Fabry's disease pathophysiology: Difference between revisions

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*Since it is inherited in an X-linked pattern,  males are [[homozygous]] and pass the disease to all daughters but no sons.
*Since it is inherited in an X-linked pattern,  males are [[homozygous]] and pass the disease to all daughters but no sons.
*Females are [[heterozygous]] with 50% chance of passing the mutated gene to both daughters and sons.
*Females are [[heterozygous]] with 50% chance of passing the mutated gene to both daughters and sons.
*[[skewed non random X chromosome inactivation|skewed nonrandom X chromosome inactivation]] may cause paradoxical nature of the disease that is seen in females,; they have a varied presentation from being [[asymptomatic]] to having very severe symptoms and having a presentation similar to that seen in males with the classical type
*[[Skewed non random X chromosome inactivation|skewed nonrandom X chromosome inactivation]] may cause paradoxical nature of the disease that is seen in females,; they have a varied presentation from being [[asymptomatic]] to having very severe symptoms and having a presentation similar to that seen in males with the classical type
*[[Gene|Gene function]]: [[GLA|GLA gene]] encodes information for [[Alpha-Galactosidase A Deficiency|alpha-Gal-A]]
*[[Gene|Gene function]]: [[GLA|GLA gene]] encodes information for [[Alpha-Galactosidase A Deficiency|alpha-Gal-A]]
*[[GLA|Gene location: GLA]] has its locus located on the  [[Chromosome X (human)|Longarm of chromosome X]] in position Xq22. It has seven [[exons]] distributed over 12,436 [[Base pairs|base pairs.]]
*[[GLA|Gene location: GLA]] has its locus located on the  [[Chromosome X (human)|Longarm of chromosome X]] in position Xq22. It has seven [[exons]] distributed over 12,436 [[Base pairs|base pairs.]]

Revision as of 17:39, 9 May 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sukaina Furniturewala, MBBS[2]

Overview

Genes involved in the pathogenesis of Fabry's disease include the GLA gene, which codes the important enzyme of alpha-galactosidase. The absence or lack of this enzyme causes Gb3 accumulation in different organs. The main pathological finding is detection of these inclusion in different cells with electron microscopies.

Pathophysiology

Physiology

Pathogenesis

Genetics

Gross pathology

Microscopic pathology

General

On microscopic histopathological analysis, tissue deposition of glycosphingolipids crystalline is a characteristic finding of Fabry's disease.

  • Glycosphingolipid inclusions morphology: coarsely lamellated appearance, maybe round with onion-skin likes structure (Myelin figures), or dense unstructured layer (Zebra bodies), some can be dark electrodense and amorphous especially in endothelial and mesangial cells.
  • Electron Microscopy: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.
  • Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable.
Light microscopy
Paraffin-embedded sections H&E staining Cytoplasm vacuolation

(swollen appearance)

Characteristic but not pathognomonic
Jones methenamine silver (JMS) staining granular and argyrophilic inclusions due to the residual carbohydrate part of glycosphingolipids
Methacrylate-embedded sections Lipid-soluble dye glycosphingolipids inclusions not routine
Frozen section Allows preservation but may lose dome details
Epon-embedded sections Toluidine blue dark blue and dark gray round spiral inclusions detect entire glycosphingolipids
Methylene blue
  • Immunofluorescence Microscopy: Negative, not react to IgG, IgM, IgA, C3, C1q antibodies.
  • Immunohistochemistry: Murine anti-Gb3 antibody id used.
Organs
Organs Light microscope Electron microscope
Skin (Angiokeratoma)
  • Hyperkeratosis
  • Hyperplastic epidermis
  • Dilated subepidermal capillaries
  • Moderate dilatation in deep vessels with partially organized fibrinous thrombi
  • Atrophic/Scarce sweat glands
  • Glycosphingolipids is generally small in skin and can be seen particularly in endothelial cells, pericytes and smooth muscle of the cutaneous capillaries, venules and arterioles.


  • large electron-dense glycosphingolipids deposits are seen in almost all cells.
Kidney
Urinary sediment
  • Protein, casts, red cells, birefringent lipid globules
Organ Histology
  • Glomeruli
    • White color
    • Enlarged and vacuolate glomerular cells (honeycomb appearance) esp; podocytes
  • Tubules
    • Vacuolated cells esp; distal tubule and Henle loop
  • Endothelial
    • Vacuolated cells esp; small arteries and arterioles
  • Smooth Muscle
    • Vacuolated cells
  • Interstitial
    • Foam and lipid-laden appearance
  • Non-specific chronic signs of kidney injury
  • Severe cases; progressive glomerular sclerosis, tubular atrophy, a varying amount of interstitial fibrosis


  • Glomeruli
    • Glycosphingolipid inclusions in every cell esp; podocytes [effacement of foot process]/ Less commonly in endothelial and mesangial cells
    • Membranofibrillary and non-immunogenic deposits in subendothelial
    • Basement membrane
      • Initial: normal
      • Progression: Thickening
    • Free-floating myelin figures in Bowman's space
  • Tubules
    • Enlarge cells contain very large glycosphingolipid
  • Endothelial
    • Inclusions are more varied in size and shape
    • Elongated and racket amorphous shaped
    • Cytoplasm swelling: decrease vessel caliber
  • Smooth muscle
    • Inclusions in arterial, arterioles, and pericytes
    • Cells may get necrosis and absent
  • Interstitial
  • Lipid inclusion in hemizygous cases
  • Indicate severe cases leading to ESRD
Heart
  • Myocyte large sarcoplasmic vacuolations [large clear space in myocytes]
  • Mild fibrosis
  • Coronary arteries typical atherosclerosis with white discoloration
  • Vessels hypertropia due to deposition of inclusions
  • Mitral and tricuspid valve: fibrosis with lipid laden cells
  • Endomyocardial sarcoplasmic myeloid bodies within the center of the myocytes
  • Concentric lamellar bodies
  • Endothelial inclusion deposition esp; interstitial capillaries
Ocular system
  • Deposition of glycosphingolipids in:
    • the endothelial, perivascular, smooth muscle of ocular and orbital vessels
    • Smooth muscle of iris and ciliary bodies
    • Perineural cell and connective tissue of lens and cornea
  • Deposition of glycosphingolipids in:
    • The basal layer of conjunctival epithelial cell
    • Surface epithelium
    • Conjunctival goblet cells
  • Hyperplasia and edema of corneal epithelial cell


References