Skip to main content

Advertisement

SpringerLink
Log in

Dorsal root ganglia in vivo morphometry and perfusion in female patients with Fabry disease

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Purpose

To examine dorsal root ganglia and the proximal nerve segments in female patients with Fabry disease by functional and morphometric magnetic resonance neurography.

Methods

In this prospective multicenter study the lumbosacral dorsal root ganglia and proximal sciatic nerve were examined in ten female patients with Fabry disease by a standardized magnetic resonance neurography protocol at 3 T. Volumes of dorsal root ganglia L3–S2, permeability of dorsal root ganglia L5 and S1 and the spinal nerve L5 as well as the cross-sectional area of the proximal sciatic nerve were compared to 16 gender-matched healthy controls.

Results

Dorsal root ganglia were symmetrically enlarged by 54% (L3), 79% (L4), 60% (L5), 94% (S1), and 106% (S2) (p < 0.001). Additionally, permeability of the blood–tissue interface was decreased by 47% (p < 0.001). This finding was most pronounced in the peripheral zone of the dorsal root ganglia, where the cell bodies of the primary sensory neurons are located (p < 0.001). While spinal nerve permeability showed no differences compared to healthy controls, proximal sciatic nerve cross-sectional area was mildly increased by 6% (p < 0.01).

Conclusion

Although heterozygous, Fabry females show severe enlarged dorsal root ganglia with a concomitant dysfunctional perfusion, even in patients with minor disease progression and in patients who are not considered for enzyme replacement therapy yet. Alterations in dorsal root ganglia volume and perfusion might serve as a very early in vivo marker for involvement of the peripheral nervous system in Fabry disease, even in patients with residual enzyme activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP, Fabry R (2008) Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 93(2):112–128. https://doi.org/10.1016/j.ymgme.2007.09.013

    Article  CAS  PubMed  Google Scholar 

  2. Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, Sorensen SA, Wilcox WR, Desnick RJ (2009) Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant 24(7):2102–2111. https://doi.org/10.1093/ndt/gfp031

    Article  PubMed  PubMed Central  Google Scholar 

  3. Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M (2007) Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 30(2):184–192. https://doi.org/10.1007/s10545-007-0521-2

    Article  CAS  PubMed  Google Scholar 

  4. Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR (2015) Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 52(5):353–358. https://doi.org/10.1136/jmedgenet-2014-102797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hughes DA, Barba Romero MA, Hollak CE, Giugliani R, Deegan PB (2011) Response of women with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS–the Fabry outcome survey. Mol Genet Metab 103(3):207–214. https://doi.org/10.1016/j.ymgme.2011.03.022

    Article  CAS  PubMed  Google Scholar 

  6. Hopkin RJ, Bissler J, Banikazemi M, Clarke L, Eng CM, Germain DP, Lemay R, Tylki-Szymanska A, Wilcox WR (2008) Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res 64(5):550–555. https://doi.org/10.1203/PDR.0b013e318183f132

    Article  PubMed  Google Scholar 

  7. Politei JM, Bouhassira D, Germain DP, Goizet C, Guerrero-Sola A, Hilz MJ, Hutton EJ, Karaa A, Liguori R, Uceyler N, Zeltzer LK, Burlina A (2016) Pain in Fabry disease: practical recommendations for diagnosis and treatment. CNS Neurosci Ther 22(7):568–576. https://doi.org/10.1111/cns.12542

    Article  PubMed  PubMed Central  Google Scholar 

  8. Uceyler N, Ganendiran S, Kramer D, Sommer C (2014) Characterization of pain in fabry disease. Clin J Pain 30(10):915–920. https://doi.org/10.1097/AJP.0000000000000041

    Article  PubMed  Google Scholar 

  9. Ramaswami U, Whybra C, Parini R, Pintos-Morell G, Mehta A, Sunder-Plassmann G, Widmer U, Beck M, Investigators FOSE (2006) Clinical manifestations of fabry disease in children: data from the Fabry outcome survey. Acta Paediatr 95(1):86–92

    Article  PubMed  Google Scholar 

  10. Godel T, Baumer P, Pham M, Kohn A, Muschol N, Kronlage M, Kollmer J, Heiland S, Bendszus M, Mautner VF (2017) Human dorsal root ganglion in vivo morphometry and perfusion in Fabry painful neuropathy. Neurology 89(12):1274–1282. https://doi.org/10.1212/WNL.0000000000004396

