Comprehensive phenotyping of RFC1-related disorder: integrating electrophysiological, brain imaging, and otoneurological data in deep phenotyping.

In 2019, a biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). In addition, biallelic expansions were shown to account for up to 22% of cases with late-onset ataxia. Since this discovery, the phenotypic spectrum reported to be associated with RFC1 expansions has extended beyond the initial conditions to include pure cerebellar ataxia, isolated somatosensory impairment, combinations of the 2, and parkinsonism, leading to a potentially broad differential diagnosis. Genetic studies suggest RFC1 expansions may be the most common genetic cause of ataxia and are likely underdiagnosed. This review summarizes the current molecular and clinical knowledge of RFC1-related disease, with a focus on the evaluation of recent phenotype associations and highlighting the current challenges in clinical pathways to diagnosis and molecular testing.

Perioperative vestibular assessment and testing

Vestibular abnormalities are common problems in the whole world, which can lead to bilateral vestibular dysfunction (BVD). That results in symptoms, such as vertigo, unsteadiness, falling, oscillopsia, and lower quality of life. The Objective of this study was to determine BVD in adults and elderlies with vertigo and unsteadiness. This study was conducted on 384 patients in two categories of adults (age range of 18-64 years) and elderlies (65 years old and above) through Electronystagmography (ENG), including caloric test and video head impulse test (vHIT). Patients called bilateral vestibular dysfunction when they have an abnormal bilateral weakness (summation of nystagmus response less than 20 for 4 stimulations and less than 12 for each ear) in caloric test and their vHIT has a gain lower than 0.6. The results of caloric tests were categorized into four groups, including normal, unilateral weakness, bilateral weakness, and central abnormalities. The obtained results revealed that the frequency of BVD is higher than previously reported data in the medical literature. The frequency of BVD was 10.9% for the investigated patients (39.1% abnormal caloric, 12.5% abnormal vHIT, and 10.9% abnormal in both tests). The 38.5% of elderly patients had bilateral abnormal results in both tests. The results of this study showed BVD in some cases by caloric and vHIT tests. Elderlies showed more cases of BVD compared to adult patients.

BackgroundThe genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population.Patients and methodsAll patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced.ResultsA genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms.ConclusionsExpansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

BackgroundCerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe...

Ataxia is a common finding in patients seen in neurological practice and can be the result of a wide variety of causes. Although cerebellar degeneration can be chronic and slowly progressive, acute cerebellar swelling due to infarction, oedema or haemorrhage can have rapid and catastrophic effects and is a true neurological emergency. Here we set out to briefly describe the clinical/anatomical correlates of cerebellar disease and to provide a broad differential diagnosis for patients who present with cerebellar ataxia. This article specifically focuses on acquired causes of cerebellar ataxia. A separate complementary article discusses common hereditary causes of cerebellar ataxia. Key Concepts Clinical syndromes associated with cerebellar dysfunction may be divided into syndromes that predominantly affect the midline cerebellar structures (gait and ocular dysfunction predominant) or the cerebellar hemisphere(s) (ipsilateral appendicular ataxia, dysarthria). Acute onset of cerebellar ataxia is most commonly associated with vascular disorders (stroke or haemorrhage), toxins or infectious aetiologies. Subacute onset cerebellar ataxia can result from a variety of causes, including infectious, neoplastic, autoimmune and metabolic abnormalities. Many of these causes of ataxia are treatable. Most slowly progressive cerebellar ataxias result from neurodegenerative aetiologies, either inherited or sporadic.

To compare video head impulse test (vHIT) and caloric test efficacy in decompensated and compensated vertigo patients and to further investigate whether vHIT alone can be used as a diagnostic tool in vertigo. This study included 25 patients diagnosed with vertigo and without any previous history of vertigo or hearing loss before their admission to our clinic. The control group consisted of 16 healthy adult volunteers. Patients were classified into 2 groups, compensated and decompensated. Video head impulse test and caloric tests were performed and the results were compared between the groups. The difference of caloric test values between control-compensated groups and compensated-decompensated groups was statistically significant (P < .001, Pearson χ2). However, there was no statistically significant difference between the compensated and control groups according to vHIT gain asymmetry values (P = .087). In the very early stages of the disease with spontaneous nystagmus, the diagnostic significance of vHIT was similar to that of the caloric test. When both sides were compared, vHIT gain asymmetry values were close to the caloric test asymmetry values. In the compensated stage, caloric test was superior to vHIT in differentiating compensated vestibular pathologies. When vHIT sensitivity was evaluated according to the bi-thermal caloric test results, the sensitivity of the vHIT gain asymmetry value was 85.71% and 23.08% for decompensated and compensated patients respectively. In the early decompensated stages of the disease with spontaneous nystagmus, vHIT shows similar diagnostic accuracy to that of the caloric test. Since patients can tolerate vHIT more easily, our results suggest that vHIT can be considered as a primary evaluation method in the early (decompensated) period of the disease and should be preferred over the caloric test during the acute phase. Caloric test is more reliable at the compensated stage. Video head impulse test is inadequate in evaluating the compensated vestibular hypofunctional states after compensation has been restored. Level 2b.

