Multisystemic neurodegeneration caused by biallelic pentanucleotide expansions in RFC1

Herrmann, Laura; Gelderblom, Mathias; Bester, Maxim; Deininger, Natalie; Schütze, Thorsten; Hidding, Ute; Groß, Caspar; Buena-Atienza, Elena; Dufke, Claudia; Gerloff, Christian; Haack, Tobias B.; Zittel, Simone

doi:10.1016/j.parkreldis.2022.01.001

Cited by 9 publications

(17 citation statements)

References 3 publications

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“…Mild cognitive impairment has been reported in 25% of the patients with biallelic (AAGGG) exp [3], and 10.5% of the patients had moderate impairment in another study [11]. Even though these patients had not received any specific diagnosis for the cognitive disorder, their neuropsychological test results or screening test scores indicated cognitive impairment [3,5,11]. We found that four patients presented with a neuropsychological profile suggesting FTD and that two of them had a psychiatric diagnosis.…”

Section: Discussionmentioning

confidence: 62%

“…Our findings support the idea that RFC1 disease is a multisystemic neurodegenerative disorder affecting not only vestibular, cerebellar and sensory functions but also cognitive domains. Indeed, cognitive impairment may have remained undiagnosed, as a detailed neuropsychological examination is required to reveal the deficits [3,5].…”

Section: Discussionmentioning

confidence: 99%

“…The phenotype implies that cerebellum, dorsal root ganglia, and vestibular system are affected, but RFC1 appears to be associated with a multisystemic involvement [3,4]. A recent study on four CANVAS patients has suggested that RFC1-related ataxia is a multisystemic neurodegenerative disorder affecting also cognitive domains and pyramidal tract neurons [5]. Furthermore, the expansion has been found in patients with other phenotypes, such as multiple system atrophy (MSA), clinically confirmed Parkinson's disease (PD) and motor neuron pathology [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Korpioja

Krüger

Hurme-Niiranen

et al. 2022

Parkinsonism & Related Disorders

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Korpioja

Krüger

Hurme-Niiranen

et al. 2022

Parkinsonism & Related Disorders

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“…Amplified transcripts were quantified using the comparative CT method and presented as normalized fold expression change (2 ∆∆Ct ). In order to assess the allelic status of the c.2876del (p.Pro959GlnfsTer24) truncating variant mapping to exon 22 in individual II, we took advantage of the presence of a c.2511T>C (p.Ser837=) (rs2066782) synonymous variant on exon 19 (Forward: 5'-TGGGAGCCAATCAAGATATCAGA-3' Reverse: 5'-GCTGCAAACACTTTCCGGGC-3') and exon 22 (Forward: 5'-CTGGAGTCTTCTGCCTGCGC-3' Reverse:5'-GGTCAAGGGCTGTACAAGTGCA-3') using both forward and reverse primers. For comparison, PCR and sequencing of exon 19 (Forward:5'-GGTGTGCACGAAGTAAAGCA-3' Reverse:5'-ATTCCACAGGCATACCAAGG-3' ) and exon 22 ( Forward:5'-TGGATCAAGGTGTGTACCGC-3' Reverse:5'-CCCGAACAGAGTAATCCCAC -3') of RFC1 were also performed on gDNA from case II.…”

Section: Real-time Quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

“…Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult onset and slowly progressive ataxia caused by the contemporary impairment of sensory neurons, the vestibular system and the cerebellum [1][2][3] . In most cases, the disease is caused by biallelic (AAGGG) n repeat expansion in the second intron of the Replication Factor Complex subunit 1 (RFC1) gene [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] . RFC1 encodes the large subunit of replication factor C, a 5-subunit DNA polymerase accessory protein required for the coordinated synthesis of both DNA strands during replication and after DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

et al. 2023

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Introduction:Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)nrepeat expansions in the second intron of the Replication Factor Complex subunit 1 (RFC1). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expands the genotypic spectrum of CANVAS by identifying point mutations inRFC1coding region associated with this condition.Methods:Fifteen individuals diagnosed with CANVAS and carrying only one heterozygous (AAGGG)nexpansion inRFC1underwent WGS or WES to test for the presence of a second variant inRFC1or other unrelated gene. To assess the impact of truncating variants onRFC1expression we tested the level of RFC1 transcript and protein on patients’ derived cell lines.Results:We identified seven patients from five unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)nexpansion together with a second truncating variantin transinRFC1, which included: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6) and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein.Discussion:Our report expands the genotype spectrum of RFC1 disease. FullRFC1sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)nexpansions. Also, it sheds further light on the pathogenesis of RFC1 CANVAS as it supports the existence of a loss of function mechanism underlying this complex neurodegenerative condition.

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Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult‐Onset Degenerative Ataxia

et al. 2023

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A BS TRACT: Background: Sporadic adult-onset ataxias without known genetic or acquired cause are subdivided into multiple system atrophy of cerebellar type (MSA-C) and sporadic adult-onset ataxia of unknown etiology (SAOA). Objectives: To study the differential evolution of both conditions including plasma neurofilament light chain (NfL) levels and magnetic resonance imaging (MRI) markers. Methods: SPORTAX is a prospective registry of sporadic ataxia patients with an onset >40 years. Scale for the Assessment and Rating of Ataxia was the primary outcome measure. In subgroups, blood samples were taken and MRIs performed. Plasma NfL was measured via a single molecule assay. Regional brain volumes were automatically measured. To assess signal changes, we defined the pons and middle cerebellar peduncle abnormality score (PMAS). Using mixed-effects models, we analyzed changes on a time scale starting with ataxia onset. Results: Of 404 patients without genetic diagnosis, 130 met criteria of probable MSA-C at baseline and 26 during follow-up suggesting clinical conversion to MSA-C. The remaining 248 were classified as SAOA. At

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Multisystemic neurodegeneration caused by biallelic pentanucleotide expansions in RFC1

Cited by 9 publications

References 3 publications

Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Cognitive impairment is not uncommon in patients with biallelic RFC1 AAGGG repeat expansion, but the expansion is rare in patients with cognitive disease

Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome

Evolution of Clinical Outcome Measures and Biomarkers in Sporadic Adult‐Onset Degenerative Ataxia

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