Familial Mediterranean Fever: Do you carry the genetic variants?

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.

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 for the mutations and other times not affecting those who are homozygous (2 copies of the mutation).

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 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.

Is it misdiagnosed?
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 diagnosis of other conditions such as fibromyalgia or arthritis with familial Mediterranean fever. Turns out there are studies showing an 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 COMT polymorphism (rs4680, AA) may combine with the heterozygous FMF mutation in causing fibromyalgia-like symptoms.
• In a study of ‘asymptomatic’ parents of children with FMF, many were found to have diagnoses of rheumatoid arthritis, rheumatic fever, and arthralgia.
• In a study on gouty arthritis, 38% were found to carry a MEFV variant that can cause familial Mediterranean fever.
• A study of lupus patients found that those carrying MEFV variants had an earlier onset of disease, more episodes of fever and pleurisy.
• 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.”

Genetic Variants:
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, but there are other mutations that aren’t covered by 23andMe.

MEFV Variant	23andMe # or rs ID	Risk Allele
A744S	i4000409	A
E148Q	rs3743930	G
F479L	i4000403	C
K695R	i4000407	C
M680I	rs28940580	G
M694I	rs28940578	T
M694V	i4000406	C
P369S	rs11466023	A
R761H	i4000410	T
V726A	rs28940579	G

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

Diet and Supplements:
There were several studies and trials of ImmunoGard, a herbal-based supplement for familial Mediterranean fever.  I don’t find it sold anywhere online, though, so I’m not sure what happened to it.  The ingredients 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.

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.

Due to the increase in IL-1B, natural inhibitors of IL-1B such as quercetin or genistein may help.  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.)

More to read:

• Interleukin-1 in the pathogenesis and treatment of inflammatory diseases
• Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management
• Diet Affects Autoinflammatory Disease Via Gut Microbes