An old disease
Parents race with time as sons age prematurely.
NATHAN Falcone is seven, a sweetheart of a boy with a shy smile and a crush on Taylor Swift. He also has age spots and trouble navigating steps. He takes drugs designed to manage osteoporosis and ward off heart attack and stroke.
Climbing the stairs of the yellow bus that takes him to first grade at Enfield Elementary, Nathan moves with the hesitance of a much older person.
Nathan and his three-year-old brother, Bennett, are tiny for their ages. Their hair is thinning, their veins prominent, their fingers clubbed. Nathan weighs 31 pounds. Bennett has six baby teeth.
While many other boys his age are playing T-ball and bounding around with the energy of puppies, Nathan struggles to get up from a low chair – his skinny legs stiff, his arms struggling to bear the weight of his tiny body. He’s hesitant to climb steep steps. The brothers have mandibuloacral dysplasia (MAD), a genetic disease so rare that they are the only people in the United States – and just the sixth and seventh people in the world – to be diagnosed.
MAD is a form of progeria, the fatal premature-ageing disease. For children with classic progeria, the average life span is 13, but because the Falcone boys’ condition is so rare, no one can say how long they might live.
Although their disease is incredibly uncommon, studying it has wider implications, informing us about how normal ageing and cardiovascular disease work.
Progeria research is advancing quickly. Fourteen years ago, the medical community knew almost nothing about the disease; last month, scientists announced that the first experimental drug to treat progeria has shown promising results, and another trial is under way.
But Phyllis and Mark Falcone feel as if they’re racing against the clock as their sons’ hair falls out and their bodies become less flexible.
“We just want them to get big, to gain weight, to get strong,” said Phyllis Falcone. “But they’re not getting better.” Her voice trembles.
“How can you accept something this hard when the worst is still to come?”
Francis Collins grew interested in progeria 30 years ago, when the young Yale postdoctoral fellow met a young woman with MAD.
“It was frustrating because – while you could see that, in this disorder, the body was ageing at an increased rate, with lots of challenges in terms of what it was doing to the bones, to the cardiovascular system – we knew almost nothing about it,” said Collins, now the director of the National Institutes of Health. “The disease was so rare that almost nobody had done much research on the conditions that fit under this genome description at all.”
At the time, Collins remembers thinking: “Wow, somebody ought to work on this.”
Two decades later, he met Scott Berns and Leslie Gordon, physician-scientists and a married couple whose son, Sam, was diagnosed with progeria in 1998. They were told to take Sam home and enjoy him – nothing could be done.
Berns and Gordon refused to accept that answer. They knew their son’s condition was fatal, but what if they could slow it? Even cure it?
So Berns and Gordon established the Progeria Research Foundation. They began a cell and tissue bank. They raised money, awarded research grants. They held scientific meetings.
In 2003, the foundation and the National Institutes of Health made public the cause of progeria – a mutation in the LMNA gene.
That single genetic misspelling causes those with progeria to produce significant amounts of progerin, a protein that is toxic to their own cells. Everyone makes progerin, especially as cells age, but healthy cells can wipe it out.
Many labs, including Collins’ own, are now examining progerin’s role in normal aging, and recent research hints that aging isn’t what people long assumed.
“It’s not just a running down of the system,” Collins said in an interview. “There’s actually an active programme to tell cells, ‘Hey, it’s time to head for the exits.’”
Using that information to help people achieve healthy ageing is still a task for the future, Collins said, but for now, progeria has provided “a new view of the ageing process”.
Last month, Gordon, who serves as medical director of the Progeria Research Foundation, announced the results of the first clinical trial for children with progeria. It showed that lonafarnib, a farnesyltransferase inhibitor (FTI) designed to treat cancer, can slow the disease’s progress.
Over two years, 28 children – 75% of all known progeria cases worldwide when the study began – showed improvement on the drug in weight, bone structure, and cardiovascular health.
“This tells us something huge, that you can actually reverse some aspect of the disease,” Gordon said. “It gives us the inspiration to go forward, to find more treatments, to step closer and closer to a cure.”
A second clinical trial is taking place at Boston Children’s Hospital; Nathan and Bennett are among the children taking a three-drug cocktail to measure its effectiveness.
Twice a day, the boys take drugs designed to help with bone density, cholesterol, and cancer, repurposed to attempt to halt their progeria symptoms.
