Fabry's disease pathophysiology
|
Fabry's disease Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Fabry's disease pathophysiology On the Web |
|
American Roentgen Ray Society Images of Fabry's disease pathophysiology |
|
Risk calculators and risk factors for Fabry's disease pathophysiology |
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 (ceramide trihexoside) into glucocerebroside in lysosomes which serve as recycling centers.
- Fabry disease is caused by mutations in the GLA gene. This gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease. GLA gene mutations that result in an absence of alpha-galactosidase A activity lead to the classic, severe form of Fabry disease. Mutations that decrease but do not eliminate the enzyme's activity usually cause the milder, late-onset forms of Fabry disease that typically affect only the heart or kidneys.
- 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, 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 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]
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 (also abbreviated as Gb3, GL-3, or ceramide trihexoside) 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.