Korea confirms 1st MEFV mutation case, opening door to better diagnosis of rare fever syndrome

“Recurrent fever symptoms are commonly referred to as hereditary recurrent fever syndromes, with the most well-known being familial Mediterranean fever (FMF). Other examples include cryopyrin-associated periodic syndrome (CAPS) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), among others. These conditions have relatively well-understood causative genes and mechanisms of onset.”

Hereditary recurrent fever syndromes (HRFS) are autoimmune inflammatory disorders characterized by recurrent episodes of high fever, abdominal pain, joint pain, and rash. FMF, CAPS, and TRAPS fall under this category. They are generally believed to be caused by genetic mutations that lead to excessive production of IL-1β, an inflammatory substance, by the immune system.

FMF is characterized by periodic fever and abdominal pain. While it is commonly found in the Middle East with a high prevalence rate, recent cases have been confirmed in two adult males in Korea. Notably, in this case, the mutation of the causative gene (MEFV: Mediterranean Fever gene) was identified for the first time in Korea through whole-genome sequencing (WGS), drawing significant attention.

In this regard, Korea Biomedical Review interviewed Professor Lee Eun-young of the Department of Rheumatology at Seoul National University Hospital to discuss the importance of improving early diagnosis for patients with rare diseases in Korea who face challenges due to diagnostic delays.

Question: What are the characteristics of FMF, a type of hereditary recurrent fever syndrome (HRFS)?

Answer: FMF is caused by mutations in the MEFV gene, leading to improper functioning of pyrin, an inflammation-regulating protein, resulting in periodic fever, abdominal pain, chest pain, and joint pain. It is inherited in an autosomal recessive manner and was previously known to be common in regions near the Mediterranean Sea; however, recent cases have also been reported in Korea.

Q: What is the significance of this case, where pathogenic MEFV gene mutations were identified in Korea for the first time?

A: Until now, there was a limitation in Korea where FMF was clinically suspected but lacked genetic evidence. However, in these two cases, pathogenic MEFV gene mutations were identified for the first time in Korea through whole-genome sequencing (WGS).

Both patients experienced fever symptoms from their teens, but the diagnosis was not made until their 30s and 40s. Considering the reality of delayed diagnosis, this case highlights the urgent need for a gene-based diagnostic system.

Q: How were the genetic mutations in the two patients identified?

A: Even if we discovered a new genetic mutation among countless others, it was impossible to determine whether it was actually associated with the disease. However, functional studies on such mutations are gradually progressing.

Furthermore, if we understand the cause of the disease and the underlying genetic mutation, we can develop targeted drugs based on that knowledge. Fortunately, when FMF was diagnosed, a new treatment modality was just being introduced, which made the diagnosis even more meaningful. Since then, the Department of Clinical Genetics at this hospital has been actively conducting genetic-based diagnosis and research.

Q: We understand that FMF is usually diagnosed in children, but this case was diagnosed in an adult.

A: One of the two cases was a patient who was initially diagnosed with adult-onset Still's disease. However, upon closer examination, the symptoms differed from those typically associated with Still's disease. In particular, the pattern of fever was different, and similar symptoms were observed in other family members of the patient. This was the case that led to genetic testing.

Another patient had a history of fever since the age of 13, and at the time of the hospital visit, the patient was in his 40s. The patient said he had lived, thinking, “This is just how I am,” and had not considered visiting the hospital again because the fever recurred, but there were no other organ abnormalities or issues.

So, when he came to the hospital, I asked, "There must have been a reason why you came to the hospital. Did you feel that the condition was worsening?" The patient responded that the intervals between fever episodes were becoming shorter, and the peak body temperature seemed to be rising. Additionally, the patient mentioned that he was considering marriage and having children, and wanted to investigate whether there might be any genetic issues. These combined reasons led him to return to the hospital.

