1. Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease
- Author
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Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschütz, A.; Cortese, A.; Reich, S.; Dominik, N.; Faber, J.; Jacobi, H.; Hartmann, A.M.; Rujescu, D.; Montaut, S.; Echaniz-Laguna, A.; Erer, S.; Schütz, V. C.; Tarnutzer, A. A.; Sturm, M.; Haack, T. B.; Vaucamps-Diedhiou, N.; Puccio, H.; Schöls, L.; Klockgether, T.; van de Warrenburg, B. P.; Paucar, M.; Timmann, D.; Hilgers, R. D.; Gazulla, J.; Strupp, M.; Moris, G.; Filla, A.; Houlden, H.; Anheim, M.; Infante, J.; Synofzik, M.; RFC1 study group, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschütz, A.; Cortese, A.; Reich, S.; Dominik, N.; Faber, J.; Jacobi, H.; Hartmann, A.M.; Rujescu, D.; Montaut, S.; Echaniz-Laguna, A.; Erer, S.; Schütz, V. C.; Tarnutzer, A. A.; Sturm, M.; Haack, T. B.; Vaucamps-Diedhiou, N.; Puccio, H.; Schöls, L.; Klockgether, T.; van de Warrenburg, B. P.; Paucar, M.; Timmann, D.; Hilgers, R. D.; Gazulla, J.; Strupp, M.; Moris, G.; Filla, A.; Houlden, H.; Anheim, M.; Infante, J.; Synofzik, M.; RFC1 study group, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
- 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 na, European Union (EU); Horizon 2020; Research and Innovation Program; BMBF; E-Rare-3 network; PREPARE; DFG; EJP-RD network; PROSPAX; Solve-RD; University of Tubingen Medical Faculty; Clinician Scientist Program; Medical Research Council; Fondazione CARIPLO; ZonMW; Hersenstichting; Gossweiler Foundation; uniQure; Radboud University Medical Centre; Suna and İnan Kıraç Foundation; Koç University School of Medicine
- Published
- 2021