Novel asymptomatic CNS findings in patients with<i>ACVR1/ALK2</i>mutations causing fibrodysplasia ossificans progressiva

Severino, Mariasavina; Bertamino, Marta; Tortora, Domenico; Morana, Giovanni; Uccella, Sarà; Bocciardi, Renata; Ravazzolo, Roberto; Rossi, Andrea; Rocco, Maja Di

doi:10.1136/jmedgenet-2016-104076

Cited by 15 publications

(24 citation statements)

References 29 publications

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“…Nonetheless, the impact of aberrant activin-A-or ACVR1/ ALK2-dependent activity with the CNS must be considered. In FOP patients [19,41] lesions or focal MRI hyperintensities along white matter pathways have been noted. Disruption of white matter integrity can indeed modulate CNS functional properties.…”

Section: Discussionmentioning

confidence: 99%

Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva

Peng

Karunakaran

Labadie

et al. 2021

Orphanet J Rare Dis

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Background Pain is a highly prevalent symptom experienced by patients across numerous rare musculoskeletal conditions. Much remains unknown regarding the central, neurobiological processes associated with clinical pain in musculoskeletal disease states. Fibrodysplasia ossificans progressiva (FOP) is an inherited condition characterized by substantial physical disability and pain. FOP arises from mutations of the bone morphogenetic protein (BMP) receptor Activin A receptor type 1 (ACVR1) causing patients to undergo painful flare-ups as well as heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. To date, the neurobiological processes that underlie pain in FOP have rarely been investigated. We examined pain and central pain mechanism in FOP as a model primary musculoskeletal condition. Central nervous system (CNS) functional properties were investigated in FOP patients (N = 17) stratified into low (0–3; 0–10 Scale) and high (≥ 4) pain cohorts using functional near-infrared spectroscopy (fNIRS). Associations among clinical pain, mental health, and physical health were also quantified using responses derived from a battery of clinical questionnaires. Results Resting-state fNIRS revealed suppressed power of hemodynamic activity within the slow-5 frequency sub-band (0.01–0.027 Hz) in the prefrontal cortex in high pain FOP patients, where reduced power of slow-5, prefrontal cortex oscillations exhibited robust negative correlations with pain levels. Higher clinical pain intensities were also associated with higher magnitudes of depressive symptoms. Conclusions Our findings not only demonstrate a robust coupling among prefrontal cortex functionality and clinical pain in FOP but lays the groundwork for utilizing fNIRS to objectively monitor and central pain mechanisms in FOP and other musculoskeletal disorders.

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Section: Discussionmentioning

confidence: 99%

Suppressed prefrontal cortex oscillations associate with clinical pain in fibrodysplasia ossificans progressiva

Peng

Karunakaran

Labadie

et al. 2021

Orphanet J Rare Dis

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“…Recent MRI studies have identified FOP patients with T2-hyperintensity of the dentate nucleus regions with dentate nucleus lesions [128,129,130,131]. T2-hyperintense lesions were also observed in frontal periventricular white matter, the spinal cord, and the dorsal pons.…”

Section: Acvr1 In the Central Nervous Systemmentioning

confidence: 99%

“…It was suggested that enhanced BMP signalling in response to demyelination could disrupt reparation since increased BMP responses reduce oligodendrocyte production and increase the number of astrocytes [132]. Additionally, some FOP patients presented either abnormal soft tissue mass surrounding the brainstem or the ventral portion of the pons or lesions in the fourth ventricle, causing hydrocephalus [128,129]. In mouse models with dysregulated BMP signalling, either by BMP4 overexpression or ACVR1 R206H mutation, demyelinated lesions and focal inflammatory changes of the CNS were observed.…”

Section: Acvr1 In the Central Nervous Systemmentioning

confidence: 99%

“…These brainstem lesions resembled the hamartomatous tissue. All patients showed brainstem dysmorphism, with bulging of the dorsal pons, a thickened pontomedullary junction, and enlarged medulla [129]. Additionally, dentate nuclei abnormalities were observed in all patients.…”

Section: Acvr1 In the Central Nervous Systemmentioning

confidence: 99%

“…The size of the brainstem lesions did not correlate with age, onset of ossification, or severity of disability. Moreover, brainstem lesions were observed in two FOP patients in the first month of life [129]. These findings possibly suggest either a congenital malformation resulting from impaired regulation of brainstem progenitors during development or early, impaired regulation of the CNS, potentially affected by inflammation and dysregulated BMP signalling due to the ACVR1 mutations [129,131].…”

Section: Acvr1 In the Central Nervous Systemmentioning

confidence: 99%

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ACVR1 Function in Health and Disease

Valer

Sánchez-de-Diego

Pimenta-Lopes

et al. 2019

Cells

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Activin A receptor type I (ACVR1) encodes for a bone morphogenetic protein type I receptor of the TGFβ receptor superfamily. It is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation. Moreover, ACVR1 has been extensively studied for its causal role in fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterised by progressive heterotopic ossification. ACVR1 is linked to different pathologies, including cardiac malformations and alterations in the reproductive system. More recently, ACVR1 has been experimentally validated as a cancer driver gene in diffuse intrinsic pontine glioma (DIPG), a malignant childhood brainstem glioma, and its function is being studied in other cancer types. Here, we review ACVR1 receptor function and signalling in physiological and pathological processes and its regulation according to cell type and mutational status. Learning from different functions and alterations linked to ACVR1 is a key step in the development of interdisciplinary research towards the identification of novel treatments for these pathologies.

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