Abstract
ObjectiveTo delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).MethodsMultimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing–based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.ResultsPrevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C–like progression (SARA points 2.5–5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.ConclusionsRFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.Classification of EvidenceThis study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
Highlights
Multimodal replication factor complex subunit 1 (RFC1) repeat screening (PCR, Southern blot, whole-exome/genome sequencing– based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxi
Classification of Evidence This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC
To prepare future treatment trials in RFC1 disease, we here leveraged a large cross-European multicenter ataxia cohort to (1) map its full phenotypic spectrum and evolution beyond CANVAS; (2) single out discriminative features of patients with RFC1-positive and RFC1-negative ataxia; and (3) map the natural disease history, including first piloting quantitative longitudinal disease progression data and preliminary sample size calculations
Summary
Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing– based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. Cohort A was designed to be likely enriched for RFC1-positive patients according to the phenotypic selection criteria, namely unsolved degenerative ataxia and at least 2 phenotypic features of CANVAS or ataxia with chronic cough[6] (ACC), that is, cerebellar ataxia, sensory neuropathy, vestibulopathy, or chronic cough (defined as an otherwise unexplained cough persisting >8 weeks).[7] Here, we aggregated 76 deep-phenotyped patients from 70 families from 14 different sites in Europe (France 13, Germany 45, Italy 2, the Netherlands 2, Sweden 1, Spain 9, Switzerland 4) This cohort had undergone exclusion of SCA1/2/3 in 49%, Friedreich ataxia in 47%, and negative whole-exome sequencing (WES) or targeted sequencing panel in 34% of patients. Phenotypic information in cohort B was limited to the mere e1370 Neurology | Volume 96, Number 9 | March 2, 2021
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