CNS demyelination in fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through noninvasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients. We consistently observed demyelinated lesions and focal inflammatory changes of the CNS in both mouse models but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.

Novel asymptomatic CNS findings in patients withACVR1/ALK2mutations causing fibrodysplasia ossificans progressiva

“…The differential diagnosis further includes exophytic low-grade gliomas and choroid plexus lesions, which can be differentiated from the FOP hamartomatous lesions by their origin, signal intensity and contrast enhancement pattern, if not already by their expansive and/or infiltrative nature 18. Finally, these brainstem hamartomatous lesions were different from the CNS lesions recently reported in patients with FOP by Kan et al 5. In their paper, the authors described two types of CNS involvement, characterised by distinct age of onset and clinical features.…”

“…In particular, patients were screened for neurological problems associated both with classic and atypical forms of the disease, such as neuropathic pain or other sensory abnormalities, myoclonus, severe headaches and developmental delay or cognitive impairment 5 7 8. In addition, patients were evaluated for the presence of neurological symptoms and signs related to the MRI lesions, including cranial nerves deficits (notably neurosensory hearing loss and vestibular problems), motor and sensory impairment and autonomic problems.…”

“…Interestingly, areas of demyelination in the central nervous system (CNS) have been described in two mouse models of dysregulated BMP signalling, including knockin mice with the recurrent FOP mutation ACVR1 R206H and the neuron-specific enolase (Nse)-BMP4 overexpression model 5. Moreover, the BMP receptors and ligands are expressed at appropriate times in the developing brain, and studies on transgenic mice overexpressing BMP4 have shown that BMP4 increases astroglial and decreases oligodendroglial lineage commitment during gliogenesis 6.…”

“…Moreover, the BMP receptors and ligands are expressed at appropriate times in the developing brain, and studies on transgenic mice overexpressing BMP4 have shown that BMP4 increases astroglial and decreases oligodendroglial lineage commitment during gliogenesis 6. Evidence of CNS involvement in FOP has recently emerged also in humans, including neurological symptoms and inflammatory lesions in adult patients,5 7 and brain malformations with mild cognitive impairment in children with FOP variants 8. Moreover, bilateral dentate nucleus lesions have been described in neurologically asymptomatic children 5 9 10…”

“…Evidence of CNS involvement in FOP has recently emerged also in humans, including neurological symptoms and inflammatory lesions in adult patients,5 7 and brain malformations with mild cognitive impairment in children with FOP variants 8. Moreover, bilateral dentate nucleus lesions have been described in neurologically asymptomatic children 5 9 10…”