Fabry's disease pathophysiology: Difference between revisions
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==Pathophysiology== | ==Pathophysiology== | ||
'''Physiology''' | '''Physiology''' | ||
*[[GLA|GLA gene]] | *[[GLA|GLA gene]] codes information for the enzyme [[Alpha-galactosidase|alpha- galactosidase]]. | ||
*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]] | *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]] that serve as recycling centres. | ||
[[File:841px-Glycosphingolipid.svg.png|396px|none|thumb|By Huckfinne - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9527371|alt=Inborn errors in Glycosphingolipids metabolism|center]] | [[File:841px-Glycosphingolipid.svg.png|396px|none|thumb|By Huckfinne - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9527371|alt=Inborn errors in Glycosphingolipids metabolism|center]] | ||
Pathophysiology | ==== Pathophysiology ==== | ||
* [[Fabry's disease|Fabry disease]] | *[[Fabry's disease|Fabry disease]] is caused by a [[Alpha-galactosidase A deficiency|deficiency of alpha-galactosidase.]] | ||
*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]]. | ||
* | *[[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 | ||
*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]] | *Improper catabolisation causes [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|globotriaosylceramide]] [[Globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase|(Gb3)]] to accumulate in [[Blood vessels|cells lining blood vessels]] in the [[skin]], [[kidney]], [[heart]], and [[nervous system]]. As a result, signs, and symptoms of [[Fabry's disease|Fabry disease]] begin to manifest. | ||
*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]]. | |||
Genetics | ==== Genetics ==== | ||
*[[Fabry's disease]] follows an [[X-linked recessive|X-linked]] | *[[Fabry's disease]] follows an [[X-linked recessive|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 gene to | *Females are [[heterozygous]] with 50% chance of passing the mutated gene to both daughters and sons. | ||
*Females | *Females 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. This paradoxical nature of the disease is seen in females as a result of the [[X chromosome inactivation|skewed non random X chromosome inactivation.]] | ||
*[[Gene|Gene | *[[Gene|Gene function]]: [[GLA|GLA gene]] encodes information for [[Alpha-Galactosidase A Deficiency|alpha-Gal-A]] | ||
*[[ | *[[GLA|Gene location: GLA]] has its locus located on the [[Chromosome X (human)|Long arm of chromosome X]] in position Xq22. It has 7 [[exons]] distributed over 12,436 [[Base pairs|base pairs.]] | ||
*Demonstrates extensive [[Allele|allelic heterogenity]] but no [[Locus (genetics)|genetic locus heterogenity.]] | |||
*585 [[mutations]] have so far been recorded for [[Fabry's disease]]. | |||
* | *[[Mutations]] demonstrated include [[Missense mutation|Missense]], [[Nonsense mutation|Non-sense point mutations]],[[Splicing (genetics)|splicing mutations]], [[Deletion (genetics)|small deletion]]/[[Genetic insertion|Insertion]], and [[Deletion mutation|large deletions]]. | ||
*[[Mutations]] | |||
Gross pathology | Gross pathology | ||
There | * There are currently no characteristic findings on gross [[pathology]] for [[Fabry's disease]]. | ||
Microscopic pathology | Microscopic pathology | ||
On | 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. | |||
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* | * | ||
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==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
<references /> | |||
Revision as of 23:10, 16 August 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Physiology
- GLA gene codes information for the 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 that serve as recycling centres.
Pathophysiology
- 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.
- Females 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. This paradoxical nature of the disease is seen in females as a result of the skewed non random X chromosome inactivation.
- 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 heterogenity but no genetic locus heterogenity.
- 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
- There are currently no characteristic findings on gross pathology for Fabry's disease.
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.