Feb. 21, 2008 — -- Carolyn and Cheryl are sisters who have lived with a mortal secret for years. A genetic mutation hangs on their family tree like poison fruit.
It killed their grandfather and their uncle and, in 1999, revealed itself in their mom, Barbara.
"I can remember saying, 'Mom, what's wrong? Mom, why can't you speak?'" said Carolyn.
Barbara couldn't speak because she couldn't sleep — at all. Inside Barbara's brain, a genetic trip wire had been crossed, and in a matter of months, she went from being a vigorous 52-year-old woman to a woman in a coma, emerging only for a few days at the very end of her life.
"They took her intubation out, and she couldn't really talk, because she [was] so dry-throated, and everything," recalled Cheryl. "And she was trying to write. And she wrote 'FFI?'"
FFI is the abbreviation for an extremely rare genetic disease called fatal familial insomnia. Those affected by FFI are forever trying and failing to fall asleep. The disease steals one's sleep, mind and ultimately one's life, and, before dying, one hovers for months in a twilight world.
"And I said, 'That's what they think it is,'" said Cheryl. "She never wanted to talk about it. She never wanted to will it to happen."
"My first thought was how dare she keep this from me," said Carolyn. "I may not have had children if I'd known."
FFI affects approximately 40 families worldwide. Barbara didn't know it when she died, but the odds were 50-50 that she'd passed it on to her daughters.
"Whether I do or do not have this disease, it cannot define me. It cannot define me," said Carolyn.
"It's my story. I get to choose whether to laugh or cry about it. It's my choice. I'm going to laugh about it. It's my day. It's my life," said Cheryl.
Researchers believe a wealthy Italian doctor unknowingly carried the original genetic mutation for FFI, 250 years ago. We don't know his name, but experts simply refer to him as Patient Zero — the first known case of the disease. By the time he died in 1765, he had passed the disease on to his children, and the curse had begun.
In its early stages, family members experienced a kind of insomnia we'd all recognize, but those sleepless nights never ended.
"I'd say, within a month, it's pretty clear that you've got a disease like no other disease," said D.T. Max, who has spent years researching the phenomenon of FFI. His book "The Family That Couldn't Sleep" traces the history of the Italian clan who first carried this cruel disease (CLICK HERE to read an excerpt).
"One, you're not sleeping. Two, you're having difficulty walking. Three, your ability to focus has gone downhill rapidly," he said. "Ordinarily, [by] the ninth month, the disease ends with death."
Many of the afflicted Italian family members were brought to San Servolo — an island asylum just a short boat ride from Venice.
Now a museum, San Servolo remains a haunting place. "There would be howls. There would be people doing uncontrollable behavior. There would be attendants chasing after them," said Max, adding that part of the treatment was simply preventing family members from hurting one another. "Generation after generation of this family was strapped, in the later stages of the disease, to a bed at night."
Records show that, throughout the 18th, 19th and 20th centuries, deaths consistent with FFI ran through the generations of the Patient Zero family.
In the 1980s, a descendant of the family named Silvano suddenly began showing symptoms of the disease. A handsome, vibrant playboy, he had lived in the shadow of this potential killer all his life.
"Silvano, I think, in his heart, knew that he was going to get the disease, and one day, he woke up , and his pupils were as small as pinpricks, and he began to sweat," said Max. "And he decided that he would not die without the family learning something, some shred of evidence about what had been killing them for generation after generation."
Silvano and other family members were filmed at the University of Bologna's sleep clinic. On the tape, Silvano looks as if he's sleepwalking. But he was really in a permanent state of pre-sleep behavior. And often, you will see him and other patients making gestures, like combing their hair or washing their hands or handling objects.
According to Dr. Elio Lugaresi, director of the sleep clinic, Silvano and the others were unable to drop into a deep REM sleep, and sleep medications only accelerated their restless descent toward death.
"We gave intravenous doses of barbiturates [in an] attempt to help the patient sleep," said Lugaresi. "The result was that they went from this pre-sleep, nonsleep, to deep coma without ever passing to a sleep stage."
Just before his death, Silvano made a remarkable and selfless offer, bequething his brain to researchers, which finally opened a window into the mystery of FFI.
Microscopic views showed that healthy proteins misfolded, triggered by genetic mutations, creating what doctors call prions. These abnormal proteins build up in the brain, forming clumps that destroy nerve cells, eventually leaving spongelike holes in the brain. Mad cow disease is also a prion disease.
"In fatal familial insomnia, most of the damage, and where the prions are accumulating, seems to be in an area of the brain called the thalamus," explained Dr. Michael Geschwind, who studies FFI at the University of California at San Francisco.
"The accumulation of the prion in the brain leads to nerve cell injury, and eventually, to nerve cell death."
Geschwind said the thalamus is the region of the brain responsible for the regulation of sleep. For reasons still not fully understood, symptoms of FFI don't show up until midlife, after child-bearing years.
Each child has a 50-50 chance of receiving the killer gene, so the disease has been unwittingly passed through generations, which brings us back to sisters Carolyn and Cheryl.
Given the opportunity to take a simple blood test to determine if they had inherited the disease, Cheryl said no. "For me, I look at it as, I can go, and they can tell me that either I do have this or I don't have this, and I can die in a car accident on the way home. I may just as easily die from cancer, or ... anything," she said.
"We all have a terminal something. If we live long enough, we're going to die from something. That's the way it goes."
Carolyn, despite having one child already and being pregnant with a second, had originally decided not to get tested for FFI. "It was not a consideration, really," she said. "Should my mother never have been born, because this is the way she was going to die? That's insane. Should my uncle never have been born, because this is how he would die? That's ... that's crazy. They were both wonderful, intelligent, loving people."
But as Carolyn moved into the last months of her pregnancy, she had a change of heart and mind, revealed in a remarkable interview, taped by Max just weeks after she decided to take the blood test.
"What made you do the test — you've already had one child?" Max asked.
"It's hanging over me all the time. Some of things I might do differently, based on the result, like retirement. ... I don't want to be like my mom, working all her life, and I'd be more prepared for my daughter," she answered. Carolyn remembers well the day her blood test came back.
"I left work. I went to the office, and I waddled in," she recalled, laughing. "[I] took my envelope, went out to my car, took a deep breath and opened it up." The results were negative. Carolyn had not inherited FFI.
"It was a hallelujah moment!" she said, but Carolyn is still worried about her sister, who hasn't learned if she is also negative.
Research labs continue to explore prion diseases, with clinical trials now testing a drug called Quinicrine, which shows promise for treating FFI. The same research may also hold benefits for more common diseases, such as Alzheimer's and Parkinson's.
"Our hope is that some patients may actually do even better than having their life prolonged; that, maybe, in some patients, the Quinicrine will actually cure them," said Geschwind.
(Click here to find out more about Fatal Familial Insomnia or visit the National Institute of Health's page on prion diseases.)