Journal of Neurology

, Volume 259, Issue 12, pp 2644–2655

CNS demyelination in fibrodysplasia ossificans progressiva

  • Lixin Kan
  • Joseph A. Kitterman
  • Daniele Procissi
  • Salin Chakkalakal
  • Chian-Yu Peng
  • Tammy L. McGuire
  • Robert E. Goldsby
  • Robert J. Pignolo
  • Eileen M. Shore
  • Frederick S. Kaplan
  • John A. Kessler
Original Communication

DOI: 10.1007/s00415-012-6563-x

Cite this article as:
Kan, L., Kitterman, J.A., Procissi, D. et al. J Neurol (2012) 259: 2644. doi:10.1007/s00415-012-6563-x

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 non-invasive 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.

Keywords

Fibrodysplasia ossificans progressiva (FOP) Animal model Demyelination Bone morphogenetic protein (BMP) ACVR1/ALK2 Magnetic resonance imaging (MRI) 

Supplementary material

415_2012_6563_MOESM1_ESM.jpg (702 kb)
Supplementary Figure 1. Hyperintense lesions on MRI correspond to areas of demyelination in the spinal cord of Nse-BMP4 mice. (A-C) Luxol fast blue staining of cross sections of Nse-BMP4 spinal cord correspond to hyperintense regions on MRI (F–H). (A) Luxol fast blue staining of white matter of an unaffected side (left side). Note the strong Luxol fast blue staining (blue) and the absence of inflammatory cells (pink). (B) Luxol fast blue staining of white matter of affected side (right side). Note the weak Luxol fast blue staining (blue) and the widespread inflammatory cells (pink). (C) Low power image of the whole section. (D&E) shows CNPase staining of neighboring section of (C). (D) White matter of unaffected side (left side). (E) White matter of affected side (right side). Note the staining in (E) is much weaker compared to (D). (F–H) MRI hyperintense regions in spinal cord of Nse-BMP4 mouse. (F) Transverse view. (G) Longitudinal top view. (H) Sagittal view of the same region. Bar = 40 µm in (A-D) (JPEG 701 kb)
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Supplementary Figure 2. Luxol fast blue staining identifies no global demyelination in the brains of chimeric ACVR1 R206H FOP knock-in mice. Low power images of sagittal brain sections from chimeric and control mice at different levels. Note that no significant global demyelination in FOP knock-in mice, comparing to control (JPEG 5549 kb)
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Supplementary Figure 3. Mutant cells in chimeric ACVR1 R206H FOP knock-in mice are more abundant in the cerebellum compared to other brain regions.MBP (green)/Neo (red) double staining of sections from chimeric (A&C) and WT (B&D) mice indicates the presence of abundant mutant cells in the cerebellum, and a consistent correlation of demyelination (absence of MBP/red) with regions containing mutant cells. (A&B) show representative staining in cerebellum of chimeric (A) and WT (B) mice. (C&D) show representative staining in the dorsal brain of comparable regions from chimeric (C) and WT (D) mice (JPEG 395 kb)
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Supplementary Figure 4. ACVR1 R206H mutant cells (neo +) and oligodendrocyte markers (CNPase) are mutually exclusive, however, many mutant cells express GFAP, a marker of astrocytes, and some mutant cells express a neuronal cell marker (β-III tubulin). (A–A”) Double staining for Neo (red)/CNPase (green). No obvious co-localization is found. (B–B”) double staining for Neo (red)/GFAP (green). Extensive co-localization is found (white arrows). (C–C”) Double staining for Neo (red)/B-III tubulin (green); some co-localization is found (white arrows) (JPEG 464 kb)
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Supplementary Figure 5. Astrocyte distribution is disrupted in the spinal cords of chimeric FOP ACVR1 R206H knock-in mice. (A&B) low power images show the global distribution of GFAP + cells in chimeric ACVR1 R206H (A) and control mice (B). Note that the normal pattern of radically oriented GFAP + cells found in control mice (B) is significantly changed in (A). Many GFAP + cells are no longer radically oriented or located in white matter regions, but there is no apparent change in the number of GFAP + cells. (C&D) high power images show the detailed morphology and distribution of GFAP + cells in ACVR1 R206H (C) and control mice (D). Bar = 200 µm in (A&B), Bar = 40 µm in (C&D) (JPEG 207 kb)
415_2012_6563_MOESM6_ESM.jpg (502 kb)
Supplementary Figure 6. FLAIR images also detect progression of hyperintense lesions in the CNS of a FOP patient. (A-B) FLAIR brain images (coronal view) of brain of patient 1 in 2006 showed isolated hyperintense lesions in white matter of the right frontal lobe, and peri-ventricular white matter (B). (A’-B’) showed the lesions in similar locations 5 years later (in 2011). Note that all lesions persisted, but the sizes of the lesions were increased in peri-ventricular white matter. In addition, many more lesions were observed at the later time point, and some of the lesions were merging with each other. C1-C12 showed additional hyperintense lesions in different brain regions (in 2011, coronal view) (JPEG 501 kb)
415_2012_6563_MOESM7_ESM.jpg (953 kb)
Supplementary Figure 7. Current working model. See DISCUSSION for details (JPEG 953 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Lixin Kan
    • 1
    • 8
  • Joseph A. Kitterman
    • 2
  • Daniele Procissi
    • 3
  • Salin Chakkalakal
    • 4
    • 7
  • Chian-Yu Peng
    • 9
  • Tammy L. McGuire
    • 9
  • Robert E. Goldsby
    • 2
  • Robert J. Pignolo
    • 4
    • 5
    • 7
  • Eileen M. Shore
    • 4
    • 6
    • 7
  • Frederick S. Kaplan
    • 4
    • 5
    • 7
  • John A. Kessler
    • 9
  1. 1.Department of NeurologyNorthwestern University, Feinberg School of MedicineChicagoUSA
  2. 2.Department of Pediatrics and Cardiovascular Research InstituteUniversity of CaliforniaSan FranciscoUSA
  3. 3.Department of Radiology, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  4. 4.Department of Orthopaedic Surgery, The Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  5. 5.Department of Medicine, The Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  6. 6.Department of Genetics, The Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  7. 7.The Center for Research in FOP and Related Disorders, The Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  8. 8.Vanda PharmaceuticalsWashingtonUSA
  9. 9.Department of NeurologyNorthwestern University, Feinberg School of MedicineChicagoUSA

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