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Neurological symptoms in individuals with fibrodysplasia ossificans progressiva

Journal of Neurology volume 259, pages 2636–2643 (2012)Cite this article

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare, disabling condition caused by gain-of-function mutations of a bone morphogenetic protein (BMP) type I receptor, leads to episodes of heterotopic ossification and resultant immobility. Neurological problems have not been associated with FOP, but neurological symptoms are commonly reported by FOP patients. To determine the prevalence of neurological symptoms and their characteristics in individuals with FOP, we conducted a survey of the 470 patient members of the International FOP Association (IFOPA) using a questionnaire about neurological symptoms. There were 168 responses (105 females, 63 males; age 1.5–68 years) from 30 countries representing 36 % of IFOPA members. Chronic neurological symptoms were reported by 86 (51 %). Prevalence of neuropathic pain (NP) was significantly increased (P < 0.001) compared to the general population, and tenfold more common in females (15 %) than males (1.6 %). Of those with NP, 94 % reported other sensory abnormalities. Prevalence of recurrent severe headaches (HA) (26 %) was similar to that in the general population, but prevalence in females with FOP (36 %) was almost fourfold greater than in males. Prevalence of NP, HA, and other sensory abnormalities was substantially higher in post-pubertal females; 33 % reported symptoms worsened during menstrual periods. Worsening of neurological symptoms during FOP flare-ups was reported by 23 %. Three patients with FOP (1.8 %) reported myoclonus, a prevalence much greater than reported in the general population (P < 0.001). Our worldwide survey indicates that neurological symptoms are common in FOP. We speculate that these symptoms are related to effects of dysregulated BMP signaling on the central and/or peripheral nervous systems.

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Notes

  1. Kan L, Kitterman JA, Procissi D, Chakkalakal S, McGuire TL, Goldsby RE, Pignolo RJ, Shore EM, Kaplan FS, Kessler, JA (2012) CNS demyelination in fibrodysplasia ossificans progressiva. Submitted to Journal of Neurology as a companion paper to this paper.

References

  1. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM (2008) Fibrodysplasia ossificans progressiva. Best Pract Res Clin Rheumatol 22:191–205

    PubMed  Article  CAS  Google Scholar 

  2. Kaplan FS, Glaser DL, Shore EM, Deirmengian GK, Gupta R, Delai P, Morhart R, Smith R, Le Merrer M, Rogers JG, Connor JM, Kitterman JA (2005) The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3–4:183–188

    Article  Google Scholar 

  3. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38:525–527

    PubMed  Article  CAS  Google Scholar 

  4. Connor JM, Evans DAP (1982) Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Jt Surg Br 64:76–83

    CAS  Google Scholar 

  5. Levy C, Lash AT, Janoff HN, Kaplan FS (1999) Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol 8:29–33

    PubMed  Article  CAS  Google Scholar 

  6. Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Pauli RM, Reardon W, Zaidi S, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM (2009) Classic and atypical fibrodysplasia ossificans progressiva phenotypes are caused by mutations in the bone morphogenetic protein type 1 receptor ACVR1. Hum Mutat 30:379–390

    PubMed  Article  CAS  Google Scholar 

  7. Kumar S, Keerthiraj B, Kesavadas C (2010) Teaching NeuroImages: MRI in fibrodysplasia ossificans progressiva. Neurology 74:e20

    Article  Google Scholar 

  8. Rasmussen BK, Jensen R, Schroll M, Olesen J (1991) Epidemiology of headache in a general population—A prevalence study. J Clin Epidemiol 44:1147–1157

    PubMed  Article  CAS  Google Scholar 

  9. Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom MC (2008) Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 137:681–688

    PubMed  Article  Google Scholar 

  10. Mohammadi MR, Ghanizadeh A, Davidian H, Mohammadi M, Norouzian M (2006) Prevalence of epilepsy and comorbidity of psychiatric disorders in Iran. Seizure 15:476–482

