Fibrodysplasia ossificans progressiva

Discovery offers hope to those trapped in 'second skeleton'
SHERYL UBELACKER
Canadian Press

U.S. researchers have isolated the defective gene responsible for one of the rarest and most "catastrophic" inherited diseases affecting humans — a condition that causes muscles and other connective tissues to turn into bone, imprisoning children for life in a second skeleton.

The disorder, known as fibrodysplasia ossificans progressiva (FOP), begins in childhood to progressively transform muscles, ligaments and tendons into ribbons, sheaths and plates of bone that cover and lock the joints, making movement impossible.

Researchers at the University of Pennsylvania and international colleagues have spent 15 years in a painstaking hunt for the gene, which they discovered in a region of chromosome 2. Their findings were reported Sunday in an online edition of Nature Genetics. "FOP is the most catastrophic disorder of extraskeletal ossification known to mankind," Dr. Fred Kaplan, director of the university's Center for Research in FOP and Related Disorders and a co-discoverer of the gene, told a Philadelphia news conference.

"The bone in FOP is perfectly normal in every way except it just should not be there." Dr. Kaplan, an orthopedic surgeon, said he was first exposed to FOP when he met two adults with the condition 18 years ago. Two years later, he met a child whose body was beginning to be locked in a carapace of extra bone — and that "lit the emotional flame" that set him and his team on a quest to find the cause and a cure for the devastating disorder.

The genetic abnormality occurs in only one in two million children, with an estimated 2,500 cases worldwide. The researchers have identified about 600 children and adults with the condition, including a handful in Canada. Children who inherit the defective gene seem normal at birth except for a tell-tale malformation of the big toe, which looks like a bunion. But between about age two and five, painful swellings that look like tumours "seize the skeletal muscles, tendons and ligaments and relentlessly transform them into bone," Dr. Kaplan said.

"Any attempt to remove this second skeleton leads to explosive growth of new bone formation and it is impossible to remove without causing more bone," Dr. Kaplan explained. "Even minor bumps and bruises cause catastrophic disability." Medical procedures that most of us take for granted — from immunizations to blood tests — can set off insidious bone growth. Needles for dental work can end up leaving an FOP patient with a permanently fused jaw.

FOP is often misdiagnosed as cancer, said Dr. Kaplan, citing the case of one young woman who had her arm amputated because doctors thought she had cancer. Not only did she lose her arm unnecessarily, but the surgery promoted even more connective tissue to harden into bone.

Eileen Shore, a professor of orthopedics and genetics at the university and co-principal investigator of the research, said FOP is caused by a single mutation in a gene known as ACVR1, which interferes with the protein switch responsible for bone-growth, turning it on when it should be shut off.

"This will lead to a direct and effective strategy for the treatment of this disease," said Dr. Shore, noting that scientists hope to find a drug that will block or get around the genetic trigger that spurs renegade bone growth in FOP. But their discovery could also lead to treatments for other conditions, such as unwanted bone that sometimes occurs after hip-replacement surgery, skull injury and osteoarthritis.

Learning to harness the switch could lead to methods of building bone in people with osteoporosis, the researchers added.

Amanda Cali, chair of the International FOP Association, said finding the gene has given hope to people with the disease and to their families. Eight Canadians, aged 10 to 40, are known to have the disorder, she said.

"This magnificent discovery allows the researchers to narrow the search for a treatment and a cure," Ms. Cali said from her home in Mountain Lakes, N.J.

Jeannie Peeper, 47, of Winter Springs, Fla., said from Philadelphia that her bony prison has left her completely immobilized, wheelchair-bound and totally dependent on others for care. She is able to move just her right hand and wrist.

"The gene discovery is an extraordinary gift to the FOP community and a monumental milestone on our road to a cure," said Ms. Peeper, who continues as a leader of the International FOP Association, despite the disabling condition.

"For me this day is truly the most extraordinary gift I have ever received, for the FOP gene to have been found in my lifetime."

Likening the ACVR1 mutation to a "molecular terrorist that turns a light bulb into an atom bomb," Dr. Kaplan conceded it will likely take years, even decades, before a treatment is found to reverse that process and liberate FOP patients from their extra armament of bone.

"There is a human component to this that is truly the inspiration for all that we do," said Dr. Kaplan, his voice breaking with emotion. "This is for us nothing less than a campaign for physical independence and personal freedom for these children.

"It was originally and it is today for and about the kids."

(Thanks to Dave Doldersum for this)