Keywords Cerebellar ataxia, neuropathy,...

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome
Mitsuhiro Aoki, Kyoko Maruta, Muhamad Asem Almansour
More than 90% of replication factor c subunit 1 (RFC1) gene-related spectrum disorders such as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) have bilateral vestibular dysfunction. A case with CANVAS presented in this paper showed repeat extension of AAGGG in the intron region of the RFC1 gene, and showed bilateral vestibular dysfunction in caloric test, vestibular evoked myogenic potential, video Head Impulse Test and rotary chair test. Visual enhanced vestibulo-ocular reflex tests also revealed abnormalities, suggesting the presence of combined lesions of the cerebellum and brainstem including vestibular nuclei...
November 2022: Brain and Nerve, Shinkei Kenkyū No Shinpo
Mitsunori Yamada
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by neuropathological changes such as loss of Purkinje cells and degeneration of the posterior column of the spinal cord. In the peripheral nervous system, CANVAS is associated with loss of ganglion cells in the dorsal root and vestibular ganglia. Some patients may show degeneration of the inferior olivary nucleus, corticospinal tracts, and the facial and trigeminal ganglia. Further research is warranted to determine whether differences in lesion distribution are attributable to differences in genetic abnormalities and their combinations...
November 2022: Brain and Nerve, Shinkei Kenkyū No Shinpo
Satoko Miyatake, Naomichi Matsumoto
Biallelic intronic repeat expansion in the RFC1 gene was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Its clinical features include late-onset cerebellar ataxia, sensory neuropathy (or neuronopathy), bilateral vestibular impairment, autonomic dysfunction, chronic cough, pyramidal sign, or parkinsonism. Repeat conformations heterogeneity is observed along with the possible phenotype-genotype correlation while its molecular pathogenesis remains uncovered...
November 2022: Brain and Nerve, Shinkei Kenkyū No Shinpo
Kunihiro Yoshida
Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) refers to a multi-system neurodegenerative disorder, with middle-age onset, which mainly presents with progressive imbalance. Imbalance is attributable to isolated or combined impairment of the cerebellar, proprioceptive, and vestibular systems. Chronic spasmodic cough, which usually precedes neurological symptoms, serves as a useful diagnostic clue to CANVAS. Diagnostic criteria have been proposed for CANVAS in 2016, based on 3 cardinal features...
November 2022: Brain and Nerve, Shinkei Kenkyū No Shinpo
Riccardo Ronco, Cecilia Perini, Riccardo Currò, Natalia Dominik, Stefano Facchini, Alice Gennari, Roberto Simone, Skye Stuart, Sara Nagy, Elisa Vegezzi, Ilaria Quartesan, Amar El-Saddig, Timothy Lavin, Arianna Tucci, Agnieszka Szymura, Luiz Eduardo Novis De Farias, Alexander Gary, Megan Delfeld, Priscilla Kandikatla, Nifang Niu, Sanjukta Tawde, Joseph Shaw, James Polke, Mary M Reilly, Nick W Wood, Emmanuele Crespan, Christopher Gomez, Jin Yun Helen Chen, Jeremy Dan Schmahmann, David Gosal, Henry Houlden, Soma Das, Andrea Cortese
BACKGROUND AND OBJECTIVE: 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)n repeat 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...
January 31, 2023: Neurology
Ana Arteche-López, Almudena Avila-Fernandez, Alejandra Damian, Emma Soengas-Gonda, Rubén Pérez de la Fuente, Patricia Ramos Gómez, Jesús Gallego Merlo, Laura Horcajada Burgos, Carlos Cemillán Fernández, Jose Miguel Lezana Rosales, Juan Francisco González Martínez, Juan Francisco Quesada-Espinosa, Marta Corton, Maria Paz Guerrero-Molina
The biallelic pathogenic repeat (AAGGG)400-2000 intronic expansion in the RFC1 gene has been recently described as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and as a major cause of late-onset ataxia. Since then, many heterozygous carriers have been identified, with an estimated allele frequency of 0.7% to 4% in the healthy population. Here, we describe in two affected CANVAS sisters the presence of the nonsense c.724C > T p.(Arg242*) variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene...