Discussing the science, Gordon speaks in the polished, professional language of a researcher.
But ask her about her son, and Gordon switches from scientist to parent – proud, quick to point out how well the high school sophomore is doing. Sam is a strong student who plays drums in the marching band in his public school and is close to becoming an Eagle Scout. He has good friends.
“He’s just a joy,” Gordon said. “He’s just growing into a wonderful young man. I think he has the same kind of happiness in his life that other kids his age have.”
But, she acknowledges, every second matters.
“Long term to me,” she said, “is not the same as long term to most people.”
Phyllis and Mark Falcone thought their dreams were modest – healthy children, soccer games, school plays. But the couple had trouble conceiving children and eventually adopted daughter Libby, now nine.
Having Nathan naturally in August 2005 was a happy surprise. But when he was still a baby, it became clear that something was wrong. He wasn’t gaining weight. His skin was shiny. His muscles were tight.
Doctors first warned that he might have progeria, then said he did not. They suspected he had a connective tissue disorder and said Nathan’s parents were not carriers, that the problem was spontaneous gene change. Then Bennett was born and started showing similar symptoms.
The MAD diagnosis came when he was an infant and Nathan was three. Both Phyllis and Mark carry the recessive gene that causes the disease, though the chances of both their biological children having MAD were small.
“When I looked at the symptoms, such as joint contractures, decreased mobility, being stooped over, diabetes, and renal failure, I felt like I couldn’t breathe,” Phyllis wrote in her journal in April 2009, the day the boys were diagnosed. “How fast will it happen? Looking at Nathan, I can’t imagine that happening to him. But look at how much he changed in three years. He already complains about his knees hurting. What is it going to be like in 10 years? I still cannot believe that Bennett will change in the same way.”
Not knowing much about the boys’ life span is tough.
Two MAD patients lived to adulthood, the Falcones were told – one to 27 and one to 37, eventually dying of kidney problems. One died at age two from an upper airway obstruction that may have been related to the disorder. Besides Nathan and Bennett, the other two known MAD patients are six- and 10-year-old sisters who live in Japan.
Twice a year, the Bennett boys travel to Boston Children’s Hospital for extensive workups for the clinical trial they’re enrolled in.
Nathan is in a regular first-grade class, with an aide to help with his physical challenges – motor skills and strength.
The juxtaposition is stark between the little boy – he loves math, he got a remote-control helicopter and a Spider Man web shooter for his birthday, did you know Libby can do a cartwheel? – and his ageing body. Other kids his age jump out of a car with ease; Nathan only recently stopped being lifted in and out.
In his first-grade school pictures, Nathan wears a green shirt and an adorable smile, but his fair hair is sparse. The day the pictures came home, they were a shock to his mother, a reminder that his disease is progressing.
“Stop-dead-in-your-tracks ... back-to-reality image,” Phyllis wrote about the photo.
Bennett is in preschool and loves it. He’s more physical than his brother, eager to wrestle, bounce on the couch, tackle new challenges.
Mark comes across as philosophical about the boys’ condition; Phyllis has a tougher time, especially as their appearances change and their bodies stiffen.
Both parents acknowledge that having boys with such a rare condition can feel lonely. There’s no progeria month or special-color ribbon.
“There are so few kids with progeria,” Mark said.
Nathan knows he has special needs, but progeria is not something he thinks about often.
The Falcones feel lucky that they have excellent health insurance (Mark works as an accountant, and Phyllis divides her time between staying home with their children and her job as a social worker) and that all the trial-related trips and medications are paid for. But the fund-raising feels urgent to them. “Nathan turning seven was a big reminder for me that time is moving along so fast, and a cure is still not in our reach,” Phyllis wrote in her journal in August. “I can’t think about medications that may happen in one month, three months, a year. I need them to happen now.”
The Falcones try not to let their thoughts veer into dark places, but it’s tough not to.
Phyllis realises her boys might not marry or have children.
“In our heads, we have a number,” she said. “I guess I’m thinking 20s.”
So they’re not raising money for the next generation of kids with progeria, or to give their boys fabulous life experiences in the time they have left.
“This is to find a cure for our boys,” Phyllis said. “Now.” – The Philadelphia Inquirer/ McClatchy Tribune Information Services