Fabry's disease pathophysiology: Difference between revisions
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{{Fabry's disease}} | {{Fabry's disease}} | ||
{{CMG}} {{AE}} {{ | {{CMG}} {{AE}} {{GhazalS}} | ||
==Overview== | ==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. | [[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 microscopy|electron]] microscopies. | ||
==Pathophysiology== | ==Pathophysiology== | ||
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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.<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 | *[[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==== | ||
*The most important characteristics | *The most important characteristics of Fabry's disease on gross pathology are: | ||
**'''Kidney''' | **'''Kidney''' | ||
***Kidney enlargement | ***Kidney enlargement | ||
***[[Renal cysts]] of cortical and parapelvic | ***[[Renal cysts]] of cortical and parapelvic | ||
***Decreased [[Kidney|cortical]] thickness | ***Decreased [[Kidney|cortical]] thickness<ref name="pmid15091117">{{cite journal| author=Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M | display-authors=etal| title=Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes. | journal=J Comput Assist Tomogr | year= 2004 | volume= 28 | issue= 2 | pages= 158-68 | pmid=15091117 | doi=10.1097/00004728-200403000-00002 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15091117 }}</ref> | ||
**'''Heart''' | **'''Heart''' | ||
***Four chamber [[cardiomegaly]]( frequently [[Left ventricular hypertrophy|LVH]] with interventricular septum hypertrophy) | ***Four chamber [[cardiomegaly]]( frequently [[Left ventricular hypertrophy|LVH]] with interventricular septum hypertrophy)<ref name="pmid17875975">{{cite journal| author=Frustaci A, Chimenti C| title=Images in cardiovascular medicine. Cryptogenic ventricular arrhythmias and sudden death by Fabry disease: prominent infiltration of cardiac conduction tissue. | journal=Circulation | year= 2007 | volume= 116 | issue= 12 | pages= e350-1 | pmid=17875975 | doi=10.1161/CIRCULATIONAHA.107.723387 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17875975 }}</ref> | ||
**'''Eye''' | **'''Eye''' | ||
***[[Conjunctiva]] | ***[[Conjunctiva]] | ||
****Ampullary and saccular [[aneurysms]] of small venules | ****Ampullary and saccular [[aneurysms]] of small venules | ||
****[[Thrombosis]] | ****[[Thrombosis]]<ref name="pmid5124844">{{cite journal| author=Velzeboer CM, de Groot WP| title=Ocular manifestations in angiokeratoma corporis diffusum (Fabry). | journal=Br J Ophthalmol | year= 1971 | volume= 55 | issue= 10 | pages= 683-92 | pmid=5124844 | doi=10.1136/bjo.55.10.683 | pmc=1208523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5124844 }}</ref> | ||
***[[Retina]] | ***[[Retina]] | ||
****Segmental dilatation and tortuosity of venules and arteries | ****Segmental dilatation and tortuosity of venules and arteries | ||
****[[Whorl-like corneal dystrophic]] pattern | ****[[Whorl-like corneal dystrophic]] pattern<ref name="pmid51248442">{{cite journal| author=Velzeboer CM, de Groot WP| title=Ocular manifestations in angiokeratoma corporis diffusum (Fabry). | journal=Br J Ophthalmol | year= 1971 | volume= 55 | issue= 10 | pages= 683-92 | pmid=5124844 | doi=10.1136/bjo.55.10.683 | pmc=1208523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5124844 }}</ref> | ||
**'''Nervous system''' | |||
***Central nervous system | |||
****[[White matter]] lesion <ref name="pmid16116124">{{cite journal| author=Fellgiebel A, Müller MJ, Mazanek M, Baron K, Beck M, Stoeter P| title=White matter lesion severity in male and female patients with Fabry disease. | journal=Neurology | year= 2005 | volume= 65 | issue= 4 | pages= 600-2 | pmid=16116124 | doi=10.1212/01.wnl.0000173030.70057.eb | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16116124 }}</ref> | |||
**** | |||
====Microscopic pathology==== | ====Microscopic pathology==== | ||
