Publication:
Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease

dc.contributor.coauthorTraschütz, A.
dc.contributor.coauthorCortese, A.
dc.contributor.coauthorReich, S.
dc.contributor.coauthorDominik, N.
dc.contributor.coauthorFaber, J.
dc.contributor.coauthorJacobi, H.
dc.contributor.coauthorHartmann, A.M.
dc.contributor.coauthorRujescu, D.
dc.contributor.coauthorMontaut, S.
dc.contributor.coauthorEchaniz-Laguna, A.
dc.contributor.coauthorErer, S.
dc.contributor.coauthorSchütz, V. C.
dc.contributor.coauthorTarnutzer, A. A.
dc.contributor.coauthorSturm, M.
dc.contributor.coauthorHaack, T. B.
dc.contributor.coauthorVaucamps-Diedhiou, N.
dc.contributor.coauthorPuccio, H.
dc.contributor.coauthorSchöls, L.
dc.contributor.coauthorKlockgether, T.
dc.contributor.coauthorvan de Warrenburg, B. P.
dc.contributor.coauthorPaucar, M.
dc.contributor.coauthorTimmann, D.
dc.contributor.coauthorHilgers, R. D.
dc.contributor.coauthorGazulla, J.
dc.contributor.coauthorStrupp, M.
dc.contributor.coauthorMoris, G.
dc.contributor.coauthorFilla, A.
dc.contributor.coauthorHoulden, H.
dc.contributor.coauthorAnheim, M.
dc.contributor.coauthorInfante, J.
dc.contributor.coauthorSynofzik, M.
dc.contributor.coauthorRFC1 study group
dc.contributor.departmentKUTTAM (Koç University Research Center for Translational Medicine)
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorBaşak, Ayşe Nazlı
dc.contributor.schoolcollegeinstituteResearch Center
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T12:42:13Z
dc.date.issued2021
dc.description.abstractObjective: 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.fulltextYES
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue9
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuEU
dc.description.sponsorshipEuropean Union (EU)
dc.description.sponsorshipHorizon 2020
dc.description.sponsorshipResearch and Innovation Program
dc.description.sponsorshipBMBF
dc.description.sponsorshipE-Rare-3 network
dc.description.sponsorshipPREPARE
dc.description.sponsorshipDFG
dc.description.sponsorshipEJP-RD network
dc.description.sponsorshipPROSPAX
dc.description.sponsorshipSolve-RD
dc.description.sponsorshipUniversity of Tubingen Medical Faculty
dc.description.sponsorshipClinician Scientist Program
dc.description.sponsorshipMedical Research Council
dc.description.sponsorshipFondazione CARIPLO
dc.description.sponsorshipZonMW
dc.description.sponsorshipHersenstichting
dc.description.sponsorshipGossweiler Foundation
dc.description.sponsorshipuniQure
dc.description.sponsorshipRadboud University Medical Centre
dc.description.sponsorshipSuna and İnan Kıraç Foundation
dc.description.sponsorshipKoç University School of Medicine
dc.description.versionPublisher version
dc.description.volume96
dc.identifier.doi10.1212/WNL.0000000000011528
dc.identifier.eissn1526-632X
dc.identifier.embargoNO
dc.identifier.filenameinventorynoIR02680
dc.identifier.issn0028-3878
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85101586876
dc.identifier.urihttps://hdl.handle.net/20.500.14288/2297
dc.keywordsAtaxia
dc.keywordsDisease progression
dc.keywordsBilateral vestibulopathy
dc.keywordsCohort studies
dc.keywordsDNA repeat expansion
dc.language.isoeng
dc.publisherWolters Kluwer
dc.relation.grantno01GM1607
dc.relation.grantno441409627
dc.relation.grantno418081722
dc.relation.grantno779257
dc.relation.grantno439-0-0
dc.relation.grantnoMR/T001712/1
dc.relation.grantno2019-1836
dc.relation.ispartofNeurology
dc.relation.urihttp://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9326
dc.subjectMedicine
dc.subjectGenetics
dc.titleNatural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorBaşak, Ayşe Nazlı
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1Research Center
local.publication.orgunit2KUTTAM (Koç University Research Center for Translational Medicine)
local.publication.orgunit2School of Medicine
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