Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy

Background GAA- FGF14 ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA- FGF14 ataxia is now needed to provide supportive diagnostic features and earlier disease recognition. Methods We performed a retrospective review of the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) to assess the presence of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles (SCPs) involvement, we verified its presence in 54 GAA- FGF14 ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we performed quantitative cerebellar segmentation in 5 affected subjects with available 3D T1-weighted images and matched controls. Results Cerebellar atrophy was documented in 33 subjects (94.3%). We observed SCP involvement in 22 subjects (62.8%) and confirmed this finding in 30/54 (55.6%) subjects from the validation cohorts. Cerebellar segmentation showed reduced mean volumes of lobules X and IV in the 5 affected individuals. Conclusions Cerebellar atrophy is a key feature of GAA- FGF14 ataxia. The frequent SCP involvement observed in different cohorts may facilitate the diagnosis. The predominant involvement of lobule X correlates with the frequently observed downbeat nystagmus. ### Competing Interest Statement A. Duquette has received consultancy honoraria from AavantiBio, Novartis, Pfizer Canada, PTC Therapeutics, and Reata Pharmaceuticals, all unrelated to the present manuscript. M. Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, and Solaxa, all unrelated to the present manuscript. B. Bender is Co-Founder, shareholder and CTO of AIRAmed GmbH. R. La Piana has received speaking honoraria from Novartis unrelated to the present manuscript. ### Funding Statement D. Pellerin has received a fellowship award from the Canadian Institutes of Health Research (CIHR). B. Brais has received funds from the Fondation Groupe Monaco and the Canadian Institutes of Health Research (grant 189963). M.C. Danzi and S. Zuckner were supported by the NIH National Institutes of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to S.Z.) and the NIH National Human Genome Research Institute (grant R21HG013397). M.Synofzik and B. Brais were supported by the European Joint Programme on Rare Diseases, as part of the PROSPAX consortium, under the EJP RD COFUND-EJP No 825575 (DFG, German Research Foundation, No 441409627). R. La Piana has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec en Sante (FRQS), and research funds from the Canadian Radiological Foundation, Canadian Institutes of Health Research (grant 506913), Ataxia Canada, the Spastic Paraplegia Foundation and Roche Canada. The authors thank the patients and their families for participating in this study. ### 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: The ethics committee of the Montreal Neurological Hospital-Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.