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]

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

Microscopic pathology

On histopathological analysis, these findings are characteristic of Fabry's disease:

• light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable. Lipid staining of a kidney biopsy may demonstrate storage cells within the glomeruli, which proves of little significance.
• Ultrastructural analysis of the heart and kidney biopsies can reveal lysosomal storage in the endomyocardial and certain renal tubular cells respectively. The ultrastructural appearance of these inclusions is whorled layers of alternating dense and pale material also called zebra bodies.