Familial Mediterranean Fever: Mimics fibromyalgia, arthritis, inflammation

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.

This article explains how to check your genetic data for Familial Mediterranean Fever mutations. People with familial Mediterranean fever can be misdiagnosed as having fibromyalgia, myofascial pain syndrome, or gouty arthritis. Genetic mutations can explain recurrent episodes of pain.

Table of Contents

What is familial Mediterranean fever (FMF)?

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

fever
pain in a joint (often different joints each episode)
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, auto-inflammatory 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, researchers find that FMF is a disease with a range of symptoms.

FMF symptoms sometimes show 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. MEFV encodes 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]

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 many 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]

On the other hand, some 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]

Long-term harm: For people 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.

Familial Mediterranean Fever is 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 makes 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 to cause 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 hydrarthrosis are more likely to carry MEFV mutations.[ref]

Trade-offs: the good part of the mutation?

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]

Familial Mediterranean Fever Genotype Report

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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 — or for i4000409 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 — or for i4000403 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 rs104895094 is — or for i4000407 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 — or for i4000406 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 — or for i4000410 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 rs28940579 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: Natural solutions for familial Mediterranean fever

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