Skip to main content

Advertisement

SpringerLink
Log in

Neuroimaging supports central pathology in familial dysautonomia

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

Abstract

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 ± 4.2 years, 3 female) and seven controls (19.1 ± 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy (1H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). 1H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

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

References

  1. Ardekani BA, Braun M, Hutton BF, Kanno I, Iida H (1995) A fully automatic multimodality image registration algorithm. J Comput Assist Tomogr 19:615–623

    Article  CAS  PubMed  Google Scholar 

  2. Ardekani BA, Guckemus S, Bachman A, Hoptman MJ, Wojtaszek M, Nierenberg J (2005) Quantitative comparison of algorithms for inter-subject registration of 3D volumetric brain MRI scans. J Neurosci Methods 142:67–76

    Article  PubMed  Google Scholar 

  3. Axelrod FB (2006) A world without pain or tears. Clin Auton Res 16:90–96

    Article  PubMed  Google Scholar 

  4. Axelrod FB, Solomon J, D’Amico R (2000) Familial dysautonomia. In: Fraunfelder FT, Roy FH, Randall J (eds) Current ocular therapy, 5th edn. WB Saunders, Philadelphia, pp 285–288

    Google Scholar 

  5. Axelrod FB, Iyer K, Fish I, Pearson J, Sein ME, Spielholz N (1981) Progressive sensory loss in familial dysatonomia. Pediatrics 65:517–522

    Google Scholar 

  6. Basser PJ, Pierpaoli C (1996) Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson 111:209–219

    Article  CAS  Google Scholar 

  7. Basser PJ, Pierpaoli C (1998) A simplified method to measure the diffusion tensor from seven MR images. Magn Reson Med 39:928–934

    Article  CAS  PubMed  Google Scholar 

  8. Baumann N, Phm-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927

    CAS  PubMed  Google Scholar 

  9. Benarroch EE (2001) Pain–autonomic interactions: a selective review. Clin Auton Res 11:343–349

    Article  CAS  PubMed  Google Scholar 

  10. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300

    Google Scholar 

  11. Bonavita S, Di Salle F, Tedeschi G (1999) Proton MRS in neurological disorders. Eur J Radiol 30:125–131

    Article  CAS  PubMed  Google Scholar 

  12. Brown WJ, Beauchemin JA, Linde LM (1964) A neuropathological study of familial dysautonomia (Riley-Day syndrome) in siblings. J Neurol Neurosurg Psychiatry 27:131–139

    Article  Google Scholar 

  13. Cheishvili D, Maayan Ch, Smith Y, Ast G, Razin A (2007) IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination. Hum Mol Genet 16:2097–2104

    Article  CAS  PubMed  Google Scholar 

  14. Clayson D, Welton W, Axelrod FB (1980) Personality development and familial dysautonomia. Pediatrics 8:636–637

    Google Scholar 

  15. Cohen P, Solomon NH (1955) Familial dysautonomia: case report with autopsy. J Pediatr 46:663–670

    Article  CAS  PubMed  Google Scholar 

  16. Convit A, McHugh PR, Wolf OT, de Leon MJ, Bobinski M, De Santi S, Roche A, Tsui W (1999) MRI volume of the amygdala: a reliable method allowing separation from the hippocampal formation. Psychiatry Res Neuroimaging 90:113–123

    Article  CAS  Google Scholar 

  17. Dong Q, Welsh RC, Chenevert TL, Carlos RC, Maly-Sundgren P, Gomez-Hassan DM, Mukherji SK (2004) Clinical applications of diffusor tensor imaging. Magn Reson Imaging 19:6–18

    Article  Google Scholar 

  18. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Roentgenol 149:351–356

    CAS  Google Scholar 

  19. Good CD, Johnsrude IS, Ashburner J, Henson RNA, Friston KJ, Frackowiak RSJ (2001) A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14:21–36

