The following information has been taken from the International Clinical Council for FOP’s Medical Guidelines, which can be downloaded here.
Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns.
Approximately 97% of people with FOP have this recurrent mutation but around 3% of affected individuals have a variant mutation in the ACVR1 gene, but all individuals with FOP have mutations in the ACVR1 gene.
Variant forms can be mild with just persistent stiffness or it can be aggressive and relentless. Some variant forms of FOP have only ever had one or two cases – this makes a rare disease even rarer.
Scientists are striving to learn and understand how the ACVR1 variant mutations are similar and different to the classic FOP ACVR1 mutation. Whatever form of FOP a person has, we all stand stronger together.
Taken from the ICC Medical Guidelines:
“Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. FOP is the most catastrophic disorder of HO in humans. Flare-ups are episodic; immobility is cumulative. A common mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, exists in all sporadic and familial cases with a classic presentation of FOP.
Approximately 97% of individuals with FOP have this recurrent mutation. Approximately 3% of affected individuals have a variant mutation in ACVR1, but all individuals with FOP have mutations in the ACVR1 gene.”
[Adapted from “FOP Variants: What Are They, Who Has Them & What Do They Mean for You? By Frederick S. Kaplan, M.D. and Eileen M. Shore, Ph.D.”]
When we started seeing FOP patients, nearly 35 years ago, it quickly became obvious that everyone shared two features: malformed big toes and progressive HO. These were clearly two characteristic clinical features and they defined classic FOP.
As we saw more patients, we recognized variability in the toe malformation that individuals had, as well as differences in the rate of progression of HO. For example, some had short, bent big toes; others had short, straight big toes; others still had long big toes and some were of normal length. But everyone had a toe malformation – most commonly characterized by a missing or malformed joint in the big toe that was obvious on physical examination, radiographs or both. Likewise, we noted variability in the rate of progression of the FOP HO – some progressed very rapidly while others progressed very slowly, and still others progressed at a more even pace. Much like other traits in any population, FOP showed a natural variation that defined the limits of the norm.
Occasionally though, we saw someone who had a feature of FOP that was WAY outside of the “normal” range – even for FOPers. This defining feature most often involved the big toes. Among these individuals, we began to recognize two groups: One group had nearly normal or completely normal-looking big toes. The other group had extremely severe toe malformations that involved other digits in the feet and the hands. In the more “severe” group, we observed additional developmental abnormalities in other organ systems. We refer to these two groups of outliers as “FOP variants” – some mild, some severe.
Approximately 97% of individuals that we have seen with FOP HO had “classic FOP”, and approximately 3% of individuals were “FOP variants.” About half the patients with FOP variants (1.5%) had a mild clinical variant and about half the patients (1.5%) had a severe variant. Again, these observations were based on clinical evaluation and preceded the discovery of the FOP gene.
After we discovered the FOP gene, we examined the DNA sequence of the FOP gene in all patients who we had seen. Remarkably, nearly every single patient who was diagnosed as having “classic FOP” – regardless of where they were on the spectrum of disease severity – had the same exact heterozygous missense activating FOP mutation: [ACVR1c.617G>A; R206H].
As remarkably, every single patient who we had identified clinically as being an “FOP variant” had a different heterozygous missense activating mutation in the ACVR1 gene. In other words, those with “classic FOP” as the clinical diagnosis had the same “classic mutation” in the FOP gene [ACVR1c.617G>A; R206H], while everyone clinically diagnosed as an “FOP variant” had a “variant mutation” in the FOP gene.
Keep in mind that FOP variants are much rarer than classic FOP.
Some of the ACVR1 variants have so far been found in only one or two affected individuals in the world, so it is difficult to make predictions about the course of FOP over time. With other variants, there may be a few affected individuals in the world, so we know a little bit more about the course that FOP variant may take over time.
So, what does this all mean for someone who has an FOP variant?
We have less knowledge and therefore less certainty about the FOP variants than we do about classic FOP; but, we and other scientists are beginning to learn more about how the ACVR1 variant mutations affect cell functions and how they are similar to and different from the classic ACVR1 mutation (Haupt et al., 2018; Mucha et al., 2018). The exact location and characteristic of the mutation in the ACVR1 gene (blueprint for the ACVR1 protein; classic vs. variant) informs the structural biologists with whom we work and collaborate to better understand the damaged workings of ACVR1 in FOP. That insight is critical to developing structural models and approaches to inactivating the damaged and overactive switch that leads to disabling HO in all forms of FOP.
* Whether someone has “classic FOP” or an “FOP variant”, all have over-activity of the bone forming BMP pathway and thus the tendency to form heterotopic bone.
* Whether someone has “classic FOP” or an “FOP variant”, the process by which they form heterotopic bone after birth is the same.
* The general precautions for FOP are the same for patients with classic FOP and FOP variants.
* The symptomatic management of flare-ups is the same for patients with classic FOP and FOP variants.
* Some of the approaches to develop medications for FOP are mutation-specific while others target the broad process of HO common to both.
*Approaches to specifically block the overactive ACVR1 receptor (encoded by the FOP gene) should be applicable to FOP variants as well as classic FOP.
* New clinical trials will likely be limited at first to patients who have classic FOP – and then later, if applicable, to those with FOP variants – based primarily on regulatory requirements.
* Every measure and pressure is being exerted to open-up applicable clinical trials to patients with FOP variants as quickly and humanly possible. This is being done right now.
*Finally, all patients with FOP – classic and variant FOP – are part of the small but powerful worldwide FOP community. There is a common thread that unites everyone with FOP.
All with FOP must stay together, speak with one voice, and learn from each other. Knowledge will lead to better treatments and a cure for all of those with FOP regardless of whether one has “classic FOP” or an “FOP variant”.
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