Course:MEDG550/Student Activities/Familial Mediterranean Fever

From UBC Wiki
Jump to: navigation, search

Familial Mediterranean Fever (FMF), also known as recurrent polyserositis or benign paroxysmal peritonitis, is a genetic condition characterized by recurrent episodes of fever and inflammation.[1] FMF is classified as an autoinflammatory disorder, a group of conditions also known as periodic fevers that are characterized by recurrent periods of inflammation and fever. [2] FMF is caused by genetic changes in a single gene called MEFV.

Clinical Features[edit | edit source]

There are two clinical presentations of FMF, Type 1 and Type 2.

Familial Mediterranean Fever Type 1[edit | edit source]

Individuals with FMF Type 1 have recurrent episodes of inflammation and fever, which develop spontaneously [3] and can last between 1-4 days.[4] The inflammation affects the linings of the lungs, abdomen, joints and, rarely, the heart and brain.[3][5] Fevers are unaffected by antibiotics and can be as high as 38-40°C.[4] More than 90% of individuals with FMF will experience abdominal pain during an episode of inflammation, and patients can also experience joint pain, such as arthritis, and chest pain from inflammation of the lungs or heart.[3][4] The episodes of fever and inflammation can occur as frequently as once a week or only once every few years[4] and the type and severity of symptoms varies between individuals.[5]

If FMF is left untreated, amyloidosis can develop.[5] Amyloidosis is the build up of the protein amyloid in the kidneys and is the most serious complication of FMF as it can lead to renal failure [6]

Familial Mediterranean Fever Type 2[edit | edit source]

Individuals with FMF Type 2 present with amyloidosis as their first clinical feature and are otherwise asymptomatic.[5]

Prevalence[edit | edit source]

As the name suggests, FMF is found predominately in people of Mediterranean descent, specifically Armenian, Turkish, Arabic, or Jewish (including North African, Iraqi, and Ashkenazi Jewish).[7] In these populations, the prevalence of individuals with FMF ranges from 1/200 to 1/1000.[4] [7] FMF has also been reported in individuals of Greek, Spanish, Italian and Japanese descent.[7]

Diagnosis[edit | edit source]

The vast majority of patients (up to 90%) are diagnosed before the age of 20, with more than half showing symptoms before the age of 10.[3] Diagnosis is clinical, based on the Tel Hashomer clinical criteria.

Tel Hashomer Clinical Criteria[8][edit | edit source]

  • Fever and
    • one additional major feature and one minor feature
    • OR
    • two minor features

Major Features[edit | edit source]

  • fever
  • abdominal pain
  • chest pain
  • joint pain
  • skin eruption, for example a rash

Minor Features[edit | edit source]

  • increased erythrocyte sedimentation rate (ESR) (a measure of how quickly red blood cells stick together)
  • leukocytosis (high white blood cell count)
  • elevated serum fibrinogen concentration (the protein fibrinogen causes the red blood cells to stick together)

Patients can also be diagnosed through molecular diagnosis, such as sequencing the MEFV gene or through a targeted pathogenic variant analysis based on the patient's ethnicity or a familial mutation.[8]

If there is an inconclusive clinical or molecular diagnosis, an individual with suspected FMF can be treated with colchicine for a trial period of 6 months to see if their symptoms improve with the medication.[8]

Treatment and Management[edit | edit source]

Treating FMF is aimed at reducing the frequency of the clinical episodes and controlling chronic inflammation between episodes to reduce the accumulation of amyloid in the kidneys.[9] The most effective medication for FMF is a drug called colchicine. Colchicine prevents inflammatory attacks and amyloid deposition.[9] Patients with severe FMF symptoms and the most pathogenic mutations may take high doses of colchicine daily, while some patients with less severe symptoms and mutations that are less associated with complications such as amyloidosis may only take colchicine during an inflammatory attack.[8]

In patients with amyloidosis, they can require dialysis or even a kidney transplant, as the accumulation of amyloid can reduce kidney function and lead to renal failure.[9]

Genetics and Inheritance[edit | edit source]

Autosomal Recessive inheritance pattern

FMF is a genetic condition caused by mutations in the MEFV gene. The normal function of the MEFV gene is the production of a protein called pyrin that is responsible for regulating the inflammatory response.[8] In individuals with FMF, the functionality of pyrin is reduced, leading to the increased inflammatory responses.[8]

FMF is inherited in an autosomal recessive manner, meaning that an individual with FMF has inherited two copies of the altered MEFV gene, one from each parent. A person who has only one altered copy of the MEFV gene is said to be a 'carrier' of FMF and is generally asymptomatic. There have been rare cases where a person can have only altered copy of the MEFV gene and show symptoms of FMF [8]. These individuals often have severely pathogenic mutations in their altered copy, and will have later onset and milder symptoms than someone with both copies altered.[8] In these cases, FMF can be inherited in an autosomal dominant pattern, where only one mutated copy of MEFV inherited from an individual's parents is enough to show symptoms.[8]

Other cases of FMF may appear to be autosomal dominant, but are actually 'pseudodominant.' This can occur when a child is born to a parent with FMF and another parent that is an asymptomatic carrier, creating the appearance of an autosomal dominant inheritance pattern.[8] This 'pseudodominance' can be clarified by molecular testing of both parents of an affected individual.

