Familial mediterranean fever pathophysiology: Difference between revisions
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{{Familial mediterranean fever}} | {{Familial mediterranean fever}} | ||
{{CMG}}; {{AE}} | {{CMG}}; {{AE}} {{Sahar}} | ||
==Overview== | ==Overview== | ||
The exact [[pathogenesis]] of [[familial mediterranean fever]] is not fully understood. However, nearly all the cases are due to a [[mutation]] in the [[MEFV]] [[gene]], which codes for a [[protein]] called pyrin. Normally, pyrin regulates the production of [[Interleukin-1|interleukin-1β]] (IL-1β), an important [[pro-inflammatory]] [[cytokine]]. When [[mutation]] occurs, [[mutated]] [[protein]] is unable to suppress [[expression]] of IL-1β, therefore an [[Inflammation|inflammatory]] response would develop results in [[clinical]] manifestation of [[FMF]]. The [[disease]] inherits in an [[autosomal recessive]] mode. However, there is an increasing number of data reporting the [[autosomal dominant]] [[inheritance]]. | |||
==Pathophysiology== | ==Pathophysiology== | ||
*Approximately, all cases are due to a [[mutation]] in the [[MEFV]] [[gene]], which codes for a [[protein]] called pyrin or marenostrin (from the original name of the Mediterranean sea, Marenostrum).<ref name="pmid10807793">{{cite journal |vauthors=Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O'Shea JJ, Rosenberg HF, Malech HL, Kastner DL |title=The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators |journal=Blood |volume=95 |issue=10 |pages=3223–31 |date=May 2000 |pmid=10807793 |doi= |url=}}</ref> | *Approximately, all cases are due to a [[mutation]] in the [[MEFV]] [[gene]], which codes for a [[protein]] called pyrin or [[marenostrin]] (from the original name of the Mediterranean sea, Marenostrum).<ref name="pmid10807793">{{cite journal |vauthors=Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O'Shea JJ, Rosenberg HF, Malech HL, Kastner DL |title=The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators |journal=Blood |volume=95 |issue=10 |pages=3223–31 |date=May 2000 |pmid=10807793 |doi= |url=}}</ref> | ||
* | *Normally, pyrin regulates the production of [[interleukin]]-1β (IL-1β), an important pro-[[inflammatory]] [[cytokine]].<ref name="ChaeKastner2015">{{cite journal|last1=Chae|first1=Jae Jin|last2=Kastner|first2=Daniel L.|title=Pathogenesis|volume=3|year=2015|pages=13–30|issn=2282-6505|doi=10.1007/978-3-319-14615-7_2}}</ref> | ||
*IL-1β has a pivotal role in [[inflammatory]] processes such as [[fever]], and [[septic shock]]. | |||
*The [[maturation]] of IL-1β depends on an [[enzyme]] called [[caspase]]-1 which is activated within inflammosomes, a cytoplasmic multiprotein platforms. | |||
*Inflammosomes will be activated upon cellular [[infection]] or [[Stress (medicine)|stress]]. | |||
*Although, it is still not clear, it has been assumed that mutant form of pyrin is unable to suppress, therefore an [[inflammatory]] response would develop results in [[clinical]] manifestation of [[FMF]].<ref name="pmid16785446">{{cite journal |vauthors=Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, Kastner DL |title=The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=26 |pages=9982–7 |date=June 2006 |pmid=16785446 |pmc=1479864 |doi=10.1073/pnas.0602081103 |url=}}</ref> | |||
===Genetics=== | ===Genetics=== | ||
*The [[MEFV]] [[gene]] is located on the short arm of [[chromosome 16 (human)|chromosome 16]] (16p13) which consists of 10 [[exons]].<ref name="pmid9288094">{{cite journal |vauthors= |title=A candidate gene for familial Mediterranean fever |journal=Nat. Genet. |volume=17 |issue=1 |pages=25–31 |date=September 1997 |pmid=9288094 |doi=10.1038/ng0997-25 |url=}}</ref> | *The [[MEFV]] [[gene]] is located on the short arm of [[chromosome 16 (human)|chromosome 16]] (16p13) which consists of 10 [[exons]].<ref name="pmid9288094">{{cite journal |vauthors= |title=A candidate gene for familial Mediterranean fever |journal=Nat. Genet. |volume=17 |issue=1 |pages=25–31 |date=September 1997 |pmid=9288094 |doi=10.1038/ng0997-25 |url=}}</ref> | ||
*The majority of [[mutations]] occur in [[exon]] 10.<ref name="pmid11464238">{{cite journal |vauthors=Touitou I |title=The spectrum of Familial Mediterranean Fever (FMF) mutations |journal=Eur. J. Hum. Genet. |volume=9 |issue=7 |pages=473–83 |date=July 2001 |pmid=11464238 |doi=10.1038/sj.ejhg.5200658 |url=}}</ref> | *The majority of [[mutations]] occur in [[exon]] 10.<ref name="pmid11464238">{{cite journal |vauthors=Touitou I |title=The spectrum of Familial Mediterranean Fever (FMF) mutations |journal=Eur. J. Hum. Genet. |volume=9 |issue=7 |pages=473–83 |date=July 2001 |pmid=11464238 |doi=10.1038/sj.ejhg.5200658 |url=}}</ref> | ||
