Fabry's disease pathophysiology: Difference between revisions
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*Moderate dilatation in deep vessels with partially organized fibrinous thrombi | *Moderate dilatation in deep vessels with partially organized fibrinous thrombi | ||
*Atrophic/Scarce sweat glands | *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 | *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. | ||
<br /> | <br /> | ||
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*large electron-dense glycosphingolipids deposits are seen in | *large electron-dense glycosphingolipids deposits are seen in almost all cells. | ||
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|Kidney | |Kidney | ||
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*'''Glomeruli''' | *'''Glomeruli''' | ||
**Glycosphingolipid inclusions in every cell esp; podocytes [effacement of foot process]/ Less commonly in endothelial and mesangial cells | **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 | **Membranofibrillary and non-immunogenic deposits in subendothelial | ||
**Basement membrane | **Basement membrane | ||
***Initial: normal | ***Initial: normal | ||
***Progression: Thickening | ***Progression: Thickening | ||
**Free-floating myelin figures in Bowman's space | **Free-floating myelin figures in Bowman's space | ||
*'''Tubules''' | *'''Tubules''' | ||
**Enlarge cells contain very large glycosphingolipid | **Enlarge cells contain very large glycosphingolipid | ||
*'''Endothelial''' | *'''Endothelial''' | ||
**Inclusions are more varied in size and shape | **Inclusions are more varied in size and shape | ||
**Elongated and racket amorphous shaped | **Elongated and racket amorphous shaped | ||
**Cytoplasm swelling: decrease vessel caliber | **Cytoplasm swelling: decrease vessel caliber | ||
*'''Smooth muscle''' | *'''Smooth muscle''' | ||
**Inclusions in arterial, arterioles, and pericytes | **Inclusions in arterial, arterioles, and pericytes | ||
**Cells may get necrosis and absent | **Cells may get necrosis and absent | ||
*'''Interstitial''' | *'''Interstitial''' | ||
*Lipid inclusion in hemizygous cases | *Lipid inclusion in hemizygous cases | ||
*Indicate severe cases leading to ESRD | *Indicate severe cases leading to ESRD | ||
Revision as of 17:16, 31 March 2022
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Fabry's disease Microchapters |
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Diagnosis |
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Fabry's disease pathophysiology On the Web |
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American Roentgen Ray Society Images of Fabry's disease pathophysiology |
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Risk calculators and risk factors for Fabry's disease pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sukaina Furniturewala, MBBS[2]
Overview
Pathophysiology
Physiology
- GLA gene codes information for the alpha-galactosidase enzyme.
- The normal function of the alpha-galactosidase enzyme is to breakdown globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) into glucocerebroside in lysosomes.
- Gb3 is produced in the catabolism pathway of Globoside, an essential glycosphingolipid in the cell membrane (RBCs and Kidney), that is mainly metabolized in the lysosome of the spleen, liver , and bone marrow.
Pathogenesis
- Fabry disease is caused by a deficiency of alpha-galactosidase.
- Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme.
- Alpha-galactosidase is a lysosomal protein responsible for breaking down globotriaosylceramide(Gb3) a fatty substance stored in various types of cardiac and renal cells
- Improper catabolisation causes globotriaosylceramide (Gb3) to accumulate in cells lining blood vessels in the skin, kidney, heart, and nervous system. As a result, signs, and symptoms of Fabry disease begin to manifest.
- Accumulation of globotriaosylceramide (Gb3) in different tissues leads to cellular death, compromised energy metabolism, small vessel injury, potassium-calcium channel dysfunction in the endothelial cells, oxidative stress,impaired autophagosome maturation, tissue ischemia, irreversible cardiac and renal tissue fibrosis.
Genetics
- Fabry's disease follows an X-linked inheritance pattern.
- 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.
- skewed non random 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 function: GLA gene encodes information for alpha-Gal-A
- Gene location: GLA has its locus located on the Long arm of chromosome X in position Xq22. It has 7 exons distributed over 12,436 base pairs.
- Demonstrates extensive allelic heterogeneity but no genetic locus heterogeneity.
- 585 mutations have so far been recorded for Fabry's disease.
- Mutations demonstrated include Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.
Gross pathology
- The most important characteristics of Fabry's disease on gross pathology are:
- Kidney
- Kidney enlargement
- Renal cysts of cortical and parapelvic
- Decreased cortical thickness
- Heart
- Four chamber cardiomegaly( frequently LVH with interventricular septum hypertrophy)
- Eye
- Conjunctiva
- Ampullary and saccular aneurysms of small venules
- Thrombosis
- Retina
- Segmental dilatation and tortuosity of venules and arteries
- Whorl-like corneal dystrophic pattern
- Conjunctiva
- Kidney
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.
| 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 |
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| Skin (Angiokeratoma) |
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| Kidney |
Urinary sediment
Organ Histology
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