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On microscopic histopathological analysis, tissue deposition of glycosphingolipids crystalline is a characteristic finding of [[Fabry's disease]]. | 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 <u>[[Endothelium|endothelial]]</u> and <u>[[Mesangial cell|mesangial]]</u> cells. | *[[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 <u>[[Endothelium|endothelial]]</u> and <u>[[Mesangial cell|mesangial]]</u> cells.<ref name="pmid16799480">{{cite journal| author=Fischer EG, Moore MJ, Lager DJ| title=Fabry disease: a morphologic study of 11 cases. | journal=Mod Pathol | year= 2006 | volume= 19 | issue= 10 | pages= 1295-301 | pmid=16799480 | doi=10.1038/modpathol.3800634 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16799480 }}</ref> | ||
*[[Electron Microscopy]]: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process. | *[[Electron Microscopy]]: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.<ref name="pmid13953819">{{cite journal| author=HENRY EW, RALLY CR| title=The renal lesion in angiokeratoma corporis diffusum (Fabry's disease). | journal=Can Med Assoc J | year= 1963 | volume= 89 | issue= | pages= 206-13 | pmid=13953819 | doi= | pmc=1921736 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13953819 }}</ref> | ||
*Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable. | *Light microscopy is not as specific in confirming FD as electron microscopy and thus is only done when electron microscopy is unavailable. | ||
* | * | ||
{| class="wikitable" | {| class="wikitable" | ||
|+Light microscopy | |+ | ||
! colspan="4" |Light microscopy | |||
|- | |- | ||
| rowspan="2" |[[Paraffin-embedded sections]] | | rowspan="2" |[[Paraffin-embedded sections]] <ref name="pmid6786101">{{cite journal| author=Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF | display-authors=etal| title=Light- and electron-microscopic histochemistry of Fabry's disease. | journal=Am J Pathol | year= 1981 | volume= 103 | issue= 2 | pages= 247-62 | pmid=6786101 | doi= | pmc=1903824 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6786101 }}</ref><ref name="pmid11688379">{{cite journal| author=Desnick RJ, Wasserstein MP, Banikazemi M| title=Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy. | journal=Contrib Nephrol | year= 2001 | volume= | issue= 136 | pages= 174-92 | pmid=11688379 | doi=10.1159/000060184 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688379 }}</ref> | ||
|[[H&E stain|H&E]] staining | |[[H&E stain|H&E]] staining | ||
|Cytoplasm vacuolation | |Cytoplasm vacuolation | ||
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|due to the residual carbohydrate part of glycosphingolipids | |due to the residual carbohydrate part of glycosphingolipids | ||
|- | |- | ||
|Methacrylate-embedded sections | |Methacrylate-embedded sections<ref name="pmid67861012">{{cite journal| author=Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF | display-authors=etal| title=Light- and electron-microscopic histochemistry of Fabry's disease. | journal=Am J Pathol | year= 1981 | volume= 103 | issue= 2 | pages= 247-62 | pmid=6786101 | doi= | pmc=1903824 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6786101 }}</ref> | ||
|Lipid-soluble dye | |Lipid-soluble dye | ||
|glycosphingolipids inclusions | |glycosphingolipids inclusions | ||
|not routine | |not routine | ||
|- | |- | ||
|[[Frozen section]] | |[[Frozen section]]<ref name="pmid67861013">{{cite journal| author=Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF | display-authors=etal| title=Light- and electron-microscopic histochemistry of Fabry's disease. | journal=Am J Pathol | year= 1981 | volume= 103 | issue= 2 | pages= 247-62 | pmid=6786101 | doi= | pmc=1903824 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6786101 }}</ref> | ||
| colspan="3" |Allows preservation but may lose dome details | | colspan="3" |Allows preservation but may lose dome details | ||
|- | |- | ||
| rowspan="2" |[[Epon-embedded sections]] | | rowspan="2" |[[Epon-embedded sections]]<ref name="pmid67861014">{{cite journal| author=Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF | display-authors=etal| title=Light- and electron-microscopic histochemistry of Fabry's disease. | journal=Am J Pathol | year= 1981 | volume= 103 | issue= 2 | pages= 247-62 | pmid=6786101 | doi= | pmc=1903824 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6786101 }}</ref> | ||
|Toluidine blue | |Toluidine blue | ||
| rowspan="2" |dark blue and dark gray round spiral inclusions | | rowspan="2" |dark blue and dark gray round spiral inclusions | ||
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|} | |} | ||
