Familial amyloidosis pathophysiology: Difference between revisions

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{{familytree |boxstyle=text-align: left; | | C01 | | C11 | | C12 | | C13 | | C14 | | C15 | | C16 |C01=Mutations:<br>•Asp18Glu<br>•Leu55Gln<br>•Asp18Gly<br>•His56Arg<br>•Asp18Asn<br>•Leu58His<br>•Val20Ile<br>•Leu58Arg<br>•Ser23Asn<br>•Thr59Lys<br>•Pro24Ser<br>•Thr60Ala<br>•Ala25Ser<br>•Glu61Lys<br>•Ala25Thr|C11=Mutations:<br>•Gly26Arg<br>•Leu60Arg<br>•Trp50Arg<br>•del60-71<br>•del70-72<br>•Leu75Pro<br>•Leu90Pro<br>•Arg173Pro<br>•Leu174Ser<br>•Leu178His|C12=Mutations:<br>•Asp187Asn<br>•Asp187Tyr|C13=Mutations:<br>•Ile56Thr<br>•Asp67His<br>•Trp64Arg<br>•Phe57Ile|C14=Mutation:<br>•Leu68Gln|C15=Mutations:<br>•Arg554Leu<br>•Glu526Val<br>•4904delG<br>•4897delT|C16=Mutations:<br>•stop78Gly<br>•stop78Ser<br>•stop78Arg}}  
{{familytree |boxstyle=text-align: left; | | C01 | | C11 | | C12 | | C13 | | C14 | | C15 | | C16 |C01=Mutations:<br>•Asp18Glu<br>•Leu55Gln<br>•Asp18Gly<br>•His56Arg<br>•Asp18Asn<br>•Leu58His<br>•Val20Ile<br>•Leu58Arg<br>•Ser23Asn<br>•Thr59Lys<br>•Pro24Ser<br>•Thr60Ala<br>•Ala25Ser<br>•Glu61Lys<br>•Ala25Thr|C11=Mutations:<br>•Gly26Arg<br>•Leu60Arg<br>•Trp50Arg<br>•del60-71<br>•del70-72<br>•Leu75Pro<br>•Leu90Pro<br>•Arg173Pro<br>•Leu174Ser<br>•Leu178His|C12=Mutations:<br>•Asp187Asn<br>•Asp187Tyr|C13=Mutations:<br>•Ile56Thr<br>•Asp67His<br>•Trp64Arg<br>•Phe57Ile|C14=Mutation:<br>•Leu68Gln|C15=Mutations:<br>•Arg554Leu<br>•Glu526Val<br>•4904delG<br>•4897delT|C16=Mutations:<br>•stop78Gly<br>•stop78Ser<br>•stop78Arg}}  
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{{familytree |boxstyle=text-align: left; | | D01 | | | | | | | | | | | | | | | | | | | | | | | | D01=<br>•Cys10Arg<br>•Leu55Pro<br>•Leu12Pro<br>•Leu55Arg<br>•Phe64Leu<br>•Val28Met<br>•Phe64Ser<br>•Val30Met<br>•Ile68Leu<br>•Val30Ala<br>•Tyr69His<br>•Val30Leu<br>•Tyr69Ile<br>•Val30Gly<br>•Lys70Asn<br>•Phe33Ile<br>•Val71Ala<br>•Phe33Leu<br>•Ile73Val<br>•Phe33Val<br>•Ser77Tyr<br>•Phe33Cys<br>•Ser77Phe<br>•Arg34Thr<br>•Tyr78Phe<br>•Lys35Asn<br>•Ala81Thr<br>•Ala36Pro<br>•Ile84Ser}}
{{familytree |boxstyle=text-align: left; | | D01 | | | | | | | | | | | | | | | | | | | | | | | | D01=<br>•Cys10Arg<br>•Leu55Pro<br>•Leu12Pro<br>•Leu55Arg<br>•Phe64Leu<br>•Val28Met<br>•Phe64Ser<br>•Val30Met<br>•Ile68Leu<br>•Val30Ala<br>•Tyr69His<br>•Val30Leu<br>•Tyr69Ile<br>•Val30Gly<br>•Lys70Asn<br>•Phe33Ile<br>•Val71Ala<br>•Phe33Leu<br>•Ile73Val<br>•Phe33Val<br>•Ser77Tyr<br>•Phe33Cys<br>•Ser77Phe<br>•Arg34Thr<br>•Tyr78Phe<br>•Lys35Asn<br>•Ala81Thr<br>•Ala36Pro<br>•Ile84Ser}}
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{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | }}

