Fabry's disease pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[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 1290 base pairs of coding part.
• 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
  • Nervous system
    • Central nervous system
      • White matter lesion

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
Nervous System	Peripheral nerves Glycosphingolipids accumulation in nerve fibers Small unmyelinated degeneration fibers loss of internal organelles in swelling axons with the accumulation of glycosphingolipids Central nervous system Diffuse glycosphingolipids storage in CNS, such as the amygdala, hypothalamus, substantia nigra, pontine reticular formation, Autonomic nerve roots, etc. Vascular involvement: smooth muscle cells of parenchymal and leptomeningeal vessels Cortical infarcts