February 2023: Clinical Genetics
Christopher J Record, Rana Alnasser Alsukhni, Riccardo Curro, Diego Kaski, John S Rubin, Huw R Morris, Andrea Cortese, Valeria Iodice, Mary M Reilly
Biallelic repeat expansions in replication factor C subunit 1 (RFC1) have recently been found to cause cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Additional features that have been described include Parkinsonism and a multiple system atrophy (MSA)-like syndrome. CANVAS can include features of dysautonomia, but they are much milder than typically seen in MSA. We report a detailed autonomic phenotype of multisystem RFC1-related disease presenting initially as CANVAS. Our patient presented aged 61 with a sensory ataxic neuropathy who rapidly developed widespread autonomic failure and Parkinsonism...
December 2022: Journal of the Peripheral Nervous System: JPNS
Anita Korpioja, Johanna Krüger, Anri Hurme-Niiranen, Eino Solje, Kasper Katisko, Joonas Lipponen, Maria Lehtilahti, Anne M Remes, Kari Majamaa, Laura Kytövuori
INTRODUCTION: The biallelic repeat expansion (AAGGG)exp in RFC1 causes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recently, cognitive impairment has been reported in patients with CANVAS and a broader neurodegenerative process associated with RFC1 has been suggested. Furthermore, rare cases of multiple system atrophy, Parkinson's disease, amyotrophic lateral sclerosis or CANVAS with features of dementia with Lewy bodies have been found. OBJECTIVE: We hypothesized that the biallelic (AAGGG)exp is associated with neurodegeneration manifested as cognitive symptoms and that atypical RFC1 disease may be found among patients with cognitive disorder...
October 2022: Parkinsonism & related Disorders
Kayli Davies, David J Szmulewicz, Louise A Corben, Martin Delatycki, Paul J Lockhart
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...
October 2022: Neurology. Genetics
Masahiro Ando, Yujiro Higuchi, Junhui H Yuan, Akiko Yoshimura, Shuntaro Higashi, Mika Takeuchi, Takahiro Hobara, Fumikazu Kojima, Yutaka Noguchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Masahiro Nagai, Hiroshi Takashima
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...
2022: Frontiers in Neurology
Laurent Magy, Pauline Chazelas, Laurence Richard, Nathalie Deschamps, Simon Frachet, Jean-Michel Vallat, Corinne Magdelaine, Frédéric Favreau, Flavien Bessaguet, Anne-Sophie Lia, Mathilde Duchesne
CANVAS, a rare disorder responsible for late-onset ataxia of autosomal recessive inheritance, can be misdiagnosed. We investigated a series of eight patients with sensory neuropathy and/or an unexplained cough, who appeared to suffer from CANVAS, and we emphasized the clinical clues for early diagnosis. Investigations included clinical and routine laboratory analyses, skin biopsy, nerve biopsy and molecular genetics. The eight patients had clinical and/or laboratory evidence of sensory neuronopathy. All but one had neuropathic pain that had started in an asymmetric fashion in two patients...
August 22, 2022: Biomedicines
Jean-Christophe Antoine
PURPOSE OF REVIEW: To stress on the diagnostic strategy of sensory neuronopathies (SNN), including new genes and antibodies. RECENT FINDING: SNN involve paraneoplastic, dysimmune, toxic, viral and genetic mechanisms. About one-third remains idiopathic. Recently, new antibodies and genes have reduced this proportion. Anti-FGFR3 and anti-AGO antibodies are not specific of SNN, although SNN is predominant and may occur with systemic autoimmune diseases. These antibodies are the only marker of an underlying dysimmune context in two-thirds (anti-FGFR3 antibodies) and one-third of the cases (anti-AGO antibodies), respectively...
October 1, 2022: Current Opinion in Neurology
Mehdi Benkirane, Dylan Da Cunha, Cecilia Marelli, Lise Larrieu, Mathilde Renaud, Jessica Varilh, Morgane Pointaux, David Baux, Olivier Ardouin, Charles Vangoethem, Magali Taulan, Benjamin Daumas Duport, Anne Bergougnoux, Anne-Gaelle Corbillé, Mireille Cossée, Raul Juntas Morales, Sylvie Tuffery-Giraud, Michel Koenig, Bertrand Isidor, Marie-Claire Vincent
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction...
