Abstract Details

Title GAA-FGF14 Disease: Defining Its Frequency, Molecular Basis, and 4-aminopyridine Response in a Large Cohort of Patients with Downbeat Nystagmus

Topic Movement Disorders

Presentation(s) P6 - Poster Session 6 (8:00 AM-9:00 AM)

Poster/Presentation
Number 3-013

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)_≥250expansions, 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)_200-249expansions may cause GAA-FGF14 disease. Finally, it provides additional evidence for treatment efficacy of 4-aminopyridine in GAA-FGF14 disease.

Authors/Disclosures
David Pellerin, MD PRESENTER	Dr. Pellerin has nothing to disclose.
Felix Heindl	Felix Heindl has nothing to disclose.
Carlo Wilke	No disclosure on file
Matt Danzi (University of Miami)	Matt Danzi has nothing to disclose.
Andreas Traschutz, MD (University of Bonn)	No disclosure on file
Catherine Ashton, MBBS (Catherine Ashton)	Dr. Ashton has nothing to disclose.
Marie-Josee Dicaire	Marie-Josee Dicaire has nothing to disclose.
Alexanne Cuillerier (Children's Hospital of Eastern Ontario Research Institute)	No disclosure on file
Giulia Del Gobbo	No disclosure on file
Kym Boycott	No disclosure on file
Jens Claassen ("LMU, Universitaet Muenchen")	No disclosure on file
Dan Rujescu	Dan Rujescu has nothing to disclose.
Annette Hartmann (Medical University of Vienna)	Annette Hartmann has nothing to disclose.
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
Bernard Brais, MD	Dr. Brais has nothing to disclose.
Michael Strupp, MD, DO, FAAN (Hospital of the Ludwig Maximilians University, Munich, Dept of Neurology)	Dr. Strupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertify. Dr. Strupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for IntraBio. Dr. Strupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Vifor, Frisenius, CH. Dr. Strupp has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Dr. Strupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers. Dr. Strupp has stock in IntraBio.
Matthis Synofzik (Hertie-Institute for Clinical Brain Research)	Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen Pharmaceuticals. Matthis Synofzik has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Orphayzme Pharmaceuticals. The institution of Matthis Synofzik has received research support from EJPRD.

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