AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS neurons.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative disorder caused by intronic biallelic, nonreference CCCTT/AAGGG repeat expansions within RFC1. To investigate how these repeats cause disease, we generated patient induced pluripotent stem cell-derived neurons (iNeurons). CCCTT/AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway function. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins. However, these proteins and repeat RNA foci were not detected in iNeurons, and overexpression of these repeats failed to induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded AAGGG allele. These deficits were neither replicated by RFC1 knockdown in control iNeurons nor rescued by RFC1 reprovision in CANVAS iNeurons. These findings support a repeat-dependent but RFC1 protein-independent cause of neuronal dysfunction in CANVAS, with implications for therapeutic development in this currently untreatable condition.

Unreliable association between self-reported sense of direction and peripheral vestibular function.

BACKGROUND: Uni- or bilateral peripheralvestibular impairment causes objective spatial orientation deficits, which can be measured using pen-and-paper-tests or sensorimotor tasks (navigation or pointing). For patients' subjective orientation abilities, questionnaires are commonly used (e.g., Santa Barbara sense of direction scale [SBSODS]). However, the relationship between subjective assessment of spatial skills and objective vestibular function has only been scarcely investigated. METHODS: A total of 177 patients (mean age 57.86 ± 17.53 years, 90 females) who presented in our tertiary Center for Vertigo and Balance Disorders underwent neuro-otological examinations, including bithermal water calorics, video head impulse test (vHIT), and testing of the subjective visual vertical (SVV), and filled out the SBSODS (German version). Correlation analyses and linear multiple regression model analyses were performed between vestibular test results and self-assessment scores. Additionally, groupwise vestibular function for patients with low, average, and high self-report scores was analyzed. RESULTS: Forty-two patients fulfilled the diagnostic criteria for bilateral vestibulopathy, 93 for chronic unilateral vestibulopathy (68 unilateral caloric hypofunction and 25 isolated horizontal vestibulo-ocular reflex deficits), and 42 patients had normal vestibular test results. SBSODS scores showed clear sex differences with higher subjective skill levels in males (mean score males: 4.94 ± 0.99, females 4.40 ± 0.94; Student's t-test: t-3.78, p < .001***). No stable correlation between objective vestibular function and subjective sense of spatial orientation was found. A multiple linear regression model could not reliably explain the self-reported variance. The three patient groups with low, average, and high self-assessment-scores showed no significant differences of vestibular function. CONCLUSION: Self-reported assessment of spatial orientation does not robustly correlate with objective peripheral vestibular function. Therefore, other methods of measuring spatial skills in real-world and virtual environments are required to disclose orientation deficits due to vestibular hypofunction.

Electrical stimulation of the vestibular nerve: evaluating effects and potential starting points for optimization in vestibular implants.

PURPOSE OF REVIEW: Oscillopsia and unsteadiness are common and highly debilitating symptoms in individuals with bilateral vestibulopathy. A lack of adequate treatment options encouraged the investigation of vestibular implants, which aim to restore vestibular function with motion-modulated electrical stimulation. This review aims to outline the ocular and postural responses that can be evoked with electrical prosthetic stimulation of the semicircular canals and discuss potential approaches to further optimize evoked responses. Particular focus is given to the stimulation paradigm. RECENT FINDINGS: Feasibility studies in animals paved the way for vestibular implantation in human patients with bilateral vestibulopathy. Recent human trials demonstrated prosthetic electrical stimulation to partially restore vestibular reflexes, enhance dynamic visual acuity, and generate controlled postural responses. To further optimize prosthetic performance, studies predominantly targeted eye responses elicited by the vestibulo-ocular reflex, aiming to minimize misalignments and asymmetries while maximizing the response. Changes of stimulation parameters are shown to hold promise to increase prosthetic efficacy, together with surgical refinements and neuroplastic effects. SUMMARY: Optimization of the stimulation paradigm, in combination with a more precise electrode placement, holds great potential to enhance the clinical benefit of vestibular implants.

Bilateral vestibulopathy - Loss of vestibular function and experience of emotions.

