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'''Physiology''' | '''Physiology''' | ||
*[[GLA|GLA gene]] - stores information for enzyme [[Alpha-galactosidase|alpha- galactosidase]]. | *[[GLA|GLA gene]] - stores information for enzyme [[Alpha-galactosidase|alpha- galactosidase]]. | ||
*Normal function of the enzyme [[alpha-galactosidase]] is to breakdown [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] ([[ | *Normal function of the enzyme [[alpha-galactosidase]] is to breakdown [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] (also abbreviated as [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|Gb3, GL-3, or ceramide trihexoside]]) into [[glucocerebroside]] in [[lysosomes]] which serve as recycling centers. | ||
[[File:Glycosphingolipid.svg|thumb| Inborn errors in Glycosphingolipids metabolism [By Huckfinne - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9527371|alt=Inborn errors in Glycosphingolipids metabolism|center]] | [[File:Glycosphingolipid.svg|thumb| Inborn errors in Glycosphingolipids metabolism [By Huckfinne - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9527371|alt=Inborn errors in Glycosphingolipids metabolism|center]] | ||
Pathophysiology | |||
* [[Fabry's disease|Fabry disease]] is an [[X-linked recessive]] inherited [[lysosomal storage disorder]] that is caused by a [[Alpha-galactosidase A deficiency|deficiency of alpha-galactosidase.]] | |||
* | * | ||
* | * | ||
*[[Alpha-galactosidase A deficiency|.]] | |||
*[[Alpha-galactosidase]] is a [[Lysosomal enzymes|lysosomal protein]] responsible for breaking down [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide(Gb3)]] a fatty substance stored in various types of [[cardiac]] and [[renal]] cells. | |||
* | |||
*[[Alpha-galactosidase]] is a [[Lysosomal enzymes|lysosomal protein]] responsible for breaking down [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] | |||
*Mutations to the [[GLA|GLA gene]] encoding [[Alpha galactosidase|α-GAL]] may result in complete loss of function of the [[enzyme]]. | *Mutations to the [[GLA|GLA gene]] encoding [[Alpha galactosidase|α-GAL]] may result in complete loss of function of the [[enzyme]]. | ||
*When [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] is not properly catabolized, it is accumulated in [[Blood vessels|cells lining blood vessels]] in the skin, cells in the [[kidney]], [[heart]], and [[nervous system]]. As a result, signs, and symptoms of [[Fabry's disease|Fabry disease]] begin to manifests.<ref><https://ghr.nlm.nih.gov/condition/fabry-disease></ref> | *When [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|(Gb3)]] is not properly catabolized, it is accumulated in [[Blood vessels|cells lining blood vessels]] in the [[skin]], cells in the [[kidney]], [[heart]], and [[nervous system]]. As a result, signs, and symptoms of [[Fabry's disease|Fabry disease]] begin to manifests.<ref><https://ghr.nlm.nih.gov/condition/fabry-disease></ref> | ||
*Accumulation of [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide (Gb3)]] in different tissues leads to [[cellular death]], [[Energy metabolism|compromised energy metabolism,]] [[Vascular injury|small vessel injury]], [[Ion channel|potassium-calcium channel dysfunction]] in the [[endothelial cells]], [[oxidative stress]], [[Phagosomes|impaired autophagosome maturation]], [[Ischemia|tissue ischemia]], [[Cardiac|irreversible cardiac]] and [[renal]] tissue [[fibrosis]]. | |||
*The threshold level of [[Galactosidases|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|alpha galactosidase A]] causes a [[glycolipid]] known as [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide (Gb3)]] to accumulate within the [[blood vessel]]s, [[Mononuclear phagocytic system|mononuclear phagocytes]], [[neurons]], other tissues, and organs. | |||
*Fabry's disease follows an [[X-linked recessive]] [[inheritance]] pattern. | |||
*A deficiency of the [[enzyme]] [[alpha galactosidase|alpha galactosidase A]] causes a [[glycolipid]] known as globotriaosylceramide ( | |||
*This accumulation leads to an impairment of their proper function. The condition affects [[Zygosity|hemizygous]] males, as well as both [[Zygosity|heterozygous]] and [[Zygosity|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 accumulation leads to an impairment of their proper function. The condition affects [[Zygosity|hemizygous]] males, as well as both [[Zygosity|heterozygous]] and [[Zygosity|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. | *This variability is thought to be due to [[X-inactivation]] patterns during [[embryonic development]] of the female. | ||
* | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Revision as of 18:39, 23 July 2020
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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.