Fabry's disease pathophysiology: Difference between revisions
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==Overview== | ==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. | |||
==Pathophysiology== | ==Pathophysiology== | ||
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*[[Fabry's disease|Fabry disease]] is caused by a [[Alpha-galactosidase A deficiency|deficiency of alpha-galactosidase.]] | *[[Fabry's disease|Fabry disease]] is caused by a [[Alpha-galactosidase A deficiency|deficiency of alpha-galactosidase.]] | ||
*Mutations to the [[GLA|GLA gene]] encoding [[Alpha galactosidase|α-GAL]] may result in complete loss of function of the [[enzyme]]. | *Mutations to the [[GLA|GLA gene]] encoding [[Alpha galactosidase|α-GAL]] may result in a complete loss of function of the [[enzyme]]. | ||
*[[Alpha-galactosidase]] is a [[Lysosomal enzymes|lysosomal protein]] responsible for breaking down [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide(Gb3)]] a fatty substance stored in various types of [[cardiac]] and [[renal]] cells | *[[Alpha-galactosidase]] is a [[Lysosomal enzymes|lysosomal protein]] responsible for breaking down [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide(Gb3)]] a fatty substance stored in various types of [[cardiac]] and [[renal]] cells | ||
*Improper | *Improper catabolism causes [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|(Gb3)]] to accumulate in [[Blood vessels|cells lining blood vessels]] in the [[skin]], [[kidney]], [[heart]], and [[nervous system]]. As a result, signs, and symptoms of [[Fabry's disease|Fabry diseasseven]] begin to manifest. | ||
*Accumulation of [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide (Gb3)]] in different tissues leads to [[cellular death]], [[Energy metabolism|compromised energy metabolism,]] [[Vascular injury|small vessel injury]], [[Ion channel|potassium-calcium channel dysfunction]] in the [[endothelial cells]], [[oxidative stress]],[[Phagosomes|impaired autophagosome maturation]], [[Ischemia|tissue ischemia]], [[Cardiac|irreversible cardiac]] and [[renal]] tissue [[fibrosis]]. | *Accumulation of [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide (Gb3)]] in different tissues leads to [[cellular death]], [[Energy metabolism|compromised energy metabolism,]] [[Vascular injury|small vessel injury]], [[Ion channel|potassium-calcium channel dysfunction]] in the [[endothelial cells]], [[oxidative stress]],[[Phagosomes|impaired autophagosome maturation]], [[Ischemia|tissue ischemia]], [[Cardiac|irreversible cardiac]] and [[renal]] tissue [[fibrosis]]. | ||
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*[[Fabry's disease]] follows an [[X-linked recessive|X-linked]] [[inheritance]] pattern. | *[[Fabry's disease]] follows an [[X-linked recessive|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. | *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]] 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)| | *[[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.]] | ||
*Demonstrates extensive [[Allele|allelic heterogeneity]] but no [[Locus (genetics)|genetic locus heterogeneity.]] | *Demonstrates extensive [[Allele|allelic heterogeneity]] but no [[Locus (genetics)|genetic locus heterogeneity.]] | ||
*585 [[mutations]] have so far been recorded for [[Fabry's disease]]. | *585 [[mutations]] have so far been recorded for [[Fabry's disease]]. | ||
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====Gross pathology==== | ====Gross pathology==== | ||
*The most important characteristics | *The most important characteristics o f Fabry's disease on gross pathology are: | ||
**'''Kidney''' | **'''Kidney''' | ||
***Kidney enlargement | ***Kidney enlargement | ||
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*Endothelial inclusion deposition esp; interstitial capillaries | *Endothelial inclusion deposition esp; interstitial capillaries | ||
|- | |- | ||
|Ocular system | |Ocular system | ||
| | | | ||
* Deposition of glycosphingolipids in: | *Deposition of glycosphingolipids in: | ||
** the endothelial, perivascular, smooth muscle of ocular and orbital vessels | **the endothelial, perivascular, smooth muscle of ocular and orbital vessels | ||
** Smooth muscle of iris and ciliary bodies | **Smooth muscle of iris and ciliary bodies | ||
** Perineural cell and connective tissue of lens and cornea | **Perineural cell and connective tissue of lens and cornea | ||
| | | | ||
* Deposition of glycosphingolipids in: | *Deposition of glycosphingolipids in: | ||
** The basal layer of conjunctival epithelial cell | **The basal layer of conjunctival epithelial cell | ||
** Surface epithelium | **Surface epithelium | ||
** Conjunctival goblet cells | **Conjunctival goblet cells | ||
* Hyperplasia and edema of corneal epithelial cell | *Hyperplasia and edema of corneal epithelial cell | ||
|} | |} | ||
<br /> | <br /> | ||
Revision as of 18:43, 15 April 2022
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Fabry's disease Microchapters |
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Fabry's disease pathophysiology On the Web |
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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
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.
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 a 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 catabolism 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 diseasseven 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 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 function: GLA gene encodes information for alpha-Gal-A
- Gene location: GLA has its locus located on the Longarm of chromosome X in position Xq22. It has seven 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 o f 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 |
|---|---|---|
| Skin (Angiokeratoma) |
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| Kidney |
Urinary sediment
Organ Histology
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| Heart |
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| Ocular system |
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