RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia

Author:

Milovanović Andona1ORCID,Dragaševic‐Mišković Nataša12,Thomsen Mirja3,Borsche Max34ORCID,Hinrichs Frauke3,Westenberger Ana3ORCID,Klein Christine3,Brüggemann Norbert34ORCID,Branković Marija1,Marjanović Ana1,Svetel Marina12,Kostić Vladimir S.12,Lohmann Katja3ORCID

Affiliation:

1. Neurology Clinic University Clinical Center of Serbia Belgrade Serbia

2. Medical Faculty University Belgrade Belgrade Serbia

3. Institute of Neurogenetics University of Lübeck Lübeck Germany

4. Department of Neurology University of Lübeck and University Hospital Schleswig‐Holstein, Campus Lübeck Lübeck Germany

Abstract

AbstractBackgroundThe newly discovered intronic repeat expansions in the genes encoding replication factor C subunit 1 (RFC1) and fibroblast growth factor 14 (FGF14) frequently cause late‐onset cerebellar ataxia.ObjectivesTo investigate the presence of RFC1 and FGF14 pathogenic repeat expansions in Serbian patients with adult‐onset cerebellar ataxia.MethodsThe study included 167 unrelated patients with sporadic or familial cerebellar ataxia. The RFC1 repeat expansion analysis was performed by duplex PCR and Sanger sequencing, while the FGF14 repeat expansion was tested for by long‐range PCR, repeat‐primed PCR, and Sanger sequencing.ResultsWe identified pathogenic repeat expansions in RFC1 in seven patients (7/167; 4.2%) with late‐onset sporadic ataxia with neuropathy and chronic cough. Two patients also had bilateral vestibulopathy. Repeat expansions in FGF14 were found in nine unrelated patients (9/167; 5.4%) with ataxia, less than half of whom presented with neuropathy and two‐thirds with global brain atrophy. Tremor and episodic features were the most frequent additional characteristics in carriers of uninterrupted FGF14 repeat expansions. Among the 122 sporadic cases, 12 (9.8%) carried an expansion in either RFC1 or FGF14, comparable to 4/45 (8.9%) among the patients with a positive family history.ConclusionsPathogenic repeat expansions in RFC1 and FGF14 are relatively frequent causes of adult‐onset cerebellar ataxia, especially among sporadic patients, indicating that family history should not be considered when prioritizing ataxia patients for testing of RFC1 or FGF14 repeat expansions.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Wiley

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