Fibrodysplasia Ossificans Progressiva (FOP
) is an autosomal dominant genetic disorder
affecting around one in two million people, in which bone
forms in muscle
s and other connective tissue
. Bridges of bone form across the joints in characteristic patterns, producing an extra skeleton
that progressively immobilizes the body. The condition is incurable
, but most patients succumb to related complications, often caused by FOP's ability to interfere with the muscles that control breathing.
FOP was first described over 300 years ago. The name of the disease was modified in the 1970s from Myositis Ossificans Progressiva to acknowledge the involvement of other soft tissue in addition to muscle. Most cases of FOP result from spontaneous egg or sperm mutation rather than parental inheritance, as restriction of movement is usually so severe that people with FOP are unable to reproduce. This makes isolating genetic markers for the disease particularly difficult, as multi-generational families with FOP are extremely rare. FOP affects about 2500 people worldwide.
Diagnosis and Symptoms
At birth, children with FOP appear normal except for unique congenital malformations of the big toe -- generally it's too small and turned inward; frequently the joint is missing. Children begin to suffer flare-ups, sometimes as early as a year after birth, in which painful swollen nodules form over the neck, back and shoulders. Over the course of a week to a month, these lesions mature into bone in a process known as heterotopic ossification. During flare-ups, immune system lymphocytes carrying elevated levels of bone morphogenetic protein 4 (BMP4) kill healthy muscle cells and trigger bone formation.
In addition to suffering periodic spontaneous flare-ups, if a person with FOP suffers an injury to soft tissue, the wound will be healed with bone. Researchers theorize lymphocytes converge at the lesion, as they do in a healthy person's injury, but secrete bone-forming BMP4 in addition to tissue-repairing substances. Even minor injuries have the potential to be permanently disabling.
Exact rate of new bone formation and progression is unpredictable, but there is a characteristic pattern to the progression. FOP flare-ups occur during the first or second decade of life over the neck, back and shoulders; they then progress along the trunk and limbs of the body, then to the abdominal wall, chest, arms and legs, and later to the hips, ankles, wrists, elbows, shoulders and jaw, slowly replacing the body's muscle with bone. Any attempt to remove the extra bone results in even more robust bone formation. The new bone is capable of growth, self-healing, and even harboring marrow.
Research, Prevention, Treatment
Drs Michael Zasloff and Fred Kaplan have been pioneers in researching and raising awareness of FOP. Observing that a) malformation of the big toe is often present at birth; and b) patterns of FOP progression correspond to patterns of skeletal development in a foetus, researchers hypothesized that FOP is caused by mutation of a single gene associated with regulating the rate and pattern of bone growth -- in effect, BMP4 is inappropriately triggered to cause the characteristic bone formation. At present, there is no way to prevent FOP, as there is no way to detect the early mutations that lead to the disease, and no known direct cause for their occurence.
Researching prevention and treatment is centered around identifying the gene that causes FOP and preventing it from causing harm. Anti-inflammatory drugs might be used to prevent the swelling that attracts lymphocytes, while thalidomide and the steroid prednisone can be used to prevent lymphocyte response. Zasloff's research has led him to the discovery of a substance in shark tissue that blocks the formation of blood vessels. The drug developed from this substance, Squalamine, is currently undergoing safety trials, and offers some hope as a potential treatment. Prof Richard Harland has discovered a protein called Noggin which blocks BMP induced bone formation. Gene therapy-based Noggin treatment offers another hope for inhibiting and potentially curing FOP.
The FOP Gene
Thanks to collaborative research between scientists and physicians in the US, UK, and France, the FOP gene has been localized to a small region on the long arm of human chromosome 4. The area was localized using genome-wide linkage analysis of DNA samples from five multi-generational families that show FOP inheritance. Researchers have identified 8 plausible candidate genes, many of which are involved in BMP4 signalling pathways, and checking them will be technically simple (though extremely labor-intensive). In the meantime, finding more multi-generational families will be essential to continuing positional cloning techniques to pinpoint the damaged gene responsible for FOP.
The BBC documentary Skeleton Key (transcript available at http://www.bbc.co.uk/science/horizon/skeletontrans.shtml)