Revision as of 00:39, 12 November 2019

Familial amyloidosis Microchapters

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

Overview


Pathophysiology

Pathogenesis

  • It is understood that amyloidosis is the result of deposition of Amyloid.[1]
  • Amyloid is an abnormal insoluble extracellular protein which may cause organic dysfunction and a wide variety of clinical syndromes.
  • These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
  • Amyloid depositions also have glycosaminoglycans and serum amyloid P component (SAP) which alter the propensity for amyloid formation.[2][3][4]
  • Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.[5]
  • Genetic mutations in different genes may lead to misfolding protein product.

Genetics

  • Familial ATTR amyloidosis is transmitted in autosomal dominant pattern but it can have a heterogeneous nature of presentation.[6][7][8]
  • Genes involved in the pathogenesis of Familial ATTR amyloidosis include:[9][10][11]
    • Transthyretin amyloidosis (ATTR)[12][13][14]
      • The most common type of familial amyloidosis.
      • Single nucleotide substitution on transthyretin gene on chromosome 18 leads to nonfunctional transthyretin protein.
      • Transthyretin protein is responsible for thyroid hormone and vitamin A transport and is produced by liver.
      • We can find normal transthyretin protein deposition in aged individuals (senile cardiac amyloid).
      • Mutant transthyretin protein accelerate the process of deposition and leads to early onset disease.
    • Apolipoprotein AI amyloidosis (A ApoAI)[15]
      • Single nucleotide substitutions in apolipoprotein AI gene.
      • The underlying pathogenesis is incomplete degradation of this protein in body.
      • The mode of inheritance in autosomal dominant with different penetrance.
    • Gelsolin amyloidosis (A Gel)[16][17]
      • Gelsolin protein is produced in skeletal muscle and macrophages.
      • 2 different mutations in gelsolin gene on chromosome 9 including Asp187Asn and Asp187Tyr leads to amyloid deposition and Gelsolin amyloidosis.
    • Lysozyme amyloidosis (A Lys)[18]
      • 4 different mutations on lysozyme gene including Ile56Thr, Asp67His, Trp64Arg, and Phe57Ile has been found to be associated with amyloidosis.
    • Cystatin C amyloidosis (A Cys)[19][20]
      • Cystatin C is a serine protease inhibitor.
      • Leu68Gln mutation in its gene leads to cystatin C amyloidosis.
    • Fibrinogen Aa-chain amyloidosis (A Fib)[21]
      • 4 different mutations including Arg554Leu, Glu526Val, 4904delG, and 4897delT has been found to be associated with amyloidosis.
    • Apolipoprotein AII amyloidosis (A ApoAII)[22]
      • It was discovered recently.
      • 3 different mutations in the stop codon for the ApoAII gene including stop78Gly, stop78Ser, and stop78Arg has been found to be associated with amyloidosis.
      • These mutations lead to an extra 21-amino acid at the carboxyl terminal end of the protein.


