Dataset Information

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 replication factor complex subunit 1 (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 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.

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 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.

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.

SUBMITTER: Traschutz A

PROVIDER: S-EPMC8055326 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Traschütz Andreas A Cortese Andrea A Reich Selina S Dominik Natalia N Faber Jennifer J Jacobi Heike H Hartmann Annette M AM Rujescu Dan D Montaut Solveig S Echaniz-Laguna Andoni A Erer Sevda S Schütz Valerie Cornelia VC Tarnutzer Alexander A AA Sturm Marc M Haack Tobias B TB Vaucamps-Diedhiou Nadège N Puccio Helene H Schöls Ludger L Klockgether Thomas T van de Warrenburg Bart P BP Paucar Martin M Timmann Dagmar D Hilgers Ralf-Dieter RD Gazulla Jose J Strupp Michael M Moris German G Filla Alessandro A Houlden Henry H Anheim Mathieu M Infante Jon J Basak A Nazli AN Synofzik Matthis M

Neurology 20210125 9

<h4>Objective</h4>To 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).<h4>Methods</h4>Multimodal <i>RFC1</i> repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep p ...[more]

PMID: 33495376

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Dataset Information

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

Objective

Methods

Results

Conclusions

Classification of evidence

Publications

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

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