Publication: Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease
dc.contributor.coauthor | Traschütz, A. | |
dc.contributor.coauthor | Cortese, A. | |
dc.contributor.coauthor | Reich, S. | |
dc.contributor.coauthor | Dominik, N. | |
dc.contributor.coauthor | Faber, J. | |
dc.contributor.coauthor | Jacobi, H. | |
dc.contributor.coauthor | Hartmann, A.M. | |
dc.contributor.coauthor | Rujescu, D. | |
dc.contributor.coauthor | Montaut, S. | |
dc.contributor.coauthor | Echaniz-Laguna, A. | |
dc.contributor.coauthor | Erer, S. | |
dc.contributor.coauthor | Schütz, V. C. | |
dc.contributor.coauthor | Tarnutzer, A. A. | |
dc.contributor.coauthor | Sturm, M. | |
dc.contributor.coauthor | Haack, T. B. | |
dc.contributor.coauthor | Vaucamps-Diedhiou, N. | |
dc.contributor.coauthor | Puccio, H. | |
dc.contributor.coauthor | Schöls, L. | |
dc.contributor.coauthor | Klockgether, T. | |
dc.contributor.coauthor | van de Warrenburg, B. P. | |
dc.contributor.coauthor | Paucar, M. | |
dc.contributor.coauthor | Timmann, D. | |
dc.contributor.coauthor | Hilgers, R. D. | |
dc.contributor.coauthor | Gazulla, J. | |
dc.contributor.coauthor | Strupp, M. | |
dc.contributor.coauthor | Moris, G. | |
dc.contributor.coauthor | Filla, A. | |
dc.contributor.coauthor | Houlden, H. | |
dc.contributor.coauthor | Anheim, M. | |
dc.contributor.coauthor | Infante, J. | |
dc.contributor.coauthor | Synofzik, M. | |
dc.contributor.coauthor | RFC1 study group | |
dc.contributor.department | KUTTAM (Koç University Research Center for Translational Medicine) | |
dc.contributor.department | School of Medicine | |
dc.contributor.kuauthor | Başak, Ayşe Nazlı | |
dc.contributor.schoolcollegeinstitute | Research Center | |
dc.contributor.schoolcollegeinstitute | SCHOOL OF MEDICINE | |
dc.date.accessioned | 2024-11-09T12:42:13Z | |
dc.date.issued | 2021 | |
dc.description.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. | |
dc.description.fulltext | YES | |
dc.description.indexedby | Scopus | |
dc.description.indexedby | PubMed | |
dc.description.issue | 9 | |
dc.description.openaccess | YES | |
dc.description.publisherscope | International | |
dc.description.sponsoredbyTubitakEu | EU | |
dc.description.sponsorship | European Union (EU) | |
dc.description.sponsorship | Horizon 2020 | |
dc.description.sponsorship | Research and Innovation Program | |
dc.description.sponsorship | BMBF | |
dc.description.sponsorship | E-Rare-3 network | |
dc.description.sponsorship | PREPARE | |
dc.description.sponsorship | DFG | |
dc.description.sponsorship | EJP-RD network | |
dc.description.sponsorship | PROSPAX | |
dc.description.sponsorship | Solve-RD | |
dc.description.sponsorship | University of Tubingen Medical Faculty | |
dc.description.sponsorship | Clinician Scientist Program | |
dc.description.sponsorship | Medical Research Council | |
dc.description.sponsorship | Fondazione CARIPLO | |
dc.description.sponsorship | ZonMW | |
dc.description.sponsorship | Hersenstichting | |
dc.description.sponsorship | Gossweiler Foundation | |
dc.description.sponsorship | uniQure | |
dc.description.sponsorship | Radboud University Medical Centre | |
dc.description.sponsorship | Suna and İnan Kıraç Foundation | |
dc.description.sponsorship | Koç University School of Medicine | |
dc.description.version | Publisher version | |
dc.description.volume | 96 | |
dc.identifier.doi | 10.1212/WNL.0000000000011528 | |
dc.identifier.eissn | 1526-632X | |
dc.identifier.embargo | NO | |
dc.identifier.filenameinventoryno | IR02680 | |
dc.identifier.issn | 0028-3878 | |
dc.identifier.quartile | Q1 | |
dc.identifier.scopus | 2-s2.0-85101586876 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14288/2297 | |
dc.keywords | Ataxia | |
dc.keywords | Disease progression | |
dc.keywords | Bilateral vestibulopathy | |
dc.keywords | Cohort studies | |
dc.keywords | DNA repeat expansion | |
dc.language.iso | eng | |
dc.publisher | Wolters Kluwer | |
dc.relation.grantno | 01GM1607 | |
dc.relation.grantno | 441409627 | |
dc.relation.grantno | 418081722 | |
dc.relation.grantno | 779257 | |
dc.relation.grantno | 439-0-0 | |
dc.relation.grantno | MR/T001712/1 | |
dc.relation.grantno | 2019-1836 | |
dc.relation.ispartof | Neurology | |
dc.relation.uri | http://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9326 | |
dc.subject | Medicine | |
dc.subject | Genetics | |
dc.title | Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease | |
dc.type | Journal Article | |
dspace.entity.type | Publication | |
local.contributor.kuauthor | Başak, Ayşe Nazlı | |
local.publication.orgunit1 | SCHOOL OF MEDICINE | |
local.publication.orgunit1 | Research Center | |
local.publication.orgunit2 | KUTTAM (Koç University Research Center for Translational Medicine) | |
local.publication.orgunit2 | School of Medicine | |
relation.isOrgUnitOfPublication | 91bbe15d-017f-446b-b102-ce755523d939 | |
relation.isOrgUnitOfPublication | d02929e1-2a70-44f0-ae17-7819f587bedd | |
relation.isOrgUnitOfPublication.latestForDiscovery | 91bbe15d-017f-446b-b102-ce755523d939 | |
relation.isParentOrgUnitOfPublication | d437580f-9309-4ecb-864a-4af58309d287 | |
relation.isParentOrgUnitOfPublication | 17f2dc8e-6e54-4fa8-b5e0-d6415123a93e | |
relation.isParentOrgUnitOfPublication.latestForDiscovery | d437580f-9309-4ecb-864a-4af58309d287 |
Files
Original bundle
1 - 1 of 1