*[[Immunofluorescence assay|Immunofluorescence]] Microscopy: Negative, not react to IgG, IgM, IgA, C3, C1q antibodies. | *[[Immunofluorescence assay|Immunofluorescence]] Microscopy: Negative, not react to [[IgG]], [[IgM]], [[IgA]], [[C3 (complement)|C3]], [[C1q antibodies]]. | ||
*Immunohistochemistry: Murine anti-Gb3 antibody id used. | *Immunohistochemistry: Murine anti-Gb3 antibody id used.<ref name="pmid6430064">{{cite journal| author=Chatterjee S, Gupta P, Pyeritz RE, Kwiterovich PO| title=Immunohistochemical localization of glycosphingolipid in urinary renal tubular cells in Fabry's disease. | journal=Am J Clin Pathol | year= 1984 | volume= 82 | issue= 1 | pages= 24-8 | pmid=6430064 | doi=10.1093/ajcp/82.1.24 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6430064 }}</ref> | ||
======Organs====== | ======Organs====== | ||
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|Skin ([[Angiokeratoma]]) | |Skin ([[Angiokeratoma]]) | ||
| | | | ||
*Hyperkeratosis | *[[Hyperkeratosis]] | ||
*Hyperplastic epidermis | *Hyperplastic epidermis | ||
*Dilated subepidermal capillaries | *Dilated subepidermal capillaries | ||
*Moderate dilatation in deep vessels with partially organized fibrinous thrombi | *Moderate dilatation in deep vessels with partially organized fibrinous thrombi<ref name="pmid6164212">{{cite journal| author=Nakamura T, Kaneko H, Nishino I| title=Angiokeratoma corporis diffusum (Fabry disease): ultrastructural studies of the skin. | journal=Acta Derm Venereol | year= 1981 | volume= 61 | issue= 1 | pages= 37-41 | pmid=6164212 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6164212 }}</ref> | ||
*Atrophic/Scarce sweat glands | *Atrophic/Scarce [[sweat glands]]<ref name="pmid116883793">{{cite journal| author=Desnick RJ, Wasserstein MP, Banikazemi M| title=Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy. | journal=Contrib Nephrol | year= 2001 | volume= | issue= 136 | pages= 174-92 | pmid=11688379 | doi=10.1159/000060184 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688379 }}</ref> | ||
*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. | *[[Glycosphingolipid|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]].<ref name="pmid4185107">{{cite journal| author=Tarnowski WM, Hashimoto K| title=New light microscopic skin findings in Fabry's disease. Study of four patients using plastic-embedded tissue. | journal=Acta Derm Venereol | year= 1969 | volume= 49 | issue= 4 | pages= 386-9 | pmid=4185107 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4185107 }}</ref> | ||
<br /> | <br /> | ||
| | | | ||
*large electron-dense glycosphingolipids deposits are seen in almost all cells. | *large electron-dense [[glycosphingolipids]] deposits are seen in almost all cells.<ref name="pmid41851072">{{cite journal| author=Tarnowski WM, Hashimoto K| title=New light microscopic skin findings in Fabry's disease. Study of four patients using plastic-embedded tissue. | journal=Acta Derm Venereol | year= 1969 | volume= 49 | issue= 4 | pages= 386-9 | pmid=4185107 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4185107 }}</ref> | ||
|- | |- | ||
|Kidney | |Kidney | ||
| | | | ||
*Protein, casts, red cells, birefringent lipid globules | ====[[Urinary sediment]]==== | ||
*[[Proteinuria|Protein]], [[Urinary casts|casts]], red cells, [[birefringent]] lipid globules | |||
=====Organ Histology===== | =====Organ Histology===== | ||
*'''Glomeruli''' | *'''[[Glomeruli]]''' | ||
**White color | **White color | ||
**Enlarged and vacuolate glomerular cells (honeycomb appearance) esp; podocytes | **Enlarged and vacuolate glomerular cells (honeycomb appearance) esp; [[podocytes]] | ||
*'''Tubules''' | *'''[[Tubules]]''' | ||
**Vacuolated cells esp; distal tubule and Henle loop | **Vacuolated cells esp; [[distal tubule]] and [[Henle loop]] | ||
*'''Endothelial''' | *'''[[Endothelium|Endothelial]]''' | ||
**Vacuolated cells esp; small arteries and arterioles | **Vacuolated cells esp; small arteries and arterioles | ||
*'''Smooth Muscle''' | *'''Smooth Muscle''' | ||
**Vacuolated cells | **Vacuolated cells | ||
*'''Interstitial''' | *'''Interstitial''' | ||
**Foam and lipid-laden appearance | **Foam and [[lipid-laden]] appearance | ||
*Non-specific chronic signs of kidney injury | *Non-specific chronic signs of kidney injury | ||
