Fabry's disease pathophysiology: Difference between revisions

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{{Fabry's disease}}
{{Fabry's disease}}


{{CMG}} {{AE}} {{SUF}}
{{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
*[[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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***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
Line 95: Line 96:
|}
|}


*[[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======
Line 107: Line 108:
|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
|
|
=====Urinary sediment=====


*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 166: 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 cells
**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 196: 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

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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

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.[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
Organs
Organs Light microscope Electron microscope
Skin (Angiokeratoma)


Kidney

Urinary sediment

Organ Histology
Heart
  • Endomyocardial sarcoplasmic myeloid bodies within the center of the myocytes[34]
  • Concentric lamellar bodies
  • Endothelial inclusion deposition esp; interstitial capillaries[35]
Ocular system
Nervous System


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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
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