Home > Publications Database > Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. > print

001     156023
005     20240722121853.0
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024 7 _ |a 1526-632X
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037 _ _ |a DZNE-2021-01155
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Traschuetz, Andreas
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245 _ _ |a Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
260 _ _ |a [S.l.]
|c 2021
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336 7 _ |a article
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336 7 _ |a Journal Article
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520 _ _ |a 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).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.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.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.This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
536 _ _ |a 353 - Clinical and Health Care Research (POF4-353)
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a RFC1 protein, human
|2 NLM Chemicals
650 _ 7 |a Replication Protein C
|0 EC 3.6.4.-
|2 NLM Chemicals
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Ataxia
|2 MeSH
650 _ 2 |a Bilateral Vestibulopathy
|2 MeSH
650 _ 2 |a Cohort Studies
|2 MeSH
650 _ 2 |a DNA Repeat Expansion
|2 MeSH
650 _ 2 |a Disease Progression
|2 MeSH
650 _ 2 |a Europe
|2 MeSH
650 _ 2 |a Exome
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Genetic Testing
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Magnetic Resonance Imaging
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Multiple System Atrophy: diagnosis
|2 MeSH
650 _ 2 |a Multiple System Atrophy: diagnostic imaging
|2 MeSH
650 _ 2 |a Multiple System Atrophy: genetics
|2 MeSH
650 _ 2 |a Phenotype
|2 MeSH
650 _ 2 |a Predictive Value of Tests
|2 MeSH
650 _ 2 |a Replication Protein C: genetics
|2 MeSH
650 _ 2 |a Turkey
|2 MeSH
650 _ 2 |a Vestibular Diseases
|2 MeSH
700 1 _ |a Cortese, Andrea
|b 1
700 1 _ |a Reich, Selina
|0 P:(DE-2719)2813732
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700 1 _ |a Dominik, Natalia
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700 1 _ |a Faber, Jennifer
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700 1 _ |a Jacobi, Heike
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700 1 _ |a Hartmann, Annette M
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700 1 _ |a Rujescu, Dan
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700 1 _ |a Montaut, Solveig
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700 1 _ |a Echaniz-Laguna, Andoni
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700 1 _ |a Erer, Sevda
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700 1 _ |a Schütz, Valerie Cornelia
|b 11
700 1 _ |a Tarnutzer, Alexander A
|b 12
700 1 _ |a Sturm, Marc
|b 13
700 1 _ |a Haack, Tobias B
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700 1 _ |a Vaucamps-Diedhiou, Nadège
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700 1 _ |a Puccio, Helene
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700 1 _ |a Schöls, Ludger
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700 1 _ |a Klockgether, Thomas
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700 1 _ |a van de Warrenburg, Bart P
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700 1 _ |a Paucar, Martin
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700 1 _ |a Timmann, Dagmar
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700 1 _ |a Hilgers, Ralf-Dieter
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700 1 _ |a Gazulla, Jose
|b 23
700 1 _ |a Strupp, Michael
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700 1 _ |a Moris, German
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700 1 _ |a Filla, Alessandro
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700 1 _ |a Houlden, Henry
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700 1 _ |a Anheim, Mathieu
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700 1 _ |a Infante, Jon
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700 1 _ |a Basak, A Nazli
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700 1 _ |a Synofzik, Matthis
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700 1 _ |a Group, RFC1 Study
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700 1 _ |a Barut, Banu Özen
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700 1 _ |a Bilgic, Basar
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700 1 _ |a Boz, Cavit
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700 1 _ |a Cauquil, Cécile
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700 1 _ |a Deininger, Natalie
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700 1 _ |a Dufke, Claudia
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700 1 _ |a Elibol, Bülent
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700 1 _ |a Erbas, Furkan
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700 1 _ |a Ertan, Sibel
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700 1 _ |a Genc, Fatma
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700 1 _ |a Giegling, Ina
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700 1 _ |a Parman, Yesim
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700 1 _ |a Rossi, Salvatore
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700 1 _ |a Salcin, Celal
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700 1 _ |a Tan, Meliha
|b 47
700 1 _ |a Taştekin, Hilal
|b 48
700 1 _ |a Tranchant, Christine
|b 49
700 1 _ |a Uygun, Günes
|b 50
700 1 _ |a Yassa, Özge Yagcioglu
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773 _ _ |a 10.1212/WNL.0000000000011528
|g Vol. 96, no. 9, p. e1369 - e1382
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