*Severe cases; progressive glomerular sclerosis, tubular atrophy, a varying amount of interstitial fibrosis | *Severe cases; [[progressive glomerular sclerosis]], tubular atrophy, a varying amount of interstitial fibrosis<ref name="pmid213829942">{{cite journal| author=Selvarajah M, Nicholls K, Hewitson TD, Becker GJ| title=Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique. | journal=Nephrol Dial Transplant | year= 2011 | volume= 26 | issue= 10 | pages= 3195-202 | pmid=21382994 | doi=10.1093/ndt/gfr084 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21382994 }}</ref> | ||
<br /> | <br /> | ||
| | | | ||
*'''Glomeruli''' | *'''[[Glomeruli]]''' | ||
**Glycosphingolipid inclusions in every cell esp; podocytes [effacement of foot process]/ Less commonly in endothelial and mesangial cells | **[[Glycosphingolipid]] inclusions in every cell esp; [[podocytes]] [effacement of foot process]/ Less commonly in [[Endothelial cell|endothelial]] and [[Mesangial cell|mesangial]] cells | ||
**Membranofibrillary and non-immunogenic deposits in subendothelial | **Membranofibrillary and non-immunogenic deposits in [[subendothelial]] | ||
**Basement membrane | **[[Basement membrane]] | ||
***Initial: normal | ***Initial: normal | ||
***Progression: Thickening | ***Progression: Thickening | ||
**Free-floating myelin figures in Bowman's space | **Free-floating myelin figures in [[Bowman's space]] | ||
*'''Tubules''' | *'''[[Tubules]]''' | ||
**Enlarge cells contain very large glycosphingolipid | **Enlarge cells contain very large [[glycosphingolipid]] | ||
*'''Endothelial''' | *'''[[Endothelial cell|Endothelial]]''' | ||
**Inclusions are more varied in size and shape | **Inclusions are more varied in size and shape | ||
**Elongated and racket amorphous shaped | **Elongated and racket amorphous shaped | ||
**Cytoplasm swelling: decrease vessel caliber | **Cytoplasm swelling: decrease vessel caliber | ||
*'''Smooth muscle''' | *'''Smooth muscle''' | ||
**Inclusions in arterial, arterioles, and pericytes | **Inclusions in arterial, [[arterioles]], and [[pericytes]] | ||
**Cells may get necrosis and absent | **Cells may get [[necrosis]] and absent | ||
*'''Interstitial''' | *'''Interstitial''' | ||
*Lipid inclusion in hemizygous cases | *Lipid inclusion in [[hemizygous]] cases | ||
*Indicate severe cases leading to ESRD | *Indicate severe cases leading to [[ESRD]]<ref name="pmid116883794">{{cite journal| author=Desnick RJ, Wasserstein MP, Banikazemi M| title=Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy. | journal=Contrib Nephrol | year= 2001 | volume= | issue= 136 | pages= 174-92 | pmid=11688379 | doi=10.1159/000060184 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11688379 }}</ref> | ||
* | * | ||
Line 165: | Line 168: | ||
|Heart | |Heart | ||
| | | | ||
*Myocyte large sarcoplasmic vacuolations [large clear space in myocytes] | *[[Myocyte]] large [[Sarcoplasmic reticulum|sarcoplasmic]] vacuolations [large clear space in myocytes] | ||
*Mild fibrosis | *Mild fibrosis<ref name="pmid12361838">{{cite journal| author=Roos JM, Aubry MC, Edwards WD| title=Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease. | journal=Cardiovasc Pathol | year= 2002 | volume= 11 | issue= 5 | pages= 277-83 | pmid=12361838 | doi=10.1016/s1054-8807(02)00118-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12361838 }}</ref> | ||
*Coronary arteries typical atherosclerosis with white discoloration | *Coronary arteries typical [[atherosclerosis]] with white discoloration<ref name="pmid16315019">{{cite journal| author=Schiffmann R, Rapkiewicz A, Abu-Asab M, Ries M, Askari H, Tsokos M | display-authors=etal| title=Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement. | journal=Virchows Arch | year= 2006 | volume= 448 | issue= 3 | pages= 337-43 | pmid=16315019 | doi=10.1007/s00428-005-0089-x | pmc=2288734 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16315019 }}</ref> | ||
*Vessels hypertropia due to deposition of inclusions | *Vessels [[hypertropia]] due to deposition of inclusions | ||
*Mitral and tricuspid valve: fibrosis with lipid laden cells | *[[Mitral valve|Mitral]] and [[Tricuspid valve|tricuspid]] valve: fibrosis with lipid laden cells<ref name="pmid16733219">{{cite journal| author=Owens CL, Russell SD, Halushka MK| title=Histologic and electron microscopy findings in myocardium of treated Fabry disease. | journal=Hum Pathol | year= 2006 | volume= 37 | issue= 6 | pages= 764-8 | pmid=16733219 | doi=10.1016/j.humpath.2006.01.021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16733219 }}</ref> | ||