*To date, approximately 300 [[Mutation|mutations]] have been reported in this [[gene]]. | |||
*Not all the reported mutations would result in the presention of the disease. | |||
*The E148Q, M680I, M694V, M694I, and V726A [[mutations]] have been observed to be responsible for more than 80% of [[FMF]] cases in the Middle Eastern region. | *The E148Q, M680I, M694V, M694I, and V726A [[mutations]] have been observed to be responsible for more than 80% of [[FMF]] cases in the Middle Eastern region. | ||
*The most common disease associated gene variants are:<ref name="Touitou2001">{{cite journal|last1=Touitou|first1=Isabelle|title=The spectrum of Familial Mediterranean Fever (FMF) mutations|journal=European Journal of Human Genetics|volume=9|issue=7|year=2001|pages=473–483|issn=1018-4813|doi=10.1038/sj.ejhg.5200658}}</ref> | *The most common [[disease]] associated [[gene]] variants are:<ref name="Touitou2001">{{cite journal|last1=Touitou|first1=Isabelle|title=The spectrum of Familial Mediterranean Fever (FMF) mutations|journal=European Journal of Human Genetics|volume=9|issue=7|year=2001|pages=473–483|issn=1018-4813|doi=10.1038/sj.ejhg.5200658}}</ref> | ||
**M694V | **M694V | ||
**V726A | **V726A | ||
| Line 18: | Line 24: | ||
**M694I | **M694I | ||
*The [[disease]] inherits in an [[autosomal recessive]] mode. However, there is an increasing number of data reporting the [[autosomal dominant]] [[inheritance]].<ref name="pmid7677151">{{cite journal |vauthors=Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M |title=Dominant inheritance in two families with familial Mediterranean fever (FMF) |journal=Am. J. Med. Genet. |volume=57 |issue=3 |pages=455–7 |date=July 1995 |pmid=7677151 |doi=10.1002/ajmg.1320570319 |url=}}</ref><ref name="pmid10787449">{{cite journal |vauthors=Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soytürk M, Akar S, Pepys MB, Tunca M, Hawkins PN |title=The genetic basis of autosomal dominant familial Mediterranean fever |journal=QJM |volume=93 |issue=4 |pages=217–21 |date=April 2000 |pmid=10787449 |doi=10.1093/qjmed/93.4.217 |url=}}</ref><ref name="pmid14679589">{{cite journal |vauthors=Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, Yagüe J |title=A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? |journal=Am. J. Med. Genet. A |volume=124A |issue=1 |pages=67–73 |date=January 2004 |pmid=14679589 |doi=10.1002/ajmg.a.20296 |url=}}</ref> | *The [[disease]] inherits in an [[autosomal recessive]] mode. However, there is an increasing number of data reporting the [[autosomal dominant]] [[inheritance]].<ref name="pmid7677151">{{cite journal |vauthors=Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M |title=Dominant inheritance in two families with familial Mediterranean fever (FMF) |journal=Am. J. Med. Genet. |volume=57 |issue=3 |pages=455–7 |date=July 1995 |pmid=7677151 |doi=10.1002/ajmg.1320570319 |url=}}</ref><ref name="pmid10787449">{{cite journal |vauthors=Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soytürk M, Akar S, Pepys MB, Tunca M, Hawkins PN |title=The genetic basis of autosomal dominant familial Mediterranean fever |journal=QJM |volume=93 |issue=4 |pages=217–21 |date=April 2000 |pmid=10787449 |doi=10.1093/qjmed/93.4.217 |url=}}</ref><ref name="pmid14679589">{{cite journal |vauthors=Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, Yagüe J |title=A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? |journal=Am. J. Med. Genet. A |volume=124A |issue=1 |pages=67–73 |date=January 2004 |pmid=14679589 |doi=10.1002/ajmg.a.20296 |url=}}</ref> | ||
*The [[incidence]] of [[Mutation|mutations]] may differ according to the ethnicity. For example M694V is the most frequently seen mutation in turkish population.<ref name="pmid15643295">{{cite journal |vauthors=Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, Tutar E, Ozen S, Topaloglu R, Yilmaz E, Arici M, Bakkaloglu A, Besbas N, Akpolat T, Dinc A, Erken E |title=Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study |journal=Medicine (Baltimore) |volume=84 |issue=1 |pages=1–11 |date=January 2005 |pmid=15643295 |doi= |url=}}</ref> | |||
==Associated Conditions== | ==Associated Conditions== | ||
[[Conditions]] associated with [[Familial mediterranean fever|Familial Mediterranean fever]] include: | [[Conditions]] associated with [[Familial mediterranean fever|Familial Mediterranean fever]] include: | ||
