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Fire in the Genes

In ancient times, a genetic mutation helped ensure Jewish survival. Today, it might be making you sick.

Michele Cohen Marill
April 23, 2019
Original photo: Library of Congress
Original photo: Library of Congress
Original photo: Library of Congress
Original photo: Library of Congress

As a genetic counselor, Beth guides people through pre-pregnancy screening for dozens of diseases, so she knows the hidden dangers that can lurk in your DNA. (She also knows the importance of maintaining privacy around genetic testing, which is why she asked to use a pseudonym.) Still, when she took her own genetic test before her third pregnancy—the test having recently been updated to include new disease markers—she was stunned by the result: She and her husband each carry a recessive mutation for familial Mediterranean fever, an obscure disease with Jewish genetic roots.

In the United States, people who tell their doctors about sudden bouts of fever, abdominal pain, and inflammation—what feels like periodic episodes of food poisoning—are often misdiagnosed as having kidney stones, appendicitis, lupus, fibromyalgia, irritable bowel syndrome, or even malingering. In Israel, doctors more often get the diagnosis correct, because it’s more prevalent. Familial Mediterranean fever mutations have been detected in about 1 in 10 Americans of Jewish ancestry; in Israel the frequency is about 1 in five. (Generally, you have to inherit mutations from both parents to develop the disease, although in up to a quarter of FMF cases, symptoms occur even with just one known inherited mutation. That makes FMF more complicated than the typical recessive genetic disease.)

After she had her third child, Beth tested her older children and discovered that her middle son inherited the FMF mutation from both her and her husband. He hasn’t developed the disease, but she keeps the information in his medical file in case symptoms emerge. In most cases, the first episodes begin in childhood, but sometimes FMF symptoms don’t appear until adulthood. “It’s not the common way of getting the diagnosis,” she said. “It’s very, very misdiagnosed and undiagnosed.”

People concerned about FMF previously could ask a physician to order a test from a private lab or could learn about it from Jewish genetic screening tests geared toward parents-to-be. But in December 2018, 23andMe began providing “carrier status” reports revealing whether customers have one of seven variants, or changes, in the MEFV gene linked to FMF, so every customer of the 23andMe Health + Ancestry product will get an FMF carrier status report. And now this ancient and little-known disease is emerging into the broader Jewish American consciousness.


Familial Mediterranean fever has an evocative name and a history to match it. Researchers have surmised from studying genetic patterns that the “founder,” the first person to develop the mutation, lived about 3,000 years ago in Mesopotamia, the cradle of civilization. Other mutations, stemming from other founders, similarly date back more than 2,500 years ago. Today, FMF is found predominantly among Jews and Arabs, Turks and Armenians—populations in historic conflict who are genetic cousins.

Like a biological parallel of the oft-told story of the Jewish people, the mutation of the MEFV gene brought pain and suffering but ultimately helped ensure survival. Pyrin, a protein named for the Greek word for fire, triggers inflammation and fever as part of the body’s first immune defense from outside invaders, such as viruses and bacteria. FMF mutations cause pyrin to be overactive.

The Black Plague, one of the most feared diseases of ancient times, brought waves of death in the Mediterranean—spreading, as we now know, from Yersinia pestis, a strain of bacteria that suppresses pyrin. People with an FMF mutation had an edge in fighting infection, even if they had no FMF symptoms, said Dan Kastner, acting clinical director of the National Human Genome Research Institute.

Rheumatologist Eldad Ben-Chetrit, director of the FMF Clinic at Hadassah University Hospital in Jerusalem, spent his career studying FMF, and he has some educated hunches about the path it traveled from its founders. Bartholomew, one of the first apostles of Jesus, is thought to have brought Christianity to Armenia. Could he and his compatriots have seeded FMF mutations there? The mutations could then have spread into the Ottoman Empire and modern-day Turkey.

Sometimes FMF pops up in unexpected places, but even then, historic events hover in the background. Some years ago, Ben-Chetrit traveled to Palma de Mallorca, a city on a Spanish island, to study 60 FMF cases among 18 families. He discovered that they were “chuetas,” descendants of Jews who had converted to Christianity, at least publicly, to save themselves from the Inquisition, and were expelled from Spain. Similarly, Jews expelled from Spain settled in North Africa, another focal point for FMF.

Yet until the mid-20th century, no one even knew that the recurrent symptoms belonged to a disease that could be passed through generations. Maimonides, known as Rambam, was a physician as well as a Torah scholar in the Middle Ages. He wrote a book of diseases, but none of them resemble FMF. Likewise, no one in the Bible had a disease that sounds like FMF.

“In biblical time, if you got sick, people just thought this was punishment from God,” said Avi Livneh, former director of the FMF Clinic at Sheba Medical Center, Tel HaShomer in Tel Aviv, which has a registry of about 10,000 Israelis with FMF.

FMF symptoms are especially confusing because they come and go, usually disappearing within 12 to 72 hours. For some people, the episodes are sporadic, perhaps triggered by stress. Others get them frequently and regularly—several times a year or every few weeks. The exact MEFV mutation makes a difference; some are associated with severe disease, while others produce mild symptoms or none at all.