    Article  CAS  PubMed  Google Scholar 

  20. Hutchinson JH, Hamilton W (1962) Familial dysautonomia in two siblings. Lancet 1:1216–1218

    Article  Google Scholar 

  21. Irwan R, Sijens PE, Potze JH, Oudkerk M (2005) Correlation of proton MR spectroscopy and diffusion tensor imaging. Magn Reson Imaging 23:851–858

    Article  PubMed  Google Scholar 

  22. Pearson J, Pytel B (1978) Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci 39:47–59

    Article  CAS  PubMed  Google Scholar 

  23. Pearson J, Axelrod FB, Dancis J (1974) Current concepts of dysautonomia: neurological defects. Ann NY Acad Sci 228:288–300

    Article  CAS  PubMed  Google Scholar 

  24. Ramnani N, Behrens TE, Penny W, Matthews PM (2004) New approaches for exploring anatomical and functional connectivity in the human brain. Biol Psychiatry 56:613–619

    Article  PubMed  Google Scholar 

  25. Rapp B (2001) The handbook of cognitive neuropsychology: what deficits reveal about the human mind. Psychology Press, Philadelphia, p 481

    Google Scholar 

  26. Riley CM, Day RL, Greely DMcL, Langford WS (1949) Central autonomic dysfunction with defective lacrimation. Pediatrics 3:468–477

    CAS  PubMed  Google Scholar 

  27. Sands SS, Giarraffa P, Axelrod FB (2006) Quality of life issues in FD. Acta Paediatr 95:457–462

    Article  PubMed  Google Scholar 

  28. Sidaros A, Engberg AW, Sidaros K, Liptrot MG, Herning M, Petersen P, Paulson OB, Jernigan TL, Rostrup E (2008) Diffusion tensor imaging durino recovery from severe traumatic brain injury and relation to clinical outcome: a longitudinal study. Brain 131:559–572

    Article  PubMed  Google Scholar 

  29. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungo MP, Liebert CE, Chadwick B, Idelson M, Reznik L, Robbins CM, Makalowskia I, Brownstein MJ, Krappmann D, Scheidereit C, Maayan CH, Axelrod FB, Gusella J (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598–605

    Article  CAS  PubMed  Google Scholar 

  30. Solitare GB, Cohen GS (1965) Peripheral autonomic nervous system lesions in congenital or familial dysautonomia. Neurology 15:321–327

    CAS  PubMed  Google Scholar 

  31. Welton W, Clayton D, Axelrod F, Levine D (1979) Intellectual development in familial dysautonomia. Pediatrics 63:708–712

    CAS  PubMed  Google Scholar 

  32. Yatsu F, Zussman W (1964) Familial dysautonomia (Riley-Day Syndrome): case report with postmortem findings. Arch Neurol 10:459–463

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was generously supported by the Dysautonomia Foundation, Inc.

Author information

Authors and Affiliations

  1. Department of Pediatrics, New York University School of Medicine, 530 First Avenue, Suite 9Q, New York, NY, 10016, USA

    Felicia B. Axelrod & Dena Berlin

  2. Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA

    Felicia B. Axelrod & Max J. Hilz

  3. Department of Psychiatry, New York University School of Medicine, New York, NY, 10016, USA

    Max J. Hilz, Po Lai Yau, David Javier, Victoria Sweat, Hannah Bruehl & Antonio Convit

  4. Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA

    Max J. Hilz

  5. Nathan Kline Institute, Orangeburg, NY, 10962, USA

    Antonio Convit

Authors
  1. Felicia B. Axelrod
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Max J. Hilz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dena Berlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Po Lai Yau
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Javier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Victoria Sweat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hannah Bruehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Antonio Convit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felicia B. Axelrod.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Axelrod, F.B., Hilz, M.J., Berlin, D. et al. Neuroimaging supports central pathology in familial dysautonomia. J Neurol 257, 198–206 (2010). https://doi.org/10.1007/s00415-009-5293-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-009-5293-1

Keywords

Search

Navigation