Clinical and functional characteristics, possible causes, and impact of chronic cough in patients with cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome (CANVAS).

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.

Chronic Cough as a Genetic Neurological Disorder? Insights from Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS).

Chronic cough is common, and in many cases unexplained or refractory to otherwise effective treatment of associated medical conditions. Cough hypersensitivity has developed as a paradigm that helps to explain clinical and research observations that frequently point towards chronic cough as a neuropathic disorder. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described neurological condition whose clinical features include gait ataxia, unsteadiness, peripheral neuropathy, and autonomic dysfunction. Chronic cough is also a common feature of the syndrome, with features of hypersensitivity, often preceding core neurological symptoms by up to 30 years or more. The genetic basis in a majority of cases of CANVAS appears to be biallelic variable repeat intron expansion sequences within RFC1, a gene normally involved in the regulation of DNA replication and repair. The same polymorphism has now been identified at an increased frequency in patients with unexplained or refractory chronic cough in the absence of defining clinical features of CANVAS. This review expands on these points, aiming to increase the awareness of CANVAS amongst clinicians and researchers working with chronic cough. We discuss the implications of a link between RFC1 disease and cough. Improved understanding of CANVAS may lead to an enhanced grasp of the pathophysiology of chronic cough, and new approaches to antitussive treatments.

Optical Genome Mapping Enables Detection and Accurate Sizing of RFC1 Repeat Expansions.

A recessive Short Tandem Repeat expansion in RFC1 has been found to be associated with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), and to be a frequent cause of late onset ataxia and sensory neuropathy. The usual procedure for sizing these expansions is based on Southern Blotting (SB), a time-consuming and a relatively imprecise technique. In this paper, we compare SB with Optical Genome Mapping (OGM), a method for detecting Structural Variants (SVs) based on the measurement of distances between fluorescently labelled probes, for the diagnosis of RFC1 CANVAS and disease spectrum. The two methods are applied to 17 CANVAS patients' blood samples and resulting sizes compared, showing a good agreement. Further, long-read sequencing is used for two patients to investigate the agreement of sizes with either SB or OGM. Our study concludes that OGM represents a viable alternative to SB, allowing for a simpler technique, a more precise sizing of the expansion and ability to expand analysis of SV in the entire genome as opposed to SB which is a locus specific method.

Clinical and pathology characterization of small nerve fiber neuro(no)pathy in cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

BACKGROUND AND PURPOSE: Biallelic mutation/expansion of the gene RFC1 has been described in association with a spectrum of manifestations ranging from isolated sensory neuro(no)pathy to a complex presentation as cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). Our aim was to define the frequency and characteristics of small fiber neuropathy (SFN) in RFC1 disease at different stages. METHODS: RFC1 cases were screened for SFN using the Neuropathic Pain Symptom Inventory and Composite Autonomic Symptom Score 31 questionnaires. Clinical data were retrospectively collected. If available, lower limb skin biopsy samples were evaluated for somatic epidermal and autonomic subepidermal structure innervation and compared to healthy controls (HCs). RESULTS: Forty patients, median age at onset 54 years (interquartile range [IQR] 49-61) and disease duration 10 years (IQR 6-16), were enrolled. Mild-to-moderate positive symptoms (median Neuropathic Pain Symptom Inventory score 12.1/50, IQR 5.5-22.3) and relevant autonomic disturbances (median Composite Autonomic Symptom Score 31 37.0/100, IQR 17.7-44.3) were frequently reported and showed scarce correlation with disease duration. A non-length-dependent impairment in nociception was evident in both clinical and paraclinical investigations. An extreme somatic denervation was observed in all patients at both proximal (fibers/mm, RFC1 cases 0.0 vs. HCs 20.5, p < 0.0001) and distal sites (fibers/mm, RFC1 cases 0.0 vs. HCs 13.1, p < 0.0001); instead only a slight decrease was observed in cholinergic and adrenergic innervation of autonomic structures. CONCLUSIONS: RFC1 disease is characterized by a severe and widespread somatic SFN. Skin denervation may potentially represent the earliest feature and drive towards the suspicion of this disorder.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): diagnostic contribution of vestibular function tests.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognised but underdiagnosed cause of late-onset hereditary ataxia. Symptoms may vary, and differential diagnoses can span several specialties. We report the case of a man in his 60 s who presented with a 10 year history of imbalance and progressive gait disturbance associated with a chronic spasmodic cough that preceded these symptoms by almost 30 years. He had previously undergone extensive testing for acquired and genetic causes of ataxia without a conclusive diagnosis. Brain MRI revealed cerebellar atrophy, and nerve conduction tests suggested a sensory ganglionopathy. Vestibular function testing was crucial for diagnosis, identifying a severe bilateral vestibulopathy. This led to the consideration of CANVAS, which was finally confirmed by genetic testing. This case raises awareness of this novel genetic disease, highlighting the importance of objective vestibular function tests in establishing an early diagnosis.

