GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohortResearch in context
David Pellerin,
Felix Heindl,
Carlo Wilke,
Matt C. Danzi,
Andreas Traschütz,
Catherine Ashton,
Marie-Josée Dicaire,
Alexanne Cuillerier,
Giulia Del Gobbo,
Kym M. Boycott,
Jens Claassen,
Dan Rujescu,
Annette M. Hartmann,
Stephan Zuchner,
Bernard Brais,
Michael Strupp,
Matthis Synofzik
Affiliations
David Pellerin
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
Felix Heindl
Department of Neurology and German Center for Vertigo and Balance Disorders, University Hospital, Ludwig-Maximilians University, Munich, Germany
Carlo Wilke
Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Matt C. Danzi
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Andreas Traschütz
Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Catherine Ashton
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Neurology, Royal Perth Hospital, Perth, WA, Australia
Marie-Josée Dicaire
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada
Alexanne Cuillerier
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Giulia Del Gobbo
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Kym M. Boycott
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
Jens Claassen
Department of Neurology, University Hospital Essen, University Duisburg-Essen, Essen, Germany; MediClin Klinik Reichshof, Reichshof-Eckenhagen, Germany
Dan Rujescu
Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
Annette M. Hartmann
Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria
Stephan Zuchner
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
Bernard Brais
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada; Centre de Réadaptation Lucie-Bruneau, Montreal, QC, Canada
Michael Strupp
Department of Neurology and German Center for Vertigo and Balance Disorders, University Hospital, Ludwig-Maximilians University, Munich, Germany
Matthis Synofzik
Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Corresponding author. Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
Summary: Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. Findings: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52–30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23–5.41; Fisher's exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49–21.27; Fisher's exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo. Interpretation: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease. Funding: This work was supported by the Clinician Scientist program “PRECISE.net” funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 “Solve-RD” from the European’s Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and—as associated partner—SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.