OBJECTIVE: The vestibular system is closely connected to emotion-processing neuronal circuits. Patients with bilateral vestibulopathy (BVP), a chronic loss of vestibular function, show remarkably lower rates of psychiatric comorbidities and vertigo-related anxiety (VRA) than those with episodic vertigo/dizziness (v/d). This study aimed to evaluate whether patients with BVP differ from those with episodic v/d in terms of VRA, general anxiety, and cognitions about body and health. METHODS: This cross-sectional study involved a subsample of 202 patients with episodic v/d (i.e., vestibular migraine, vestibular paroxysmia, or Menière's disease) and 43 patients with BVP. All patients underwent standardised neurological/neurotological examinations, structured clinical interviews (SCID-I), and self-report questionnaires, such as the Vertigo Handicap Questionnaire (VHQ), Beck Anxiety Inventory (BAI), Trait Anxiety from the State-Trait-Anxiety Inventory (STAI-T), and Cognitions About Body and Health questionnaire (CABAH). Non-parametric tests were used for analysis. Due to multiple testing, the significance level was set at p ≤ .008. RESULTS: Patients with episodic v/d exhibited higher VRA levels than those with BVP. However, this difference was not statistically significant (p = .04; r = 0.15, small effect). Additionally, patients with BVP reported more catastrophizing cognitions (p < .001; r = 0.25, small effect) and bodily weakness (p = .003; r = 0.22, small effect) compared to those with episodic v/d. There were no differences in general anxiety levels (BAI and STAI-T) between patients with v/d and those with BVP. CONCLUSION: Patients with episodic v/d and BVP differed in their appraisal (cognition). The difference in VRA (subjective feeling) was not statistically significant. These preliminary results are discussed using a component approach to emotions.

[Subacute ataxia associated with cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS)]. / Ataxia subaguda asociada a ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS).

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.

El síndrome de ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS) es un trastorno neurodegenerativo progresivo que se manifiesta en etapas tardías de la vida. Su base genética ha sido recientemente identificada en el gen que codifica la subunidad 1 del factor C de replicación (RFC1). Presentamos el caso de una mujer de 62 años con una historial de desequilibrio y deterioro de la marcha de presentación bifásica, con un inicio rápido de los síntomas seguido de un deterioro neurológico lento y progresivo. El proceso diagnóstico fue complejo y se realizaron numerosas pruebas para descartar causas adquiridas y genéticas de la ataxia, arribando al diagnóstico de ataxia cerebelosa de inicio tardío idiopática. Ulteriormente, las pruebas de función vestibular identificaron una grave vestibulopatía bilateral. Esto llevó a considerar el CANVAS entre los diagnósticos, que finalmente fue confirmado mediante pruebas genéticas (expansión bialélica del penta-nucleótido AAGGG en el gen RFC1). Este caso subraya la importancia de esta nueva enfermedad genética y su variante de presentación subaguda y enfatiza la relevancia de las pruebas objetivas de función vestibular en las ataxias consideradas idiopáticas para lograr un diagnóstico adecuado y un eventual asesoramiento genético a la descendencia.

[Rehabilitation in bilateral vestibulopathy: trends and perspectives]. / Reabilitatsiya patsientov s dvustoronnei vestibulopatiei: tendentsii i perspektivy razvitiya.

A review of the literature on rehabilitation methods for bilateral vestibulopathy is presented using RSCI, Scopus and PubMed databases. The principles and effectiveness of physical vestibular rehabilitation, vestibular implants, galvanic vestibular stimulation, and biofeedback-based sensory substitution and augmentation systems are described. The advantages and disadvantages of each method and perspectives for their improvement are presented.

[Bilateral vestibulopathy and sensorineural hearing loss in necrobiotic xanthogranuloma, multiple myeloma and amiloidosis]. / Dvustoronnyaya vestibulopatiya i sensonevral'naya tugoukhost' u patsienta s nekroticheskoi ksantogranulemoi, mnozhestvennoi mielomoi i amiloidozom.

This article describes a rare case of necrotic xanthogranuloma in a 46-year-old patient who presented with the development of periorbital xanthelasms, progressive bilateral sensorineural hearing loss and bilateral vestibulopathy, followed by multiple myeloma and amyloidosis. For several years, the patient underwent standard rehabilitation for chronic sensorineural hearing loss and was fitted with a hearing aid. During hospitalisation for exacerbation of chronic bronchitis, monoclonal gammopathy was identified, and later, after careful examination and repeated biopsies, necrotic xanthogranuloma, multiple myeloma and AL-amyloidosis were confirmed. Targeted immunochemotherapy resulted in improvement of hearing and significant recovery of the vestibuloocular reflex bilaterally.

Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1).

