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 inheritance pattern. Since it is also manifests in women who are heterozygous in different severity due to X chromosome inactivation it being called X linked recessive disease is misleading.
- Since its an X linked inheritance males are homozygous and pass the disease to all daughters but not son.
- Females are heterozygous with 50% chance of passing the gene to daughter and sons.
- Females can present with a varied type of presentation from being asymptomatic to having severe symptoms like in the classic form of the disease seen in males due to skewed non random X chromosome inactivation.
- Gene location: GLA gene encodes information for alpha-Gal-A
- Locus: Long arm of chromosome X
- Position: Xq22
- GLA has 7 exons over 12,436 base pairs.
- Extensive allelic heterogenity but no genetic locus heterogenity.
- Mutations comprise of Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.
- 585 mutations have been recorded for Fabry's disease.
Gross pathology
There is no charactristic findings on gross pathology for Fabry's disease.
Microscopic pathology
On microscopic histopathological analysis, these findings are characteristic of Fabry's disease: