Vestibular Areflexia Research Articles

Frequency and Phenotype of RFC1 Repeat Expansions in Bilateral Vestibulopathy.

Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP. The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification). Biallelic AAGGG repeat expansions in RFC1 were identified in 10/127 patients (8%) with BVP and 1/41 with probable BVP. Heterozygous expansions in 10/127 patients were enriched compared with those in reference populations. RFC1-related BVP manifested at a median age of 60 years (range 34-72 years) and co-occurred predominantly with mild polyneuropathy (10/11). Additional cerebellar involvement (7/11) was subtle and limited to oculomotor signs in early stages, below recognition of classic cerebellar ataxia, neuropathy, and vestibular areflexia syndrome. Clear dysarthria, appendicular ataxia, or cerebellar atrophy developed 6-8 years after onset. Dysarthria, absent patellar reflexes, and downbeat nystagmus best discriminated RFC1-positive BVP from RFC1-negative BVP, but neither sensory symptoms nor fine motor problems. Video head impulse gains of patients with RFC1-positive BVP were lower relative to those of patients with RFC1-negative BVP and decreased until 10 years disease duration, indicating a potential progression and outcome marker for RFC1-disease. This study identifies RFC1 as the first-and frequent-monogenic cause of BVP. It characterizes RFC1-related BVP as part of the multisystemic evolution of RFC1 spectrum disease, with implications for designing natural history studies and future treatment trials. This study provides Class II evidence that RFC1 repeat expansions cause BVP.

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families.

Frequency-dependent tuning of the human vestibular “sixth sense” by transcranial oscillatory currents

ObjectiveThe vestibular cortex is a multisensory associative region that, in neuroimaging investigations, is activated by slow-frequency (1–2 Hz) galvanic stimulation of peripheral receptors. We aimed to directly activate the vestibular cortex with biophysically modeled transcranial oscillatory current stimulation (tACS) in the same frequency range. MethodsThirty healthy subjects and one rare patient with chronic bilateral vestibular deafferentation underwent, in a randomized, double-blind, controlled trial, to tACS at slow (1 or 2 Hz) or higher (10 Hz) frequency and sham stimulations, over the Parieto-Insular Vestibular Cortex (PIVC), while standing on a stabilometric platform. Subjective symptoms of motion sickness were scored by Simulator Sickness Questionnaire and subjects’ postural sways were monitored on the platform. ResultstACS at 1 and 2 Hz induced symptoms of motion sickness, oscillopsia and postural instability, that were supported by posturographic sway recordings. Both 10 Hz-tACS and sham stimulation on the vestibular cortex did not affect vestibular function. As these effects persisted in a rare patient with bilateral peripheral vestibular areflexia documented by the absence of the Vestibular-Ocular Reflex, the possibility of a current spread toward peripheral afferents is unlikely. Conversely, the 10 Hz-tACS significantly reduced his chronic vestibular symptoms in this patient. ConclusionsWeak electrical oscillations in a frequency range corresponding to the physiological cortical activity of the vestibular system may generate motion sickness and postural sways, both in healthy subjects and in the case of bilateral vestibular deafferentation. SignificanceThis should be taken into account as a new side effect of tACS in future studies addressing cognitive functions. Higher frequencies of stimulation applied to the vestibular cortex may represent a new interventional option to reduce motion sickness in different scenarios.

RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% (n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Māori alleles' [(AAAGG)exp(AAGGG)exp], two samples were compound heterozygous for the Māori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients.

CANVAS, a sensory neuronopathy to look for in ataxia

Sensory neuronopathies name the degeneration of peripheral sensory neurons in dorsal root ganglia. Among the genetic causes, CANVAS could be the most frequent. CANVAS is a clinical entity associating cerebellar ataxia, sensory neuronopathy and vestibular areflexia due to biallelic expansions in RFC1. This study reports the 18 individuals with sensory neuronopathy tested for RFC1 expansion in our center. The clinical picture showed that chronic cough was a frequent sign beginning before the onset of other symptoms. CANVAS is an underestimated cause of late-onset sensory and cerebellar ataxia that needs to be tested for widely now that the molecular cause is known.

N°293 – Electrophysiological features of the peripheral neuropathy in cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS)

N°293 – Electrophysiological features of the peripheral neuropathy in cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS)

0979 Obstructive Sleep Apnea in a Patient with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS)

Abstract Introduction Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a rare disorder caused by an autosomal recessive biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene. Clinical features include gait disturbances, impaired vibratory sensation, autonomic dysfunction, cough, and slow disease progression. Spinocerebellar ataxias are frequently associated with sleep disturbances, including REM sleep behavior disorders, insomnia, obstructive sleep apnea (OSA), and central sleep apnea. This is thought to be secondary to involvement of several nervous system structures including the cerebellum. OSA is caused by repeated obstruction of the pharyngeal airway leading to sleep disturbances and fatigue. It is likely that cerebellar insults such as CANVAS may play a role in upper airway obstruction and resultant OSA. However, there is little characterization of this relationship in the medical literature. Report of case(s) We report a case of a 52-year-old female with a past medical history of CANVAS, anxiety, and depression who was referred to sleep medicine for evaluation of worsening daytime fatigue and fragmented sleep. She reported daytime sleepiness, morning headaches, and gasping arousals. Her Epworth sleepiness scale score was markedly elevated at 19 (normal < 10), and she was subsequently referred for home polysomnography testing for sleep apnea. Home sleep testing revealed an apnea-hypopnea index of 12.5 events/hour and a minimum oxygen saturation of 85%. Conclusion This patient is at higher risk for sleep disruption due to her diagnosis of CANVAS. She presented with excessive daytime sleepiness and was found to have mild OSA on home sleep testing. Little is known about the presentation of OSA in patients with CANVAS. OSA treatment has the potential to improve sleep symptoms, quality of life, and mood disruption in this patient with an otherwise progressive and disabling neurologic disorder. Therefore early recognition and intervention of OSA are important in the care of patients with CANVAS. Given the disease’s progressive nature and lack of a cure, it is necessary to ameliorate quality of life however possible. OSA leads to persistent fatigue and may result in psychiatric disturbances, therefore, it is necessary to address sleep disturbances secondary to movement disorders to combat these outcomes. Support (if any)

Characterization of a chronic cough in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a common cause of late-onset ataxia that often presents with chronic cough. This study is the first to characterize the CANVAS cough both objectively and subjectively. A cross-sectional study of 13 patients was conducted. Medical records and available esophagram, modified barium swallow study, esophageal manometry, and video laryngostroboscopy data were reviewed. Leicester cough questionnaire (LCQ) and Eating Assessment Tool-10 were administered to evaluate quality of life (QoL) impairments and dysphagia symptoms, respectively. CANVAS history questionnaire was developed to characterize the clinical course. 92% of patients endorsed chronic cough that preceded gait instability by a median of 16 years. Cough was dry (67%), disturbed sleep (75%), triggered by various factors, including talking, eating, and dry/spicy foods, did not respond to standard reflux therapy, and inconsistently responded to neuromodulators and superior laryngeal nerve injections. Despite perceived cough severity worsening or remaining constant in most patients, no correlation was found between cough duration and total LCQ scores. Patients reported significantly more negative social QoL impacts compared to physical QoL impacts. Ataxia duration and years of cough before ataxia symptoms were directly and inversely correlated with total LCQ scores, respectively. Imaging data revealed esophageal dysmotility (71%), vestibular penetration (57%), vestibular aspiration (14%), supraglottic compression (63%), vocal fold lesions/atrophy (50%), and arytenoid erythema (38%). Chronic cough is a hallmark presenting symptom in CANVAS with predominantly psychosocial QoL effects and unrecognized laryngeal alterations. In cases of idiopathic, refractory chronic cough, genetic testing for CANVAS should be considered, especially in association with sensory, cerebellar, and/or vestibular involvement. VI.

