RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia

Abstract

BackgroundThe 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.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia

“…Previous studies had shown that GAA-FGF14 ataxia may not be as common in the Japanese ataxia cohort (1.1%) [10]. In this study, GAA-FGF14 ataxia comprised only 0.3% (2/664) of our Chinese undiagnosed LOCA cohort, which was substantially lower than the French Canadian ataxia cohort (61%), European ataxia cohorts (5.4-51%), Indian ataxia cohort (10%), Brazilian ataxia cohorts (9%) and Australian ataxia cohorts (9.5%) [1,[3][4][5][6][7]. As we were preparing this report, we noticed that another research group found the low frequency (1.3%) of GAA-FGF14 ataxia in Chinese LOCA cohort [9].…”

“…Expansion of intronic pure GAA repeats (expansion ≥250 triples) in FGF14 (GAA-FGF14) has been demonstrated to interfere with FGF14 transcription, resulting in GAA-FGF14 ataxia [1]. Although GAA-FGF14 ataxia was shown to be a common cause of SCA in French Canadian ataxia cohort (61%) [1] and European ataxia cohorts (5.4-51%) [3][4][5][6][7], it appeared relatively uncommon in Chinese (1.3%) and Japanese (1.1%) populations [8][9][10].…”