 
 
 
 
 
 
 
 
 
 
 
 
 
genes involved in familial amyloidosis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transthyretin (TTR)
 
Apolipoprotein AI
 
Gelsolin
 
Lysozyme
 
Cystatin C
 
Fibrinogen Aa-chain
 
Apolipoprotein AII
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mutations:
•Asp18Glu
•Leu55Gln
•Asp18Gly
•His56Arg
•Asp18Asn
•Leu58His
•Val20Ile
•Leu58Arg
•Ser23Asn
•Thr59Lys
•Pro24Ser
•Thr60Ala
•Ala25Ser
•Glu61Lys
•Ala25Thr
 
Mutations:
•Gly26Arg
•Leu60Arg
•Trp50Arg
•del60-71
•del70-72
•Leu75Pro
•Leu90Pro
•Arg173Pro
•Leu174Ser
•Leu178His
 
Mutations:
•Asp187Asn
•Asp187Tyr
 
Mutations:
•Ile56Thr
•Asp67His
•Trp64Arg
•Phe57Ile
 
Mutation:
•Leu68Gln
 
Mutations:
•Arg554Leu
•Glu526Val
•4904delG
•4897delT
 
Mutations:
•stop78Gly
•stop78Ser
•stop78Arg
 

•Cys10Arg
•Leu55Pro
•Leu12Pro
•Leu55Arg
•Phe64Leu
•Val28Met
•Phe64Ser
•Val30Met
•Ile68Leu
•Val30Ala
•Tyr69His
•Val30Leu
•Tyr69Ile
•Val30Gly
•Lys70Asn
•Phe33Ile
•Val71Ala
•Phe33Leu
•Ile73Val
•Phe33Val
•Ser77Tyr
•Phe33Cys
•Ser77Phe
•Arg34Thr
•Tyr78Phe
•Lys35Asn
•Ala81Thr
•Ala36Pro
•Ile84Ser
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Associated Conditions

Conditions associated with amyloidosis include:[23]

  • MEN2A

Gross Pathology

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

  • Porcelain like or waxy appearance
  • Enlargement

Images

Nodular deposits of amyloid on the pleural surfaces.[24]
Cut section of an inguinal lymph node showing firm and waxy consistency.[25]
A slice of the affected node (left) has turned black after treatment with Lugol's solution. A piece of normal myometrium (right) treated similarly with no reaction is also shown.[26]


Microscopic Pathology

On microscopic histopathological analysis, amyloidosis is characterized by:[8][27]

  • Green birefringence under polarized light after Congo red staining (appears red under normal light)
  • Linear non-branching fibrils (indefinite length with an approximately same diameter)
  • Distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril

Images

Small bowel duodenum with amyloid deposition Congo red.[28]
Amyloidosis (black arrows) in a lymph node after staining with Congo Red.[29]
Green birefringence under polarized light.[30]