The first medical report came as “an unsolved diagnostic problem” in 1908, a case study detailing the plight of a 16-year-old Jewish girl with weekly bouts of fever and abdominal pain. In 1945, New York allergist Sheppard Siegal described five patients with what he called “benign paroxysmal peritonitis.”

Finally, in 1955, Harry Heller, a physician and researcher at Tel HaShomer Hospital in Tel Aviv (now Sheba Medical Center), gave it an enduring name: familial Mediterranean fever. The diagnostic features—primarily, short attacks of fever and painful inflammation in the abdomen, joints, or chest that occur at least three times—came to be known as the Tel HaShomer criteria. (Responding to FMF treatment, or FMF symptoms in a close family member, are also indicators. It’s possible to have attacks of fever alone.)

Still, the medical mystery wasn’t completely solved. Almost 20 years later, a young woman came to see gastroenterologist and internist Stephen Goldfinger at Massachusetts General Hospital in Boston. She was almost suicidal over her frequent attacks of pain and fever. Doctors didn’t have much to offer, but Goldfinger recalled a colleague who had given colchicine to a patient with gout and FMF. The gout treatment worked on the FMF, too.

Colchicine has been the primary treatment for FMF ever since. It is a medicine derived from the autumn crocus, a remedy for swelling that dates back to ancient Egypt. FMF is rarely life-threatening, but the treatment prevents the worst possible outcome: buildup of abnormal protein in the abdomen, leading to kidney failure.

In 1997, two research teams—one American and one French, both working with the Israeli researchers—raced to find the gene for FMF. Their findings, published within a week of each other, helped unlock not just FMF but the workings of the innate immune system.

“The reason animals have evolved an inflammatory process is to protect against organisms prevalent in our world,” said Kastner, leader of the American team that discovered MEFV. “If you didn’t have these processes, your body would be invaded by bacteria or viruses.”

But when your innate immune system is overactive, as with FMF, inflammation and fever impair instead of protect.


Rachel (also a pseudonym) has been sick, on and off, for about 15 years. “Kidney stones,” a doctor told her when she complained of intense abdominal pain. She strained her urine, day after day for months, but never caught a stone.

Her knee swelled up and an MRI indicated a problem with a ligament. Surgeons were startled to discover nothing wrong with her ligament. They simply stitched her back up.

She complained of frequent fever and intense fatigue. But that resulted in vague, catchall diagnoses. She had chronic fatigue syndrome. She had chronic, recurring mononucleosis. She had unspecified allergies. She had psychosomatic illness.

Rachel learned to navigate the stormy times by slowing down and reducing her stress. Then, at age 42, she decided to pursue single motherhood. The sperm donor she selected was from Greece, and a DNA test showed he was a carrier of FMF.

No problem, she thought. She wasn’t from the Mediterranean. But when she had the genetic testing suggested by her doctor, she was shocked to discover that she also had an FMF mutation. “Here I am trying to conceive, and all of the sudden this reality opens up,” she said.

Most people with FMF symptoms have inherited two mutations; she has only one. FMF is thought to be more common in Sephardic or Mizrahi (Middle Eastern) Jews, but she is Ashkenazi with ancestors from Poland and Hungary. Complicating matters, she may have acquired an additional chronic inflammatory condition along with her FMF.

“It’s a complex disease,” said rheumatologist Jonathan Hausmann, who runs autoinflammatory clinics at Beth Israel Deaconess and Boston Children’s Hospital. “It’s important to look at the mutation in the context of a person and their symptoms and their life.”


It has become easier to find out if you have an FMF mutation, but not necessarily to get the context.

Last December, 23andMe began reporting on seven variants, or mutations, of FMF. Hundreds of mutations have been detected, but 23andMe selected the ones most commonly associated with the disease. 23andMe reports if people carry one or two variants, but it is careful to emphasize that the test is not diagnostic. It encourages customers to seek medical advice if they think they might have the disease. “We do know that it’s a condition that’s underrecognized,” said Altovise Ewing, medical science liaison. “We’re doing all we can to help equip our customers with the information that hopefully will be powerful and help people arrive at a diagnosis sooner or be aware of their carrier status and risk to family members.”

If a 23andMe screen fails to show an FMF variant, you could still be a carrier. That’s because 23andMe only looks at “hot spots” on the MEFV gene and doesn’t do whole gene sequencing, said Estie Rose, a genetic counselor with JScreen, a national nonprofit carrier-screening program that seeks to prevent Jewish genetic diseases. JScreen provides more comprehensive testing than 23andMe, screening for more than 200 genetic diseases, including FMF.

The disease is actually diagnosed from the symptoms, not from genetic testing. And the name can be misleading. Some people with FMF have no family connection to the Mediterranean or Middle East.

When Janine Jagger, an epidemiologist at the University of Virginia in Charlottesville, was diagnosed with FMF, she traced her ancestors back to the Puritans. She wonders if her forebears brought the mutation from the British Isles, or if someone in her family line picked it up on sea travel in some murky dalliance. Genomic sequencing eventually detected a mutation near, but not on, the MEFV gene.

She founded the Familial Mediterranean Fever Foundation to support patients as they seek their own answers, both medical and ancestral. “Patients want to know everything,” said Jagger, “and they’ll decide what to make of the information.”


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Michele Cohen Marill is a health and medical writer based in Atlanta.