| | | | ||
*Endomyocardial sarcoplasmic myeloid bodies within the center of the myocytes | *Endomyocardial sarcoplasmic myeloid bodies within the center of the [[myocytes]]<ref name="pmid123618382">{{cite journal| author=Roos JM, Aubry MC, Edwards WD| title=Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease. | journal=Cardiovasc Pathol | year= 2002 | volume= 11 | issue= 5 | pages= 277-83 | pmid=12361838 | doi=10.1016/s1054-8807(02)00118-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12361838 }}</ref> | ||
*Concentric lamellar bodies | *Concentric lamellar bodies | ||
*Endothelial inclusion deposition esp; interstitial capillaries | *[[Endothelium|Endothelial]] inclusion deposition esp; interstitial capillaries<ref name="pmid167332192">{{cite journal| author=Owens CL, Russell SD, Halushka MK| title=Histologic and electron microscopy findings in myocardium of treated Fabry disease. | journal=Hum Pathol | year= 2006 | volume= 37 | issue= 6 | pages= 764-8 | pmid=16733219 | doi=10.1016/j.humpath.2006.01.021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16733219 }}</ref> | ||
|- | |- | ||
|Ocular system | |Ocular system | ||
| | | | ||
*Deposition of glycosphingolipids in: | *Deposition of [[Glycosphingolipid|glycosphingolipids]] in: | ||
**the endothelial, perivascular, smooth muscle of ocular and orbital vessels | **the [[Endothelium|endothelial]], perivascular, smooth muscle of [[ocular]] and [[Orbit (anatomy)|orbital]] vessels | ||
**Smooth muscle of iris and ciliary bodies | **Smooth muscle of [[Iris (anatomy)|iris]] and [[Ciliary body|ciliary]] bodies | ||
**Perineural cell and connective tissue of lens and cornea | **Perineural cell and connective tissue of [[Lens (anatomy)|lens]] and [[cornea]]<ref name="pmid4335185">{{cite journal| author=Font RL, Fine BS| title=Ocular pathology in fabry's disease. Histochemical and electron microscopic observations. | journal=Am J Ophthalmol | year= 1972 | volume= 73 | issue= 3 | pages= 419-30 | pmid=4335185 | doi=10.1016/0002-9394(72)90071-2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4335185 }}</ref> | ||
| | | | ||
*Deposition of glycosphingolipids in: | *Deposition of [[Glycosphingolipid|glycosphingolipids]] in: | ||
**The basal layer of conjunctival epithelial cell | **The [[basal layer]] of [[conjunctival]] epithelial cell | ||
**Surface epithelium | **Surface epithelium | ||
**Conjunctival goblet | **Conjunctival [[goblet cell]]<nowiki/>s<ref name="pmid3934620">{{cite journal| author=Macrae WG, Ghosh M, McCulloch C| title=Corneal changes in Fabry's disease: a clinico-pathologic case report of a heterozygote. | journal=Ophthalmic Paediatr Genet | year= 1985 | volume= 5 | issue= 3 | pages= 185-90 | pmid=3934620 | doi=10.3109/13816818509006132 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3934620 }}</ref> | ||
*Hyperplasia and edema of corneal epithelial cell | *[[Hyperplasia]] and edema of [[Corneal epithelium|corneal]] epithelial cell<ref name="pmid51248443">{{cite journal| author=Velzeboer CM, de Groot WP| title=Ocular manifestations in angiokeratoma corporis diffusum (Fabry). | journal=Br J Ophthalmol | year= 1971 | volume= 55 | issue= 10 | pages= 683-92 | pmid=5124844 | doi=10.1136/bjo.55.10.683 | pmc=1208523 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5124844 }}</ref> | ||
|- | |||
|Nervous System | |||
| colspan="2" | | |||
*'''[[Peripheral nerves]]''' | |||
**[[Glycosphingolipid|Glycosphingolipids]] accumulation in [[nerve fibers]] | |||
**Small [[unmyelinated]] degeneration fibers | |||
**loss of internal organelles in swelling [[axons]] with the accumulation of glycosphingolipids <ref name="pmid6278363">{{cite journal| author=Cable WJ, Dvorak AM, Osage JE, Kolodny EH| title=Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves. | journal=Neurology | year= 1982 | volume= 32 | issue= 4 | pages= 347-53 | pmid=6278363 | doi=10.1212/wnl.32.4.347 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6278363 }}</ref> | |||
*'''[[Central nervous system]]''' | |||
