Journal Article

DZNE-2021-01155

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.

Traschuetz, A. (First author)DZNE* ; Cortese, A. ; Reich, S.DZNE* ; Dominik, N. ; Faber, J.DZNE* ; Jacobi, H.DZNE* ; 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.DZNE* ; Klockgether, T.DZNE* ; 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. ; Basak, A. N. ; Synofzik, M.DZNE* ; Group, R. S. (Collaboration Author) ; Barut, B. Ö. ; Bilgic, B. ; Boz, C. ; Cauquil, C. ; Deininger, N. ; Dufke, C. ; Elibol, B. ; Erbas, F. ; Ertan, S. ; Genc, F. ; Giegling, I. ; Parman, Y. ; Rossi, S. ; Salcin, C. ; Tan, M. ; Taştekin, H. ; Tranchant, C. ; Uygun, G. ; Yassa, Ö. Y.

2021
Ovid [S.l.]

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Please use a persistent id in citations: doi:10.1212/WNL.0000000000011528

Abstract: 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.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Ataxia (MeSH) ; Bilateral Vestibulopathy (MeSH) ; Cohort Studies (MeSH) ; DNA Repeat Expansion (MeSH) ; Disease Progression (MeSH) ; Europe (MeSH) ; Exome (MeSH) ; Female (MeSH) ; Genetic Testing (MeSH) ; Humans (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Multiple System Atrophy: diagnosis (MeSH) ; Multiple System Atrophy: diagnostic imaging (MeSH) ; Multiple System Atrophy: genetics (MeSH) ; Phenotype (MeSH) ; Predictive Value of Tests (MeSH) ; Replication Protein C: genetics (MeSH) ; Turkey (MeSH) ; Vestibular Diseases (MeSH) ; RFC1 protein, human ; Replication Protein C

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Patient Studies Bonn (Patient Studies Bonn)
3. Patient Studies (AG Klockgether)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; ; ; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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