Just a quick preface: I am NOT a licensed physician. I am a high school student who enjoys researching interesting medical phenomena. I just enjoy writing about medicine and science!
Fibrodysplasia Ossificans Progressiva (FOP) is a genetic condition that is inherited in an
autosomal dominant pattern, meaning that only one mutated gene is required to express the condition. This is because the mutated gene is always dominant, thus it is always expressed. Interestingly, patients with FOP almost always have an identical mutation on their ACVR1 gene. In fact, the typical FOP patient has the exact same amino acid substitution at the exact same location on their ACVR1 protein. Also, most cases of FOP occur as a result of a de novo mutation, meaning that there is no family history of the condition. The ACVR1 gene is responsible for providing the instructions to create activin receptor type-1 proteins or ACVR1 proteins. The ACVR1 protein is found in many tissues including skeletal muscle and cartilage, its job is to manage or control the development of bones and muscles specifically the process of ossification; which is the gradual replacement of cartilage by bone. ACVR1 proteins are known as serine-threonine kinase transmembrane signal transduction proteins. Without getting too far into complex biochemistry, this means that the ACVR1 proteins convert the signals from bone morphogenetic proteins or BMPs to recruit transcription factors that transcribe DNA into RNA and finally create proteins; this signaling process is known as the BMP/SMAD pathway. The BMP/SMAD pathway is essentially the pathway responsible for signaling and initiating bone development. The mutation in the ACVR1 gene causes a change in the glycine-serine activation domain, which results in the ACVR1 protein to bind less tightly to its inhibitory ligand, therefore over stimulating the BMP/SMAD pathway. The overstimulation of the BMP/SMAD pathway results in endothelial cells, cells that line blood vessels, to transform to mesenchymal stem cells, which are multipotent stem cells, meaning that they can produce more than one type of specialized cells, and then finally transform into bone. Mesenchymal stem cells are able to differentiate to osteoblasts, osteocytes, chondrocytes, and adipocytes. In order to understand the process in which bone forms, we should fully understand what each of these cells do. Osteoblasts are responsible for rebuilding the skeleton by filling damaged areas with collagen and then laying down crystals of calcium and phosphorus. Osteocytes are osteoblasts that get trapped under layers of bone. Chondrocytes are responsible for maintaining cartilage. Adipocytes are responsible for promoting bone formation and increasing bone mass by repressing the sympathetic nervous system. The trademark symptom of FOP is the gradual ossification of tissue into bone. The newly formed excess bone is called heterotopic bone. The pathophysiology of heterotopic ossification, or excess bone development, can be described in four steps. The first step is soft tissue damage, essentially some stimulus causes damage to soft tissue. Next is angiogenesis fibroproliferation, which is responsible for the new formation of blood vessels and the accumulation of myofibroblasts which help to maintain the structural integrity in connective tissues. Then chondrogenesis occurs, which is the process of cartilage formation from mesenchyme tissue. The final step is osteogenesis which is the new formation of bone. In patients with FOP, the condition causes de novo osteogenesis, a process that occurs during embryonic skeletal development, to occur abnormally during early childhood. The de novo osteogenesis results in heterotropic ossification that occurs episodically in the form of flare-ups in patients with FOP. Flare-ups can be caused by trauma, a viral infection, or essentially anything that results in inflammation. As a result of the variety of things that can spark new heterotopic ossification, patients with FOP often live very protected and sedentary lifestyles,
as even a minor injury can cause more inflammation and permanent bone growth. Even things like going to the dentist and maintaining oral hygiene can become increasingly difficult as the soft tissue around the jaw gradually turns to bone. Symptoms of FOP include bone formation in muscle and ligaments and connective tissue, malformations of the big toe, spontaneous flare-ups of inflammation or soft tissue swelling, increased flare-ups after injury, viral illness, or immunizations, difficulty moving, frequent injury due to falling, bone growth in the chest can restrict breathing, increased risk of respiratory infection, difficulty talking, and difficulty eating. In fact, FOP is the most disabling condition of ectopic skeletogenesis in humans. The prognosis for someone with FOP is not good and most patients are bedridden by the time they are in their 30s and they usually die before they reach 40. A lot of this can be attributed to the lack of treatment options because the condition is so rare, the incidence of FOP is 1 in 2 million and there are only about 800 living cases. In addition to the rarity, FOP is also an incredibly unique condition as it is one of the most specific disease-causing mutations in the human genome, and is the only known inherited activating mutation of a BMP receptor that causes a human disease. Therefore, studying FOP provides the only basis for understanding the clinical effects of mutations in the BMP/ SMAD signaling pathway. As a result, the treatment options for FOP are fairly limited in success and effectiveness. The most effective treatment option is corticosteroids which help to reduce the inflammation that causes heterotopic ossification.
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