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000156023 0247_ $$2doi$$a10.1212/WNL.0000000000011528
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000156023 037__ $$aDZNE-2021-01155
000156023 041__ $$aEnglish
000156023 082__ $$a610
000156023 1001_ $$0P:(DE-2719)9000792$$aTraschuetz, Andreas$$b0$$eFirst author$$udzne
000156023 245__ $$aNatural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
000156023 260__ $$a[S.l.]$$bOvid$$c2021
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000156023 520__ $$aTo 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.
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000156023 650_7 $$2NLM Chemicals$$aRFC1 protein, human
000156023 650_7 $$0EC 3.6.4.-$$2NLM Chemicals$$aReplication Protein C
000156023 650_2 $$2MeSH$$aAdult
000156023 650_2 $$2MeSH$$aAged
000156023 650_2 $$2MeSH$$aAtaxia
000156023 650_2 $$2MeSH$$aBilateral Vestibulopathy
000156023 650_2 $$2MeSH$$aCohort Studies
000156023 650_2 $$2MeSH$$aDNA Repeat Expansion
000156023 650_2 $$2MeSH$$aDisease Progression
000156023 650_2 $$2MeSH$$aEurope
000156023 650_2 $$2MeSH$$aExome
000156023 650_2 $$2MeSH$$aFemale
000156023 650_2 $$2MeSH$$aGenetic Testing
000156023 650_2 $$2MeSH$$aHumans
000156023 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000156023 650_2 $$2MeSH$$aMale
000156023 650_2 $$2MeSH$$aMiddle Aged
000156023 650_2 $$2MeSH$$aMultiple System Atrophy: diagnosis
000156023 650_2 $$2MeSH$$aMultiple System Atrophy: diagnostic imaging
000156023 650_2 $$2MeSH$$aMultiple System Atrophy: genetics
000156023 650_2 $$2MeSH$$aPhenotype
000156023 650_2 $$2MeSH$$aPredictive Value of Tests
000156023 650_2 $$2MeSH$$aReplication Protein C: genetics
000156023 650_2 $$2MeSH$$aTurkey
000156023 650_2 $$2MeSH$$aVestibular Diseases
000156023 7001_ $$aCortese, Andrea$$b1
000156023 7001_ $$0P:(DE-2719)2813732$$aReich, Selina$$b2
000156023 7001_ $$aDominik, Natalia$$b3
000156023 7001_ $$0P:(DE-2719)2811327$$aFaber, Jennifer$$b4
000156023 7001_ $$0P:(DE-2719)2811564$$aJacobi, Heike$$b5
000156023 7001_ $$00000-0003-0689-4335$$aHartmann, Annette M$$b6
000156023 7001_ $$aRujescu, Dan$$b7
000156023 7001_ $$aMontaut, Solveig$$b8
000156023 7001_ $$aEchaniz-Laguna, Andoni$$b9
000156023 7001_ $$aErer, Sevda$$b10
000156023 7001_ $$aSchütz, Valerie Cornelia$$b11
000156023 7001_ $$aTarnutzer, Alexander A$$b12
000156023 7001_ $$aSturm, Marc$$b13
000156023 7001_ $$aHaack, Tobias B$$b14
000156023 7001_ $$aVaucamps-Diedhiou, Nadège$$b15
000156023 7001_ $$aPuccio, Helene$$b16
000156023 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b17
000156023 7001_ $$0P:(DE-2719)2810314$$aKlockgether, Thomas$$b18
000156023 7001_ $$avan de Warrenburg, Bart P$$b19
000156023 7001_ $$aPaucar, Martin$$b20
000156023 7001_ $$00000-0003-1935-416X$$aTimmann, Dagmar$$b21
000156023 7001_ $$00000-0002-5945-1119$$aHilgers, Ralf-Dieter$$b22
000156023 7001_ $$aGazulla, Jose$$b23
000156023 7001_ $$aStrupp, Michael$$b24
000156023 7001_ $$aMoris, German$$b25
000156023 7001_ $$aFilla, Alessandro$$b26
000156023 7001_ $$00000-0002-2866-7777$$aHoulden, Henry$$b27
000156023 7001_ $$aAnheim, Mathieu$$b28
000156023 7001_ $$aInfante, Jon$$b29
000156023 7001_ $$aBasak, A Nazli$$b30
000156023 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b31
000156023 7001_ $$aGroup, RFC1 Study$$b32$$eCollaboration Author
000156023 7001_ $$aBarut, Banu Özen$$b33
000156023 7001_ $$aBilgic, Basar$$b34
000156023 7001_ $$aBoz, Cavit$$b35
000156023 7001_ $$aCauquil, Cécile$$b36
000156023 7001_ $$aDeininger, Natalie$$b37
000156023 7001_ $$aDufke, Claudia$$b38
000156023 7001_ $$aElibol, Bülent$$b39
000156023 7001_ $$aErbas, Furkan$$b40
000156023 7001_ $$aErtan, Sibel$$b41
000156023 7001_ $$aGenc, Fatma$$b42
000156023 7001_ $$aGiegling, Ina$$b43
000156023 7001_ $$aParman, Yesim$$b44
000156023 7001_ $$aRossi, Salvatore$$b45
000156023 7001_ $$aSalcin, Celal$$b46
000156023 7001_ $$aTan, Meliha$$b47
000156023 7001_ $$aTaştekin, Hilal$$b48
000156023 7001_ $$aTranchant, Christine$$b49
000156023 7001_ $$aUygun, Günes$$b50
000156023 7001_ $$aYassa, Özge Yagcioglu$$b51
000156023 773__ $$0PERI:(DE-600)1491874-2$$a10.1212/WNL.0000000000011528$$gVol. 96, no. 9, p. e1369 - e1382$$n9$$pe1369 - e1382$$tNeurology$$v96$$x1526-632X$$y2021
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