    PubMed  Article  Google Scholar 

  11. Glaser DL, Rocke DM, Kaplan FS (1998) Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 346:110–116

    PubMed  Article  Google Scholar 

  12. Caviness JN, Alving LI, Maraganore DM, Black RA, McDonnell SK, Rocca WA (1999) The incidence and prevalence of myoclonus in Olmsted County, Minnesota. Mayo Clin Proc 74:565–569

    PubMed  Article  CAS  Google Scholar 

  13. Brown P, Rothwell JC, Thompson PD, Marsden CD (1994) Propriospinal myoclonus: evidence for spinal “pattern” generators in humans. Mov Disord 9:571–576

    PubMed  Article  CAS  Google Scholar 

  14. Walker JS, Carmody JJ (1998) Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 86:1257–1262

    PubMed  CAS  Google Scholar 

  15. Mogil JS, Bailey AL (2010) Sex and gender differences in pain and analgesia. Prog Brain Res 186:141–157

    PubMed  Google Scholar 

  16. Jazin E, Cahill L (2010) Sex differences in molecular neuroscience: from fruit flies to humans. Nat Rev Neurosci 11:9–17

    PubMed  Article  CAS  Google Scholar 

  17. Silberstein SD, Merriam GR (1993) Sex hormones and headache. J Pain Symptom Manage 8:98–114

    PubMed  Article  CAS  Google Scholar 

  18. Foldvary-Schaeffer N, Harden C, Herzog A, Falcone T (2004) Hormones and seizures. Cleve Clin J Med 71(suppl 2):S11–S18

    Article  Google Scholar 

  19. DiCesare PE, Nimni ME, Peng L, Yazdi M, Cheung DT (1991) Effects of indomethacin on demineralized bone-induced heterotopic ossification in the rat. J Orthop Res 9:855–861

    PubMed  Article  CAS  Google Scholar 

  20. Iñiguez MA, Rodriguez A, Volpert OV, Fresno M, Redondo JM (2003) Cyclooxygenase-2: a therapeutic target in angiogenesis. Trends Mol Med 9:73–78

    PubMed  Article  Google Scholar 

  21. Levitz CL, Cohen RB, Zasloff MA, Kaplan FS (1992) The role of prostaglandins in the pathogenesis of fibrodysplasia ossificans progressiva. Calcif Tissue Int 50:387 (Abstract)

    Google Scholar 

  22. Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, Gierthmühlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihöfner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Üçeyler N, Valet M, Wasner G, Treede R-D (2010) Quantitative sensory testing in the German research network on neuropathic pain: somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 150:439–450

    PubMed  Article  CAS  Google Scholar 

  23. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM (2009) The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest 119:3462–3472

    PubMed  CAS  Google Scholar 

  24. Shafritz AB, Shore EM, Gannon FH, Zasloff MA, Taub R, Muenke M, Kaplan FS (1996) Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. New Engl J Med 335:555–561

    PubMed  Article  CAS  Google Scholar 

  25. Billings PC, Fiori JL, Brentwood JL, O’Connell MP, Jiao X, Nussbaum B, Caron RJ, Shore EM, Kaplan FS (2008) Dysregulated BMP signaling and enhanced osteogenic differentiation of connective tissue progenitor cells from patients with fibrodysplasia ossificans progressiva. J Bone Miner Res 23:305–313

    PubMed  Article  CAS  Google Scholar 

  26. Wang Y, Cheng X, He Q, Zheng Y, Kim DH, Whittemore SR, Cao QL (2011) Astrocytes from contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins. J Neurosci 31:6053–6058

    PubMed  Article  CAS  Google Scholar 

  27. Gomes WA, Mehler MF, Kessler JA (2003) Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev Biol 255:164–177

    PubMed  Article  CAS  Google Scholar 

  28. Sabo JK, Aumann TD, Merlo D, Kilpatrick TJ, Cate HS (2011) Remyelination is altered by bone morphogenetic protein signaling in demyelinated lesions. J Neurosci 31:4504–4510

    PubMed  Article  CAS  Google Scholar 

  29. Kan L, Hu M, Gomes WA, Kessler JA (2004) Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype. Am J Pathol 165:1107–1115