INTRODUCTION: A common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000. AIM: In patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL). METHODS: Clinical and functional data were collected for the 33 included patients undergoing CC studies in our specialized unit. Performed were an etiological study of CC following European Respiratory Society recommendations, a genetic study of RFC1 mutations, and Rydel-Seiffer fork testing to detect possible peripheral vibratory sensitivity impairment. Administered to evaluate QoL were 4 questionnaires. RESULTS: Prevalence of biallelic (AAGGG)exp in RFC1 was 6.1% (n=2) overall, increasing to 7.1% in the RCC subgroup, and to 33.3% in the Rydel-Seiffer fork altered results subgroup. Prevalence of monoallelic (AAGGG)exp in RFC1 was 18.2% (n=6) overall, rising to 50.0% (n=2) in the UCC subgroup. CONCLUSION: Genetic screening for (AAGGG)exp in RFC1, and also use of the Rydel-Seiffer fork test, should be considered in specialized CC consultations for patients with RCC and UCC. Detecting possible CANVAS symptoms in CC studies would identify candidates for early genetic screening, of interest in reducing the disease burden for patients and health systems alike.

A rare case report of bilateral vestibulopathy due to otosyphilis.

RATIONALE: Bilateral vestibulopathy is an important cause of imbalance. There are multiple etiologies of bilateral vestibulopathy (BVP), but reports of BVP due to otosyphilis are rare. PATIENT CONCERNS: A 39-year-old male was referred to our medical center due to vertigo, persistent dizziness and gait disturbance for 2 months. DIAGNOSES: Bilateral vestibulopathy due to otosyphilis was considered in this case, as confirmed through analyses of vestibular function, laboratory tests, and penicillin treatment. INTERVENTIONS: The patient was was treated with a high dose of penicillin G (24 × 106 IU/d) for 14 days. OUTCOMES: The patient's symptoms had improved greatly following treatment, with dizziness and gait disturbance having completely resolved at 3 months following hospital discharge. LESSONS: Bilateral vestibulopathy should be considered when evaluating patients with acute or subacute persistent dizziness. Clinicians should also be aware of the potential for otosyphilis among patients who report BVP.

Full-body kinematics and head stabilisation strategies during walking in patients with chronic unilateral and bilateral vestibulopathy.

Chronic imbalance is a frequent and limiting symptom of patients with chronic unilateral and bilateral vestibulopathy. A full-body kinematic analysis of the movement of patients with vestibulopathy would provide a better understanding of the impact of the pathology on dynamic tasks such as walking. Therefore, this study aimed to investigate the global body movement during walking, its variability (assessed with the GaitSD), and the strategies to stabilise the head (assessed with the head Anchoring Index). The full-body motion capture data of 10 patients with bilateral vestibulopathy (BV), 10 patients with unilateral vestibulopathy (UV), and 10 healthy subjects (HS) walking at several speeds (slow, comfortable, and fast) were analysed in this prospective cohort study. We observed only a few significant differences between groups in parts of the gait cycle (shoulder abduction-adduction, pelvis rotation, and hip flexion-extension) during the analysis of kinematic curves. Only BV patients had significantly higher gait variability (GaitSD) for all three walking speeds. Head stabilisation strategies depended on the plan of motion and walking speed condition, but BV and UV patients tended to stabilise their head in relation to the trunk and HS tended to stabilise their head in space. These results suggest that GaitSD could be a relevant biomarker of chronic instability in BV and that the head Anchoring Index tends to confirm clinical observations of abnormal head-trunk dynamics in patients with vestibulopathy while walking.

Bilateral vestibulopathy as the initial presentation of CANVAS.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a slowly progressing autosomal recessive ataxic disorder linked to an abnormal biallelic intronic (most commonly) AAGGG repeat expansion in the replication factor complex subunit 1 (RFC1). While the clinical diagnosis is relatively straightforward when the three components of the disorder are present, it becomes challenging when only one of the triad (cerebellar ataxia, neuropathy or vestibular areflexia) manifests. Isolated cases of Bilateral Vestibulopathy (BVP) or vestibular areflexia that later developed the other components of CANVAS have not been documented. We report four cases of patients with chronic imbalance and BVP that, after several years, developed cerebellar and neuropathic deficits with positive genetic testing for RFC1. Our report supports the concept that CANVAS should be considered in every patient with BVP of unknown etiology, even without the presence of the other triad components. This is especially important given that about 50% of cases in many BVP series are diagnosed as idiopathic, some of which may be undiagnosed CANVAS.