[Bilateral peripheral vestibulopathy]. / Dvustoronnyaya perifericheskaya vestibulopatiya.

Bilateral vestibulopathy is a relatively widespread and at the same time rarely diagnosed cause of chronic postural instability. Numerous toxic factors, dysmetabolic, autoimmune and neurodegenerative processes can lead to this condition. The main clinical manifestations of bilateral vestibulopathy are balance disorders and visual disturbances (oscillopsia), which can significantly increase the risks of falls in such patients. In addition, cognitive and affective disorders, which also reduce the quality of life in patients with bilateral vestibulopathy, have been described and actively studied in recent years. The diagnosis of bilateral vestibulopathy is based on the results of a clinical neurovestibular study, including a dynamic visual acuity test and a Halmagyi test. A video head impulse test, a bithermal caloric test and a sinusoidal rotation test are used as instrumental methods confirming the dysfunction of the peripheral vestibular system. However, they are still not widespread in neurological practice. Treatment of bilateral vestibulopathy is reduced to vestibular rehabilitation. Encouraging results have been obtained in a number of studies using galvanic vestibular stimulation and the use of vestibular implants. In addition, cognitive rehabilitation methods are currently being developed, which presumably can also improve compensation for bilateral vestibular loss.

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

INTRODUCTION: Pathogenic 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. METHODS: We 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. RESULTS: Biallelic 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. CONCLUSION: Pathogenic 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.

Bilateral vestibulopathy and disabling vertigo: A CARE case series.

INTRODUCTION: The term bilateral vestibulopathy (BV) was recently defined by the Bárány Society. Loss of otolith function was not included in their criteria. Although spontaneous progression to complete bilateral impairment of vestibular function is expected, it is unlikely that patients with advanced BV will continue to present episodes of intense vertigo. Here, following CARE case report guidelines, we report the case of patients meeting the criteria for BV and still disabled by vertigo. CASE SERIES: Three patients evaluated in our department meeting the Bárány criteria for definite BV but still complaining of disabling rotatory vertigo were included. All underwent clinical and instrumental vestibular examination. The observations are reported. CONCLUSION: In case of BV, the conservation of a stable otolithic reference frame could allow patients to optimize postural strategy. It would be useful to revisit a classification of BV by stages, by introducing an evaluation of otolithic function and postural control for possible subsequent vestibular implantation.

Prevalence of bilateral vestibulopathy among older adults above 65 years on the indication of vestibular impairment and the association with Dynamic Gait Index and Dizziness Handicap Inventory.

PURPOSE: To estimate the prevalence of bilateral vestibulopathy (BV) and evaluate the association with, and concurrent validity of the Dynamic Gait Index (DGI) and the Dizziness Handicap Inventory (DHI) in diagnosing BV based on video head impulse test (vHIT) among older adults ≥65 years referred to a geriatric falls clinic on suspicion of vestibular impairment. MATERIALS AND METHODS: The vHIT was applied as a reference standard of BV to estimate diagnostic parameters for optimal cut-off scores of DGI and DHI applied separately and in combination. RESULTS: Two-hundred medical records were reviewed (70% women, mean age 79.4 years). The prevalence of BV was 9%. DGI was weakly associated with BV: Odds Ratio (OR) 1.15 (95% confidence interval (CI): 1.01; 1.31), with a 93% sensitivity and 47% specificity of a cut-off score of 16. The total score of DHI showed no association with BV: OR 1.01 (95% CI: 0.98; 1.04). The concurrent validity for BV and DGI and/or DHI were found to be inadequate. CONCLUSIONS: A prevalence of 9% underlines the relevance for assessment of BV. Only a weak association between DGI and/or DHI and BV was found. Thus, vHIT remains the preferred test for detecting BV in geriatric fall assessments.IMPLICATIONS FOR REHABILITATIONBilateral vestibulopathy (BV) has numerous negative consequences for older adults and the prevalence is high among older adults referred to a geriatric falls clinic on suspicion of vestibular impairment.The Dynamic Gait Index (DGI) and the Dizziness Handicap Inventory (DHI) are not valid alternatives to the Video Head Impulse Test (vHIT) when assessing BV among geriatric outpatients.

[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 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late-onset ataxia. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to three patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss-of-function as the cause of the disease.

Head impulse testing in bilateral vestibulopathy in patients with genetically defined CANVAS.

