What is familial Mediterranean fever? The genetic disorder causes painful inflammation

Baby Alexander cried so much - sometimes all night - that neighbors complained. As a toddler, he pointed to the pain in his stomach and also said his legs hurt. He ran high fevers. The symptoms recurred every two to three months and subsided after three days.

"I took him to the pediatrician and to the ER several times, and they said it was viral and give him Tylenol," said his mother, Elizabeth Marfazelian. "But they also told me they wanted to remove his appendix."

Around the time Alexander was 4 years old, Marfazelian was working as an inpatient gastroenterology nurse practitioner. There, she encountered a patient with similar symptoms as her son, whose condition was diagnosed.

The next time she went to the ER with Alexander, she insisted the doctor order a genetic test. On seeing the results, Marfazelian's supervisor referred her to a specialty clinic at UCLA Health.

The Familial Mediterranean Fever Program at UCLA is the only one in the Western Hemisphere dedicated to the autoinflammatory condition. Patients with undiagnosed FMF may periodically suffer for years from excruciating abdominal pain, fever and painful inflammation in other parts of the body such as the joints and the chest. Without treatment, there is a risk of developing amyloidosis, which can lead to kidney failure.

"Their attacks last for two to three days, and in between, they're completely well and go about their daily lives," said Dr. Terri Getzug, the program's director and a clinical professor of gastroenterology at the David Geffen School of Medicine at UCLA. "And this can happen again at variable intervals - once or twice a year or twice a week. In the meantime, they're getting colonoscopies and endoscopies and numerous CT scans and trials on different medicines and unnecessary surgeries."

FMF is an inherited condition that particularly affects those of Arab, Armenian, Jewish, Turkish and other ethnic backgrounds originating in the Mediterranean region.

"It's a rare disease, but in Los Angeles it doesn't seem so rare because we have many people from these populations at risk," said Dr. Wayne Grody, the program's co-director and a professor in the departments of pathology and laboratory medicine, pediatrics, and human genetics at the Geffen School of Medicine. "It's most prevalent, due to the high carrier rate, in people of Armenian descent. And we have more Armenians in Los Angeles than anywhere except Armenia itself."

Alexander's genetic test revealed he had characteristic FMF mutations. Marfazelian, her husband and her husband's parents are all carriers of the disease. Parents who are healthy but carriers of the mutation have a 25% chance of an affected child with each pregnancy.

When they mentioned the diagnosis to extended family members, they learned FMF was familiar enough to be known as "Armenian disease."

After a long and thorough consultation, Grody, an attending physician in the department of pediatrics, prescribed a daily pill of colchicine. Now 8 years old, Alexander's attacks have mostly stopped, except for breakthrough flares brought on by stress or rigorous physical activity.

"We were so lucky that my son was diagnosed at an early age," said Marfazelian. "There's no cure for this, so it's going to be lifelong for him. I know there's going to be a lot of stressors down the line that will flare him up: school, work, girlfriend, college. But hopefully, the medication will minimize those."

A unique clinic

Periodic fevers like FMF have been known since ancient times. In the second century, Greek physician Galen correlated different phases of the moon with cyclic fevers. And a herbal form of colchicine - derived from the dried seeds of the autumn crocus plant - was used since the 11th century for gout and joint pain. As to why it arose, it's been theorized that FMF gave populations increased resistance to deadly bubonic plague.

The most common of the periodic fevers was officially termed "familial Mediterranean fever" in 1958. Only a few years later, gastroenterologists Dr. Arthur D. Schwabe and Dr. Sherman Mellinkoff established the FMF program at UCLA Health, spurred by the frequency of patients in the ER. Their research contributed to using colchicine as a treatment in 1972.

But it was not until 1997 that the genetic drivers of the disease were uncovered. The MEFV gene on chromosome 16 codes for the protein pyrin, which is involved in an inflammatory pathway. This is usually activated when the body encounters an infection, such as a bacteria or virus.

"But when the MEFV gene is mutated, it allows the inflammatory reaction to start spontaneously without an infection," said Grody, founding director of the UCLA Molecular Diagnostics Laboratories. "The neutrophils, a type of white blood cell, start multiplying and releasing cytokines. You can get a cytokine storm where the body itself is causing a lot of pain and misery. We don't actually know why those white blood cells start this and why it's on a cycle."

Grody joined the program 25 years ago after seeing calls for a medical geneticist in the clinic. But he soon learned that DNA testing is not essential for diagnosis. Instead, he and Getzug find the clues to diagnosis in a detailed patient history, the method used since the program's founding.

When Schwabe invited Getzug to the FMF clinic during her internship 40 years ago, the experience left a lasting impression on her.

"I remember Dr. Schwabe would have the children stand up on the table, and they would be having their FMF symptoms and growth retardation," Getzug said. "And just by taking a history from the parents, without any technology, he would make the diagnosis, put them on colchicine, and their lives were changed."

She has preserved that model in the diagnosis and treatment clinic held every third Thursday of the month, in which each patient's appointment includes not just meeting with the program's directors but medical students, residents and fellows from different backgrounds in medicine.

"I have the trainees present the patient," said Getzug, "and all together we discuss what's going on, involving the patient in the discussion. They really feel heard and taken seriously. And for a lot of them, that's never happened."

At a recent Thursday clinic in a small and brightly lit conference room, each patient sat with staff to discuss symptoms.

The first patient described attacks that came "out of the clear blue" four times a year. The next patient had lost her appetite and a significant amount of weight. The third one was diagnosed last year and prescribed colchicine but never started the medication, anxious about using it for life. "It's like taking a vitamin," assured Getzug.

These diverse experiences will be compiled into a digital registry of more than 700 patients, reflecting the largest rare-disease cohort in North America.

"The other arm of it is a biobank of blood samples to do some basic research and understand why some patients present in infancy, some not till adulthood - why some respond to colchicine and some don't," said Grody.

Another treatment

Also providing reassurance to the patient anxious about medication was Nazeli Khodaverdyan, 22, a volunteer in the clinic and fourth-year UCLA student who relied on colchicine for years until it was no longer effective in preventing attacks. About 15-20% of those with FMF do not respond to colchicine.

Though her dosage was increased over the years, Khodaverdyan would get debilitating flare-ups a few times a month, especially when she was stressed.

At age 15, wrenching pain landed her in the hospital in the middle of the night. A rheumatologist switched her from colchicine to canakinumab, an immunosuppressant which is injected into her thigh every four weeks. In the seven years since she began the treatment, she has only had two moderate flare-ups.

"I came to terms with it when I was young," she said. "There was a lot of anger, a lot of sadness, a lot of depression, but also a lot of humor. Might as well make the best of it, and that's what I'm doing now."

That a single medication is available to relieve patients' symptoms is rare among genetic diseases.

"So many of our diseases have no treatment, and they're devastating for newborns or later in life," said Grody, speaking of the myriad conditions he sees as a geneticist. "It's so rewarding to actually have a disease that's treatable with an inexpensive medicine and really changes people's lives."

Tags: health | genetics | race and ethnicity | research