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*[[GLA|GLA gene]] codes information for the [[Alpha-galactosidase|alpha-galactosidase]] enzyme.
*[[GLA|GLA gene]] codes information for the [[Alpha-galactosidase|alpha-galactosidase]] enzyme.
*The normal function of the [[alpha-galactosidase]] enzyme 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]].
*The normal function of the [[alpha-galactosidase]] enzyme 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]].
*[[Gb3]] is produced in the catabolism pathway of [[Globoside]], an essential [[glycophingolipids|glycosphingolipid]] in the cell membrane ([[RBC]]s and Kidney), that is mainly metabolized in the [[lysosome]] of the [[spleen]], [[liver]] , and [[bone marrow]].
*[[Gb3]] is produced in the catabolism pathway of [[Globoside]], an essential [[glycophingolipids|glycosphingolipid]] in the cell membrane ([[RBC]]s and Kidney), that is mainly metabolized in the [[lysosome]] of the [[spleen]], [[liver]] , and [[bone marrow]].<ref name="pmid345762505">{{cite journal| author=Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S | display-authors=etal| title=Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies. | journal=Int J Mol Sci | year= 2021 | volume= 22 | issue= 18 | pages=  | pmid=34576250 | doi=10.3390/ijms221810088 | pmc=8465525 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34576250  }}</ref>


====Pathogenesis====
====Pathogenesis====
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*[[Fabry's disease|Fabry disease]] is caused by a [[Alpha-galactosidase A deficiency|deficiency of alpha-galactosidase.]]
*[[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 a complete loss of function of the [[enzyme]].
*Mutations to the [[GLA|GLA gene]] encoding [[Alpha galactosidase|α-GAL]] may result in a 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
*[[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.<ref name="pmid33673160">{{cite journal| author=Kok K, Zwiers KC, Boot RG, Overkleeft HS, Aerts JMFG, Artola M| title=Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions. | journal=Biomolecules | year= 2021 | volume= 11 | issue= 2 | pages=  | pmid=33673160 | doi=10.3390/biom11020271 | pmc=7918333 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33673160  }}</ref>
*Improper catabolism 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 diseasseven]] begin to manifest.
*Improper catabolism 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 diseasseven]] begin to manifest.<ref name="pmid345762502">{{cite journal| author=Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S | display-authors=etal| title=Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies. | journal=Int J Mol Sci | year= 2021 | volume= 22 | issue= 18 | pages=  | pmid=34576250 | doi=10.3390/ijms221810088 | pmc=8465525 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34576250  }}</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]].
*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]].<ref name="pmid345762504">{{cite journal| author=Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S | display-authors=etal| title=Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies. | journal=Int J Mol Sci | year= 2021 | volume= 22 | issue= 18 | pages=  | pmid=34576250 | doi=10.3390/ijms221810088 | pmc=8465525 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34576250  }}</ref>


