Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease

Abstract

Objective:To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of RFC1-repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).Methods:Multimodal RFC1 repeat screening (PCR, southern blot, whole-exome/genome (WES/WGS)-based approaches) combined with cross-sectional and longitudinal deep-phenotyping in (i) cross-European cohort A (70 families) with ≥2 features of CANVAS and/or ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families) with unselected late-onset ataxia.Results:Prevalence 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 Asians, and even by WES. 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 and/or dystonia (11%). Ataxia progression was ∼1.3 SARA points/year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1]), but also included early falls, variable non-linear phases of MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total to detect 50% reduced progression.Conclusions:RFC1-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 Evidence:This study provides Class II evidence that RFC1-repeat expansions are associated with CANVAS and ACC.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice

“…9 CANVAS is worldwide the second most prevalent recessive ataxia after FA. 10 In the Turkish cohort under study, 15 index patients and 3 affected Fm of 202 were found to carry the pathogenic intronic expansion, ranking CANVAS in our cohort at the third position after FA and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Turkish patients with CANVAS presented with a late-onset ataxia and an unexplained dry cough described to begin at young ages.…”

“…Turkish patients with CANVAS presented with a late‐onset ataxia and an unexplained dry cough described to begin at young ages. The triad of symptoms, including cerebellar ataxia, neuropathy, and vestibulopathy, was present in eight patients; vestibulopathy was, in the majority of cases, detected after a detailed ear, nose, and throat examination, and thus easily can be missed in routine neurological examination 10 …”

“…The biallelic expansion in the Alu element of the RFC1 gene has been recently described to give rise to a late‐onset ataxia, cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), which often presents with a triad of symptoms 9 . CANVAS is worldwide the second most prevalent recessive ataxia after FA 10 . In the Turkish cohort under study, 15 index patients and 3 affected Fm of 202 were found to carry the pathogenic intronic expansion, ranking CANVAS in our cohort at the third position after FA and autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS).…”

“…The triad of symptoms, including cerebellar ataxia, neuropathy, and vestibulopathy, was present in eight patients; vestibulopathy was, in the majority of cases, detected after a detailed ear, nose, and throat examination, and thus easily can be missed in routine neurological examination. 10 Nonrepeat Dominant and Recessive Ataxia Cases Identified by WES WES was performed in 251 probands, 45 with AD and 176 with AR inheritance; 30 were sporadic, of whom 26 had an AO of ≤40 years. Disease-causing variants in genes associated with dominant ataxias were identified in nine families, corresponding to a diagnostic yield of 19.6%.…”

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias

“…It thus fulfills the requirements of primary datasets that can be used to describe natural history progression models and plan treatment trials in almost all of the most frequent ARCAs, including pharmacometric modeling of outcome measures and treatment effects. For example, for RFC1-ataxia, it has helped to reveal multisystemic phenotypes mimicking cerebellar type multiple system atrophy and progressive supranuclear palsy, and hyperkinetic movement disorders such as chorea and dystonia, and provided first sample size calculations based on longitudinal SARA assessments (24). For COQ8A/ADCK3-ataxia, the ARCA Registry facilitated the delineation of clinico-genetic associations, and the longitudinal analysis of SARA scores has provided the first systematic, groupbased evidence for a possible treatment effect of coenzyme Q10 (25).…”