References

  1. Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  2. Pepys MB, Rademacher TW, Amatayakul-Chantler S, Williams P, Noble GE, Hutchinson WL, Hawkins PN, Nelson SR, Gallimore JR, Herbert J (June 1994). "Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure". Proc. Natl. Acad. Sci. U.S.A. 91 (12): 5602–6. doi:10.1073/pnas.91.12.5602. PMC 44044. PMID 8202534.
  3. Tan SY, Pepys MB (November 1994). "Amyloidosis". Histopathology. 25 (5): 403–14. doi:10.1111/j.1365-2559.1994.tb00001.x. PMID 7868080.
  4. Botto M, Hawkins PN, Bickerstaff MC, Herbert J, Bygrave AE, McBride A, Hutchinson WL, Tennent GA, Walport MJ, Pepys MB (August 1997). "Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene". Nat. Med. 3 (8): 855–9. doi:10.1038/nm0897-855. PMID 9256275.
  5. Wechalekar AD, Gillmore JD, Hawkins PN (June 2016). "Systemic amyloidosis". Lancet. 387 (10038): 2641–2654. doi:10.1016/S0140-6736(15)01274-X. PMID 26719234.
  6. Hund E, Linke RP, Willig F, Grau A (February 2001). "Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment". Neurology. 56 (4): 431–5. doi:10.1212/wnl.56.4.431. PMID 11261421.
  7. Gertz MA (June 2017). "Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges". Am J Manag Care. 23 (7 Suppl): S107–S112. PMID 28978215.
  8. 8.0 8.1
  9. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  10. Benson, Merrill D (2003). "The hereditary amyloidoses". Best Practice & Research Clinical Rheumatology. 17 (6): 909–927. doi:10.1016/j.berh.2003.09.001. ISSN 1521-6942.
  11. Scriver, Charles (2001). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. ISBN 978-0079130358.
  12. Robbins J (1976). "Thyroxine-binding proteins". Prog. Clin. Biol. Res. 5: 331–55. PMID 61594.
  13. Westermark P, Sletten K, Johansson B, Cornwell GG (April 1990). "Fibril in senile systemic amyloidosis is derived from normal transthyretin". Proc. Natl. Acad. Sci. U.S.A. 87 (7): 2843–5. doi:10.1073/pnas.87.7.2843. PMC 53787. PMID 2320592.
  14. Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, Andersen O, Karlberg I, Nordén G, Nakazato M (September 1991). "Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30)". Clin. Genet. 40 (3): 242–6. doi:10.1111/j.1399-0004.1991.tb03085.x. PMID 1685359.
  15. Borhani DW, Rogers DP, Engler JA, Brouillette CG (November 1997). "Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation". Proc. Natl. Acad. Sci. U.S.A. 94 (23): 12291–6. doi:10.1073/pnas.94.23.12291. PMC 24911. PMID 9356442.
  16. Maury CP, Kere J, Tolvanen R, de la Chapelle A (December 1990). "Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene". FEBS Lett. 276 (1–2): 75–7. doi:10.1016/0014-5793(90)80510-p. PMID 2176164.
  17. de la Chapelle A, Tolvanen R, Boysen G, Santavy J, Bleeker-Wagemakers L, Maury CP, Kere J (October 1992). "Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187". Nat. Genet. 2 (2): 157–60. doi:10.1038/ng1092-157. PMID 1338910.
  18. Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ (April 1993). "Human lysozyme gene mutations cause hereditary systemic amyloidosis". Nature. 362 (6420): 553–7. doi:10.1038/362553a0. PMID 8464497.
  19. Gudmundsson G, Hallgrímsson J, Jónasson TA, Bjarnason O (1972). "Hereditary cerebral haemorrhage with amyloidosis". Brain. 95 (2): 387–404. doi:10.1093/brain/95.2.387. PMID 4655034.
  20. Ghiso J, Pons-Estel B, Frangione B (April 1986). "Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases". Biochem. Biophys. Res. Commun. 136 (2): 548–54. doi:10.1016/0006-291x(86)90475-4. PMID 3707586.
  21. Uemichi T, Liepnieks JJ, Benson MD (February 1994). "Hereditary renal amyloidosis with a novel variant fibrinogen". J. Clin. Invest. 93 (2): 731–6. doi:10.1172/JCI117027. PMC 293912. PMID 8113408.
  22. Benson MD, Liepnieks JJ, Yazaki M, Yamashita T, Hamidi Asl K, Guenther B, Kluve-Beckerman B (March 2001). "A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene". Genomics. 72 (3): 272–7. doi:10.1006/geno.2000.6499. PMID 11401442.
  23. Hofstra RM, Sijmons RH, Stelwagen T, Stulp RP, Kousseff BG, Lips CJ, Steijlen PM, Van Voorst Vader PC, Buys CH (August 1996). "RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia". J. Invest. Dermatol. 107 (2): 215–8. doi:10.1111/1523-1747.ep12329651. PMID 8757765.
  24. By Yale Rosen from USA - Amyloidosis, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=31127928
  25. By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377537238/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629764
  26. By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377538012/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629740
  27. Röcken C, Shakespeare A (February 2002). "Pathology, diagnosis and pathogenesis of AA amyloidosis". Virchows Arch. 440 (2): 111–122. doi:10.1007/s00428-001-0582-9. PMID 11964039.
  28. By Michael Feldman, MD, PhDUniversity of Pennsylvania School of Medicine - http://www.healcentral.org/healapp/showMetadata?metadataId=38717, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=870218
  29. By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559787/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629716
  30. By Ed Uthman, MD - https://www.flickr.com/photos/euthman/377559955/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629705

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