*Certain type of [[vasculitis]] such as:<ref name="pmid31031761">{{cite journal |vauthors=Abbara S, Grateau G, Ducharme-Bénard S, Saadoun D, Georgin-Lavialle S |title=Association of Vasculitis and Familial Mediterranean Fever |journal=Front Immunol |volume=10 |issue= |pages=763 |date=2019 |pmid=31031761 |doi=10.3389/fimmu.2019.00763 |url=}}</ref> | *Certain type of [[vasculitis]] such as:<ref name="pmid31031761">{{cite journal |vauthors=Abbara S, Grateau G, Ducharme-Bénard S, Saadoun D, Georgin-Lavialle S |title=Association of Vasculitis and Familial Mediterranean Fever |journal=Front Immunol |volume=10 |issue= |pages=763 |date=2019 |pmid=31031761 |doi=10.3389/fimmu.2019.00763 |url=}}</ref> | ||
** [[IgA vasculitis]] | ** [[IgA]] [[vasculitis]] | ||
**[[PAN]]-like [[vasculitis]] with more perirenal [[bleeding]] and [[CNS]] involvement | **[[PAN]]-like [[vasculitis]] with more perirenal [[bleeding]] and [[CNS]] involvement | ||
*[[Hereditary angioedema]]<ref name="BahceciGenel2015">{{cite journal|last1=Bahceci|first1=Semiha Erdem|last2=Genel|first2=Ferah|last3=Gulez|first3=Nesrin|last4=Nacaroglu|first4=Hikmet T.|title=Coexistence of hereditary angioedema in a case of familial Mediterranean fever with partial response to colchicine|journal=Central European Journal of Immunology|volume=1|year=2015|pages=115–116|issn=1426-3912|doi=10.5114/ceji.2015.50843}}</ref> | *[[Hereditary angioedema]]<ref name="BahceciGenel2015">{{cite journal|last1=Bahceci|first1=Semiha Erdem|last2=Genel|first2=Ferah|last3=Gulez|first3=Nesrin|last4=Nacaroglu|first4=Hikmet T.|title=Coexistence of hereditary angioedema in a case of familial Mediterranean fever with partial response to colchicine|journal=Central European Journal of Immunology|volume=1|year=2015|pages=115–116|issn=1426-3912|doi=10.5114/ceji.2015.50843}}</ref> | ||
Latest revision as of 18:12, 7 June 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]
Overview
The exact pathogenesis of familial mediterranean fever is not fully understood. However, nearly all the cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin. Normally, pyrin regulates the production of interleukin-1β (IL-1β), an important pro-inflammatory cytokine. When mutation occurs, mutated protein is unable to suppress expression of IL-1β, therefore an inflammatory response would develop results in clinical manifestation of FMF. The disease inherits in an autosomal recessive mode. However, there is an increasing number of data reporting the autosomal dominant inheritance.
Pathophysiology
- Approximately, all cases are due to a mutation in the MEFV gene, which codes for a protein called pyrin or marenostrin (from the original name of the Mediterranean sea, Marenostrum).[1]
- Normally, pyrin regulates the production of interleukin-1β (IL-1β), an important pro-inflammatory cytokine.[2]
- IL-1β has a pivotal role in inflammatory processes such as fever, and septic shock.
- The maturation of IL-1β depends on an enzyme called caspase-1 which is activated within inflammosomes, a cytoplasmic multiprotein platforms.
- Inflammosomes will be activated upon cellular infection or stress.
- Although, it is still not clear, it has been assumed that mutant form of pyrin is unable to suppress, therefore an inflammatory response would develop results in clinical manifestation of FMF.[3]
Genetics
- The MEFV gene is located on the short arm of chromosome 16 (16p13) which consists of 10 exons.[4]
- The majority of mutations occur in exon 10.[5]
- To date, approximately 300 mutations have been reported in this gene.
- Not all the reported mutations would result in the presention of the disease.
- The E148Q, M680I, M694V, M694I, and V726A mutations have been observed to be responsible for more than 80% of FMF cases in the Middle Eastern region.
- The most common disease associated gene variants are:[6]
- M694V
- V726A
- M680I
- M694I
- The disease inherits in an autosomal recessive mode. However, there is an increasing number of data reporting the autosomal dominant inheritance.[7][8][9]
- The incidence of mutations may differ according to the ethnicity. For example M694V is the most frequently seen mutation in turkish population.[10]
Associated Conditions
Conditions associated with Familial Mediterranean fever include:
- Certain type of vasculitis such as:[11]
- IgA vasculitis
- PAN-like vasculitis with more perirenal bleeding and CNS involvement
- Hereditary angioedema[12]
- FMF has been associated with some neurological disorders such as:
- Whether these disorders are a manifestation of FMF or not still need to be cleared.
