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Journal of Neurology

, Volume 259, Issue 12, pp 2636–2643 | Cite as

Neurological symptoms in individuals with fibrodysplasia ossificans progressiva

  • Joseph A. KittermanEmail author
  • Jonathan B. Strober
  • Lixin Kan
  • David M. Rocke
  • Amanda Cali
  • Jeannie Peeper
  • Jennifer Snow
  • Patricia L. R. Delai
  • Rolf Morhart
  • Robert J. Pignolo
  • Eileen M. Shore
  • Frederick S. Kaplan
Original Communication

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.

Keywords

ACVR1 Bone morphogenetic protein 4 Substance P 

Notes

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.

Supplementary material

415_2012_6562_MOESM1_ESM.doc (128 kb)
Supplementary material 1 (DOC 129 kb)

References

  1. 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 22:191–205PubMedCrossRefGoogle Scholar
  2. 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 3–4:183–188CrossRefGoogle Scholar
  3. 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 38:525–527PubMedCrossRefGoogle Scholar
  4. 4.
    Connor JM, Evans DAP (1982) Fibrodysplasia ossificans progressiva. The clinical features and natural history of 34 patients. J Bone Jt Surg Br 64:76–83Google Scholar
  5. 5.
    Levy C, Lash AT, Janoff HN, Kaplan FS (1999) Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol 8:29–33PubMedCrossRefGoogle Scholar
  6. 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 30:379–390PubMedCrossRefGoogle Scholar
  7. 7.
    Kumar S, Keerthiraj B, Kesavadas C (2010) Teaching NeuroImages: MRI in fibrodysplasia ossificans progressiva. Neurology 74:e20CrossRefGoogle Scholar
  8. 8.
    Rasmussen BK, Jensen R, Schroll M, Olesen J (1991) Epidemiology of headache in a general population—A prevalence study. J Clin Epidemiol 44:1147–1157PubMedCrossRefGoogle Scholar
  9. 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 137:681–688PubMedCrossRefGoogle Scholar
  10. 10.
    Mohammadi MR, Ghanizadeh A, Davidian H, Mohammadi M, Norouzian M (2006) Prevalence of epilepsy and comorbidity of psychiatric disorders in Iran. Seizure 15:476–482PubMedCrossRefGoogle Scholar
  11. 11.
    Glaser DL, Rocke DM, Kaplan FS (1998) Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Relat Res 346:110–116PubMedCrossRefGoogle Scholar
  12. 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 74:565–569PubMedCrossRefGoogle Scholar
  13. 13.
    Brown P, Rothwell JC, Thompson PD, Marsden CD (1994) Propriospinal myoclonus: evidence for spinal “pattern” generators in humans. Mov Disord 9:571–576PubMedCrossRefGoogle Scholar
  14. 14.
    Walker JS, Carmody JJ (1998) Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg 86:1257–1262PubMedGoogle Scholar
  15. 15.
    Mogil JS, Bailey AL (2010) Sex and gender differences in pain and analgesia. Prog Brain Res 186:141–157PubMedGoogle Scholar
  16. 16.
    Jazin E, Cahill L (2010) Sex differences in molecular neuroscience: from fruit flies to humans. Nat Rev Neurosci 11:9–17PubMedCrossRefGoogle Scholar
  17. 17.
    Silberstein SD, Merriam GR (1993) Sex hormones and headache. J Pain Symptom Manage 8:98–114PubMedCrossRefGoogle Scholar
  18. 18.
    Foldvary-Schaeffer N, Harden C, Herzog A, Falcone T (2004) Hormones and seizures. Cleve Clin J Med 71(suppl 2):S11–S18CrossRefGoogle Scholar
  19. 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 9:855–861PubMedCrossRefGoogle Scholar
  20. 20.
    Iñiguez MA, Rodriguez A, Volpert OV, Fresno M, Redondo JM (2003) Cyclooxygenase-2: a therapeutic target in angiogenesis. Trends Mol Med 9:73–78PubMedCrossRefGoogle Scholar
  21. 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. 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 150:439–450PubMedCrossRefGoogle Scholar
  23. 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 119:3462–3472PubMedGoogle Scholar
  24. 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 335:555–561PubMedCrossRefGoogle Scholar
  25. 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 23:305–313PubMedCrossRefGoogle Scholar
  26. 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 31:6053–6058PubMedCrossRefGoogle Scholar
  27. 27.
    Gomes WA, Mehler MF, Kessler JA (2003) Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev Biol 255:164–177PubMedCrossRefGoogle Scholar
  28. 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 31:4504–4510PubMedCrossRefGoogle Scholar
  29. 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 165:1107–1115PubMedCrossRefGoogle Scholar
  30. 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 112:2759–2772PubMedCrossRefGoogle Scholar
  31. 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 75:215–219Google Scholar
  32. 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 301:243–248PubMedGoogle Scholar
  33. 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 126:762–764PubMedCrossRefGoogle Scholar
  34. 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 81:21–25PubMedCrossRefGoogle Scholar
  35. 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 423:275–279PubMedCrossRefGoogle Scholar
  36. 36.
    Kitterman JA, Kantanie S, Rocke DM, Kaplan FS (2005) Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116:e654–e661PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Joseph A. Kitterman
    • 1
    • 2
    Email author
  • Jonathan B. Strober
    • 1
    • 3
  • Lixin Kan
    • 4
  • David M. Rocke
    • 5
    • 6
  • Amanda Cali
    • 7
  • Jeannie Peeper
    • 7
  • Jennifer Snow
    • 7
  • Patricia L. R. Delai
    • 8
  • Rolf Morhart
    • 9
  • Robert J. Pignolo
    • 10
  • Eileen M. Shore
    • 10
  • Frederick S. Kaplan
    • 10
  1. 1.Department of PediatricsUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Cardiovascular Research InstituteUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Department of NeurologyUniversity of California San FranciscoSan FranciscoUSA
  4. 4.Department of NeurologyNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.Division of Biostatistics, Department of Public Health Sciences, School of MedicineUniversity of California DavisDavisUSA
  6. 6.Department of BiostatisticsUniversity of California DavisDavisUSA
  7. 7.International Fibrodysplasia Ossificans Progressiva AssociationWinter SpringsUSA
  8. 8.Orthopaedic Department of Santa Casa de Misericórdia de São Paulo School of MedicineSão PauloBrazil
  9. 9.Department of PediatricsKlinikum Garmisch-Partenkirchen GmbHGarmisch-PartenkirchenGermany
  10. 10.Department of Orthopaedic Surgery, Perelman School of Medicine, Center for Research in FOP and Related DisordersUniversity of PennsylvaniaPhiladelphiaUSA

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