Familial Mediterranean Fever: Often misdiagnosed!

Familial Mediterranean fever (FMF) is a genetic condition of inflammatory episodes that cause painful joints, pain in the abdomen, or pain in the chest —  often accompanied by a fever. This condition often shows up first in childhood with unexplained fever and aches and pains.

FMF is an auto-inflammatory condition, meaning that the body’s inflammatory system is overly active. Sometimes people with familial Mediterranean fever are diagnosed with having various pain-related conditions such as fibromyalgia, myofascial pain syndrome, or gouty arthritis.

What is familial Mediterranean fever?

FMF is an auto-inflammatory (genetic) conditions that causes intermittent, recurrent episodes that can include:

  • fever
  • pain in a joint
  • inflammation / pain in the abdomen or chest

Sometimes the inflammation can cause a rash or headache as well as inflaming the membrane around the spinal cord or testicles.

Triggering FMF episodes:

For about half of FMF patients, the episodes are preceded by a prodromal period – feeling off and knowing that the joint pain and fever or night sweats are coming.[ref]

Commonly there is a triggering event before an episode. Triggers include:[ref]

  • infection (such as getting a cold)
  • stress
  • traveling
  • getting your period
  • cold exposure
  • certain drugs

FMF is a genetic disease:

FMF was classically thought of as an “autosomal recessive” genetic disease, which required the inheritance of two mutated genes.

With the recent prevalence of genetic testing,  studies are showing that this is a disease with a range of symptoms sometimes showing up in those who are heterozygous (one copy) for the mutations and other times not affecting those who are homozygous (2 copies).

MEFV, the gene responsible for familial Mediterranean fever, codes for a protein called pyrin, which interacts with the immune system. Pyrin regulates interleukin-1 beta (IL1B), which is a cytokine important in inflammatory responses including fever.[ref]  Interleukin-18 (IL18) is also elevated in patients with MEFV mutations.[ref]

To emphasize, while there are over 310 different MEFV mutations that have been identified and linked to familial Mediterranean fever, there are a few (E148Q, M680I, M694I, M694V, and V726A – listed below) that “account for as much as 80% of FMF cases in classically affected populations”.[ref]

Results of recent research show that up to 30% of FMF cases are heterozygous (one copy) for a MEFV mutation.[ref]

Many people who carry one or two copies of the MEFV mutation have no symptoms.  Researchers theorize that there may be another genetic mutation also involved –  or environmental factors.  A recent study found that those with European ancestry usually have milder symptoms than those of Mediterranean ancestry.[ref] The gut microbiome may also be involved, with changes to the microbiome found in those in acute attacks.[ref]

For those with frequent attacks, the long-term consequences of FMF  can include amyloidosis and kidney failure, so definitely talk with your doctor if you have the genetic variants along with symptoms.

Colchicine, a prescription medication also used for gout, can help prevent the long-term consequences for those with frequent attacks.

Often misdiagnosed as fibromyalgia, gout, or arthritis

Aching joints or muscles, pain in the abdomen, pain across the chest — these symptoms describe a number of different rheumatoid-type diagnoses.

Numerous studies show an overlap of conditions with symptoms similar to FMF.

It isn’t clear if the presence of the MEFV gene variants make the original diagnosis more likely –  or if patients were misdiagnosed in the first place.

  • A study of fibromyalgia patients and their families found that 15% carried heterozygous mutations for familial Mediterranean fever as well as having elevated levels of IL-1B (also found in FMF patients). The study theorizes that a COMT genetic variant (rs4680, A/A) may combine with the heterozygous FMF mutation in causing fibromyalgia-like symptoms.[ref]
  • In a study of ‘asymptomatic’ parents of children with FMF, many were found to have diagnoses of rheumatoid arthritis, rheumatic fever, and arthralgia.[ref]
  • In a study on gouty arthritis, 38% were found to carry a MEFV variant that can cause familial Mediterranean fever.[ref]
  • A study of lupus patients found that those carrying MEFV variants had an earlier onset of disease, more episodes of fever and pleurisy.[ref]
  • An LA Times article from 2009 explains “Even today, many patients bear the scars of needless appendectomies. Others are mistakenly diagnosed with such ailments as diverticulitis, pancreatitis, pleurisy, and lupus — even psychiatric disorders — until a light goes on and patients are finally placed on colchicine.”
  • A small study of people with myofascial pain syndrome found that 75% of them carried one copy of the MEFV mutation.[ref]
  • 70% of patients with neurological symptoms in Behçet’s or Sweets Disease have MEFV mutations.[ref]
  • People with Palindromic rheumatism and intermittent hydrarthosis are more likely to carry MEFV mutations.[ref]

Trade-offs:

For many deleterious mutations that are relatively common in the population, there is a trade-off between the mutation symptoms and resistance to disease.

Example: people with sickle cell anemia have resistance to malaria…  Thus, people with the sickle cell mutation that live in areas with malaria are more likely to survive childhood and pass on the mutation to their children.