References
- ↑ Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O'Shea JJ, Rosenberg HF, Malech HL, Kastner DL (May 2000). "The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators". Blood. 95 (10): 3223–31. PMID 10807793.
- ↑ Chae, Jae Jin; Kastner, Daniel L. (2015). "Pathogenesis". 3: 13–30. doi:10.1007/978-3-319-14615-7_2. ISSN 2282-6505.
- ↑ Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, Kastner DL (June 2006). "The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production". Proc. Natl. Acad. Sci. U.S.A. 103 (26): 9982–7. doi:10.1073/pnas.0602081103. PMC 1479864. PMID 16785446.
- ↑ "A candidate gene for familial Mediterranean fever". Nat. Genet. 17 (1): 25–31. September 1997. doi:10.1038/ng0997-25. PMID 9288094.
- ↑ Touitou I (July 2001). "The spectrum of Familial Mediterranean Fever (FMF) mutations". Eur. J. Hum. Genet. 9 (7): 473–83. doi:10.1038/sj.ejhg.5200658. PMID 11464238.
- ↑ Touitou, Isabelle (2001). "The spectrum of Familial Mediterranean Fever (FMF) mutations". European Journal of Human Genetics. 9 (7): 473–483. doi:10.1038/sj.ejhg.5200658. ISSN 1018-4813.
- ↑ Yuval Y, Hemo-Zisser M, Zemer D, Sohar E, Pras M (July 1995). "Dominant inheritance in two families with familial Mediterranean fever (FMF)". Am. J. Med. Genet. 57 (3): 455–7. doi:10.1002/ajmg.1320570319. PMID 7677151.
- ↑ Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soytürk M, Akar S, Pepys MB, Tunca M, Hawkins PN (April 2000). "The genetic basis of autosomal dominant familial Mediterranean fever". QJM. 93 (4): 217–21. doi:10.1093/qjmed/93.4.217. PMID 10787449.
- ↑ Aldea A, Campistol JM, Arostegui JI, Rius J, Maso M, Vives J, Yagüe J (January 2004). "A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?". Am. J. Med. Genet. A. 124A (1): 67–73. doi:10.1002/ajmg.a.20296. PMID 14679589.
- ↑ Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, Tutar E, Ozen S, Topaloglu R, Yilmaz E, Arici M, Bakkaloglu A, Besbas N, Akpolat T, Dinc A, Erken E (January 2005). "Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study". Medicine (Baltimore). 84 (1): 1–11. PMID 15643295.
- ↑ Abbara S, Grateau G, Ducharme-Bénard S, Saadoun D, Georgin-Lavialle S (2019). "Association of Vasculitis and Familial Mediterranean Fever". Front Immunol. 10: 763. doi:10.3389/fimmu.2019.00763. PMID 31031761.
- ↑ Bahceci, Semiha Erdem; Genel, Ferah; Gulez, Nesrin; Nacaroglu, Hikmet T. (2015). "Coexistence of hereditary angioedema in a case of familial Mediterranean fever with partial response to colchicine". Central European Journal of Immunology. 1: 115–116. doi:10.5114/ceji.2015.50843. ISSN 1426-3912.
- ↑ Yahalom G, Kivity S, Lidar M, Vaknin-Dembinsky A, Karussis D, Flechter S, Ben-Chetrit E, Livneh A (September 2011). "Familial Mediterranean fever (FMF) and multiple sclerosis: an association study in one of the world's largest FMF cohorts". Eur. J. Neurol. 18 (9): 1146–50. doi:10.1111/j.1468-1331.2011.03356.x. PMID 21299735.
- ↑ Kalyoncu U, Eker A, Oguz KK, Kurne A, Kalan I, Topcuoglu AM, Anlar B, Bilginer Y, Arici M, Yilmaz E, Kiraz S, Calguneri M, Karabudak R (March 2010). "Familial Mediterranean fever and central nervous system involvement: a case series". Medicine (Baltimore). 89 (2): 75–84. doi:10.1097/MD.0b013e3181d5dca7. PMID 20517179.
- ↑ Luger S, Harter PN, Mittelbronn M, Wagner M, Foerch C (2013). "Brain stem infarction associated with familial Mediterranean fever and central nervous system vasculitis". Clin. Exp. Rheumatol. 31 (3 Suppl 77): 93–5. PMID 23710607.
- ↑ Capron J, Grateau G, Steichen O (2013). "Is recurrent aseptic meningitis a manifestation of familial Mediterranean fever? A systematic review". Clin. Exp. Rheumatol. 31 (3 Suppl 77): 127–32. PMID 24064026.