Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan

Ando, Masahiro; Higuchi, Yujiro; Yuan, Jun‐Hui; Yoshimura, Akinobu; Higashi, Shuntaro; Takeuchi, Mika; Hobara, Takahiro; Kojima, Fumikazu; Noguchi, Yutaka; Takei, Jun; Hiramatsu, Yoshihiro; Nozuma, Satoshi; Sakiyama, Yusuke; Hashiguchi, Akihiro; Matsuura, Eiji; Okamoto, Yuji; Nagai, Masahiro; Takashima, Hiroshi

doi:10.3389/fneur.2022.952493

Cited by 8 publications

(14 citation statements)

References 23 publications

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“…Subsequently, the remaining undiagnosed patients without a family history of autosomal dominant inheritance were screened for RFC1 repeat expansions. The detailed workflow has been described previously, 8 , 9 and the study flowchart is shown in Figure 1A . Age of onset distribution in our cerebellar ataxia cohort are summarized in Table S1 .…”

Section: Methodsmentioning

confidence: 99%

“…In Japan, approximately 73% of patients with hereditary ataxia, including late‐onset cerebellar ataxia, remain undiagnosed. 8 Based on recent advancements, we conducted a thorough analysis of the FGF14 GAA repeat expansion using a diagnostic strategy integrating long‐range polymerase chain reaction (LR‐PCR), repeat‐primed PCR (RP‐PCR), and long‐read sequencing using Oxford Nanopore Technology platforms. We successfully identified FGF14 pathogenic repeat expansions from 12 patients who exhibited remarkable clinical variability.…”

Section: Introductionmentioning

confidence: 99%

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Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Ando,

Higuchi,

Yuan

et al. 2023

Ann Clin Transl Neurol

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Background and ObjectivesThe GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late‐onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan.MethodsWe collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat‐primed PCR, and long‐read sequencing.ResultsPathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270–316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow‐up study conducted after a mean period of 6 years did not reveal any significant progression.DiscussionThis study highlights the importance of FGF14 GAA repeat analysis in patients with late‐onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA‐FGF14‐related diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Ando,

Higuchi,

Yuan

et al. 2023

Ann Clin Transl Neurol

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“…Genetically undiagnosed younger onset cases were also included because such cases have been reported as positive for RFC1 expansions. 13 - 15 In addition, the growing number of studies performed thus far on this relatively recently described disease indicated an expansion of the phenotypic spectrum and the genetic heterogeneity, which possibly remain not fully elucidated. 10 , 12 , 13 , 15 , 26 - 30 Therefore, we cannot exclude the possibility of identifying positive younger-age cases.…”

Section: Discussionmentioning

confidence: 99%

“… 13 - 15 In addition, the growing number of studies performed thus far on this relatively recently described disease indicated an expansion of the phenotypic spectrum and the genetic heterogeneity, which possibly remain not fully elucidated. 10 , 12 , 13 , 15 , 26 - 30 Therefore, we cannot exclude the possibility of identifying positive younger-age cases. Ten out of 194 patients tested (5.2%) have been diagnosed with the pathogenic AAGGG repeat expansion in a homozygous state.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, it has been suggested that phenotypic overlap is more likely to exist between diseases (i.e., CMT and an RFC1 -related disease with somatosensory loss; MSA and an RFC1 -related disease with autonomic dysfunction and/or parkinsonism). 10 Furthermore, while the reported mean age at onset is high in most of the cases, patients with an earlier age at onset, such as the third decade or even earlier at 19, 13 15, 14 or 10 years old, 15 have been described. It is also remarkable that smaller repeat expansion lengths (100–160 AAGGG repeats) have been reported as disease-causative for MSA.…”

Section: Introductionmentioning

confidence: 99%

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RFC1 Repeat Distribution in the Cypriot Population

Votsi,

Tomazou,

Nicolaou

et al. 2024

Neurol Genet

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Background and Objectives The intronic biallelic AAGGG expansion in the replication factor C subunit 1 ( RFC1 ) gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known. Our main objectives were to study the prevalence of the pathogenic AAGGG expansion in the Cypriot population, to further characterize the RFC1 repeat locus allele distribution, and to search for possible novel repeat configurations. Methods Cypriot undiagnosed patients, in the majority presenting at least with cerebellar ataxia and non-neurologic disease controls, were included in this study. A combination of conventional methods was used, including standard PCR flanking the repeat region, repeat-primed PCR, long-range PCR, and Sanger sequencing. Bioinformatics analysis of already available in-house short-read whole-genome sequencing data was also performed. Results A large group of undiagnosed patients (n = 194), mainly presenting with pure ataxia or with ataxia accompanied by neuropathy or additional symptoms, as well as a group of non-disease controls (n = 100), were investigated in the current study. Our findings include the diagnosis of 10 patients homozygous for the pathogenic AAGGG expansion and a high percentage of heterozygous AAGGG carriers in both groups. The benign AAAAG n , AAAGG n , and AAGAG n configurations were also identified in our cohorts. We also report and discuss the identification of 2 recently reported novel and possibly benign repeat configurations, AAAGGG n and AAGAC n , thus confirming their existence in another distinct population, and we highlight an increased frequency of the AAAGGG n in the patient group, including a single case of homozygosity. Discussion Our findings indicate the existence of genetic heterogeneity regarding the RFC1 repeat configurations and that the AAGGG pathogenic expansion is a frequent cause of ataxia in the Cypriot population.

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RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia

Milovanović,

Dragaševic‐Mišković,

Thomsen

et al. 2024

Movement Disord Clin Pract

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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.

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Genetic and clinical features of cerebellar ataxia with RFC1 biallelic repeat expansions in Japan

Cited by 8 publications

References 23 publications

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan

RFC1 Repeat Distribution in the Cypriot Population

RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia

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