GAA-FGF14 Disease: Defining Its Frequency, Molecular Basis, and 4-aminopyridine Response in a Large Cohort of Patients with Downbeat Nystagmus
David Pellerin1, Felix Heindl2, Carlo Wilke3, Matt Danzi4, Andreas Traschutz3, Catherine Ashton5, Marie-Josee Dicaire1, Alexanne Cuillerier6, Giulia Del Gobbo6, Kym Boycott6, Jens Claassen7, Dan Rujescu8, Annette Hartmann9, Stephan Zuchner4, Bernard Brais1, Michael Strupp2, Matthis Synofzik3
1Department of Neurology and Neurosurgery, McGill University, 2Department of Neurology and German Center for Vertigo and Balance Disorders, Ludwig-Maximilians University, 3University of Tübingen, 4University of Miami School of Medicine, 5Department of Neurology, Royal Perth Hospital, 6Children’s Hospital of Eastern Ontario Research Institute, 7University Duisburg-Essen, 8Medical University of Vienna, Dept. Psychiatry and Psychotherapy, 9Medical University of Vienna
Objective:
Reassess the clinical and molecular spectrum of GAA-FGF14 disease by studying the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in patients with idiopathic downbeat nystagmus (DBN) syndromes and their phenotypic spectrum. Provide real-world and placebo-controlled data on 4-aminopyridine treatment response.
Background:
GAA-FGF14 disease/SCA27B is a novel neurodegenerative condition caused by FGF14 (GAA)≥250 expansions, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be determined. With 30% of DBN cases remaining etiologically undiagnosed (“idiopathic”), DBN syndromes may represent a common endophenotypic cluster of GAA-FGF14 disease.
Design/Methods:
Multi-modal cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping, assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomized double-blind 4-aminopyridine trial, and genotyping of the FGF14 repeat.
Results:
Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in the DBN cohort. Additional cerebellar oculomotor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of (GAA)≥250-FGF14 patients. FGF14 (GAA)200-249 expansions were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2,191; OR, 15.20; 95%CI, 7.52-30.80; p=9.876e-14). The phenotype of (GAA)200-249-FGF14 patients closely mirrored that of (GAA)≥250-FGF14 patients. (GAA)≥250-FGF14 and (GAA)200-249-FGF14 patients showed a substantial clinician-reported (80%, 33/41) and self-reported (59%, 32/54) response to 4-aminopyridine treatment, significantly greater compared to (GAA)<200-FGF14 patients (31%, 5/16; OR, 8.63; 95%CI, 2.08-41.96; p=0.001; and 11%, 2/19; OR, 11.96; 95%CI, 2.45-117.27; p=0.0003, respectively). Placebo-controlled video-oculography data of four (GAA)≥250-FGF14 patients showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo.
Conclusions:
This study shows that FGF14 GAA expansions are a highly frequent genetic cause of DBN syndromes and defines DBN as a common endophenotypic cluster of GAA-FGF14 disease. It provides preliminary evidence that FGF14 (GAA)200-249 expansions may cause GAA-FGF14 disease. Finally, it provides additional evidence for treatment efficacy of 4-aminopyridine in GAA-FGF14 disease.