    Article  PubMed  Google Scholar 

  11. Gadoth N, Sandbank U (1983) Involvement of dorsal root ganglia in Fabry’s disease. J Med Genet 20(4):309–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Godel T, Pham M, Heiland S, Bendszus M, Baumer P (2016) Human dorsal-root-ganglion perfusion measured in-vivo by MRI. Neuroimage 141:81–87. https://doi.org/10.1016/j.neuroimage.2016.07.030

    Article  PubMed  Google Scholar 

  13. Cuenod CA, Balvay D (2013) Perfusion and vascular permeability: basic concepts and measurement in DCE-CT and DCE-MRI. Diagn Interv Imaging 94(12):1187–1204. https://doi.org/10.1016/j.diii.2013.10.010

    Article  CAS  PubMed  Google Scholar 

  14. Kaye EM, Kolodny EH, Logigian EL, Ullman MD (1988) Nervous system involvement in Fabry’s disease: clinicopathological and biochemical correlation. Ann Neurol 23(5):505–509. https://doi.org/10.1002/ana.410230513

    Article  CAS  PubMed  Google Scholar 

  15. Whybra C, Kampmann C, Krummenauer F, Ries M, Mengel E, Miebach E, Baehner F, Kim K, Bajbouj M, Schwarting A, Gal A, Beck M (2004) The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet 65(4):299–307. https://doi.org/10.1111/j.1399-0004.2004.00219.x

    Article  CAS  PubMed  Google Scholar 

  16. Toth C, Brussee V, Cheng C, Zochodne DW (2004) Diabetes mellitus and the sensory neuron. J Neuropathol Exp Neurol 63(6):561–573

    Article  CAS  PubMed  Google Scholar 

  17. Rahman MH, Jha MK, Kim JH, Nam Y, Lee MG, Go Y, Harris RA, Park DH, Kook H, Lee IK, Suk K (2016) Pyruvate dehydrogenase kinase-mediated glycolytic metabolic shift in the dorsal root ganglion drives painful diabetic neuropathy. J Biol Chem 291(11):6011–6025. https://doi.org/10.1074/jbc.M115.699215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Choi L, Vernon J, Kopach O, Minett MS, Mills K, Clayton PT, Meert T, Wood JN (2015) The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain. Neurosci Lett 594:163–168. https://doi.org/10.1016/j.neulet.2015.01.084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all patients for their valuable cooperation in this study. The authors thank Véronique Schwehr and Merle Brunnée for support in recruitment and examination of healthy volunteers. T.G. is supported by a postdoctoral fellowship from the Medical Faculty of the University of Heidelberg. A.K. received travel Grants and speaker honoraria from Shire, Sanofi Genzyme and Amicus. N.M. received travel Grants, research Grants and speaker honoraria from Shire, Sanofi Genzyme and Amicus. M.B. received Grants from the German Research Council (SFB 1158). J.K. received a research Grant and personal fees from Alnylam Pharmaceuticals, and personal fees from Pfizer Pharmaceuticals. S.H. was supported by a Grant from the German Research Council (SFB 1118). V.M. was supported by a Grant from the Märta and Erik Karberg Foundation for Medical Research.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Victor-Felix Mautner and Philipp Bäumer contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Neuroradiology, Neurological University Clinic, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany

    Tim Godel, Moritz Kronlage, Daniel Schwarz, Jennifer Kollmer, Sabine Heiland, Martin Bendszus & Philipp Bäumer

  2. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Anja Köhn & Nicole Muschol

  3. Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Victor-Felix Mautner

  4. Department of Radiology, German Cancer Research Institute, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Philipp Bäumer

Authors
  1. Tim Godel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anja Köhn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole Muschol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Moritz Kronlage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Schwarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer Kollmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sabine Heiland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin Bendszus
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Victor-Felix Mautner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Philipp Bäumer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tim Godel.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Godel, T., Köhn, A., Muschol, N. et al. Dorsal root ganglia in vivo morphometry and perfusion in female patients with Fabry disease. J Neurol 265, 2723–2729 (2018). https://doi.org/10.1007/s00415-018-9053-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-018-9053-y

Keywords

Search

Navigation