Biallelic <scp><i>RFC1</i></scp> pentanucleotide repeat expansions in Greek patients with late‐onset ataxia

Kontogeorgiou, Zoi; Kartanou, Chrisoula; Tsirligkani, Chrysanthi; Anagnostou, Evangelos; Rentzos, Michael; Stefanis, Leonidas; Karadima, Georgia

doi:10.1111/cge.13960

Cited by 14 publications

(18 citation statements)

References 12 publications

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“…It is notable that our diagnostic yield of RFC1 repeat expansions was lower than that in other ataxia cohorts (1.8 vs. 3.2-22%) (1,(18)(19)(20). This may be accounted for by the inclusion of cases with MSA in our case series, and the predominant sporadic cases (80%) without family history and consanguinity.…”

Section: Discussionmentioning

confidence: 59%

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

Ando

Higuchi²,

Yuan³

et al. 2022

Front. Neurol.

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The recessive intronic pentanucleotide repeat AAGGG expansion of replication factor complex subunit 1 (RFC1) is associated with cerebellar ataxia, sensory neuropathy, and vestibular areflexia syndrome. And the clinical spectrum has been continuously expanding. We conducted this study to demonstrate the clinical and genetic features of a large-scale case series of Japanese patients with cerebellar ataxia with RFC1 repeat expansions. We examined 1,289 Japanese patients with cerebellar ataxia and analyzed RFC1 repeat expansions in 840 patients, excluding those with genetic diagnoses or an autosomal dominant inheritance pattern. For individuals where no product was obtained by flanking polymerase chain reaction (PCR), repeat-primed PCR was performed using primers specific for the following four repeat motifs: AAAAG, AAAGG, AAGGG, and ACAGG. RFC1 analysis revealed multitype biallelic pathogenic repeat expansions in 15 patients, including (AAGGG)exp/(AAGGG)exp in seven patients, (ACAGG)exp/(ACAGG)exp in three patients, (AAGGG)exp/(ACAGG)exp in four patients, and (AAGGG)exp/(AAAGG)15(AAGGG)exp in one patient. Clinical analysis showed various combinations of cerebellar ataxia, vestibular dysfunction, neuropathy, cognitive decline, autonomic dysfunction, chronic cough, pyramidal tract disorder, parkinsonism, involuntary movement, and muscle fasciculation. Pathological RFC1 repeat expansions account for 1.8% (15/840) of undiagnosed patients with cerebellar ataxia and sporadic/recessive/unclassified inheritance. Screening of RFC1 repeat expansions should be considered in patients with cerebellar ataxia, irrespective of their subtype and onset age.

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Section: Discussionmentioning

confidence: 59%

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

Ando

Higuchi²,

Yuan³

et al. 2022

Front. Neurol.

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“…The true prevalence of this phenotype in RFC1 -related disease is currently difficult to gauge because the recent retrospective studies, by their very nature, lack consistent data on formal vestibular function testing and may be under-recognizing the presence of peripheral vestibular hypofunction. 4 , 13 , 16 Of interest Gisatulin et al 8 reported this phenotypic combination in one of the only studies to date where all participants have received objective vestibular assessment.…”

Section: Major Phenotypic Characteristics Of Rfc1 ...mentioning

confidence: 99%

“…Unfortunately, several studies have neglected to perform the relevant investigations and have instead relied on bedside assessments or incompletely described methodology. 4,[10][11][12][13]16 Key examples of this are the clinical vs video head impulse test (HIT) and the bedside vs electrophysiologic assessment of somatosensory function. 40,41 The exception here may be an absence of cerebellar atrophy on MRI in the early stage of cerebellar disease where bedside examination findings may be more sensitive than MRI findings.…”

Section: Neuropathologymentioning

confidence: 99%

“…Notably, the phenotypic spectrum associated with RFC1 expansions has broadened beyond the classical CAN-VAS presentation. Allowing for the fact that dysautonomia and a chronic cough was described in the early CANVAS literature, 6,7 biallelic RFC1 expansions have been reportedly associated with ataxia of purely cerebellar origin, 8,9 isolated somatosensory (because both peripheral neuropathy and neuronopathy [ganglionopathy] have been reported in RFC1related disease, the term somatosensory, which covers both pathologies, is used) impairment, [10][11][12] and combinations of the 2, 9,[13][14][15][16] in addition to parkinsonism. [17][18][19][20][21] Therefore, it can be difficult to both decide who is appropriate to test and where to source molecular testing.…”

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confidence: 99%

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RFC1 -Related Disease

et al. 2022

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In 2019, a biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). In addition, biallelic expansions were shown to account for up to 22% of cases with late-onset ataxia. Since this discovery, the phenotypic spectrum reported to be associated with RFC1 expansions has extended beyond the initial conditions to include pure cerebellar ataxia, isolated somatosensory impairment, combinations of the 2, and parkinsonism, leading to a potentially broad differential diagnosis. Genetic studies suggest RFC1 expansions may be the most common genetic cause of ataxia and are likely underdiagnosed. This review summarizes the current molecular and clinical knowledge of RFC1-related disease, with a focus on the evaluation of recent phenotype associations and highlighting the current challenges in clinical pathways to diagnosis and molecular testing.

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“…Most recently, two European groups demonstrated that bi-allelic [(AAGGG)exp/(AAGGG)exp] of RFC1 account for 30–34% of their patients with pure sensory ataxic neuropathy or idiopathic axonal polyneuropathy ( 8 , 24 ). Our findings further supported their observation, albeit not as high as their prevalence, and validated its commonness not only in European studies but also in Asian studies.…”

Section: Discussionmentioning

confidence: 99%

Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy

et al. 2022

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Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

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Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late‐onset ataxia

Cited by 14 publications

References 12 publications

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

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

RFC1 -Related Disease

Multi-type RFC1 repeat expansions as the most common cause of hereditary sensory and autonomic neuropathy

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