While I was reporting two cases to the Korean authorities, there was also a patient from Egypt. That patient was brought in by a Korean friend. The patient reported periodic fever. The patient also mentioned that his brother had the same symptoms, and upon reviewing the medical history, many symptoms were strongly consistent with FMF. We immediately conducted a genetic test, which confirmed that the patient also had the same genetic mutation. In the end, these three cases were unique instances that happened to come to my attention within a year.

Q: If the fever is periodic, it must be quite difficult for patients in their daily lives. What are the actual symptoms?

A: Fever typically begins suddenly and lasts between 12 hours and 72 hours. Patients experience prodromal symptoms, including abdominal pain and muscle aches, and some may feel a sense of impending fever. When the fever rises, daily activities become difficult, and while fever-reducing medications may provide temporary relief, they do not address the underlying issue. This condition significantly impacts the patient's quality of life.

Q: Why does it take so long to diagnose this disease?

A: First, it is a rare disease. Many medical professionals are unfamiliar with FMF. Second, its symptoms are very similar to those of infectious diseases. When fever recurs, infections, tumors, or immune disorders are often suspected first.

FMF is often confused with adult-onset Still's disease, which also presents with unexplained fever as a primary symptom. The problem is that without genetic testing, it is difficult to confirm the diagnosis. In Korea, FMF diagnosis requires confirmation of the MEFV mutation to be covered by insurance, which limits access to diagnosis.

Q: We heard that one of the cases identified this time did not respond to colchicine treatment. What is the treatment strategy in such cases?

A: Colchicine is the first-line treatment for FMF and is effective in most patients. However, some patients do not respond or cannot tolerate it due to side effects. In such cases, IL-1 inhibitors are considered a viable option. A representative example is canakinumab (brand name: Ilaris), which has been covered by insurance in Korea since last year. One patient whose fever remained uncontrolled despite colchicine eventually used an IL-1 inhibitor, and a clear response was observed after administration. This also has significant diagnostic value.

Q: Despite reimbursement, we hear that the use of IL-1 inhibitors is still limited in Korea. What are the institutional limitations?

A: There is a significant difference compared to Japan. In Japan, IL-1 inhibitors can be used even if a genetic mutation is not confirmed, as long as FMF is clinically suspected. However, in Korea, reimbursement is only possible if an MEFV gene mutation is confirmed.

Even if patients desperately want treatment, if the mutation is not confirmed, the prescription itself is impossible. Recently, the Korean College of Rheumatology established a society for the study of extremely rare adult diseases to expand genetic diagnosis and identify undiagnosed cases; however, institutional barriers remain high.

Q: Given the importance of genetic testing for insurance coverage, is the infrastructure for genetic testing well established?

A: The cost of genetic testing ranges from 1 million won ($720) to 1.2 million won when paid out-of-pocket. Currently, testing is possible through programs supported by pharmaceutical companies or research institutions, but it is uncertain how long these programs will continue.

Additionally, genetic testing is not just about the test. It requires the ability to interpret the results and understand their implications. Moreover, not just any test will suffice. The test must be tailored to the specific purpose to yield meaningful results.

Q: What do you think are the complementary measures needed to improve the diagnosis and treatment environment for FMF in the future?

A: Due to the nature of ultra-rare diseases, N-of-1 trials (treatment attempts on a single patient) are important. However, the current reimbursement criteria are too rigid, and even researcher-initiated clinical trials are often difficult to conduct. Treatment approaches based on the judgment and expertise of physicians should be made possible, and there is a need to shift to a peer-reviewed review system. The system's flexibility is crucial for patients with rare diseases.

Q: Do you have a message you would like to convey to medical professionals and patients?

A: When recurrent fever occurs, it should not be dismissed as a simple infection, but rather viewed with suspicion.

In particular, if fever occurs periodically and other causes, such as infection or tumors, are ruled out, the possibility of hereditary recurrent fever syndrome should be considered. Genetic testing is not as difficult to access as one might think, and a diagnosis can be a decisive clue that changes a patient's life. I hope that patients will have more options available to them in terms of both diagnosis and treatment.