Genetic Counselling[edit | edit source]

Individuals who have FMF, a family history of FMF, or are a member of one of the at-risk ethnicities can attend a genetic counselling session to learn more about the condition, as well as to discuss carrier testing and prenatal diagnosis options if applicable.

Parents of a child with FMF can meet with a genetic counsellor to discuss the chance of having another child with the condition. As FMF is generally inherited in an autosomal recessive manner, the chance of another child with FMF is 25%. As some cases of FMF are inherited in an autosomal dominant pattern, the genetic status of the parents can be important to know to clarify cases of pseudodominance and discuss the exact risk for each family.[10]

If the exact pathogenic variants of the MEFV gene are known in a particular family, there is the option of carrier testing for at-risk relatives and also prenatal diagnosis such as amniocentesis or chorionic villus sampling in subsequent pregnancies.[8]

It can be important to test siblings, parents, and children of an affected individual, even if they appear asymptomatic. Cases of FMF Type 2 show amyloidosis as the first symptom, and so individuals who have a molecular diagnosis of FMF can begin preventative treatment with colchicine[10]

Genotype-Phenotype Correlations[edit | edit source]

There have been over 250 mutations identified in the MEFV gene[3] and specific mutations in MEFV are associated with differences in symptoms and severity. This is termed as genotype-phenotype relationship, where different genetic changes show a different clinical presentation.

For example, the M694V mutation is associated with the development of amyloidosis[10] and patients with this mutation in both copies of the MEFV gene can be less responsive to colchicine treatment.[11] The notation 'M694V' represents when one amino acid in the protein has been changed to another at a particular location. Individuals who have both copies of the MEFV gene with the M694V mutation tend to have an earlier age of onset and have more symptoms of arthritis and joint pain.[12] Other examples include the mutation T577N, which has been associated with autosomal dominant FMF[13] and E148Q, which has been argued to cause a mild form of FMF in some individuals.[5]

Patient Resources[edit | edit source]

Living with Periodic Fevers

FMF & AID Global Association

The Canadian Amyloidosis Support Network

Systemic Autoinflammatory Disease (SAID) Support

References[edit | edit source]

  1. Ben-Chetrit E, Touitou I. (2009). Familial Mediterranean Fever in the World. Arthrit Care Res 61(10):1447-1453.
  2. Ciccarelli F, De Martinis M, Ginaldi L. (2013). An Update on Autoinflammatory Diseases. Curr Med Chem 21(3):261-269.
  3. 3.0 3.1 3.2 3.3 3.4 Sari I, Birlik M, Kasifoglu T. (2014). Familial Mediterranean fever: an updated review. Eur J Rheumatol" "'1'(1):21-33.
  4. 4.0 4.1 4.2 4.3 4.4 Manna PR. Familial Mediterranean Fever. Orphanet encyclopedia, January, 2012, http://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=342
  5. 5.0 5.1 5.2 5.3 5.4 Shohat M, Halpern GJ. (2011). Familial Mediterranean fever – a review. Genet Med 13:487-498.
  6. Familial Mediterranean Fever. Genetic and Rare Diseases Information Center, January, 2012, https://rarediseases.info.nih.gov/diseases/6421/familial-mediterranean-fever/cases/33603
  7. 7.0 7.1 7.2 Gattorno M. Familial Mediterranean Fever. Springer International Publishing Switzerland; 2015.
  8. 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 Shohat, M. 2000 Aug 8 [Updated 2016 Dec 15]. Familial Mediterranean Fever. Gene Reviews. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227/
  9. 9.0 9.1 9.2 Ozen S, Demikraya E, Erer B et al. (2016). EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75:644-651.
  10. 10.0 10.1 10.2 Ben-Chetri E, Sagi M. (2001). Genetic counselling in familial Mediterranean fever: has the time come? Rheumatology 40(6):606-609.
  11. Soylemezoglu O, Arga M, Fidan K, et al. (2010). Unresponsiveness to colchicine therapy in patients with familial Mediterranean fever homozygous for the M694V mutation. J Rheumatol 37:182–189.
  12. Tunca M, Akar S, Onen F, et al. (2005). Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84:1–11.
  13. Stoffels M, Szperl A, Simon A, et al. (2014). MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis 73:455–61.