Vital Reports

What is FOP?

Fibrodysplasia Ossificans Progressiva (FOP) is one of the rarest and most debilitating genetic disorders, affecting approximately 1 in 1 million people worldwide, regardless of gender, race, or ethnicity. This condition leads to the abnormal development of bone in places where it shouldn’t be, such as ligaments, muscles, and other soft tissues. Over time, these tissues gradually transform into bone, effectively locking joints in place and severely restricting movement.

FOP is progressive and unpredictable, with bone growth often occurring in response to injury, inflammation, or even spontaneously. Unlike normal bone growth, the extra bone formed in FOP does not remodel or break down over time, making movement increasingly difficult and, in some cases, leading to total immobility. The ossification process follows a typical pattern, often beginning in the neck, spine, and shoulders before spreading to the limbs. Eventually, FOP can restrict the ability to eat, breathe, and speak as bone formation affects the jaw and ribcage. Dr. Frederick Kaplan, a professor at the University of Pennsylvania’s Perelman School of Medicine refers to FOP as, “A medical nightmare in which the body turns itself to stone”.

Causes and Genetic Mutation

FOP is caused by a mutation in the ACVR1 gene, which plays a crucial role in bone and muscle development. This gene provides instructions for making the ACVR1 protein, a part of the bone morphogenetic protein (BMP) family responsible for regulating bone and cartilage growth. Normally, the ACVR1 protein is only activated at appropriate times to support skeletal maturation. However, in individuals with FOP, mutations cause the receptor to be activated too frequently, leading to excessive bone formation in areas where it doesn’t belong.

Progression of the Disease

FOP typically begins in early childhood, often starting with movement restrictions in the neck and back before gradually affecting other parts of the body. As the condition progresses, bone forms outside the normal skeletal structure, replacing soft tissue and making movement increasingly difficult. Even minor injuries, injections, or surgeries can trigger flare-ups, accelerating the bone growth process. Over time, patients may lose the ability to perform basic movements like bending their arms, turning their heads, or even walking.

Current Treatments and Research

There is currently no cure for FOP, but recent medical advancements have led to treatments that help manage symptoms and slow disease progression.

FDA-Approved Treatment: Sohonos (Palovarotene)

In 2021, the U.S. FDA approved Sohonos (palovarotene), a drug that targets retinoic acid receptor gamma (RARγ) to reduce abnormal bone formation. This marks a significant breakthrough in FOP treatment. Palovarotene works by inhibiting excess bone growth, particularly during flare-ups when new ossification is most likely to occur. Clinical trials showed that the drug was able to reduce the volume of heterotopic bone formation, potentially preserving mobility for longer periods. While it does not reverse existing bone growth, it provides a much-needed option for managing FOP and delaying its debilitating effects.

However, like all treatments, Sohonos comes with limitations and potential side effects, including joint pain, dry skin, and an increased risk of early growth plate closure in children, which may lead to shorter stature. Due to these concerns, its use is carefully monitored, and it is primarily recommended for patients who have already reached skeletal maturity.

Other Treatment Approaches:

• Corticosteroids: Short-term use of corticosteroids, like prednisone (a medication mostly used to suppress the immune system and decrease inflammation), can help manage inflammation during flare-ups.
• Assistive Devices & Therapy: While physical therapy must be approached cautiously to avoid triggering bone growth, adaptive devices can help maintain mobility.
• Planned Avoidance of Injury: Since trauma can accelerate bone growth, patients must take extra precautions to avoid injuries and unnecessary medical procedures.

Ongoing Research and Future Prospects

Scientists continue to explore promising treatments, including:

• Garetosmab (an anti-activin A monoclonal antibody) – designed to block signals that promote excess bone growth.
• Antisense-mediated therapy (LNA gapmers) – a technique that aims to selectively silence the mutated ACVR1 gene and prevent excessive ossification.
• Gene-editing techniques like CRISPR, which could potentially correct the ACVR1 mutation in the future.

Living with FOP

Despite its challenges, individuals with FOP can still lead fulfilling lives with proper management and support. Increased awareness, early diagnosis, and continued research provide hope for improved treatments and, potentially, a cure in the future.

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