Teaching Video NeuroImage: One Bedside Test, 2 Clinical Signs

A 60-year-old patient had progressive imbalance. Examination revealed saccadic smooth pursuit, downbeat nystagmus, ataxia of stance and gait, and reduced vibration sense. Video head impulse and caloric testing both showed vestibulo-ocular reflex (VOR) deficits (figure). The patient has cerebellar ataxia with neuronopathy and vestibular areflexia syndrome.1,2 Slow head turns while looking at an earth-fixed target produce saccadic rather than smooth compensatory eye movements (Videos 1) due to impairment of both the VOR and smooth pursuit (the visually enhanced VOR): 1 simple bedside test, 2 clinical signs, and 1 precise diagnosis.

Generation and heterozygous repair of human iPSC lines from three individuals with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) carrying biallelic AAGGG expansions in RFC1

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a progressive neurodegenerative disorder predominantly caused by biallelic AAGGG expansions in the second intron of the RFC1 gene. Here, we used a simultaneous reprogramming and CRISPR-Cas9 genome editing approach to generate three patient iPSC lines with homozygous AAGGG expansions along with three heterozygous gene corrected iPSC lines. The iPSC lines expressed pluripotency markers, had a normal karyotype, and were able to differentiate into all three embryonic germ layers. These mutant and corrected iPSC lines will be a valuable tool for studying the molecular mechanisms underlying CANVAS.

Association of biallelic RFC1 expansion with early-onset Parkinson's disease.

The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%-3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40-48 years and their disease course had been unremarkable apart from the early onset. Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit

IntroductionPathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. MethodsWe recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. ResultsBiallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. ConclusionPathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

Ultrasound of peripheral nerves distinguishes inherited sensory neuronopathy of cerebellar ataxia with neuropathy and vestibular areflexia syndrome from inherited axonopathy.

Introduction/Aims Recent studies have shown that ultrasound of peripheral nerves can distinguish inherited sensory neuronopathy from acquired axonopathy with a high degree of accuracy. In this study we aimed to determine whether ultrasound can also distinguish inherited sensory neuronopathy from inherited axonopathy. Methods We compared the ultrasound cross-sectional areas (CSAs) of the median, ulnar, sural, and tibial nerves of retrospectively recruited patients with cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), in whom sensory neuronopathy is a cardinal feature, with Charcot-Marie-Tooth type 2 (CMT2) disease patients, who have an inherited axonopathy, using the Kruskal-Wallis test and receiver-operating characteristic curves. Results There were 17 patients with CANVAS and 18 with CMT2. The upper limb nerve CSAs were significantly smaller in CANVAS than in CMT2 (P < .001), with the CSAs of the median nerve at mid-forearm and ulnar nerve at mid-arm being a third or less the size of those of the CMT2 patients. Nerve ultrasound reliably distinguished CANVAS from CMT2 with ROC areas under the curve between 0.97 and 0.99. The lower limb CSAs of the two patient groups were not significantly different. Discussion Ultrasound of the upper limb nerves distinguishes CANVAS sensory neuronopathy from inherited axonopathy with high accuracy and can therefore be proposed as a reliable additional tool in the investigation of these diseases.

New Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome cases are caused by the presence of a nonsense variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene.

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. Further RNA analysis demonstrated a reduced expression of the p.Arg242* allele in patients confirming an efficient nonsense-mediated mRNA decay. We also highlight the importance of considering the sequencing of the RFC1 gene for the diagnosis, especially in patients with CANVAS diagnosis carriers of the AAGGG repeat expansion.

Neuropathological Findings in Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome

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. To date, aggregates of abnormal proteins such as intranuclear inclusion bodies characteristic of this disease have not been identified in the nervous system.

RFC1 Gene: Function and Intronic Repeat Expansion Causing Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome

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.

