Cramp-fasciculation syndrome phenotype of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) due to RFC1 repeat expansion

Синдром CANVAS (мозжечковая атаксия, невропатия и вестибулярная арефлексия) - аутосомно-рецессивная атаксия с поздним дебютом, обусловленная носительством биаллельной экспансии (AAGGG)n во 2-м интроне гена RFC1. До настоящего момента отсутствуют сведения о распространенности данного заболевания в российских семьях. Нами был проведен поиск биаллельной экспансии AAGGG-повторов у 35 российских пациентов с поздней мозжечковой атаксией. Верифицированы 5 пациентов (14,3%) с синдромом CANVAS и характерной клинической картиной. CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia) is a late-onset autosomal recessive ataxia due to biallelic (AAGGG)n repeat expansion in the 2nd intron of the RFC1 gene. There is no information on the CANVAS prevalence in Russian families. We searched for biallelic expansion of AAGGG repeats in 35 Russian patients with late-onset cerebellar ataxia. Five patients (14.3%) with CANVAS syndrome and a characteristic clinical picture were verified.

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Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Brain ◽

10.1093/brain/awz418 ◽

2020 ◽

Vol 143 (2) ◽

pp. 480-490 ◽

Cited By ~ 22

Author(s):

Andrea Cortese ◽

Stefano Tozza ◽

Wai Yan Yau ◽

Salvatore Rossi ◽

Sarah J Beecroft ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Late Onset ◽

Sensory Neuropathy ◽

Repeat Expansion ◽

Cerebellar Dysfunction ◽

Full Spectrum ◽

Ataxic Neuropathy ◽

Walking Aids ◽

Repeat Expansions ◽

Walking Difficulty

Abstract Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

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Spinocerebellar ataxia type 6

Neurology ◽

10.1212/wnl.49.5.1238 ◽

1997 ◽

Vol 49 (5) ◽

pp. 1238-1243 ◽

Cited By ~ 101

Author(s):

R. Matsumura ◽

N. Futamura ◽

Y. Fujimoto ◽

S. Yanagimoto ◽

H. Horikawa ◽

...

Keyword(s):

Family History ◽

Cerebellar Ataxia ◽

Age At Onset ◽

Repeat Expansion ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Cag Repeat Expansion ◽

Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

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C9ORF72 Intermediate Repeat Expansion in a Patient With Psychiatric Disorders and Progressive Cerebellar Ataxia

The Neurologist ◽

10.1097/nrl.0000000000000147 ◽

2017 ◽

Vol 22 (6) ◽

pp. 245-246 ◽

Cited By ~ 2

Author(s):

Mario Meloni ◽

Rita Farris ◽

Paolo Solla ◽

Marcello M. Mascia ◽

Francesco Marrosu ◽

...

Keyword(s):

Psychiatric Disorders ◽

Cerebellar Ataxia ◽

Repeat Expansion ◽

Progressive Cerebellar Ataxia

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Molecular epidemiology of hereditary ataxia in Finland

BMC Neurology ◽

10.1186/s12883-021-02409-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Joonas Lipponen ◽

Seppo Helisalmi ◽

Joose Raivo ◽

Ari Siitonen ◽

Hiroshi Doi ◽

...

Keyword(s):

Molecular Epidemiology ◽

Cerebellar Ataxia ◽

Point Mutations ◽

Repeat Expansion ◽

Unknown Etiology ◽

Routine Diagnostics ◽

Charcot Marie Tooth ◽

Single Deletion ◽

Repeat Expansions ◽

Sporadic Ataxia

Abstract Background The genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population. Patients and methods All patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced. Results A genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms. Conclusions Expansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

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C9ORF72 repeat expansion is not a significant cause of late onset cerebellar ataxia syndrome

Journal of the Neurological Sciences ◽

10.1016/j.jns.2014.10.042 ◽

2014 ◽

Vol 347 (1-2) ◽

pp. 322-324 ◽

Cited By ~ 8

Author(s):

Cheng-Tsung Hsiao ◽

Pei-Chien Tsai ◽

Yi-Chu Liao ◽

Yi-Chung Lee ◽

Bing-Wen Soong

Keyword(s):

Cerebellar Ataxia ◽

Late Onset ◽

Repeat Expansion ◽

C9orf72 Repeat Expansion ◽

Ataxia Syndrome

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Cloning of the gene for autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7) reveals a highly unstable CAG repeat expansion

Neuromuscular Disorders ◽

10.1016/s0960-8966(97)87325-7 ◽

1997 ◽

Vol 7 (6-7) ◽

pp. 467

Author(s):

Gilles David ◽

Nacer Abbas ◽

Giovanni Stevanin ◽

Alexandra Durr ◽

Gael Yvert ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Dominant ◽

Repeat Expansion ◽

Cag Repeat ◽

Autosomal Dominant Cerebellar Ataxia ◽

Macular Dystrophy ◽

Cag Repeat Expansion

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Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes

Neurology ◽

10.1212/wnl.0000000000010744 ◽

2020 ◽

Vol 95 (21) ◽

pp. e2912-e2923

Author(s):

Maria Gisatulin ◽

Valerija Dobricic ◽

Christine Zühlke ◽

Yorck Hellenbroich ◽

Vera Tadic ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Late Onset ◽

Intron Retention ◽

Repeat Expansion ◽

Healthy Controls ◽

Neighboring Gene ◽

Number Of Patients ◽

C Subunit ◽

Factor C ◽

Pentanucleotide Repeat

ObjectiveTo determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses.MethodsIn this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR.ResultsMassive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800–1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7–137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found.ConclusionsA biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.

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