    PubMed  Article  CAS  Google Scholar 

  30. Kan L, Lounev VY, Pignolo RJ, Duan L, Liu Y, Stock SR, McGuire TL, Lu B, Gerard NP, Shore EM, Kaplan FS, Kessler JA (2011) Substance P signaling mediates BMP-dependent heterotopic ossification. J Cell Biochem 112:2759–2772

    PubMed  Article  CAS  Google Scholar 

  31. Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, Sando N, Zasloff MA, Kaplan FS (1993) The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Jt Surg Am 75:215–219

    CAS  Google Scholar 

  32. Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS (1994) Age- and joint-specific risk of initial heterotopic ossification in patients with fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 301:243–248

    PubMed  Google Scholar 

  33. Lanchoney TF, Cohen RB, Rocke DM, Zasloff MA, Kaplan FS (1995) Permanent heterotopic ossification at the injection site after diphtheria-tetanus-pertussis immunizations in children who have fibrodysplasia ossificans progressiva. J Pediatr 126:762–764

    PubMed  Article  CAS  Google Scholar 

  34. Luchetti W, Cohen RB, Hahn GV, Rocke DM, Helpin M, Zasloff M, Kaplan FS (1996) Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:21–25

    PubMed  Article  CAS  Google Scholar 

  35. Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS (2004) Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 423:275–279

    PubMed  Article  Google Scholar 

  36. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS (2005) Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116:e654–e661

    PubMed  Article  Google Scholar 

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Acknowledgments

The authors thank the FOP patients and their families who participated in this study, and the staff members of the IFOPA who provided assistance with the study. This study was supported in part by the International Fibrodysplasia Ossificans Progressiva Association, the Center for Research in FOP and Related Disorders, the Ian Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine (to FSK), the Penn Center for Musculoskeletal Disorders, and the National Institutes of Health (NIH R01-AR41916).

Conflicts of interest

None.

Author information

Affiliations

  1. Department of Pediatrics, University of California San Francisco, Box 0734, San Francisco, CA, 94143, USA

    Joseph A. Kitterman & Jonathan B. Strober

  2. Cardiovascular Research Institute, University of California San Francisco, Box 0734, San Francisco, CA, 94143, USA

    Joseph A. Kitterman

  3. Department of Neurology, University of California San Francisco, San Francisco, CA, 94143, USA

    Jonathan B. Strober

  4. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Lixin Kan

  5. Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, CA, USA

    David M. Rocke

  6. Department of Biostatistics, University of California Davis, Davis, CA, USA

    David M. Rocke

  7. International Fibrodysplasia Ossificans Progressiva Association, Winter Springs, FL, USA

    Amanda Cali, Jeannie Peeper & Jennifer Snow

  8. Orthopaedic Department of Santa Casa de Misericórdia de São Paulo School of Medicine, São Paulo, Brazil

    Patricia L. R. Delai

  9. Department of Pediatrics, Klinikum Garmisch-Partenkirchen GmbH, Garmisch-Partenkirchen, Germany

    Rolf Morhart

  10. Department of Orthopaedic Surgery, Perelman School of Medicine, Center for Research in FOP and Related Disorders, University of Pennsylvania, Philadelphia, PA, USA

    Robert J. Pignolo, Eileen M. Shore & Frederick S. Kaplan

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  1. Joseph A. Kitterman
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  2. Jonathan B. Strober
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  10. Robert J. Pignolo
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  11. Eileen M. Shore
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  12. Frederick S. Kaplan
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Corresponding author

Correspondence to Joseph A. Kitterman.

Additional information

Co-submitted manuscript: CNS Demyelination in Fibrodysplasia Ossificans Progressiva by Kan L, et al.

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Kitterman, J.A., Strober, J.B., Kan, L. et al. Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. J Neurol 259, 2636–2643 (2012). https://doi.org/10.1007/s00415-012-6562-y

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  • DOI: https://doi.org/10.1007/s00415-012-6562-y

Keywords

  • ACVR1
  • Bone morphogenetic protein 4
  • Substance P