FMF, formerly known as Familial Mediterranean Fever, is one of the rarest inherited diseases to have spread throughout the Mediterranean area, specifically in the Middle East. It is an autoinflammatory genetic disorder that directly attacks the innate immune system by inhibiting any means for the immune system to protect itself. FMF is caused by a mutation in the gene MEFV, which codes for the protein pyrin. Pyrin plays a significant role in regulating inflammation, specifically by leading the migration of white blood cells to the sites of inflammation when needed and helping the immune system fight against disease. However, it took almost 1,000 years to track the cause of this disease. In 1997, an experiment was conducted using positional cloning, a method used by scientists to identify the locus of a disease-causing gene on a chromosome. Through positional cloning, scientists were able to identify that this mutation on the MEFV gene was located on chromosome 16.
This is a solely hereditary disease, meaning that it is not infectious and cannot be "caught" simply from being around someone who has FMF. Upon delving deeper into the hereditary aspect of this disease, we discover that a child who has FMF can inherit the mutated gene from either one or both parents. However, they only need to receive the mutated gene from one parent to have Familial Mediterranean Fever, as it is an autosomal recessive disease. Therefore, an individual who undergoes testing for this disease and receives a positive diagnosis for FMF can expect it to be passed down through generations of their family. Although FMF may sound like a frightening disease, it is easily treatable. If an individual with this disease identifies it during childhood and takes the initiative to receive proper treatment, they can usually lead a relatively normal life.
The main clinical symptom of Familial Mediterranean Fever is reflected in the name of the disease itself: recurring episodes of fevers. These fevers begin very early in childhood and can last anywhere from 4 to 6 hours. Usually, these attacks are accompanied by a rash and fever. Patients describe their fever attacks as causing severe abdominal, joint, and lung pain. While these fevers usually subside on their own, the recurring nature of the disease can negatively affect the growth pattern of those who have it, especially younger patients such as children. Without treatment to prevent these attacks, the disease can lead to serious and permanent kidney damage, possibly resulting in kidney failure. Some extremely rare complications caused by FMF include inflammation of the heart and the membrane surrounding the brain and spinal cord, which can be just as dangerous as kidney failure.
The diagnosis for this disease is confirmed through testing to determine whether or not there is a mutation on the MEFV gene. The usual treatment offered to patients suffering from this disease is Colchicine, classified as an anti-gout agent. Colchicine works by halting the natural processes within our bodies that cause inflammatory responses. Patients are prescribed Colchicine to take once or twice a day orally for their entire lives to control the fever attacks caused by FMF. As mentioned earlier, individuals who adhere to this treatment regimen can lead long and normal lives.
The gene associated with Familial Mediterranean Fever is MEFV, whose locus is located on the short arm of chromosome 16. MEFV is responsible for coding the protein pyrin, which controls our white blood cells and plays a significant role in our immune system and inflammatory responses. Pyrin is often at the forefront of our body's response to pathogen infections or anything that might disrupt our immune systems. Some consider it similar to the "guard" mechanism in plants. By controlling our white blood cells, pyrin can initiate an immune response to pathogens, as these white blood cells release chemicals that can break down the source of infection.
Auto Inflammatory response to mutation in MEFV gene commonly found in FMF (Source)
FMF is caused by a mutation in the MEFV gene. There are believed to be over a hundred different mutations on the MEFV gene that can cause FMF, as all these mutations relate to the function of pyrin and its inhibition. These mutations typically occur in exons 2, 3, 5, and 10. Due to the inconclusive nature of this disease, despite its official categorization as an autosomal recessive disease, there have been instances of FMF appearing in an autosomal dominant pattern. The M694V deletion mutation has been the most common MEFV mutation found in the analysis of families exhibiting a dominant pattern of inheritance. Given its prevalence in the MENA region, the carrier rate of the MEFV gene in certain areas has been found to be as high as 1 in 3, making it a common occurrence in some Mediterranean regions.
Due to the mutation in the MEFV gene discussed earlier, pyrin is not properly coded and is not fully functional. This mutation in MEFV reduces the activity of pyrin and leads to a prolonged inflammatory response, as the protein's ability to signal the immune system is significantly diminished. In a normal MEFV gene, pyrin is coded and forms the pyrin inflammasome complex, which secretes pro-inflammatory cytokines to protect the immune system by promoting the production of immune cells. However, due to the reduced activity of pyrin in patients with FMF, there is a delay in the release of pro-inflammatory cytokines, leaving their immune systems highly vulnerable. The improper inflammatory responses caused by the lack of pyrin are what induce the painful fevers and abdominal pains often observed in those diagnosed with FMF.
In conclusion, I strongly believe that there are thousands of different possibilities that can still be explored regarding the origins of this disease and its unlikely appearance. Although there is not as much research being conducted on FMF today, many different researchers have proposed their own ideas for the causes of this disease. For example, the hypothesis that Yersinia Pestis, the zoonotic bacterium responsible for the Black Death in the 1800s, is responsible for the origins of FMF and its counteractive properties to pyrin. However, I believe that with more direct analysis of patients currently suffering from this disease and their family ancestry, we can uncover more about the properties of pyrin itself and its active role in the immune system.
My name is Alicia Boubrit and through many resources made available to me by Elio Academy, I was able to conduct research on the fascinating Familial Mediterranean Fever, better known as FMF. I had never conducted any type of biological research in my life before working with Elio Academy, Elio Academy took my knowledge on all things medical or biological and extended it to apply my understanding to the real world. I was fully immersed in this program, even across the sea in Algeria, and my fellow peers on the topics we were learning and how those topics were pillars of modern medicine. I was able to work with a mentor that helped guide me into paths of medicine that I could pursue further into the future. I am so grateful for the opportunity granted to me by Elio Academy, especially the hard work that was put into helping me reach my full potential.
The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.