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Spokane, Washington  Est. May 19, 1883

Gene linked to disease that turns muscle to bone

Thomas H. Maugh II Los Angeles Times

Researchers have discovered the gene that causes one of the rarest congenital disorders, a disease called FOP that turns muscle and tendons into bone, forming a second skeleton that in time renders the patient immobile like a statue.

The disease strikes fewer than one in every 2 million people and is so rare that most physicians misdiagnose the disorder, prescribing treatments that generally make the condition worse.

Only about 600 patients are known, and the majority of them become bedridden by their 30s. There is no treatment – removing the excess bone only makes it grow back faster.

The discovery of the FOP gene could eventually lead to the first treatments for the disease, according to Dr. Frederick S. Kaplan and his colleagues at the University of Pennsylvania School of Medicine.

The finding, reported today in the journal Nature Genetics, could lead to new treatments for a variety of other bone diseases that involve either excessive or insufficient bone growth.

“This is a fantastic advance for an absolutely horrible disease,” said Dr. Joseph Kitterman of the University of California, San Francisco, who was not involved in the research.

FOP, formally known as fibrodysplasia ossificans progressiva, is apparent at birth, by toes that are unusually short and point outward laterally.

Other symptoms can begin appearing any time during the first 25 years of life. The first signs are typically swellings on the arm, neck or shoulders, accompanied by severe pain. The pain may fade after a few weeks, but the swellings remain.

By the time patients are teenagers, they usually cannot raise their arms above their heads. As muscles around the lungs are converted to bone, breathing becomes more difficult. Trauma, such as bruises, injections and biopsies, accelerate the process.

“This is the only genetic disorder I know of in which one organ is converted into a different one,” Kaplan said. “The new bone is totally normal. It is just in the wrong place at the wrong time.”

Kitterman, whose stepgrandson has the disease, recently surveyed all the known patients with FOP and reported last November in the journal Pediatrics that 87 percent of them were misdiagnosed by one or more doctors before their condition was correctly identified.

Nearly 50 percent of them received permanent injuries from inappropriate treatment. Kitterman’s stepgrandson, like others, received cancer chemotherapy. Kaplan cited one girl whose arm was amputated because doctors thought she had cancer.

Over the years, it became clear that the problems were related to a protein called bone morphogenetic protein, which is known to be linked to bone growth. But finding the gene has been difficult because few families include more than one afflicted generation.

Although the gene was known to be autosomal dominant – meaning that, if one parent has it, each child has a 50 percent chance of inheriting the disease – most cases involve a spontaneous mutation in the patient at conception.

Kaplan and his colleague Eileen M. Shore assembled five families in which the disease struck at least two generations.

In each of the families, they identified a defective form of a gene called ACVR1 that is the blueprint for a protein that regulates bone morphogenetic protein.

A change in one nucleotide leads to a change in the protein that prevents bone morphogenetic protein from binding properly. The same nucleotide change was subsequently found in virtually all other FOP patients.

“The importance,” Kaplan said, “is that this immediately suggests a treatment strategy, although it could be years or decades before an actual treatment is found.”