====Genetics====
====Genetics====
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*[[Fabry's disease]] follows an [[X-linked recessive|X-linked]] [[inheritance]] pattern.
*[[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.
*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 are [[heterozygous]] with 50% chance of passing the mutated gene to both daughters and sons.<ref name="pmid203014694">{{cite journal| author=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW | display-authors=etal| title=GeneReviews® | journal= | year= 1993 | volume=  | issue=  | pages=  | pmid=20301469 | doi= | pmc= | url= }}</ref>
*[[Skewed non random X chromosome inactivation|skewed nonrandom X chromosome inactivation]] may cause paradoxical nature of the disease that is seen in females,; they 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
*[[Skewed non random X chromosome inactivation|Skewed nonrandom X chromosome inactivation]] may cause paradoxical nature of the disease that is seen in females,; they 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.<ref name="pmid25974833">{{cite journal| author=Echevarria L, Benistan K, Toussaint A, Dubourg O, Hagege AA, Eladari D | display-authors=etal| title=X-chromosome inactivation in female patients with Fabry disease. | journal=Clin Genet | year= 2016 | volume= 89 | issue= 1 | pages= 44-54 | pmid=25974833 | doi=10.1111/cge.12613 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25974833  }}</ref>
*[[Gene|Gene function]]: [[GLA|GLA gene]] encodes information for [[Alpha-Galactosidase A Deficiency|alpha-Gal-A]]
*[[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)|Longarm of chromosome X]] in position Xq22. It has seven [[exons]] distributed over 12,436 [[Base pairs|base pairs.]]
*[[GLA|Gene location: GLA]] has its locus located on the  [[Chromosome X (human)|Longarm of chromosome X]] in position Xq22. It has seven [[exons]] distributed over 1290 [[base pairs]] of coding part. <ref name="pmid21290673">{{cite journal| author=Mehta A, Beck M, Sunder-Plassmann G| title=Fabry Disease: Perspectives from 5 Years of FOS | journal= | year= 2006 | volume=  | issue=  | pages=  | pmid=21290673 | doi= | pmc= | url= }}</ref><ref name="pmid7911050">{{cite journal| author=Eng CM, Desnick RJ| title=Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. | journal=Hum Mutat | year= 1994 | volume= 3 | issue= 2 | pages= 103-11 | pmid=7911050 | doi=10.1002/humu.1380030204 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7911050  }}</ref>
*Demonstrates extensive [[Allele|allelic heterogeneity]] but no [[Locus (genetics)|genetic locus heterogeneity.]]
*Demonstrates extensive [[Allele|allelic heterogeneity]] but no [[Locus (genetics)|genetic locus heterogeneity.]]<ref name="pmid212906732">{{cite journal| author=Mehta A, Beck M, Sunder-Plassmann G| title=Fabry Disease: Perspectives from 5 Years of FOS | journal= | year= 2006 | volume=  | issue=  | pages=  | pmid=21290673 | doi= | pmc= | url= }}</ref>
*585 [[mutations]] have so far been recorded for [[Fabry's disease]].
*585 [[mutations]] have so far been recorded for [[Fabry's disease]].<ref name="pmid21092187">{{cite journal| author=Germain DP| title=Fabry disease. | journal=Orphanet J Rare Dis | year= 2010 | volume= 5 | issue=  | pages= 30 | pmid=21092187 | doi=10.1186/1750-1172-5-30 | pmc=3009617 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21092187  }}</ref>
*[[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]] 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]].<ref name="pmid212906733">{{cite journal| author=Mehta A, Beck M, Sunder-Plassmann G| title=Fabry Disease: Perspectives from 5 Years of FOS | journal= | year= 2006 | volume=  | issue=  | pages=  | pmid=21290673 | doi= | pmc= | url= }}</ref>


====Gross pathology====
====Gross pathology====
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{| class="wikitable"
{| class="wikitable"
|+Light microscopy
|+
!
! colspan="4" |Light microscopy
!
!
!
|-
|-
| rowspan="2" |[[Paraffin-embedded sections]]
| rowspan="2" |[[Paraffin-embedded sections]]

Revision as of 19:57, 15 May 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sukaina Furniturewala, MBBS[2]

Overview

Genes involved in the pathogenesis of Fabry's disease include the GLA gene, which codes the important enzyme of alpha-galactosidase. The absence or lack of this enzyme causes Gb3 accumulation in different organs. The main pathological finding is detection of these inclusion in different cells with electron microscopies.

Pathophysiology

Physiology

Pathogenesis

Genetics

Gross pathology

Microscopic pathology

General

On microscopic histopathological analysis, tissue deposition of glycosphingolipids crystalline is a characteristic finding of Fabry's disease.

  • Glycosphingolipid inclusions morphology: coarsely lamellated appearance, maybe round with onion-skin likes structure (Myelin figures), or dense unstructured layer (Zebra bodies), some can be dark electrodense and amorphous especially in endothelial and mesangial cells.
  • Electron Microscopy: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.
  • Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable.
Light microscopy
Paraffin-embedded sections H&E staining Cytoplasm vacuolation

(swollen appearance)

