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, and is most often accompanied by a fever.  This condition often shows up first in childhood with unexplained fever and aches and pains.

FMF is often misdiagnosed as various pain-related conditions such as fibromyalgia, myofascial pain syndrome, or gouty arthritis.

What is familial Mediterranean fever?

Genetics Home Reference explains “Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or a headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. In about half of affected individuals, attacks are preceded by mild signs and symptoms known as a prodrome. Prodromal symptoms include mildly uncomfortable sensations in the area that will later become inflamed or more general feelings of discomfort.”

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

But with the prevalence of genetic testing, new 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 is the gene responsible for familial Mediterranean fever, and it 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.

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) that “may account for as much as 80% of FMF cases in classically affected populations”. [study]

It has also been found that up to 30% of FMF cases may be just heterozygous (one copy) for a MEFV mutation.

Since many who are heterozygous or homozygous have no symptoms, it is thought that there may be another genetic mutation also involved or environmental factors (or both).  A recent study found that those with European ancestry usually have milder symptoms than those of Mediterranean ancestry.  The gut microbiome may also be involved with changes to the microbiome found in those in acute attacks.

For those with frequent attacks, the long-term consequences can include amyloidosis and kidney failure, so definitely talk with your doctor if you have the genetic variants along with symptoms.  There is a prescription medication, colchicine, that can help prevent the long-term consequences for those with frequent attacks.

Often misdiagnosed as fibromyalgia or arthritis

Fever with achiness for a few days — sounds like just being frequently sick with a virus or something! Aching joints or muscles, pain in the abdomen, pain across the chest — could be a number of different rheumatoid-like illnesses. This made me wonder if there is an overlap between the diagnosis of other conditions such as fibromyalgia or arthritis with familial Mediterranean fever. Turns out there are studies showing overlap of conditions similar to FMF, although it isn’t clear if 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]

Genetics of FMF:

Check your 23andMe raw data for the following variants. (v.4 and v.5 ) These are some of the more common variants that can cause FMF; there are also other mutations that aren’t covered by 23andMe data.  (Note that all are giving in the plus or forward orientation to match with 23andMe data)

Check your genetic data for rs61732874 (23andMe i4000409v4, v5; AncestryDNA):

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

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: normal

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: normal

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: normal

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: normal

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: normal

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: normal

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: normal

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: normal

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: normal

Interestingly, a recent study found that those who carry the MTHFR C677T and A1298C variants were more susceptible to familial Mediterranean fever.


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 is found in Andrographis extract, which 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.  Quercetin is found 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.  It found that only stressful events 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.

More to read:

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4 Comments on “Familial Mediterranean Fever: Often misdiagnosed!

  1. Why only 23andme data? Should be possible with data from any provider, no? (Ancestry.com, etc).

    Any recommendations on how to proceed with that?

    • Yes – the rsid numbers will be the same for any genetic data. The ones that start with an ‘i’ are an internal numbering system for 23andMe. Snpedia.com has the rsid’s that go along with the i numbers that are listed above.
      The reason that I link to 23andMe is that they have an easy interface to check your data, and AncestyDNA doesn’t.
      For Ancestry.com, you will need to download your raw data file and then search through the data. It is a text file, so you could search it using something like Notepad (Windows) or TextEdit (Mac). To me, it is easier to import the text file into Excel (it is tab delimited) and then search. I have an article on GeneticLifehacks about importing 23andMe into Excel (https://www.geneticlifehacks.com/creating-your-own-genetics-reports-for-free/), and the process with the Ancestry.com would be similar.
      I’ve had it on my list to write a blog post on using Ancestry.com data for a while now, but I keep coming up with more fun topics to blog about :-) I’ll put it back on the top of the list.
      Hope this helps,

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