Fabry's disease pathophysiology

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.

• 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.^[1]

• 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.^[2]
• 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.^[3]
• 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.^[4]

• 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.^[5]
• 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.^[6]
• 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. ^[7][8]
• Demonstrates extensive allelic heterogeneity but no genetic locus heterogeneity.^[9]
• 585 mutations have so far been recorded for Fabry’s disease.^[10]
• Mutations demonstrated include Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.^[11]

• The most important characteristics of Fabry’s disease on gross pathology are:
  • Kidney
    • Kidney enlargement
    • Renal cysts of cortical and parapelvic
    • Decreased cortical thickness^[12]
  • Heart
    • Four chamber cardiomegaly( frequently LVH with interventricular septum hypertrophy)^[13]
  • Eye
    • Conjunctiva
      • Ampullary and saccular aneurysms of small venules
      • Thrombosis^[14]
    • Retina
      • Segmental dilatation and tortuosity of venules and arteries
      • Whorl-like corneal dystrophic pattern^[15]
  • Nervous system
    • Central nervous system
      • White matter lesion ^[16]

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.^[17]
• Electron Microscopy: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.^[18]
• Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable.

• Immunofluorescence Microscopy: Negative, not react to IgG, IgM, IgA, C3, C1q antibodies.
• Immunohistochemistry: Murine anti-Gb3 antibody id used.^[24]