BACKGROUND: To investigate the association between disease duration and the severity of bilateral vestibulopathy in individuals with complete or incomplete CANVAS (Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome) and biallelic RFC1 repeat expansions. METHODS: Retrospective analysis of clinical data and the vestibulo-ocular reflex quantified by the video head impulse test in 20 patients with confirmed biallelic RFC1 repeat expansions. RESULTS: Vestibulo-ocular reflex gain at first admittance 6.9 ± 5.0 years after disease onset was 0.16 [0.15-0.31] (median [interquartile range]). Cross-sectional analysis revealed that gain reduction was associated with disease duration. Follow-up measurements were available for ten individuals: eight of them exhibited a progressive decrease of the vestibulo-ocular reflex gain over time. At the first visit, six of all patients (30%) did not show clinical signs of cerebellar ataxia. CONCLUSIONS: Our data suggest a pathological horizontal head impulse test, which can easily be obtained in many outpatient clinics, as a sign of bilateral vestibulopathy in genetically confirmed CANVAS that can precede clinically accessible cerebellar ataxia at least in a subset of patients. The presumably continuous decline over time possibly reflects the neurodegenerative character of the disease. Thus, genetic testing for RFC1 mutations in (isolated) bilateral vestibulopathy might allow disease detection before the onset of cerebellar signs. Further studies including a wider spectrum of vestibular function tests are warranted in a prospective design.

Impact on daily mobility and risk of falling in bilateral vestibulopathy.

OBJECTIVE: To study the behavioral relevance of postural and ocular-motor deficits on daily activity and risk of falling in patients with bilateral vestibular hypofunction (BVH). METHODS: Thirty patients with BVH and 30 age- and gender-matched healthy controls participated in a continuous 2-week assessment of daily activities and mobility using a body-worn inertial sensor and a 6-month prospective fall risk assessment. At inclusion, patients and controls further underwent a multi-modal clinical, score- and instrument-based assessment of general health and balance status. We analyzed the relationship between clinical, lab-, and sensor-based measures and their validity to identify those patients at a risk of general, frequent, and severe falling. RESULTS: Patients exhibited impairments in daily activity in particular in terms of reduced ambulatory activity (p = 0.009). 43% of patients experienced falls (13% in controls, p = 0.008) and 70% of these patients reported recurrent falling (0% in controls, p = 0.001) during prospective assessment. Severe fall-related injuries that would require medical attention neither occurred in patients nor in controls. Classificatory models based on multi-modal clinical, lab-, and sensor-based measures of balance and mobility identified patients who fell with an accuracy of 93% and patients who recurrently fell with an accuracy of 89%. CONCLUSION: BVH is linked to particular impairments of patients' daily activities which in turn are related to patients' fall risk. Hence, off-laboratory measures of daily mobility may supplement standard clinical assessment in BVH to more adequately capture the burden of disease and to reliably identify those patients at a specific risk of falling.

A Possible Mechanism for Flecainide Induced Dizziness.

OBJECTIVE: Flecainide is an oral class IC antiarrhythmic drug whose most common extracardiac adverse reactions are "dizziness" and "visual disturbances." We describe a case of flecainide associated- bilateral vestibulopathy and a literature review of this drug's effect on the vestibular system. PATIENT: Sixty-nine-year-old man with a 3-month history of unsteadiness and dizziness after an increase in the dose of flecainide. INTERVENTIONS: Otologic examination, video head-impulse test, vestibular evoked myogenic potentials, pure tone audiometry and high-resolution magnetic resonance imaging. RESULTS: Otologic examination, including the head-impulse test, and vestibular testing revealed bilateral vestibulopathy. CONCLUSIONS: Dizziness is a common extracardiac adverse reaction of Flecainide. Based on the clinical case that we present and the literature review carried out, we hypothesized that a possible mechanism by which flecainide might cause dizziness and visual disturbances is bilateral vestibulopathy.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (canvas): an important cause of late-onset ataxia with unique clinical features.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slowly progressive disorder characterized by cerebellar ataxia, sensory neuropathy and bilateral vestibulopathy. Recently, a biallelic intronic AAGGG repeat expansion, (AAGGG)exp, in the Replication Factor C1 (RFC1) gene was identified as the cause of this disorder. In this study, we describe the phenotypic features of five patients from five different families diagnosed as CANVAS. The mean age at onset was 49.00 ± 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. The mean age at onset was 49.00 ± 9.05 years (between 34 and 56 years) and the most frequent presenting symptom in CANVAS was gait ataxia, followed by sensory disturbances. Persistent coughing was prominent in three patients, and it preceded the onset of ataxia and sensory symptoms in two patients. Parental consanguinity was present in three patients. Two patients showed symptoms or signs suggesting autonomic involvement. Sural nerve biopsy revealed axonal neuropathy in two patients. Our study describes clinical findings, histopathological features and diagnostic clues of CANVAS from Turkey, a country with a high consanguineous marriage rate. Repeat expansion in the RFC1 gene should be considered in all cases with late-onset ataxia, especially when sensory disturbances, vestibular involvement and persistent coughing coexist.

Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant.

BACKGROUND: Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms. METHODS: Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks-Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants' results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant). RESULTS: The median scores at baseline and at 6 months on the Bruininks-Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, -1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, -0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait. CONCLUSIONS: Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.).

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

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.

A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.