Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic.
Ontology highlight
ABSTRACT:
SUBMITTER: Cortese A
PROVIDER: S-EPMC8311668 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
Publications
Mutation in <i>RNF170</i> causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic.
Cortese Andrea A Callegari Ilaria I Currò Riccardo R Vegezzi Elisa E Colnaghi Silvia S Versino Maurizio M Alfonsi Enrico E Cosentino Giuseppe G Valente Enzamaria E Gana Simone S Tassorelli Cristina C Pichiecchio Anna A Rossor Alexander M AM Bugiardini Enrico E Biroli Antonio A Di Capua Daniela D Houlden Henry H Reilly Mary M MM Reilly Mary M MM
Journal of neurology, neurosurgery, and psychiatry 20200917 11
Similar Datasets
Project description: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.
| S-EPMC8629873 | biostudies-literature
Project description:Purpose of reviewDiagnosis of ataxic disorders is an important clinical challenge upon which prognostication, management, patient solace, and, above all, the hope of future treatment all rely. Heritable diseases and the possibility of affected offspring carry the added burden of portending adverse health, social and financial ramifications.Recent findingsCerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited multisystem ataxia compromising cerebellar, vestibular, and sensory function. It is not uncommon, but despite early attempts the genetic defect is yet to be identified. As the search for the causative gene continues, we have found it useful to further define this syndrome in terms of its likely phenotype.SummaryWe propose staged diagnostic criteria based on the identified pathology in CANVAS. We envisage that these criteria will aid the clinician in diagnosing CANVAS and the researcher in further elucidating this complex disorder.
| S-EPMC4753833 | biostudies-literature
Project description:OBJECTIVE: The syndrome of cerebellar ataxia with bilateral vestibulopathy was delineated in 2004. Sensory neuropathy was mentioned in 3 of the 4 patients described. We aimed to characterize and estimate the frequency of neuropathy in this condition, and determine its typical MRI features. METHODS: Retrospective review of 18 subjects (including 4 from the original description) who met the criteria for bilateral vestibulopathy with cerebellar ataxia. RESULTS: The reported age at onset range was 39-71 years, and symptom duration was 3-38 years. The syndrome was identified in one sibling pair, suggesting that this may be a late-onset recessive disorder, although the other 16 cases were apparently sporadic. All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion. In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. MRI scans showed cerebellar atrophy in 16, involving anterior and dorsal vermis, and hemispheric crus I, while 2 were normal. The inferior vermis and brainstem were spared. CONCLUSIONS: Sensory neuropathy is an integral component of this syndrome. It may result in severe sensory loss, which contributes significantly to the disability. The MRI changes are nonspecific, but, coupled with loss of sensory nerve action potentials, may aid diagnosis. We propose a new name for the condition: cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS).
| S-EPMC3115806 | biostudies-other
Project description:BackgroundCerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a relatively common cause of late-onset progressive ataxia, is a genetic disease characterised by biallelic pentanucleotide AAGGG repeat expansion in intron 2 of the replication factor complex subunit 1 gene. Herein, we describe the first molecularly confirmed CANVAS family with five affected siblings from Turkey.Case presentationThe family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them; two were healthy and asymptomatic. Chronic cough was the first symptom reported in all five siblings, followed by the development of sensory symptoms, oscillopsia and imbalance. Clinical head impulse test (HIT) was positive in all cases and video HIT performed on three patients revealed very low vestibulo-ocular reflex gains bilaterally. Magnetic resonance imaging and nerve conduction studies revealed cerebellar atrophy and sensory neuronopathy, respectively. RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in all five cases.ConclusionGenetic screening for CANVAS should be considered in all patients with late-onset ataxia, sensory disturbances and vestibular involvement, especially in the presence of chronic cough.
| S-EPMC11438076 | biostudies-literature
Project description:Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is an hereditary autosomal recessive disease. Recent studies propose including chronic cough (CC) as a symptom of CANVAS. For 10 patients with CANVAS as genetically confirmed by biallelic expansion of the AAGG repeat motif (AAGGGexp) in intron 2 of replication factor C subunit 1 (RFC1), our aim was, as a multidisciplinary team, to describe clinical and functional characteristics and possible causes of CC following European Respiratory Society (ERS) recommendations, and to evaluate CC impact on quality of life (QoL) using self-administered questionnaires (Cough Severity Diary, Leicester Cough Questionnaire, Discrete Emotions Questionnaire, and EQ-5D-5L). In all 10 patients, the CC was a dry cough that developed several years prior to the neurological symptoms (mean 14.2 years); 7 patients had symptoms compatible with gastroesophageal reflux (GER), 5 with pathological GER diagnosed by 24-h esophageal pH testing, and 6 patients had impaired esophageal motility diagnosed by high-resolution esophageal manometry, most frequently ineffective peristalsis. Although further studies are required for confirmation, we conclude that CC may be a characteristic prodrome of CANVAS and may be related to GER and esophageal disorders. Furthermore, CC affects patients' QoL, especially in the psychosocial sphere.