The effect of increased listening effort on the balance performance of patients with compensated vestibular lesion.

OBJECTIVES: This study investigated the effects of listening effort (LE) on balance in patients with compensated vestibular deficits compared to healthy peers. METHODS: The subjects included two main groups: a control group of 15 healthy subjects and a study group of 19 patients with compensated vestibular pathology. The computerized dynamic posturography test (CDP) was conducted without the speech-in-noise task as a baseline, then the participant was subjected to a dual task in which the auditory task (speech-in-noise sentences) was given as the primary task, and the balance function test was the secondary task. RESULTS: WITHIN-GROUP ANALYSIS: The study group showed statistically significantly worse values of all body balance parameters under dual-task than the baseline in all conditions. These differences were much higher under the compliant platform conditions. However, these findings were not statistically significant in the control group. BETWEEN-GROUP ANALYSIS: The study group showed a statistically significant decline in body balance reactions compared to the control group under dual-task with increased listening effort and the compliant platform. Study subgroup analysis revealed statistically significant differences between patients with unilateral vestibular loss (UVL) and those with bilateral vestibular loss (BVL) in the unstable platform condition. CONCLUSION: Our study regarding implementing a dual-tasking paradigm as a measure of LE during the evaluation of chronic vestibular patients with CDP demonstrated how dual-tasking with increased LE affects postural stability. Because of this, patients will probably be more prone to tripping and falling in multitasking situations, as found in real-world settings. This fact should be taken into consideration while testing patients with chronic vertigo and compensated states at VNG. A dual-task paradigm helps uncover the unrevealed pathology.

The VertiGO! Trial protocol: A prospective, single-center, patient-blinded study to evaluate efficacy and safety of prolonged daily stimulation with a multichannel vestibulocochlear implant prototype in bilateral vestibulopathy patients.

BACKGROUND: A combined vestibular (VI) and cochlear implant (CI) device, also known as the vestibulocochlear implant (VCI), was previously developed to restore both vestibular and auditory function. A new refined prototype is currently being investigated. This prototype allows for concurrent multichannel vestibular and cochlear stimulation. Although recent studies showed that VCI stimulation enables compensatory eye, body and neck movements, the constraints in these acute study designs prevent them from creating more general statements over time. Moreover, the clinical relevance of potential VI and CI interactions is not yet studied. The VertiGO! Trial aims to investigate the safety and efficacy of prolonged daily motion modulated stimulation with a multichannel VCI prototype. METHODS: A single-center clinical trial will be carried out to evaluate prolonged VCI stimulation, assess general safety and explore interactions between the CI and VI. A single-blind randomized controlled crossover design will be implemented to evaluate the efficacy of three types of stimulation. Furthermore, this study will provide a proof-of-concept for a VI rehabilitation program. A total of minimum eight, with a maximum of 13, participants suffering from bilateral vestibulopathy and severe sensorineural hearing loss in the ear to implant will be included and followed over a five-year period. Efficacy will be evaluated by collecting functional (i.e. image stabilization) and more fundamental (i.e. vestibulo-ocular reflexes, self-motion perception) outcomes. Hearing performance with a VCI and patient-reported outcomes will be included as well. DISCUSSION: The proposed schedule of fitting, stimulation and outcome testing allows for a comprehensive evaluation of the feasibility and long-term safety of a multichannel VCI prototype. This design will give insights into vestibular and hearing performance during VCI stimulation. Results will also provide insights into the expected daily benefit of prolonged VCI stimulation, paving the way for cost-effectiveness analyses and a more comprehensive clinical implementation of vestibulocochlear stimulation in the future. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04918745. Registered 28 April 2021.

RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile.

OBJECTIVES: The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome. METHODS: We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN. RESULTS: Biallelic RFC1 AAGGG expansions were identified in 15/65 patients with idiopathic DBN (23%). None of the 102 GAA-FGF14-positive patients, but 2/36 (6%) of patients with presumed secondary DBN carried biallelic RFC1 expansions. The DBN syndrome in RFC1-positive patients was characterized by additional cerebellar impairment in 100% (15/15), bilateral vestibulopathy (BVP) in 100% (15/15), and polyneuropathy in 80% (12/15) of cases. Compared to GAA-FGF14-positive and genetically unexplained patients, RFC1-positive patients had significantly more frequent neuropathic features on examination and BVP. Furthermore, vestibular function, as measured by the video head impulse test, was significantly more impaired in RFC1-positive patients. DISCUSSION: Biallelic RFC1 expansions are a common monogenic cause of DBN syndrome.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

A clinical 3D pointing test differentiates spatial memory deficits in dementia and bilateral vestibular failure.

