CANVAS was first so-named in 2011 to refer to a series of patients with late-onset slowly progressing cerebellar ataxia, bilateral vestibular areflexia, and axonal sensory neuropathy [24]. Orthostatic hypotension was also noted to be a common feature in many such individuals [25], as was neuropathic pain and chronic cough [26].

The clinical features of CANVAS are summarised in the Figure. The median age of onset of core neurological symptoms is 52 years, and males and females appear to be affected equally [27]. The presence of pairs of sibling cases in original case series was an early pointer to a genetic basis of possible recessive inheritance, as discussed further below [28]. Initial neurological symptoms are sensory loss or paraesthesia, unsteadiness, poor balance and falls (often more prominent in the dark), dizziness and oscillopsia [29]. Dysarthria and dysphasia can then develop, usually as later features, along with orthostatic hypotension and other autonomic symptoms such as dry mouth and eyes, urinary retention, and erectile dysfunction [30]. As below, chronic cough associated with CANVAS can pre-date classical neurological symptoms by 30 years [27, 31]. Neuropathic pain is also common, and can be particularly troublesome, with allodynia and dysaethesia [26, 32].

Ataxia is due to a combination of cerebellar dysfunction and an axonal neuropathy-driven defective proprioception, with or without a failure of vestibular function. The relative timing of onset of each of the three components is variable, contributing to delay in diagnosis of CANVAS [6].

Clinical signs include those of a cerebellar disorder such as gaze-evoked nystagmus, broken pursuits, dysarthria, and dysphagia (Table 1). Bilateral vestibular impairment can be demonstrated by a reduced or absent vestibular-ocular reflex, such as through a failure of eye stabilisation during head rotation, tested clinically by the head impulse test [6, 33]. Proprioception defects manifest clinically as abnormal vibration and joint position sense testing.

The neurological deficits of CANVAS usually progress slowly but irreversibly over years, and clinical management is currently supportive. In one case series the onset of autonomic dysfunction was apparent a median of five years after the appearance of gait ataxia, dysarthria at 8 years, and dysphagia at 10 years, with substantial variability in the timing and the severity of each, including in the need for walking aids or wheelchair dependence [34].

Peripheral sensory nerve conduction is invariably abnormal in established cases of CANVAS, and to a greater degree in the lower limbs than upper, whereas motor conduction is largely unimpaired [27]. Spinal cord and cerebellar atrophy is commonly seen on magnetic resonance imaging.

Muscle histology is typically normal, whilst sensory nerve biopsy demonstrates a substantial reduction in numbers of large and small myelinated fibres, an absence of axonal regeneration, and no evidence of demyelination [27]. Descriptions of postmortem examinations have noted changes focussed on the cerebellum and spinal cord. In particular, there is substantial dorsal root ganglionopathy and depletion of cerebellar Purkinje cells, especially obvious in the vermis [35]. In keeping with autonomic dysfunction there was also loss of neurones within the vagal nucleus in one report [36].

Independent work by two separate groups, through linkage analysis, whole genome sequencing and other techniques, has recently identified specific polymorphisms in the gene encoding replication factor complex subunit 1 (RFC1) in > 90% of both sporadic and familial cases of clinically diagnosed CANVAS [8, 9]. Cases possessed biallelic (homozygous) AAGGG repeat expansion sequences within the second intron of RFC1 [37]. This finding has subsequently been replicated in other case series of varied ethnicity, although with some variations in the specific expanded pentanucleotide repeat sequence including uninterrupted ACAGG, AAAGG and AGGGC and mixed motif AAAGG-AAGGG and AGAGG-AAAGG [7, 38,39,40].

The normal function of RFC1 relates to coordinating DNA repair and replication [41]. In particular, the five-subunit gene product replication factor C is termed a clamp loader, functioning to load ring-shaped sliding clamps onto replicating DNA, which in turn tether polymerases to facilitate nucleic acid chain extension [42]. However, it is as yet unknown exactly how specific RFC1 variants lead to disease. The presence of the repeat expansion sequence is hypothesised to alter the three-dimensional DNA structure of RFC1. Although > 100 repeats of the abnormal motif appear to be required to cause disease, it seems to be the nature of the particular repeated pentanucleotide motif rather than the absolute number of repeats that is responsible for pathology [37]. Despite this, no alteration in the RFC1 RNA transcript or protein product has yet been identified in individuals with clinically defined CANVAS, and understanding of the process of disease development remains poor [8]. However, it is of interest that mutations in other genes of DNA repair are associated with several neurodegenerative disorders including xeroderma pigmentosum and ataxia-telangiectasia [43]. Ataxia and neuropathy are common to all of these, suggesting a particular vulnerability of peripheral nerves and the cerebellum to DNA damage.

Following the identification of the putative genetic basis of CANVAS, a wider category of RFC1-associated late-onset neurological syndromes has been identified [37]. The majority lie along a spectrum which includes CANVAS, including isolated axonal sensory neuropathy [44], and complex cerebellar ataxia with neuropathy [45]. A few cases who developed Parkinsonism or cognitive dysfunction in later disease stages were have also been reported [37]. The penetrance and extent of variable expressivity of pathogenic biallelic AAGGG repeat expansion sequences is not clear. In European populations the allele frequency of RFC1 AAGGG expansion is estimated at ~ 1–5% of healthy individuals [8, 9], giving a homozygous genotype frequency at birth of 0.25% to 1 in 10,000. Full penetrance would suggest CANVAS to be a more common disease than is currently recognised. Although misdiagnosis of this recently described syndrome appears common, the true prevalence of RFC1-related disease is uncertain [27].