Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

The association of bilateral vestibulopathy with cerebellar ataxia was first reported in 1991 and delineated as a distinct syndrome with a characteristic and measurable clinical sign--an absent visually enhanced vestibulo-ocular reflex--in 2004. We reviewed 27 patients with this syndrome and show that a non-length-dependent sensory deficit with absent sensory nerve action potentials is an integral component of this syndrome, which we now call "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS). All patients had brain MRI and 22/27 had evidence of cerebellar atrophy involving anterior and dorsal vermis, as well as the hemispheric crus I. Brain and temporal bone pathology in one patient showed marked loss of Purkinje cells and of vestibular, trigeminal, and facial ganglion cells, but not of spiral ganglion cells. There are two sets of sibling pairs, suggesting CANVAS is a late-onset recessive disorder. The characteristic clinical sign-the visual vestibulo-ocular reflex deficit-can be demonstrated and measured clinically using video-oculography.

Objective: The syndrome of cerebellar ataxia with bilateral vestibulopathy was delineated in 2004. Sensory neuropathy was mentioned in 3 of the 4 patients described. We aimed to characterize and estimate the frequency of neuropathy in this condition, and determine its typical MRI features. Methods:Retrospective review of 18 subjects (including 4 from the original description) who met the criteria for bilateral vestibulopathy with cerebellar ataxia. Results:The reported age at onset range was 39-71 years, and symptom duration was 3-38 years. The syndrome was identified in one sibling pair, suggesting that this may be a late-onset recessive disorder, although the other 16 cases were apparently sporadic. All 18 had sensory neuropathy with absent sensory nerve action potentials, although this was not apparent clinically in 2, and the presence of neuropathy was not a selection criterion. In 5, the loss of pinprick sensation was virtually global, mimicking a neuronopathy. However, findings in the other 11 with clinically manifest neuropathy suggested a length-dependent neuropathy. MRI scans showed cerebellar atrophy in 16, involving anterior and dorsal vermis, and hemispheric crus I, while 2 were normal. The inferior vermis and brainstem were spared.

Objective: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit.Method: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem.Results: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. Conclusion:The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia-in other words, it is a "neuronopathy" rather than a "neuropathy." Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation. An abnormal visually enhanced vestibulo-ocular reflex (VVOR) represents a compound impairment of the 3 key corrective oculomotor reflexes, namely, smooth pursuit, the vestibulo-ocular reflex (VOR), and the opticokinetic reflex. We refer the reader to our earlier work for details of the VVOR.1 While the initial description of a syndrome of cerebellar ataxia and bilateral vestibulopathy noted the presence of a peripheral neuropathy in 3 of the 4 index cases, we later showed that in 18 patients a peripheral nerve disease was an integral component of the syndrome we renamed cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS).2 At this time, we noted that a neuronopathy (ganglionopathy) could not be definitively excluded. Subsequently, temporal bone histopathology 1 revealed a vestibular, facial, and trigeminal sensory neuronopathy. In an effort to unify the underlying pathology in CANVAS, we speculated that the peripheral sensory deficit, invariably seen in this syndrome, was more likely to be a neuronopathy than a neuropathy. Our efforts at testing this hypothesis were initially limited by the difficulty in differentiating these 2 entities with conventional neurophysiologic protocols. On obtaining the first spinal cord postmortem samples in cases of diagnosed CANVAS, it appears that the peripheral sensory deficit in CANVAS may be due to a dorsal root ganglionopathy. We hope to develop neurophysiologic protocols that may be used to identify this pathology in the living patient.

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BackgroundThe head impulse test (HIT) is a recognised clinical sign of the high frequency vestibulo-ocular reflex (VOR), which can be quantified with video-oculography. This measures the VOR gain as the ratio of angular eye velocity to angular head velocity. Although normative data is available for VOR gain with video-oculography, most normal studies in general include small numbers of subjects and do not include analysis of variation of VOR gain with age. The purpose of our study was to establish normative data across 60 control subjects aged 20 to 80 years to represent a population distribution.MethodsSixty control subjects without any current or previous form of brain disorder or vertigo participated in this study and form the basis for future comparison to patients with vestibular lesions. The relationship between the horizontal vestibulo-ocular reflex (HVOR) velocity gain and age was analysed using a mixed regression model with a random effect for subjects. Differences in testing technique were assessed to ensure reliability in results.ResultsThe mean HVOR velocity gain of 60 normal subjects was 0.97 (SD = 0.09) at 80 ms and 0.94 (SD = 0.10) at 60 ms. The 2 SD lower limit of normal HVOR velocity gain was 0.79 at 80 ms and 0.75 at 60 ms. No HVOR velocity gain fell below 0.76 and 0.65 at 80 ms and 60 ms respectively. The HVOR velocity gain declined by 0.012 and 0.017 per decade as age increased at 80 ms and 60 ms respectively. A non-physiologically high horizontal HVOR velocity gain was found to occur in tests where passive HITs were predictable in direction and time and where target distance was below 0.70 m.ConclusionsNormative data with respect to HVOR velocity gain decreases slightly with age, but with careful attention to methodology the 2 SD lower limit of normal is relatively robust across a wide age range and into the eighth decade, without requirement for adjustment with age.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.