**Diffuse [[Glycosphingolipid|glycosphingolipids]] storage in [[CNS]], such as the [[amygdala]], [[hypothalamus]], [[substantia nigra]], [[pontine reticular formation]], [[Autonomic nerve roots]], etc. | |||
**Vascular involvement: smooth muscle cells of parenchymal and [[leptomeningeal]] vessels | |||
**Cortical infarcts <ref name="pmid184102732">{{cite journal| author=Okeda R, Nisihara M| title=An autopsy case of Fabry disease with neuropathological investigation of the pathogenesis of associated dementia. | journal=Neuropathology | year= 2008 | volume= 28 | issue= 5 | pages= 532-40 | pmid=18410273 | doi=10.1111/j.1440-1789.2008.00883.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18410273 }}</ref><ref name="pmid3133979">{{cite journal| author=Kaye EM, Kolodny EH, Logigian EL, Ullman MD| title=Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation. | journal=Ann Neurol | year= 1988 | volume= 23 | issue= 5 | pages= 505-9 | pmid=3133979 | doi=10.1002/ana.410230513 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3133979 }}</ref> | |||
** | |||
** | |||
|} | |} | ||
<br /> | <br /> | ||
Line 195: | Line 211: | ||
{{Reflist|2}} | {{Reflist|2}} | ||
<references /> | <references /> | ||
[[Category:Needs english review]] |
Latest revision as of 10:24, 14 July 2022
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] Associate Editor(s)-in-Chief: Ghazal Sanadgol, M.D.[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
- GLA gene codes information for the alpha-galactosidase enzyme.
- The normal function of the alpha-galactosidase enzyme is to breakdown globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) into glucocerebroside in lysosomes.
- Gb3 is produced in the catabolism pathway of Globoside, an essential glycosphingolipid in the cell membrane (RBCs and Kidney), that is mainly metabolized in the lysosome of the spleen, liver , and bone marrow.[1]
Pathogenesis
- Fabry disease is caused by a deficiency of alpha-galactosidase.
- Mutations to the GLA gene encoding α-GAL may result in a 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.[2]
- Improper catabolism 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 diseasseven begin to manifest.[3]
- 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.[4]
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.[5]
- 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.[6]
- Gene function: GLA gene encodes information for alpha-Gal-A.
- Gene location: GLA has its locus located on the Longarm of chromosome X in position Xq22. It has seven exons distributed over 1290 base pairs of coding part. [7][8]
- Demonstrates extensive allelic heterogeneity but no genetic locus heterogeneity.[9]
- 585 mutations have so far been recorded for Fabry's disease.[10]
- Mutations demonstrated include Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.[11]
Gross pathology
- The most important characteristics of Fabry's disease on gross pathology are:
- Kidney
- Kidney enlargement
- Renal cysts of cortical and parapelvic
- Decreased cortical thickness[12]
- Heart
- Four chamber cardiomegaly( frequently LVH with interventricular septum hypertrophy)[13]
- Eye
- Conjunctiva
- Ampullary and saccular aneurysms of small venules
- Thrombosis[14]
- Retina
- Segmental dilatation and tortuosity of venules and arteries
- Whorl-like corneal dystrophic pattern[15]
- Conjunctiva
- Nervous system
- Central nervous system
- White matter lesion [16]
- Central nervous system
- Kidney
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.[17]
- Electron Microscopy: The most accurate method for detection of glycosphingolipids depositions. preserved whole glycosphingolipids during the preparation process.[18]
- 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 [19][20] | 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[21] | Lipid-soluble dye | glycosphingolipids inclusions | not routine |
Frozen section[22] | Allows preservation but may lose dome details | ||
Epon-embedded sections[23] | 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.[24]
Organs
Organs | Light microscope | Electron microscope |
---|---|---|
Skin (Angiokeratoma) |
|
|
Kidney |
Urinary sediment
Organ Histology
|
|
Heart |
|
|
Ocular system |
|
|
Nervous System |
|
References
- ↑ 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). - ↑ 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). - ↑ 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). - ↑ 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). - ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW; et al. (1993). "GeneReviews®". PMID 20301469.