Characteristic but not pathognomonic
Jones methenamine silver (JMS) staining granular and argyrophilic inclusions due to the residual carbohydrate part of glycosphingolipids
Methacrylate-embedded sections Lipid-soluble dye glycosphingolipids inclusions not routine
Frozen section Allows preservation but may lose dome details
Epon-embedded sections Toluidine blue dark blue and dark gray round spiral inclusions detect entire glycosphingolipids
Methylene blue
  • Immunofluorescence Microscopy: Negative, not react to IgG, IgM, IgA, C3, C1q antibodies.
  • Immunohistochemistry: Murine anti-Gb3 antibody id used.
Organs
Organs Light microscope Electron microscope
Skin (Angiokeratoma)
  • Hyperkeratosis
  • Hyperplastic epidermis
  • Dilated subepidermal capillaries
  • Moderate dilatation in deep vessels with partially organized fibrinous thrombi
  • Atrophic/Scarce sweat glands
  • Glycosphingolipids is generally small in skin and can be seen particularly in endothelial cells, pericytes and smooth muscle of the cutaneous capillaries, venules and arterioles.
  • large electron-dense glycosphingolipids deposits are seen in almost all cells.
Kidney
Urinary sediment
  • Protein, casts, red cells, birefringent lipid globules
Organ Histology
  • Glomeruli
    • White color
    • Enlarged and vacuolate glomerular cells (honeycomb appearance) esp; podocytes
  • Tubules
    • Vacuolated cells esp; distal tubule and Henle loop
  • Endothelial
    • Vacuolated cells esp; small arteries and arterioles
  • Smooth Muscle
    • Vacuolated cells
  • Interstitial
    • Foam and lipid-laden appearance
  • Non-specific chronic signs of kidney injury
  • Severe cases; progressive glomerular sclerosis, tubular atrophy, a varying amount of interstitial fibrosis
  • Glomeruli
    • Glycosphingolipid inclusions in every cell esp; podocytes [effacement of foot process]/ Less commonly in endothelial and mesangial cells
    • Membranofibrillary and non-immunogenic deposits in subendothelial
    • Basement membrane
      • Initial: normal
      • Progression: Thickening
    • Free-floating myelin figures in Bowman's space
  • Tubules
    • Enlarge cells contain very large glycosphingolipid
  • Endothelial
    • Inclusions are more varied in size and shape
    • Elongated and racket amorphous shaped
    • Cytoplasm swelling: decrease vessel caliber
  • Smooth muscle
    • Inclusions in arterial, arterioles, and pericytes
    • Cells may get necrosis and absent
  • Interstitial
  • Lipid inclusion in hemizygous cases
  • Indicate severe cases leading to ESRD
Heart
  • Myocyte large sarcoplasmic vacuolations [large clear space in myocytes]
  • Mild fibrosis
  • Coronary arteries typical atherosclerosis with white discoloration
  • Vessels hypertropia due to deposition of inclusions
  • Mitral and tricuspid valve: fibrosis with lipid laden cells
  • Endomyocardial sarcoplasmic myeloid bodies within the center of the myocytes
  • Concentric lamellar bodies
  • Endothelial inclusion deposition esp; interstitial capillaries
Ocular system
  • Deposition of glycosphingolipids in:
    • the endothelial, perivascular, smooth muscle of ocular and orbital vessels
    • Smooth muscle of iris and ciliary bodies
    • Perineural cell and connective tissue of lens and cornea
  • Deposition of glycosphingolipids in:
    • The basal layer of conjunctival epithelial cell
    • Surface epithelium
    • Conjunctival goblet cells
  • Hyperplasia and edema of corneal epithelial cell


References

  1. ↑ Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S; et al. (2021). "Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies". Int J Mol Sci. 22 (18). doi:10.3390/ijms221810088. PMC 8465525 Check |pmc= value (help). PMID 34576250 Check |pmid= value (help).
  2. ↑ Kok K, Zwiers KC, Boot RG, Overkleeft HS, Aerts JMFG, Artola M (2021). "Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions". Biomolecules. 11 (2). doi:10.3390/biom11020271. PMC 7918333 Check |pmc= value (help). PMID 33673160 Check |pmid= value (help).
  3. ↑ Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S; et al. (2021). "Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies". Int J Mol Sci. 22 (18). doi:10.3390/ijms221810088. PMC 8465525 Check |pmc= value (help). PMID 34576250 Check |pmid= value (help).
  4. ↑ Tuttolomondo A, Simonetta I, Riolo R, Todaro F, Di Chiara T, Miceli S; et al. (2021). "Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies". Int J Mol Sci. 22 (18). doi:10.3390/ijms221810088. PMC 8465525 Check |pmc= value (help). PMID 34576250 Check |pmid= value (help).
  5. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW; et al. (1993). "GeneReviews®". PMID 20301469.
  6. ↑ Echevarria L, Benistan K, Toussaint A, Dubourg O, Hagege AA, Eladari D; et al. (2016). "X-chromosome inactivation in female patients with Fabry disease". Clin Genet. 89 (1): 44–54. doi:10.1111/cge.12613. PMID 25974833.
  7. ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
  8. ↑ Eng CM, Desnick RJ (1994). "Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene". Hum Mutat. 3 (2): 103–11. doi:10.1002/humu.1380030204. PMID 7911050.
  9. ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
  10. ↑ Germain DP (2010). "Fabry disease". Orphanet J Rare Dis. 5: 30. doi:10.1186/1750-1172-5-30. PMC 3009617. PMID 21092187.
  11. ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
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