Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease
Andreas Traschütz, Andrea Cortese, Selina Reich, Natalia Dominik, Jennifer Faber, Heike Jacobi, Annette M. Hartmann, Dan Rujescu, Solveig Montaut, Andoni Echaniz‐Laguna, Sevda Erer, Valerie Schütz, Alexander A. Tarnutzer, Marc Sturm, Tobias B. Haack, Nadège Vaucamps-Diedhiou, Hélène Puccio, Lüdger Schöls, Thomas Klockgether, Bart P.C. van de Warrenburg, Martin Paucar, Dagmar Timmann, R.-D Hilgers, José Gazulla, Michael Strupp, Germán Morís, Alessandro Filla, Henry Houlden, Mathieu Anheim, Jon Infante, A. Nazli Basak, Matthis Synofzik, on behalf of the RFC1 Study Group, Banu Özen Barut, Başar Bılgıç, Cavit Boz, Cécile Cauquil, Natalie Deininger, Claudia Dufke, Bülent Elibol, Furkan Erbas, Sibel Ertan, Fatma Genç, Ina Giegling, Yeşim Parman, Salvatore Rossi, Celal Salcin, Meli̇ha Tan, Hilal Taştekin, Christine Tranchant, Günes Uygun, Özge Yağcıoğlu Yassa
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: 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.