Fabry's disease pathophysiology
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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
- 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 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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| Heart |
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| Ocular system |
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