Abstract Details

Title The FGF14-SCA27B GAA•TTC Repeat Shows a Marked Somatic Expansion Bias in the Cerebellum

Topic Movement Disorders

Presentation(s) S4 - Movement Disorders: Basic Science (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

Background Spinocerebellar ataxia 27B (SCA27B) is a common late-onset autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that the disease process is restricted to the cerebellum. Although the expanded repeat is highly unstable during intergenerational transmission, whether it exhibits somatic instability remains unknown.

Objective To study the somatic instability profile of the FGF14 GAA•TTC repeat across serial blood samples, fibroblasts, induced pluripotent stem cells (iPSCs), and post-mortem brains.

Design/Methods We determined the GAA•TTC repeat length and expansion index, which measures the degree of somatic expansion, on 156 serial blood samples from 69 individuals, fibroblasts and iPSCs from three SCA27B patients, and post-mortem brain tissues from six controls and six SCA27B patients. We also performed methylation analysis of FGF14 in the post-mortem cerebellar hemisphere of four controls and four SCA27B patients using targeted long-read nanopore sequencing.

Results Blood samples exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. There was minimal difference in the length of the expanded GAA•TTC tract between blood samples, fibroblasts, and iPSCs. In the brain, the GAA•TTC repeat was remarkably stable across the 15 regions analyzed, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. The levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. Furthermore, we found no significant difference in methylation of FGF14, its promoters, or the region surrounding the repeat locus between patients and controls.

Conclusions Our study revealed that the FGF14 repeat exhibits a unique cerebellar-specific expansion bias, potentially accounting for the pure cerebellar involvement in SCA27B.

Authors/Disclosures
David Pellerin, MD PRESENTER	Dr. Pellerin has nothing to disclose.
Jean-Loup Méreaux, MD	The institution of Dr. Méreaux has received research support from Fondation pour la Recherche Médicale FRM. The institution of Dr. Méreaux has received research support from Biogen.
Susana Boluda	Susana Boluda has nothing to disclose.
Matt Danzi (University of Miami)	Matt Danzi has nothing to disclose.
Marie-Josee Dicaire	Marie-Josee Dicaire has nothing to disclose.
Claire-Sophie Davoine, Engineer	Mrs. DAVOINE has nothing to disclose.
David Genís Batlle, MD	Dr. GENÍS BATLLE has nothing to disclose.
Guinevere Spurdens	Miss Spurdens has nothing to disclose.
Jillian Hammond	Ms. Hammond has nothing to disclose.
Brandon Gerhart	Mr. gerhart has nothing to disclose.
Mathilde Renaud, MD, PhD	Prof. Renaud has nothing to disclose.
Céline BONNET, MD	Prof. BONNET has nothing to disclose.
Jill S. Napierala, PhD (University of Texas Southwestern Medical Center)	Dr. Napierala has nothing to disclose.
Ira Deveson, PhD	Dr. Deveson has nothing to disclose.
Marek Napierala, PhD	The institution of Dr. Napierala has received research support from NIH and FARA.
Alexis Brice, MD	Dr. Brice has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for ICM.
Laura Molina-Porcel, MD, PhD	Dr. Molina-Porcel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen.
Danielle D. Seilhean, MD, PhD	Prof. SEILHEAN 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.
Alexandra Durr, MD (Salpetriere Hospital - Universite Pierre Et Marie Curie)	The institution of Dr. Durr has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Durr has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics. The institution of Dr. Durr has received research support from NIH. The institution of Dr. Durr has received research support from BIOGEN. The institution of Dr. Durr has received research support from MINORYX. The institution of Dr. Durr has received research support from TRIPLETS THERAPEUTICS. The institution of Dr. Durr has received research support from Servier. The institution of Dr. Durr has received research support from ANR. The institution of Dr. Durr has received research support from PTC.
Bernard Brais, MD	Dr. Brais has nothing to disclose.

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