November 21, 2022: Brain
Melissa Barghigiani, Giovanna De Michele, Alessandra Tessa, Tommasina Fico, Gemma Natale, Francesco Saccà, Chiara Pane, Nunzia Cuomo, Anna De Rosa, Sabina Pappatà, Giuseppe De Michele, Filippo M Santorelli, Alessandro Filla
We screened 62 late-onset ataxia patients for the AAGGG pathological expansion in the RFC-1 gene that, when biallelic, causes Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS). Nine patients tested positive. Six had a previous diagnosis of sporadic adult-onset ataxia (SAOA) and three of multisystem atrophy type C (MSA-C). Further six patients were heterozygous for the pathological RFC-1 expansion, four with an initial diagnosis of MSA-C and two of SAOA. In comparison with CANVAS, MSA-C patients had faster progression and shorter disease duration to walking with aids...
October 2022: Journal of Neurology
Fabiana Colucci, Daniela Di Bella, Chiara Pisciotta, Elisa Sarto, Francesca Gualandi, Marcella Neri, Alessandra Ferlini, Elena Contaldi, Maura Pugliatti, Davide Pareyson, Mariachiara Sensi
INTRODUCTION: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e., parkinsonism, motor neuron involvement, cognitive decline); no behavioral symptoms have been reported yet. CASE REPORT: We report an Italian family that met the diagnostic criteria for CANVAS, and RFC1-expansion was detected in five of seven...
August 2022: Neurological Sciences
Max Borsche, Vera Tadic, Inke R König, Katja Lohmann, Christoph Helmchen, Norbert Brüggemann
BACKGROUND: To investigate the association between disease duration and the severity of bilateral vestibulopathy in individuals with complete or incomplete CANVAS (Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome) and biallelic RFC1 repeat expansions. METHODS: Retrospective analysis of clinical data and the vestibulo-ocular reflex quantified by the video head impulse test in 20 patients with confirmed biallelic RFC1 repeat expansions. RESULTS: Vestibulo-ocular reflex gain at first admittance 6...
June 2022: Brain and Behavior
Sizhe Zhang, Lu Shen, Bin Jiao
With the development of the sequencing technique, more than 40 repeat expansion diseases (REDs) have been identified during the past two decades. Moreover, the clinical features of these diseases show some commonality, and the nervous system, especially the cognitive function was affected in part by these diseases. However, the specific cognitive domains impaired in different diseases were inconsistent. Here, we survey literature on the cognitive consequences of the following disorders presenting cognitive dysfunction and summarizing the pathogenic genes, epidemiology, and different domains affected by these diseases...
2022: Frontiers in Aging Neuroscience
Satoko Miyatake, Kunihiro Yoshida, Eriko Koshimizu, Hiroshi Doi, Mitsunori Yamada, Yosuke Miyaji, Naohisa Ueda, Jun Tsuyuzaki, Minori Kodaira, Hiroyuki Onoue, Masataka Taguri, Shintaro Imamura, Hiromi Fukuda, Kohei Hamanaka, Atsushi Fujita, Mai Satoh, Takabumi Miyama, Nobuko Watanabe, Yusuke Kurita, Masaki Okubo, Kenichi Tanaka, Hitaru Kishida, Shigeru Koyano, Tatsuya Takahashi, Yoya Ono, Kazuhiro Higashida, Nobuaki Yoshikura, Katsuhisa Ogata, Rumiko Kato, Naomi Tsuchida, Yuri Uchiyama, Noriko Miyake, Takayoshi Shimohata, Fumiaki Tanaka, Takeshi Mizuguchi, Naomichi Matsumoto
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION...
April 29, 2022: Brain
Marie Beaudin, Mario Manto, Jeremy D Schmahmann, Massimo Pandolfo, Nicolas Dupre
Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement...
May 2022: Nature Reviews. Neurology
Dinkar Kulshreshtha, Jacky Ganguly, Mandar Jog
Biallelic intronic repeat expansion in the replication factor complex unit 1 (RFC1) gene has recently been described as a cause of late onset ataxia with degeneration of the cerebellum, sensory pathways and the vestibular apparatus. This condition is termed cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Since the identification of this novel gene mutation, the phenotypic spectrum of RFC1 mutations continues to expand and includes not only CANVAS but also slowly progressive cerebellar ataxia, ataxia with chronic cough (ACC), isolated sensory neuropathy and multisystemic diseases...
May 2022: Journal of Movement Disorders
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