Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia

Thiago J.R. Rezende, Isaac M. Adanyeguh, Filippo Arrigoni, Benjamin Bender, Fernando Cendes, Louise A. Corben, Andreas Deistung, Martin Delatycki, Imis Dogan, Gary F. Egan, Sophia L. Göricke, Nellie Georgiou-Karistianis, Pierre Gilles Henry, Diane Hutter, Neda Jahanshad, James M. Joers, Christophe Lenglet, Tobias Lindig, Alberto R.M. Martinez, Andrea MartinuzziGabriella Paparella, Denis Peruzzo, Kathrin Reetz, Sandro Romanzetti, Ludger Schöls, Jörg B. Schulz, Matthis Synofzik, Sophia I. Thomopoulos, Paul M. Thompson, Dagmar Timmann, Ian H. Harding, Marcondes C. França

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. Objective: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. Methods: We performed a cross-sectional analysis of cervical spinal cord (C1–C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. Results: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < −0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. Conclusions: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

Original languageEnglish (US)
Pages (from-to)45-56
Number of pages12
JournalMovement Disorders
Issue number1
StatePublished - Jan 2023

Bibliographical note

Funding Information:
P.M.T. and N.J. received a research grant from Biogen, Inc., unrelated to the topic of this manuscript. P.‐G.H. and C.L. received research grants from Minoryx Therapeutics. C.L. also received support by a research grant from Biogen Inc. for activities unrelated to the topic of this manuscript. L.S. served as an advisory board member for VICO Therapeutics. M.S. received consultancy honorary from Janssen Pharmaceuticals, Ionis Pharmaceuticals, and Orphazyme Pharmaceuticals, all unrelated to this manuscript.

Funding Information:
The methods of harmonization and multisite data analysis elements of this work were supported by National Institutes of Health (NIH) Big Data to Knowledge (BD2K) program grant U54 EB020403 and grants from the Australian National Health and Medical Research Council (Fellowship 1106533, Grant 1184403). FARA (Friedreich's Ataxia Research Alliance, grant 92133) and FAPESP (São Paulo Research Foundation) also supported this study through CEPID/BRAINN (grant 2013/07559‐3), the German Research Foundation (DFG; DE 2516/1‐1 and TI 239/17‐1), and the European Joint Programme on Rare Diseases, under the EJP RD COFUND‐EJP N° 825575 as part of the PROSPAX consortium (to M.S. and D.T. via DFG). Center for Magnetic Resonance Research (CMRR) at the University of Minnesota was supported by NIH grants P41 EB027061 and P30 NS076408. P.‐G.H. and C.L. also acknowledge support by grants from the FARA, GoFAR, Ataxia UK, and the Bob Allison Ataxia Research Center. The funding agencies did not interfere with the design of the study, collection of data, or drafting of the manuscript.

Publisher Copyright:
© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


  • ENIGMA-ataxia
  • Friedreich's ataxia
  • MRI
  • SCT
  • spinal cord

Center for Magnetic Resonance Research (CMRR) tags

  • ANDI

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia'. Together they form a unique fingerprint.

Cite this