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

Brain ◽  
2020 ◽  
Vol 143 (2) ◽  
pp. 480-490 ◽  
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.

CANVAS is a common form of late-onset hereditary ataxia

2020 ◽  
pp. 51-52
Author(s):  
Е.П. Нужный ◽  
Н.Ю. Абрамычева ◽  
Е.Г. Воробьева ◽  
Е.О. Иванова ◽  
Ю.А. Шпилюкова ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Clinical Picture ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Repeat Expansion ◽  
Hereditary Ataxia ◽  
Recessive Ataxia ◽  
Autosomal Recessive Ataxia

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.

scholarly journals Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): from clinical diagnosis towards genetic testing

2021 ◽  
Vol 33 (4) ◽  
pp. 301-310
Author(s):  
Andreas Thieme ◽  
Christel Depienne ◽  
Dagmar Timmann
Keyword(s):  
Cerebellar Ataxia ◽  
Chronic Cough ◽  
Late Onset ◽  
Neurological Diseases ◽  
Brain Mri ◽  
Genetic Research ◽  
Sensory Nerve ◽  
Repeat Expansions ◽  
Factor C ◽  
Pentanucleotide Repeat

Abstract The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1-associated neurological diseases remains uncertain although first studies suggest that RFC1-related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.

scholarly journals Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

2020 ◽  
Author(s):  
Mathieu Dupré ◽  
Ruben Hermann ◽  
Caroline Froment Tilikete
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Genetic Disorder ◽  
Axonal Neuropathy ◽  
Sensory Neuropathy ◽  
Bilateral Vestibulopathy ◽  
Familial Form ◽  
Vestibulo Ocular Reflex ◽  
Classical Triad ◽  
Factor C

Abstract The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.

scholarly journals Molecular epidemiology of hereditary ataxia in Finland

BMC Neurology ◽  
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.

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

2014 ◽  
Vol 347 (1-2) ◽  
pp. 322-324 ◽  
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

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

Neurology ◽  
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.

scholarly journals RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia

2020 ◽  
Vol 65 (12) ◽  
pp. 1143-1147
Author(s):  
Mai Tsuchiya ◽  
Haitian Nan ◽  
Kishin Koh ◽  
Yuta Ichinose ◽  
Lihua Gao ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Japanese Patients ◽  
Repeat Expansion

Late-onset cerebellar ataxia due to Gordon Holmes Syndrome

2020 ◽  
Vol 79 ◽  
pp. e113-e114
Author(s):  
C.-Y. Kok ◽  
T.-Y. Tee ◽  
A. Karim ◽  
H. Leong
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset

scholarly journals RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

2021 ◽  
Author(s):  
Matteo Tagliapietra ◽  
Davide Cardellini ◽  
Moreno Ferrarini ◽  
Silvia Testi ◽  
Sergio Ferrari ◽  
...  
Keyword(s):  
Care Center ◽  
Axonal Neuropathy ◽  
Tertiary Care ◽  
Sensory Neuropathy ◽  
Nerve Fibers ◽  
Repeat Expansion ◽  
Sural Nerve Biopsy ◽  
Prevalence Odds Ratio ◽  
Axonal Polyneuropathy ◽  
Factor C

Abstract Background A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. “Chronic Idiopathic Axonal Polyneuropathy” (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. Methods We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. Results The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio—POR 6.73 CI 95% 2.79–16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = − 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03–58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17–22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. Conclusions This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

Sign in / Sign up

Export Citation Format

Share Document