Researchers have found that people with familial Mediterranean fever mutations do have a positive trade-off: resistance to Yersinia pestis, the bacteria that causes the plague.[ref][ref]


Genetic mutations that cause Familial Mediterranean Fever:

Member’s – log in to see your data. Not a member? Join now.
Check your 23andMe or AncestryDNA raw data for the following variants. These are some of the more common variants that can cause FMF; be advised that other mutations aren’t covered by 23andMe data.

Check your genetic data for rs61732874 (23andMe i4000409 v4, v5; AncestryDNA):

  • A/A: FMF variant A744S (two copies)
  • A/C: one copy of FMF variant
  • C/C: typical

Members: Your genotype for rs61732874 is .

Check your genetic data for rs3743930 ( 23andMe v4, v5; AncestryDNA):

  • G/G: FMF variant E148Q (two copies)
  • C/G: one copy of FMF variant
  • C/C: typical

Members: Your genotype for rs3743930 is .

Check your genetic data for rs104895083 (23andMe i4000403 v4, v5):

  • C/C: FMF variant F479L (two copies)
  • C/G: one copy of FMF variant
  • G/G: typical

Members: Your genotype for rs104895083 is .

Check your genetic data for rs104895094 ( 23andMe i4000407 v4, v5):

  • C/C: FMF variant K695R (two copies)
  • C/T: one copy of FMF variant
  • T/T: typical

Members: Your genotype for i400040 is .

Check your genetic data for rs28940580 ( 23andMe v4, v5):

  • G/G: FMF variant M680I (two copies)
  • C/G: one copy of FMF variant
  • C/C: typical

Members: Your genotype for rs28940580 is .

Check your genetic data for rs28940578 (23andMe v4, v5; AncestryDNA):

  • T/T: FMF variant M694I (two copies)
  • C/T: one copy of FMF variant
  • C/C: typical

Members: Your genotype for rs28940578 is .

Check your genetic data for rs61752717 (23andMe i4000406 v4, v5):

  • C/C: FMF variant M694V (two copies)
  • C/T: one copy of FMF variant
  • T/T: typical

Members: Your genotype for rs61752717 is .

Check your genetic data for rs11466023 (23andMe v4, v5):

  • A/A: FMF variant P369S (two copies)
  • A/G: one copy of FMF variant
  • G/G: typical

Members: Your genotype for rs11466023 is .

Check your genetic data for rs104895097 (23andMe i4000410 v4, v5 ; AncestryDNA):

  • T/T: FMF variant R761H (two copies)
  • C/T: one copy of FMF variant
  • C/C: typical

Members: Your genotype for rs104895097 is .

Check your genetic data for rs28940579 (23andMe v4, v5; AncestryDNA):

  • G/G: FMF variant V726A (two copies)
  • A/G: one copy of FMF variant
  • A/A: typical

Members: Your genotype for rs2894057 is .

Interestingly, a recent study found carriers of the MTHFR C677T and A1298C variants (check your data here) were more susceptible to familial Mediterranean fever.[ref]


Lifehacks

Herbal Supplements?

There were several studies and clinical trials of ImmunoGard, a herbal-based supplement for familial Mediterranean fever which showed positive results.[ref][ref] I can’t find it sold online anywhere, though.

The ingredients of ImmunoGard included “Andrographolide (4 mg/tablet), Eleuteroside E, Schisandrins and Glycyrrhizin,”.  Andrographolide, found in Andrographis extract, is an herb used for boosting the immune system and included in some Lyme disease protocols. Schisandrins is from Eleutherococcus senticosus (Siberian ginseng), and glycyrrhizin is found in licorice.

Due to the increase in IL-1B, natural inhibitors of IL-1B such as quercetin or genistein may help.[ref][ref] This is just a guess on my part, though, and I haven’t found any studies specific to FMF with either of these flavonoids.  You can find quercetin in many fruits and vegetables as well as being available as a supplement. (Quercetin is a methyl donor, so use it with caution if you are sensitive to methyl supplements.)

Avoid Stress

A study of triggers of FMF attacks looked at stress, physical activity, and high-fat diet.  Findings included only stressful events that were linked to FMF, and neither physical activity nor a high-fat diet was a trigger. So avoiding stress may help to decrease FMF attacks.[ref]

Gut Microbiome

The gut microbiome may also contribute to both the likelihood of having FMF and the frequency of attacks.  Here is a great open-access article on the topic: Probiotic Lactobacillus acidophilus Strain INMIA 9602 Er 317/402 Administration Reduces the Numbers of Candida albicans and Abundance of Enterobacteria in the Gut Microbiota of Familial Mediterranean Fever Patients  The strain of probiotic used in the study is not one that I can find available online.


Related Genes and Topics:

Quercetin: Scientific studies + genetic connections
Quercetin is a natural flavonoid that acts both as an antioxidant and anti-inflammatory. This potent flavonoid is found in low levels in many fruits and vegetables, including elderberry, apples, and onions. As a supplement, quercetin has many positive health benefits.

Rheumatoid Arthritis Genes
Rheumatoid arthritis is caused by an immune system attack on the joints, causing thickening and inflammation of the joint capsule. It is caused by a combination of genetic susceptibility and environmental triggers.

 

 

 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.