A number sign (#) is used with this entry because of evidence that cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by a homozygous repeat expansion, AAGGG(n), (AAAGG)10-25(AAGGG)n, or (AAAGG)10-25(AAGGG)n(AAAGG)4-6, in the RFC1 gene (102579) or by compound heterozygosity for the repeat expansion and a truncating mutation in RFC1. The reference allele is a simple tandem pentanucleotide AAAAG repeat of 11, (AAAAG)11.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive adult-onset, slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia, impaired vestibular function bilaterally, and non-length-dependent sensory neuropathy (summary by Szmulewicz et al., 2011).

Migliaccio et al. (2004) reported 4 unrelated patients, 2 males and 2 females, with a syndrome comprising cerebellar ataxia and bilateral vestibulopathy with impaired ability of the eye velocity to match head velocity. All had a characteristic sign on clinical examination: impairment of the visually enhanced vestibuloocular reflex (VVOR), or 'doll's head reflex,' in which a normal individual shows compensatory saccades when the head is slowly and smoothly oscillated from side to side while trying to view an earth-fixed target straight ahead. None of the patients had a family history of a similar disorder. Each patient presented between 50 and 60 years of age with slowly increasing gait ataxia and later developed dysarthria. All had problems standing and showed a positive Romberg test. Limb ataxia was less prominent. Detailed vestibuloocular testing showed impaired smooth pursuit, impaired vestibuloocular reflex, and impaired optokinetic reflex. Gaze-evoked nystagmus was present under certain conditions. Three patients had clinical and electrophysiologic evidence of a sensory peripheral neuropathy. Sural nerve biopsy of 1 patient showed a severe axonal neuropathy. None had extrapyramidal features. Brain MRI showed cerebellar atrophy. Genetic testing for several common spinocerebellar ataxias (see, e.g., SCA1, 164400) was negative.

Szmulewicz et al. (2011) reported retrospective data on 27 patients, including the 4 reported by Migliaccio et al. (2004), with a syndrome including cerebellar ataxia, neuropathy, and vestibular areflexia, which they termed 'CANVAS.' The median age at onset was 60 years (range, 33-71), and most (20 patients) presented with gait imbalance. Other presenting features included dysesthesia (8), oscillopsia (5), dizziness (2), and intrinsic falls (1). All patients had saccadic smooth pursuit, gaze-evoked nystagmus, gait and limb ataxia, and dysarthria. Brain MRI showed cerebellar atrophy in 22 patients. Detailed vestibular function testing showed that all had bilateral vestibulopathy manifest as decreased visual acuity on vertical head shaking, absent or reduced horizontal nystagmus on caloric stimulation, and absent or reduced nystagmus in response to constant acceleration rotational testing. VVOR deficit was demonstrated by videooculography. Hearing was unaffected. Temporal bone and brain pathology of 1 patient showed atrophy of the vestibular nerves and vestibular, trigeminal, and facial ganglion cells, but not of the cochlear ganglion cells. There was also a loss of cerebellar Purkinje cells. There was a non-length-dependent neuropathy with areflexia and decreased vibration and pinprick sensation in the upper and lower limbs associated with absence of sensory nerve action potentials.

Cortese et al. (2019) reported 23 affected individuals, either sib pairs or first cousins, from 11 unrelated families with CANVAS. They subsequently identified 33 additional patients with sporadic occurrence of the disorder. All patients were of European descent. The mean age at onset was 54 (range, 35-73 years), and most patients presented with unsteadiness or dizziness, particularly in the dark, and/or distal numbness. Patients had peripheral neuropathy and cerebellar dysfunction, usually associated with cerebellar atrophy on brain imaging, and most also had vestibular dysfunction. Nerve conduction studies showed a nonlength-dependent sensory neuropathy with no motor abnormalities, and sural nerve biopsies showed loss of myelinated fibers. Less common features included cough and autonomic abnormalities, such as urinary urgency, erectile dysfunction, and blood pressure dysregulation. Neuropathologic examination of 1 patient showed severe widespread loss of Purkinje cells and gliosis in the cerebellum. There were no pathologic cytoplasmic or intranuclear inclusions or abnormal RNAi foci in the cerebellar cortex.

Beecroft et al. (2020) reported 13 Maori patients with CANVAS, 2 from Cook Island and 11 from New Zealand. The mean age of symptom onset, excluding patient M2 V:1, was 55 years. Ten of 13 patients had dysarthria, 7 of 13 had sensory symptoms, and 3 of 9 had vestibular symptoms. Eight of 10 patients had a cough, 8 of 12 had autonomic dysfunction, 12 of 12 had an ataxic gait, 7 of 12 had nystagmus, 7 of 12 had reduced reflexes, and 9 of 11 had limb ataxia. Brain MRI or CT findings showed vermal atrophy in 9 of 10 patients, and a video head impulse test (vHIT) was abnormal in 9 of 10 patients. Two of 5 patients had an REM sleep behavior disorder. Patient M2 V:1, aged 20 years, had symptom onset at age 6 years, was wheelchair-dependent at age 8, and had profound limb ataxia at age 20. Brain MRI at age 6 years showed increased signal in the cerebellar peduncles and dorsal brainstem. It was thought that she had an early onset form of the disorder.

