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Open Access 21-02-2024 | Downbeat Nystagmus | Letter to the Editors

RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile

Authors: David Pellerin, Felix Heindl, Andreas Traschütz, Dan Rujescu, Annette M. Hartmann, Bernard Brais, Henry Houlden, Claudia Dufke, Olaf Riess, Tobias Haack, Michael Strupp, Matthis Synofzik

Published in: Journal of Neurology | Issue 5/2024

Abstract

Objectives

The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients (“idiopathic”), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome.

Methods

We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN.

Results

Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients.

Discussion

Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.

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Title: RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile
Authors: David Pellerin
Felix Heindl
Andreas Traschütz
Dan Rujescu
Annette M. Hartmann
Bernard Brais
Henry Houlden
Claudia Dufke
Olaf Riess
Tobias Haack
Michael Strupp
Matthis Synofzik
Publication date: 21-02-2024
Publisher: Springer Berlin Heidelberg
Keywords: Downbeat Nystagmus
Bilateral Vestibulopathy
Polyneuropathy
Published in: Journal of Neurology / Issue 5/2024
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-024-12229-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile

Abstract

Objectives

Methods

Results

Discussion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Discussion

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