Instability of simple DNA repeats has been known as a common cause of hereditary ataxias for over 20 years. Routine genetic diagnostics of these phenotypically similar diseases still rely on an iterative workflow for quantification of repeat units by PCR-based methods of limited precision. We established and validated clinical nanopore Cas9-targeted sequencing, an amplification-free method for simultaneous analysis of 10 repeat loci associated with clinically overlapping hereditary ataxias. The method combines target enrichment by CRISPR-Cas9, Oxford Nanopore long-read sequencing and a bioinformatics pipeline using the tools STRique and Megalodon for parallel detection of length, sequence, methylation and composition of the repeat loci. Clinical nanopore Cas9-targeted sequencing allowed for the precise and parallel analysis of 10 repeat loci associated with adult-onset ataxia and revealed additional parameter such as FMR1 promotor methylation and repeat sequence required for diagnosis at the same time. Using clinical nanopore Cas9-targeted sequencing we analysed 100 clinical samples of undiagnosed ataxia patients and identified causative repeat expansions in 28 patients. Parallel repeat analysis enabled a molecular diagnosis of ataxias independent of preconceptions on the basis of clinical presentation. Biallelic expansions within RFC1 were identified as the most frequent cause of ataxia. We characterized the RFC1 repeat composition of all patients and identified a novel repeat motif, AGGGG. Our results highlight the power of clinical nanopore Cas9-targeted sequencing as a readily expandable workflow for the in-depth analysis and diagnosis of phenotypically overlapping repeat expansion disorders.

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...

BackgroundIntronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1-related cerebellar ataxia,...

Background:Cerebellar 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.Methods:Caloric 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.Results:Reduced 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.Conclusion:Genetic 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.

Background/Objectives: Children with sensorineural hearing loss (SNHL) can develop, or have concurrent vestibular hypofunction (VH). Assessing the vestibular function is challenging in the pediatric population. The objective of the current study was to identify the most effective test battery for objectively diagnosing and screening VH in children with SNHL. Methods: A two-center retrospective chart review included 71 children aged six months to 18 years old with unilateral or bilateral SNHL. Testing consisted of the video head impulse test (VHIT), the caloric test and cervical vestibular evoked myogenic potential (cVEMP). Pairwise agreement between tests was calculated by the proportion of overall agreement and unweighted Cohen's kappa. Results: Vestibular hypofunction was diagnosed less often by cVEMP compared to VHIT or the caloric test. The overall disagreement observed between VHIT and cVEMP and the caloric test and cVEMP was explained by a higher proportion of ears diagnosed with VH by VHIT (18 versus four) or the caloric test (14 versus 0). Several cases with normal cVEMP responses had abnormal test results for VHIT (18 of 71 ears) or the caloric test (14 of 32 ears). VHIT and the caloric test showed a moderate inter-test agreement (Kappa 0.591; p = 0.018). Conclusions: VHIT and the caloric test had a higher likelihood of diagnosing VH, as opposed to cVEMP. It would therefore be advised to use VHIT or the caloric test as the first-line vestibular test for children with SNHL to screen for VH. The clinical value of cVEMP seems low in children with SNHL.

Objectives This study aims to evaluate semicircular canal function using video head impulse test (vHIT) in patients with peripheral vestibular disorders without nystagmus. Methods Patients who underwent vHIT were enrolled in this study, and the proportion of abnormal findings on vHIT in patients without nystagmus was investigated. In addition, the results of vestibular testing were investigated in cases in which both vHIT and caloric testing were performed in patients without nystagmus. Results Forty-six patients (23.4%) of 197 patients who had no abnormal findings on the nystagmus tests, including the gaze nystagmus test, positional nystagmus test, and positioning nystagmus test, showed dysfunction in at least one semicircular canal on vHIT. The most frequent diagnosis was vestibular schwannoma (14/46, 30.4%), and cases with bilateral vestibular dysfunction were also included (12/46, 26.1%). A disorganized pattern of catch-up saccade was observed more frequently in patients with subjective symptoms of dizziness/vertigo compared to those without subjective symptoms. Although the sensitivity of vHIT was low compared to caloric testing, vHIT could detect isolated vertical canal dysfunction not detected by caloric testing. Conclusions vHIT is considered to be a useful test for patients without nystagmus, as vHIT could detect abnormalities in approximately one-quarter of patients without nystagmus. vHIT is considered to be one of the first tests to be performed following nystagmus testing, including the gaze nystagmus test, the positional nystagmus test, and the positioning nystagmus test. On the other hand, there are some cases in which vHIT shows no abnormality while caloric testing shows canal paresis. It is necessary to perform vHIT, bearing in mind that there are abnormalities that cannot be detected by vHIT alone.

Background and Objectives Video head impulse tests (vHITs) and caloric tests are widely used to assess the loss of vestibular function in acute vestibular neuritis. Although previous studies have reported on the results of each test, longitudinal comparison of these tests is rare. In the present study, vHITs and caloric tests were performed in patients with unilateral vestibular neuritis during the acute phase and after a long follow-up period (＞6 months). The goal of this study was to evaluate the changes in vHIT and caloric test results and to analyze the relationships between them. Subjects and Method Between September 2013 and December 2015, charts from 13 patients with unilateral vestibular neuritis were retrospectively reviewed. Among the 13 patients, caloric tests and vHITs were performed in 9 and 10 patients, respectively. Results of the vHITs and caloric tests were analyzed and the changes were compared. Results During the acute phase of vestibular neuritis, the results of the caloric test showed an increase in canal paresis (CP), and the results of the vHIT showed a decrease in horizontal gain. Although subjective symptoms improved in all patients after a long follow-up period (mean: 13.9 months), the occurrence of CP determined from the caloric test was not significantly changed (p;=0.889). On the other hand, the mean horizontal gain of the vHIT had improved significantly (p;＜0.05). Conclusion While CP determined from the caloric test did not change after a long follow-up period, the decreased horizontal gain in the vHIT was significantly recovered in patients with unilateral vestibular neuritis. Key words: Caloric test ㆍ Vestibular neuritis ㆍ Video head impulse test