- ↑ 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.
- ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
- ↑ 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.
- ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
- ↑ Germain DP (2010). "Fabry disease". Orphanet J Rare Dis. 5: 30. doi:10.1186/1750-1172-5-30. PMC 3009617. PMID 21092187.
- ↑ Mehta A, Beck M, Sunder-Plassmann G (2006). "Fabry Disease: Perspectives from 5 Years of FOS". PMID 21290673.
- ↑ Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M; et al. (2004). "Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes". J Comput Assist Tomogr. 28 (2): 158–68. doi:10.1097/00004728-200403000-00002. PMID 15091117.
- ↑ Frustaci A, Chimenti C (2007). "Images in cardiovascular medicine. Cryptogenic ventricular arrhythmias and sudden death by Fabry disease: prominent infiltration of cardiac conduction tissue". Circulation. 116 (12): e350–1. doi:10.1161/CIRCULATIONAHA.107.723387. PMID 17875975.
- ↑ Velzeboer CM, de Groot WP (1971). "Ocular manifestations in angiokeratoma corporis diffusum (Fabry)". Br J Ophthalmol. 55 (10): 683–92. doi:10.1136/bjo.55.10.683. PMC 1208523. PMID 5124844.
- ↑ Velzeboer CM, de Groot WP (1971). "Ocular manifestations in angiokeratoma corporis diffusum (Fabry)". Br J Ophthalmol. 55 (10): 683–92. doi:10.1136/bjo.55.10.683. PMC 1208523. PMID 5124844.
- ↑ Fellgiebel A, Müller MJ, Mazanek M, Baron K, Beck M, Stoeter P (2005). "White matter lesion severity in male and female patients with Fabry disease". Neurology. 65 (4): 600–2. doi:10.1212/01.wnl.0000173030.70057.eb. PMID 16116124.
- ↑ Fischer EG, Moore MJ, Lager DJ (2006). "Fabry disease: a morphologic study of 11 cases". Mod Pathol. 19 (10): 1295–301. doi:10.1038/modpathol.3800634. PMID 16799480.
- ↑ HENRY EW, RALLY CR (1963). "The renal lesion in angiokeratoma corporis diffusum (Fabry's disease)". Can Med Assoc J. 89: 206–13. PMC 1921736. PMID 13953819.
- ↑ Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF; et al. (1981). "Light- and electron-microscopic histochemistry of Fabry's disease". Am J Pathol. 103 (2): 247–62. PMC 1903824. PMID 6786101.
- ↑ Desnick RJ, Wasserstein MP, Banikazemi M (2001). "Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy". Contrib Nephrol (136): 174–92. doi:10.1159/000060184. PMID 11688379.
- ↑ Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF; et al. (1981). "Light- and electron-microscopic histochemistry of Fabry's disease". Am J Pathol. 103 (2): 247–62. PMC 1903824. PMID 6786101.
- ↑ Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF; et al. (1981). "Light- and electron-microscopic histochemistry of Fabry's disease". Am J Pathol. 103 (2): 247–62. PMC 1903824. PMID 6786101.
- ↑ Faraggiana T, Churg J, Grishman E, Strauss L, Prado A, Bishop DF; et al. (1981). "Light- and electron-microscopic histochemistry of Fabry's disease". Am J Pathol. 103 (2): 247–62. PMC 1903824. PMID 6786101.
- ↑ Chatterjee S, Gupta P, Pyeritz RE, Kwiterovich PO (1984). "Immunohistochemical localization of glycosphingolipid in urinary renal tubular cells in Fabry's disease". Am J Clin Pathol. 82 (1): 24–8. doi:10.1093/ajcp/82.1.24. PMID 6430064.
