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Art of Medicine: Fabry

The image above shows myelinosomes, also known as “zebra bodies” for their appearance on tangential sectioning.  Myelinosomes are seen in Fabry disease, a rare x-linked recessive genetic disorder caused by the defective activity of the enzyme alpha-galactosidase A.   Renal, cardiac, and cerebrovascular involvement is common and can be fatal by the 4th decade without enzyme replacement therapy.   Alpha galactosidase A deficiency results in accumulation of globotriaosylceramide within podocytes of glomeruli, tubules, myocytes, and endothelium.  Globotriaosylceramide accumulation results in the formation of myelinosomes. Since myelinosomes are lipid-derived, they are maintained on osmium fixation, but are lost with exposure to xylenes in...

Diagnose This (April 23, 2018)

What is your diagnosis?   ​   ​ ​   ​   ​ ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​ ​   ​ ​   ​ ​   ​ ​     ​   ​   ​ ​...

Pushing Glass (March 23, 2018)

These images are from the kidney biopsy of a 70-year-old woman with a history of hypertension and valvular heart disease presenting with renal failure and serum creatinine of 4 mg/dl. The findings are suggestive of a mutation in which of the following genes: A. Podocin B. Glucocerebrosidase C. a-galactosidase A D. Nephrin E. Phospholipase C Answer: C The images highlight podocytes loaded with numerous myelinosomes. There are only a few causes that can cause such accumulation, most notably Fabry disease. However, rare secondary causes to be considered include drugs such as chloroquine and chloroquine-like drugs (e.g., Plaquenil), amiodarone, aminoglycoside antibiotics,...

Fabry Disease in Female Carriers

A renal biopsy was performed on a 51 year old female with strong family history of Fabry disease and a known carrier of an alpha-glycosidase gene (GLA) pathogenic variant. At the time of the biopsy, the patient had no renal or extrarenal manifestations. The biopsy shows glomeruli with prominent visceral epithelial cells (podocytes) displaying ample vacuolated cytoplasm (Fig 1, H&E; Fig 2, Jones). Furthermore, electron microscopy shows numerous large, lamellated lipid vacuoles (myeloid bodies or zebra bodies) within the podocytes, characteristic of Fabry disease (Fig 3). Fabry disease is an X-linked disorder caused by GLA mutation and the resulting deficiency...

Fabry Disease and IgA

A 34-year-old Asian female underwent a renal biopsy as part of the workup for progressively worsening renal function (Cr = 1.6 mg/dl) and non-nephrotic proteinuria (3.1 g/g). The light microscopic findings (Fig 1) are highly suspicious for Fabry disease. The glomeruli are enlarged and show frequent visceral epithelial cells displaying abundant vacuolated/ foamy cytoplasm. Furthermore, toluidine blue stain (not shown) highlights the lipid granules within the cytoplasm of the podocytes. Interestingly, immunofluorescence (Fig 2) shows mesangial immune deposits which stain positive for IgA, kappa and lambda. The displayed electron micrograph (Fig 3) shows evidence of a dual disease. The podocytes...

Diagnose This! (September 11, 2017)

What is your diagnosis?      ​   ​ ​   ​   ​ ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​   ​ ​   ​ ​   ​ ​   ​ ​     ​   ​   ​...

Fabrys

This biopsy shows glomeruli with visceral epithelial cells (podocytes) displaying ample vacuolated cytoplasm (Fig 1), which is highlighted on a toluidine blue stain (Fig 2). More importantly, the electron microscopy shows numerous large, lamellated lipid vacuoles (myeloid bodies) within the podocytes, which are characteristic of Fabry disease (Fig 3). Fabry disease is an X-linked recessive disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A, which catalyzes the cleavage of glycosphingolipids.  Deficiency of this enzyme results in lysosomal accumulation of globotriaosylceramide in the heart, kidney, eye, nerves, sweat glands and vascular endothelium.  Specifically, within the kidney, globotriaosylceramide may accumulate...

Fabry EM

Electron photomicrograph of a glomerular podocyte showing the characteristic electron dense laminated inclusions of Fabry disease. Fabry is a lysosomal storage disease with X-linked inheritance. Mutations in the gene for the enzyme alpha galactosidase A (GLA) result in accumulation of a glycolipid known as globotriaosylceramide (GL-3) in tissues including the kidney.