Familial Mediterranean Fever (FMF): causes, symptoms, diagnosis, treatment

By Cristiano Antonino On May 18, 2023

Familial Mediterranean fever (FMF) is a rare autoinflammatory disease that is genetically transmitted and manifests itself with recurrent episodes of fever and inflammation

Familial Mediterranean fever (FMF) is a genetically transmitted disease

It belongs to the group of autoinflammatory diseases that are rare diseases characterised by recurrent episodes of fever and inflammation.

This disease is most common in populations of the Mediterranean basin such as Italians (especially South Italy and islands), Turks, Arabs, Jews, Armenians.

Familial Mediterranean fever is caused by alterations (called mutations) in a gene called MEFV, located on chromosome number 16.

The gene contains the information necessary for the production of a protein called pyrin or marenostrin, which is one of the factors involved in controlling inflammation.

When the gene is mutated the protein produced is altered, inflammation is out of control and the disease results.

Familial Mediterranean fever is transmitted as an autosomal recessive trait

This means that in order to be sick, patients must have inherited both mutated MEFV genes: both the one inherited with the maternal chromosome 16 and the one inherited with the paternal chromosome 16.

This also means that both parents are carriers of the disease.

Sometimes, individuals such as the parents of children with familial Mediterranean fever, who have a mutation in only one copy of the gene (so-called heterozygotes), may also present with symptoms and need treatment.

Familial Mediterranean fever usually occurs before the age of 10

It is characterised by recurrent febrile episodes that occur with variable frequency, start rapidly and last 1-2 days.

In 95% of cases, along with fever, there are symptoms such as vomiting and diarrhoea, but above all abdominal pain, which can sometimes be so intense as to resemble appendicitis or another surgical condition.

Affected patients may also present with chest pain, testicular pain or swelling, a skin change (called erysipelas-like rash), and joint pain or swelling.

The joint swelling usually affects a single joint (usually knee or ankle) that may be so swollen that it is impossible to walk properly.

In some patients there is a reddish skin reaction on the affected joint.

Disease attacks can start spontaneously or be triggered by certain factors such as both physical and psychological stress, the menstrual cycle and an irregular lifestyle.

The disease is diagnosed on the basis of the patient’s history and medical examination

If performed during fever, blood tests show a sharp increase in values indicating inflammation (white blood cells, ESR, CRP, serum amyloid A).

If, however, they are performed when there are no acute symptoms, the indices of inflammation may be slightly altered or completely normal.

The diagnosis is confirmed by molecular analysis of the MEFV gene.

This genetic analysis is performed at specialised genetic laboratories and is therefore not available at all laboratories.

It is important that the result of the genetic test is interpreted by doctors with experience in this field, because not all mutations found in the gene cause disease.

There are in fact some mutations, so-called polymorphisms, that are considered harmless, i.e. they do not cause any problems and are also found in healthy people.

Individuals carrying these polymorphisms, (even if present in duplicate) are to be considered healthy and not sick.

If the genetic analysis is interpreted incorrectly, there is a risk of considering subjects who in reality are not ill.

Most patients respond well to Colchicine, a drug extracted from a plant, which is taken by mouth.

The effectiveness of the therapy is manifested by the complete disappearance of fever and other associated symptoms.

In a small percentage of patients, Colchicine is not effective

In these cases, biological drugs directed against a molecule (called interleukin-1) are used.

Interleukin-1 is overproduced by the immune system due to a mutation in the MEFV gene and is the cause of the inflammation in this disease.

The drug is called Canakinumab. The therapy, whatever it is, must be taken for life. If the therapy is discontinued, the symptoms return.

If the therapy is taken correctly and above all regularly, patients will not develop any complications and will have an excellent quality of life without any limitations.

If, on the other hand, the disease is not diagnosed or the therapy is not taken correctly, patients with Familial Mediterranean Fever are at risk of developing a serious complication called amyloidosis, i.e. an accumulation of amyloid substance – a build-up of protein in the form of fibres or fibrils – in various organs and tissues that can damage the functions of various organs (especially the kidney).

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