- ↑ Nakamura T, Kaneko H, Nishino I (1981). "Angiokeratoma corporis diffusum (Fabry disease): ultrastructural studies of the skin". Acta Derm Venereol. 61 (1): 37–41. PMID 6164212.
- ↑ Desnick RJ, Wasserstein MP, Banikazemi M (2001). "Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy". Contrib Nephrol (136): 174–92. doi:10.1159/000060184. PMID 11688379.
- ↑ Tarnowski WM, Hashimoto K (1969). "New light microscopic skin findings in Fabry's disease. Study of four patients using plastic-embedded tissue". Acta Derm Venereol. 49 (4): 386–9. PMID 4185107.
- ↑ Tarnowski WM, Hashimoto K (1969). "New light microscopic skin findings in Fabry's disease. Study of four patients using plastic-embedded tissue". Acta Derm Venereol. 49 (4): 386–9. PMID 4185107.
- ↑ Selvarajah M, Nicholls K, Hewitson TD, Becker GJ (2011). "Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique". Nephrol Dial Transplant. 26 (10): 3195–202. doi:10.1093/ndt/gfr084. PMID 21382994.
- ↑ Desnick RJ, Wasserstein MP, Banikazemi M (2001). "Fabry disease (alpha-galactosidase A deficiency): renal involvement and enzyme replacement therapy". Contrib Nephrol (136): 174–92. doi:10.1159/000060184. PMID 11688379.
- ↑ Roos JM, Aubry MC, Edwards WD (2002). "Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease". Cardiovasc Pathol. 11 (5): 277–83. doi:10.1016/s1054-8807(02)00118-7. PMID 12361838.
- ↑ Schiffmann R, Rapkiewicz A, Abu-Asab M, Ries M, Askari H, Tsokos M; et al. (2006). "Pathological findings in a patient with Fabry disease who died after 2.5 years of enzyme replacement". Virchows Arch. 448 (3): 337–43. doi:10.1007/s00428-005-0089-x. PMC 2288734. PMID 16315019.
- ↑ Owens CL, Russell SD, Halushka MK (2006). "Histologic and electron microscopy findings in myocardium of treated Fabry disease". Hum Pathol. 37 (6): 764–8. doi:10.1016/j.humpath.2006.01.021. PMID 16733219.
- ↑ Roos JM, Aubry MC, Edwards WD (2002). "Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease". Cardiovasc Pathol. 11 (5): 277–83. doi:10.1016/s1054-8807(02)00118-7. PMID 12361838.
- ↑ Owens CL, Russell SD, Halushka MK (2006). "Histologic and electron microscopy findings in myocardium of treated Fabry disease". Hum Pathol. 37 (6): 764–8. doi:10.1016/j.humpath.2006.01.021. PMID 16733219.
- ↑ Font RL, Fine BS (1972). "Ocular pathology in fabry's disease. Histochemical and electron microscopic observations". Am J Ophthalmol. 73 (3): 419–30. doi:10.1016/0002-9394(72)90071-2. PMID 4335185.
- ↑ Macrae WG, Ghosh M, McCulloch C (1985). "Corneal changes in Fabry's disease: a clinico-pathologic case report of a heterozygote". Ophthalmic Paediatr Genet. 5 (3): 185–90. doi:10.3109/13816818509006132. PMID 3934620.
- ↑ Velzeboer CM, de Groot WP (1971). "Ocular manifestations in angiokeratoma corporis diffusum (Fabry)". Br J Ophthalmol. 55 (10): 683–92. doi:10.1136/bjo.55.10.683. PMC 1208523. PMID 5124844.
- ↑ Cable WJ, Dvorak AM, Osage JE, Kolodny EH (1982). "Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves". Neurology. 32 (4): 347–53. doi:10.1212/wnl.32.4.347. PMID 6278363.
- ↑ Okeda R, Nisihara M (2008). "An autopsy case of Fabry disease with neuropathological investigation of the pathogenesis of associated dementia". Neuropathology. 28 (5): 532–40. doi:10.1111/j.1440-1789.2008.00883.x. PMID 18410273.
- ↑ Kaye EM, Kolodny EH, Logigian EL, Ullman MD (1988). "Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation". Ann Neurol. 23 (5): 505–9. doi:10.1002/ana.410230513. PMID 3133979.