Fabry's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Physiology
- GLA gene - stores information for enzyme alpha- galactosidase.
- Normal function of the enzyme alpha-galactosidase is to breakdown globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) into glucocerebroside in lysosomes which serve as recycling centers.
Pathophysiology
- Fabry disease is an X-linked recessive inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase.
- .
- Alpha-galactosidase is a lysosomal protein responsible for breaking down globotriaosylceramide(Gb3) a fatty substance stored in various types of cardiac and renal cells.
- Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme.
- When globotriaosylceramide (Gb3) is not properly catabolized, it is accumulated in cells lining blood vessels in the skin, cells in the kidney, heart, and nervous system. As a result, signs, and symptoms of Fabry disease begin to manifests.[1]
- 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.
- The threshold level of alpha- Gal A is 30-35% of the mean normal. uptodate (16).
Genetics
- Fabry's disease follows an X-linked recessive inheritance pattern.
- A deficiency of the enzyme alpha galactosidase A causes a glycolipid known as globotriaosylceramide (Gb3) to accumulate within the blood vessels, mononuclear phagocytes, neurons, other tissues, and organs.
- This accumulation leads to an impairment of their proper function. The condition affects hemizygous males, as well as both heterozygous and homozygous females; males tend to experience the most severe clinical symptoms, while females vary from virtually no symptoms to those as serious as males.
- This variability is thought to be due to X-inactivation patterns during embryonic development of the female.