Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic.
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ABSTRACT:
SUBMITTER: Cortese A
PROVIDER: S-EPMC8311668 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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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
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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.
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Project description:Diagnosis 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.Cerebellar 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.We 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.
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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).
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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.
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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.
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Project description:BackgroundCerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) presents an unpredictable and uneven clinical development of cerebellar ataxia, neuropathy, and vestibular areflexia. The aim of this study is to report the variability of vestibular test results in genetically confirmed patients with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome.MethodsCaloric testing, video head impulse test (vHIT), and rotatory chair testing were performed in 7 patients who presented pathogenic repeat expansions in the replication factor complex unit 1 gene related to cerebellar ataxia, neuropathy, and vestibular areflexia syndrome.ResultsReduced vestibulo-ocular reflex (VOR) gain was observed in 100% of the patients in rotatory chair testing. Three of them had bilateral areflexia in caloric testing while 2 showed unilateral hypofunction and 2 had no alterations in the test. Only 1 patient had bilateral abnormal vHIT with gains under 0.6 in both ears.ConclusionGenetic testing allows an early diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, whereby the vestibular system may be affected to different degrees. Rotatory chair testing has a higher sensitivity for the detection of vestibular hypofunction in these patients. Caloric testing can provide additional information. vHIT might underdiagnose patients with mild-to-moderate vestibulopathy.
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