| S-EPMC10896788 | biostudies-literature
Project description:Numerous neurological disorders are linked to sequences rich in guanine repeats found in introns, exons, and regulatory regions of genes. These sequences have been observed to form stable G-quadruplex (GQ) structures both in vitro and in vitro. Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), a slowly progressive neurodegenerative disorder, is associated with the biallelic expansion of (AAGGG)n pathogenic repeats in the second intron of the RFC1 gene. Though these G-rich pathogenic repeats in other neurological diseases are associated with protein loss of function, RNA gain of function, and/or protein gain of function, not much is known about the pathological mechanism associated with CANVAS. Herein, we report the formation of stable GQ conformations in the CANVAS-associated repeats i.e., r(AAGGG)n, where 'r' stands for RNA. These GQs are critical regulators in neurological disorders leading to RNA foci formation and RNA binding protein sequestration. They also alter other causative processes like intron retention, which leads us to hypothesize a toxic Proteinopathy mechanism in CANVAS. Various biophysical and biomolecular assays characterized the interactions of three aggregation-prone RNA-binding proteins (RBPs): heterogeneous nuclear ribonucleoprotein H1/F (hnRNP H1/F), and DGCR8 with different pathogenic repeats [(AAGGG)9] in vitro, further affirming the hypothesis. The biophysical observations are further supported by molecular dynamics analysis and cell-based studies, putting us a step closer to elucidating the pathological mechanism(s) in CANVAS neuropathy, paving the way for the development of innovative therapeutic interventions.
| S-EPMC11564700 | biostudies-literature
Project description:(1) Background: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by late-onset cerebellar ataxia, bilateral vestibulopathy, and sensory neuronopathy mostly due to biallelic RFC1 expansion. (2) Objectives: The aim of this case series is to describe vestibular, gait, and speech alterations in CANVAS via a systematic approach. (3) Methods: All patients (n = 5) underwent a standardized clinical-instrumental examination, including the perceptual and acoustic analysis of speech, instrumental gait, and balance analysis (posturographic data were acquired using a force plate [Kistler, Winterthur, Switzerland] while 3D gait analysis, inclusive of surface electromyography, was acquired using a motion capture system [SMART DX, BTS Bioengineering, Milan, Italy], a wireless electromyograph [FreeEMG, BTS Bioengineering, Milan, Italy]), and vestibular assessment with video-oculography. (4) Results: Five patients were included in the analysis: three females (patients A, B, C) and two males (patients D and E) with a mean age at evaluation of 62 years (SD ± 15.16, range 36-74). The mean age of symptoms' onset was 55.6 years (SD ± 15.04, range 30-68), and patients were clinically and instrumentally evaluated with a mean disease duration of 6.4 years (SD ± 0.54, range 6-7). Video-Frenzel examination documented spontaneous downbeat nystagmus enhanced on bilateral gaze in all patients, except for one presenting with slight downbeat nystagmus in the supine position. All patients exhibited different degrees of symmetrically reduced VOR gain for allsix semicircular canals on the video-head impulse test and an unexpectedly normal ("false negative") VOR suppression, consistent with combined cerebellar dysfunction and bilateral vestibular loss. Posturographic indices were outside their age-matched normative ranges in all patients, while 3D gait analysis highlighted a reduction in ankle dorsiflexion (limited forward rotation of the tibia over the stance foot during the stance phase of gait and fatigue of the dorsiflexor muscles) and variable out-of-phase activity of plantar flexors during the swing phase. Finally, perceptual-acoustic evaluation of speech showed ataxic dysarthria in three patients. Dysdiadochokinesis, rhythm instability, and irregularity were observed in the oral diadochokinesis task. (5) Conclusions: CANVAS is a recently discovered syndrome that is gaining more and more relevance within late-onset ataxias. In this paper, we aimed to contribute to a detailed description of its phenotype.
| S-EPMC10605709 | biostudies-literature
Project description: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.
| S-EPMC7009469 | biostudies-literature
Project description:BackgroundBiallelic variants in polyribonucleotide-nucleotidyltransferase-1 (PNPT1) have been associated with a range of phenotypes from syndromic hearing loss to Leigh's syndrome. More recently, heterozygous variants in PNPT1, have been reported in three families with cerebellar ataxia and prominent sensory neuropathy.MethodsWhole genome sequencing was performed in two families with autosomal dominant sensory ataxic neuropathy (SAN).ResultsSegregating heterozygous splice site (c.2014-3C>G) and nonsense (p.Arg715Ter) variants were detected in both families. All patients initially presented with an isolated SAN clinically and neurophysiologically with subsequent variable cerebellar involvement.ConclusionWe report two heterozygous PNPT1 variants in two families with a predominant SAN, including the novel p.Arg715Ter. This strengthens the argument of PNPT1 causing dominant disease and highlights a new cause for dominantly inherited SAN.
| S-EPMC11807841 | biostudies-literature
Project description:Background and objectiveCerebellar 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. The objective of this study was to expand the genotypic spectrum of CANVAS by identifying sequence variants in RFC1-coding region associated with this condition.MethodsFifteen individuals diagnosed with CANVAS and carrying only 1 heterozygous (AAGGG)n expansion in RFC1 underwent whole-genome sequencing or whole-exome sequencing to test for the presence of a second variant in RFC1 or other unrelated gene. To assess the effect of truncating variants on RFC1 expression, we tested the level of RFC1 transcript and protein on patients' derived cell lines.ResultsWe identified 7 patients from 5 unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)n expansion together with a second truncating variant in trans in RFC1, which included the following: 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.DiscussionOur report expands the genotype spectrum of RFC1 disease. Full RFC1 sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)n expansions. In addition, it sheds further light on the pathogenesis of RFC1 CANVAS because it supports the existence of a loss-of-function mechanism underlying this complex neurodegenerative condition.
| S-EPMC9931080 | biostudies-literature