocytes

Molecular description
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● Wide molecular heterogeneity (Rev Med Interne 2010;31 Suppl 2:S275)

Differential diagnosis
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● Foam cell change of Gaucher’s disease, gangliosidoses, fucosidosis, mucopolysaccharidoses (all have different intracellular distribution and ultrastructural features of inclusions, lack electron dense myeloid bodies and can detect by laboratory assays)
● Treatment with chloroquine, amiodarone or aminoglycosides (have similar myelin-like figures, Hum Pathol 2003;34:285)

End of Kidney non-tumor > Hereditary renal disease > Fabry’s disease

Ref Updated: 6/8/12


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