Spinal cord damage in Friedreich’s ataxia: Results from the ENIGMA-Ataxia

Objective Spinal cord damage is a hallmark of Friedreich ataxia (FRDA), but its progression and clinical correlates remain unclear. Here we performed a characterization of cervical spinal cord structural abnormalities in a large multisite FRDA cohort. Methods We performed a cross-sectional analysis of cervical spinal cord (C1 to C4) cross-sectional area (CSA) and eccentricity using MRI data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched controls. 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 controls, 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, while CSA appears to decrease progressively, eccentricity remains stable over time. Interpretation 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 DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas 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. ### Competing Interest Statement PMT and NJ received a research grant from Biogen, Inc., unrelated to the topic of this manuscript. PGH and CL received research grants from Minoryx Therapeutics. CL also received support by a research grant from Biogen Inc. for activities unrelated to the topic of this manuscript. LS served as an advisory board member for VICO Therapeutics. MS received consultancy honorary from Janssen Pharmaceuticals, Ionis Pharmaceuticals and Orphazyme Pharmaceuticals, all unrelated to this manuscript. ### Funding Statement The methods of harmonization and multi-site data analysis elements of this work were supported by NIH Big Data to Knowledge (BD2K) program grant number 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 (Sao 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 by the European Joint Programme on Rare Diseases (EJPRD), under the EJP RD COFUND-EJP N 825575 as part of the PROSPAX consortium (to M.S. and D.T. via DFG, German Research Foundation). CMRR at the University of Minnesota is supported by grants NIH P41 EB027061 and P30 NS076408. PGH and CL also acknowledge support by grants from the FARA, GoFAR, Ataxia UK and the Bob Allison Ataxia Research Center. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data collection, analysis, and contributions to this project were approved by the human research ethics body at each site as defined here: Aachen (IRB RWTH Aachen University, project EK 083/15); Campinas (IRB University of Campinas, project CAAE 29869520.8.3001.5404); Conegliano (IRB IRCCS Eugenio Medea, project 155/CE-Medea); Essen (IRB Essen University Hospital, project 15-6404-BO); Melbourne (IRB Monash Health, project #13201B)15; Minnesota (IRB University of Minnesota, STUDY00009047); Tubingen (IRB University of Tuebingen, project 598/2011BO1). Multisite data aggregation and analysis was approved the Monash University Human Research and Ethics Committee (project #12372). All data was fully anonymized prior to aggregation, including assignment of new subject identifier codes. 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