A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the <i>ACVR1</i> gene

Cappato, Serena; Traberg, Rasa; Gintautienė, Jolita; Zara, Federico; Bocciardi, Renata

doi:10.1002/mgg3.1774

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…ALK2 R206H has been shown to induce basal leaky BMP signaling in the absence of BMP ligands and hyper-responsiveness upon BMP ligand stimulation that was initially thought to result in the ectopic endochondral ossification in FOP [15][16][17]28]. Later, additional FOP mutations have been identified in both GS domain and kinase domain of ALK2, which are associated with the disease onset ages and the extent of heterotopic ossification [5,10,[29][30][31][32].…”

Section: Bmp Signaling and Fopmentioning

confidence: 99%

Recent progress in drug development for fibrodysplasia ossificans progressiva

Hao

2022

Mol Cell Biochem

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Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.

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Section: Bmp Signaling and Fopmentioning

confidence: 99%

Recent progress in drug development for fibrodysplasia ossificans progressiva

Hao

2022

Mol Cell Biochem

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“…Shortly thereafter, our finding that Activin A activates ACVR1 R206H was independently verified and extended to an additional nine FOP-causing variants of ACVR1 [30], firmly establishing the role of Activin A as the culprit ligand for HO in FOP. Multiple independent studies have verified this result since its initial publication [32,[46][47][48][49]. (A) When BMPs associate with ACVR1 along with its partner type II receptors (ACVR2A, ACVR2B, and BMPR2), the resulting complex drives the phosphorylation of Smad1/5/8.…”

Section: Fop Variant Acvr1 Is Activated By Activin Whereas Wild Type ...mentioning

confidence: 89%

How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva

Srinivasan,

Arostegui,

Goebel

et al. 2024

Biomolecules

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1FOP) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1FOP by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1FOP and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP’s pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.

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“…Other therapies such as art therapy, music therapy, dance and theater are tools in creative processes with the aim of improving deficiencies by favoring well-being. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]…”

Section: Discussionmentioning

confidence: 99%

Rehabilitation in fibrodysplasia ossificans progressive - experience Report

Costa¹,

Helfenstein²,

Amaral³

2023

IPMRJ

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Introduction: Fibrodysplasia Ossificans Progressiva causes gradual limitation of joint range of motion by heterotopic osteogenesis in various connective tissue structures. It is a rare autosomal dominant disease and is correlated with the presence of congenital malformation of the bilateral hallux valgus, presence of ossification that appears spontaneously or precipitated by trauma. Method: The search for the respective titles for FOP and Rehabilitation via a bibliographic review in the Pubmed database, the titles and abstracts were discriminated when they did not bring in their content the treatment of this disease. Results and Discussion: The 9-year-old patient comes with complaints of pain in the joints of the shoulders, elbows, cervical and thoracic spine. Slow walking, structural deformities in the axial axis of the cervico-thoracic spine, decreased shoulder abduction up to 15°, limited elbow flexion and extension. The FOP treatment strategy is a comprehensive program of activities to prevent the myriad possibilities of trauma, from avoiding unnecessary surgical procedures, injections and even biopsies. Dry needling or acupuncture techniques are always contraindicated. Hydrotherapy turns out to be another useful tool in the process of preventing and relieving injuries, contributing to physical conditioning in a safe environment with low impact and cardiopulmonary performance. From the clinical observations, there will be indication of orthoses, auxiliary means for locomotion or adapted wheelchairs. Devices with voice command facilitate some daily activities, encouraging music therapy, dance or theater also favors the well-being of these patients. Conclusion: The disease has some striking characteristics that favor early diagnosis. Injury prevention, medical management of acute painful flare-ups, and rehabilitation are pillars of treatment. There is still no curative treatment, however, the determination of a therapeutic plan prevents future trauma and can guarantee an adequate prognosis even though it is difficult and full of functional limitations for patients.

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A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene

Cited by 6 publications

References 28 publications

Recent progress in drug development for fibrodysplasia ossificans progressiva

Recent progress in drug development for fibrodysplasia ossificans progressiva

How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva

Rehabilitation in fibrodysplasia ossificans progressive - experience Report

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