Which are the causes of Familial Mediterranean Fever?

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation in various parts of the body. It primarily affects individuals of Mediterranean descent, including those of Sephardic Jewish, Armenian, Turkish, and Arab origin. FMF is caused by mutations in the MEFV gene, which encodes a protein called pyrin. This gene is responsible for regulating the body's inflammatory response, and mutations in it lead to an overactive immune system.

Genetic Mutations: The main cause of FMF is genetic mutations in the MEFV gene. These mutations are inherited in an autosomal recessive manner, meaning that an affected individual must inherit two copies of the mutated gene (one from each parent) to develop the condition. The MEFV gene mutations associated with FMF include M694V, V726A, M680I, and E148Q, among others. These mutations disrupt the normal functioning of pyrin, leading to increased inflammation and the characteristic symptoms of FMF.

Inflammatory Response: The MEFV gene mutations in FMF result in an abnormal inflammatory response. Pyrin normally helps regulate the production of a protein called interleukin-1 beta (IL-1β), which is involved in the body's immune response. In individuals with FMF, the mutated pyrin protein fails to properly control IL-1β production, leading to excessive inflammation. This uncontrolled inflammation causes the recurrent episodes of fever and other symptoms associated with FMF.

Triggers: While genetic mutations are the underlying cause of FMF, certain triggers can precipitate the onset of symptoms. These triggers vary among individuals but commonly include physical or emotional stress, infections, menstruation, and certain medications. It is important for individuals with FMF to identify their specific triggers and take appropriate measures to avoid or manage them, as this can help reduce the frequency and severity of FMF episodes.

Role of Neutrophils: Neutrophils are a type of white blood cell that play a crucial role in the body's immune response. In FMF, the mutated pyrin protein affects the function of neutrophils, leading to their increased activation and release of inflammatory substances. This abnormal neutrophil activity contributes to the inflammation seen in FMF and the associated symptoms.

Environmental Factors: While FMF is primarily a genetic disorder, certain environmental factors may influence its severity and presentation. Studies have suggested that factors such as diet, exposure to certain infections, and other external triggers may modulate the inflammatory response in individuals with FMF. However, more research is needed to fully understand the interplay between genetic and environmental factors in the development and progression of FMF.

Conclusion: Familial Mediterranean Fever is primarily caused by genetic mutations in the MEFV gene, leading to an abnormal inflammatory response. Triggers such as stress, infections, and medications can precipitate FMF episodes. The dysfunction of neutrophils and potential environmental factors also contribute to the development and severity of FMF. Understanding the causes of FMF is crucial for accurate diagnosis, appropriate management, and ongoing research to develop targeted therapies for this chronic autoinflammatory disorder.