Weber et al. (2023) reported 2 unrelated patients with CANVAS. Case 1, a 62-year-old man, presented with progressive ataxia, cerebellar signs, and hand myotonia. He developed gait problems at 37 years of age and had a chronic cough since age 20 years. On examination, he had proprioceptive ataxia, absent deep tendon reflexes, and sensory abnormalities. Other findings included action tremor, dysarthria, and vertical nystagmus. He had symptoms of dysautonomia, including orthostatic hypotension, tachycardia, and abnormal temperature regulation. Brain MRI showed mild cerebellar atrophy involving the vermis. Case 2, a 38-year-old man, presented with cerebellar and proprioceptive ataxia, which started at age 32 with gait abnormalities. On examination, he had decreased vibration sense at the ankles, cerebellar ataxia, dysarthria, and brisk deep tendon reflexes and fasciculations of the lower limbs. He had a chronic cough since age 18 years. EMG showed generalized sensory neuronopathy. Brain MRI showed cerebellar atrophy of the vermis and cerebellar hemispheres

Szmulewicz et al. (2011) reported 2 sets of affected sib pairs with CANVAS, suggesting autosomal recessive inheritance.

In 25 affected individuals from 11 unrelated families with CANVAS, Cortese et al. (2019) identified a homozygous expanded 5-bp intronic repeat, AAGGG(n), in the RFC1 gene. The variant, which was found by a combination of linkage analysis and whole-genome and whole-exome sequencing, was confirmed by Sanger sequencing. Screening of an additional cohort of 150 patients with sporadic late-onset ataxia identified the recessive AAGGG(n) expansion in 33 patients (22%). Haplotype analysis showed that all affected individuals from the 11 families and 32 of the sporadic cases shared the same haplotype. The reference allele, a simple tandem pentanucleotide AAAAG repeat of 11, (AAAAG)11, was replaced by a variable number of expanded pentanucleotide AAGGG repeated units. The expansion size varied across different families, ranging from about 400 to 2,000 repeats, but the majority of cases had about 1,000 repeats. Repeat size was relatively stable in sibs, and there was no association between age at onset and repeat size. There were no instances of vertical transmission; all families studied consisted of affected sibs or first cousins in the same generation. Patient cells showed normal expression levels of RFC1 mRNA and protein, and postmortem brain tissue from 1 CANVAS patients had normal levels of RFC1 and FXN (606829) compared to controls. However, patient cells showed some evidence of altered pre-mRNA processing with an increase in the retention of intron 2 compared to controls. Patient fibroblasts did not show increased susceptibility to DNA damage. Cortese et al. (2019) noted that their studies did not show evidence of a loss-of-function effect.

Beecroft et al. (2020) identified a biallelic (AAAGG)10-25(AAGGG)n intronic repeat expansion of the RFC1 gene (102579.0002) in 13 patients with CANVAS: 2 from a Cook Island Maori family, 6 from a New Zealand Maori family, and 5 from unrelated New Zealand Maori families. Two of the affected individuals also had an additional repeat sequence, (AAAGG)4-6, at the distal end of the repeat sequence. A common haplotype was identified in these patients, suggesting a founder effect, with the most recent common ancestor estimated to date to 1369-1499 CE. There were no apparent phenotypic differences between this patient cohort and patients with the (AAGGG)n repeat expansion (102579.0001).

In 2 patients with CANVAS, Benkirane et al. (2022) identified compound heterozygous mutations in the RFC1 gene, an AAGGG repeat expansion on one allele in both patients and a nonsense mutation (R388X; 102579.0003) in patient 1 and a frameshift mutation (c.575delA; 102579.0004) in patient 2. In both patients, RFC1 expression was reduced from the allele with the truncating mutation. Benkirane et al. (2022) concluded that CANVAS likely results from a loss-of-function of RFC1. Clinical features in these 2 patients did not differ from what had been reported in patients with homozygosity for repeat expansion mutations in RFC1.

Weber et al. (2023) identified compound heterozygous mutations in the RFC1 gene in 2 unrelated patients with CANVAS; both patients had an AAGGG repeat expansion on one allele with a different mutation on the other allele, c.2535+2T-C (102579.0005) or c.2690+1G-A (102579.0006). Both patients had an earlier onset of disease than that reported for classical CANVAS.

Associations Pending Confirmation

For discussion of a possible association between an autosomal dominant form of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and variation in the ELF2 gene, see 619798.0001.