Whole-Genome and Long-Read Sequencing Identify a Novel Mechanism in RFC1 Resulting in CANVAS Syndrome.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) results from biallelic intronic pentanucleotide repeats in RFC1. We describe an adult male proband with progressive imbalance, cerebellar atrophy, somatosensory neuronopathy, and absence of peripheral vestibular function for whom clinical testing demonstrated a heterozygous RFC1 expansion consistent with an unaffected carrier. We performed whole-genome sequencing (WGS) on peripheral blood DNA samples from the proband and his unaffected mother. We performed DNA long-read sequencing and synthesized complementary DNA from RNA using peripheral blood from the proband. WGS confirmed the maternally inherited RFC1 expansion and identified a rare, nonsense RFC1 variant: c.C1147T; p.R383X in the proband but not the maternal DNA sample. RFC1 variants were confirmed in trans with long-read sequencing. Functional studies demonstrated the absence of complementary DNA (cDNA) transcript from the c.C1147T; p.R383X variant supporting nonsense-mediated decay of this transcript. We report an adult with CANVAS due to compound heterozygous pathogenic RFC1 variants: the pathogenic intronic pentanucleotide expansion confirmed in trans with a nonsense variant. This report represents a novel molecular mechanism for CANVAS. Sequencing for RFC1 should be considered for adults meeting clinical criteria for the CANVAS phenotype if only a heterozygous pathogenic RFC1 expansion is identified.

RFC1 CANVAS/Spectrum Disorder: Historical Details and Clinical Diversity

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. In 2019, a biallelic intronic AAGGG repeat expansion (AAGGG)exp in the replication factor complex subunit 1 gene (RFC1) was identified as a genetic contributor to CANVAS, and (ACGGG)exp in RFC1 was subsequently confirmed as a causative factor for CANVAS. Genetic screening for RFC1 has shown that CANVAS is an overlooked entity in patients with cerebellar ataxia or sensory neuropathy, which highlights more restricted phenotypes that exclusively involve one of the aforementioned systems. The phenotypic spectrum of RFC1-related disorders has been expanding since the discovery of (AAGGG)exp or (ACGGG)exp in the RFC1. Studies have reported atypical features, including parkinsonism, motor neuron involvement, cognitive decline, and sleep disorders. Currently, a wide variety of clinical conditions associated with biallelic intronic pentanucleotide repeat expansion in RFC1 are classified as RFC1 CANVAS/spectrum disorder.

Motor Neuron Involvement in RFC1 CANVAS/Spectrum Disorders

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by the triad of cerebellar ataxia, bilateral vestibular impairment, and sensory neuropathy. The responsible anatomical region for the sensory disturbance in CANVAS is reportedly the dorsal root ganglion, which suggests neuronopathy rather than neuropathy as the pathomechanism of this peripheral nervous system disorder. Early on, motor neuron involvement was considered rare in CANVAS. The etiology of CANVAS includes the homozygous pentanucleotide repeat expansion within the RFC1 gene, resulting in diverse phenotypes and motor deficits such as brisk reflex, extensor plantar responses, or spasticity of the upper motor neurons and muscle wasting, weakness, cramp, or fasciculation of the lower motor neurons. CANVAS patients with AAGGG repeat expansions may show motor neuron involvement, with considerable variation in the reported frequencies. In contrast, although some patients with ACAGG repeat expansions also show motor neuron involvement, its frequency remains elusive.

Chronic Cough in CANVAS

Among patients with RFC1 spectrum disorders represented by the phenotype of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), at least 60% are known to manifest chronic, paroxysmal, and spasmodic dry cough. Chronic cough is a key diagnostic feature of RFC1-related diseases. It is often the first symptom and, in some cases, precedes neurological symptoms such as ataxia and sensory disturbance for more than 30 years. Although the pathogenesis of the cough remains unclear, it is possible that impairment of the vagus nerve, which includes an afferent pathway of the cough reflex, or the cerebellum would have contributed to the generation of the cough.