BACKGROUND: Deficits in spatial memory, orientation, and navigation are often neglected early signs of cognitive impairment or loss of vestibular function. Real-world navigation tests require complex setups. In contrast, simple pointing at targets in a three-dimensional environment is a basic sensorimotor ability which provides an alternative measure of spatial orientation and memory at bedside. The aim of this study was to test the reliability of a previously established 3D-Real-World Pointing Test (3D-RWPT) in patients with cognitive impairment due to different neurodegenerative disorders, bilateral vestibulopathy, or a combination of both compared to healthy participants. METHODS: The 3D-RWPT was performed using a static array of targets in front of the seated participant before and, as a transformation task, after a 90-degree body rotation around the yaw-axis. Three groups of patients were enrolled: (1) chronic bilateral vestibulopathy (BVP) with normal cognition (n = 32), (2) cognitive impairment with normal vestibular function (n = 28), and (3) combined BVP and cognitive impairment (n = 9). The control group consisted of age-matched participants (HP) without cognitive and vestibular deficits (n = 67). Analyses focused on paradigm-specific mean angular deviation of pointing in the azimuth (horizontal) and polar (vertical) spatial planes, of the preferred pointing strategy (egocentric or allocentric), and the resulting shape configuration of the pointing array relative to the stimulus array. Statistical analysis was performed using age-corrected ANCOVA-testing with Bonferroni correction and correlation analysis using Spearman's rho. RESULTS: Patients with cognitive impairment employed more egocentric pointing strategies while patients with BVP but normal cognition and HP used more world-based solutions (pBonf 5.78 × 10-3**). Differences in pointing accuracy were only found in the azimuth plane, unveiling unique patterns where patients with cognitive impairment showed decreased accuracy in the transformation tasks of the 3D-RWPT (pBonf < 0.001***) while patients with BVP struggled in the post-rotation tasks (pBonf < 0.001***). Overall azimuth pointing performance was still adequate in some patients with BVP but significantly decreased when combined with a cognitive deficit. CONCLUSION: The 3D-RWPT provides a simple and fast measure of spatial orientation and memory. Cognitive impairment often led to a shift from world-based allocentric pointing strategy to an egocentric performance with less azimuth accuracy compared to age-matched controls. This supports the view that cognitive deficits hinder the mental buildup of the stimulus pattern represented as a geometrical form. Vestibular hypofunction negatively affected spatial memory and pointing performance in the azimuth plane. The most severe spatial impairments (angular deviation, figure frame configuration) were found in patients with combined cognitive and vestibular deficits.

Cerebellar Ataxia With Neuropathy and Vestibular Areflexia Syndrome Due to Replication Factor C Subunit 1 Gene Repeat Expansion.

ABSTRACT: A 56-year-old man was born to consanguineous parents. He experienced slow-progressing sensory disturbances in the upper extremities. T1-weighted images showed cerebellar atrophy. 123I-IMP SPECT revealed reduced cerebral blood flow in the cerebellum. 123I-FP-CIT SPECT showed low uptake of dopamine transporter in the bilateral tail of the striatum. 123I-MIBG scintigraphy shows a decreased heart-to-mediastinum ratio. Flanking polymerase chain reaction suggested biallelic repeat expansion in intron 2 of RFC1, and subsequent repeat-primed polymerase chain reaction revealed ACAGG repeat expansion. Thus, he was diagnosed as cerebellar ataxia with neuropathy and vestibular areflexia syndrome.

Pseudo-eye-of-the-tiger sign in cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

The well-known eye-of-the-tiger sign features bilateral and symmetrical changes in the globus pallidus, with a central area of high signal and peripheral low signal on T2-weighted MRI. Although formally considered pathognomonic of pantothenate kinase-associated neurodegeneration (PKAN), there are other neurodegenerative or genetic diseases showing similar findings. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset ataxia, that was recently associated with biallelic AAGGG repeat expansion in the RFC1 gene. Although its predominant MRI finding is cerebellar atrophy, there may be other less common associated findings. Our aim is to present two cases of CANVAS with associated (pseudo-)eye-of-the-tiger sign, highlighting the possibility of yet another differential diagnosis for this imaging sign.