Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion

Abstract

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.

Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

“…Clinical evidence of cerebellar dysfunction is given by the combination of cerebellar-type dysarthria, appendicular ataxia, truncal ataxia and cerebellar-type ocular motor deficits. The main frequently reported ocular motor cerebellar signs are jerky smooth pursuit, gaze-evoked nystagmus, downbeat nystagmus and saccadic dysmetria [8,14,17,[23][24][25]. Other clinical ocular motor cerebellar signs such as saccadic intrusions or oscillations, periodic alternating nystagmus, central positional nystagmus, skew deviation or esotropia have not been reported so far [26].…”

Mutation in RNF170 causes sensory ataxic neuropathy with vestibular areflexia: a CANVAS mimic

“…There is a narrow differential diagnosis for a sensory ganglionopathy which includes paraneoplastic (anti-Hu antibodies), autoimmune (Sjogren Syndrome,), toxic (cisplatin, pyridoxine) and genetic causes (Friedreich's ataxia and mitochondrial disease due to POLG1 mutations) causes (2). More recently biallelic AAGGG expansion in Replication Factor complex subunit 1 have been identified as a major cause of sensory ataxia neuropathy, often with cerebellar and vestibular involvement (CANVAS) (3,4). However, a significant fraction of patients with a sensory ganglionopathy remain genetically undiagnosed.…”

Reply to: “Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions”

“…3 Since the identification of RFC1 expansions in CANVAS we have seen this disorder as a clinical spectrum. 4 This ranges from mild ataxia with sensory neuropathy, to the CANVAS clinical syndrome, through to a more rapidly progressive ataxia with parkinsonism, autonomic dysfunction, and an abnormal dopamine transporter scan; a clinical overlap between CANVAS and multiple systems atrophy, with RFC1 expansions on repeatprimed PCR and Southern blotting (unpublished data). We predict that the phenotypic spectrum associated with the RFC1 repeat expansion is likely to be broader than previously described as in the report of da Silva Schmitt and colleagues.…”