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.
Highlights
Imbalance, together with dizziness and falls, is one of the leading causes of neurological disability with an estimated prevalence of up to 30% in adults over 65 years of age (Lin and Bhattacharyya, 2012; Hartholt et al, 2019)
Clinical involvement of the main systems affected in replication factor complex subunit 1 (RFC1) repeat expansion associated CANVAS were defined as follows: (i) sensory neuropathy/neuronopathy: sensory symptoms and/or abnormal sensory examination including sensory ataxia; (ii) bilateral vestibulopathy: presence of head movement-induced oscillopsia and/or abnormal head impulse test; and (iii) cerebellar dysfunction: cerebellar dysarthria and/or dysphagia, abnormal eye movements
From the 363 recruited cases, we identified 105 patients carrying the biallelic AAGGG repeat expansion in RFC1
Summary
Together with dizziness and falls, is one of the leading causes of neurological disability with an estimated prevalence of up to 30% in adults over 65 years of age (Lin and Bhattacharyya, 2012; Hartholt et al, 2019). Since the original descriptions of this syndrome (Bronstein et al, 1991), there have been a growing number of studies describing the clinical features of CANVAS (Migliaccio et al, 2004; Szmulewicz et al, 2011; Wu et al, 2014; Cazzato et al, 2016; Infante et al, 2018; Pelosi et al, 2018; Taki et al, 2018). These descriptions are useful, these reports were limited by the inclusion of patients using purely clinical criteria (Szmulewicz et al, 2016). The detailed phenotypic spectrum of RFC1 repeat expansion has yet to be fully elucidated
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