Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
Adult
Aged
Ataxia
Bilateral Vestibulopathy
Cohort Studies
DNA Repeat Expansion
Disease Progression
Europe
Exome
Female
Genetic Testing
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Multiple System Atrophy
/ diagnosis
Phenotype
Predictive Value of Tests
Replication Protein C
/ genetics
Turkey
Vestibular Diseases
Journal
Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060
Informations de publication
Date de publication:
02 03 2021
02 03 2021
Historique:
received:
09
07
2020
accepted:
21
11
2020
pubmed:
27
1
2021
medline:
16
3
2021
entrez:
26
1
2021
Statut:
ppublish
Résumé
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 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.
Identifiants
pubmed: 33495376
pii: WNL.0000000000011528
doi: 10.1212/WNL.0000000000011528
pmc: PMC8055326
doi:
Substances chimiques
RFC1 protein, human
0
Replication Protein C
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1369-e1382Subventions
Organisme : Medical Research Council
ID : MR/T001712/1
Pays : United Kingdom
Investigateurs
Banu Özen Barut
(BÖ)
Basar Bilgic
(B)
Cavit Boz
(C)
Cécile Cauquil
(C)
Natalie Deininger
(N)
Claudia Dufke
(C)
Bülent Elibol
(B)
Furkan Erbas
(F)
Sibel Ertan
(S)
Fatma Genc
(F)
Ina Giegling
(I)
Yesim Parman
(Y)
Salvatore Rossi
(S)
Celal Salcin
(C)
Meliha Tan
(M)
Hilal Taştekin
(H)
Christine Tranchant
(C)
Günes Uygun
(G)
Özge Yagcioglu Yassa
(ÖY)
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Références
Mov Disord. 2017 Jun;32(6):853-864
pubmed: 28467028
J Neurol. 2018 Jun;265(6):1454-1462
pubmed: 29696497
Neurology. 2008 Aug 26;71(9):670-6
pubmed: 18725592
J Vestib Res. 2014;24(5-6):465-74
pubmed: 25564090
Lancet Neurol. 2016 Dec;15(13):1346-1354
pubmed: 27839651
Dysphagia. 2017 Oct;32(5):626-635
pubmed: 28474131
J Pediatr. 2000 Feb;136(2):225-31
pubmed: 10657830
Front Genet. 2019 Nov 22;10:1219
pubmed: 31824583
Mov Disord. 2017 Mar;32(3):332-345
pubmed: 28195350
Neuron. 2019 Feb 20;101(4):560-583
pubmed: 30790538
Neurol Genet. 2020 May 20;6(3):e440
pubmed: 32582864
Neurol Clin Pract. 2016 Feb;6(1):61-68
pubmed: 26918204
Mov Disord. 2020 Jul;35(7):1277-1279
pubmed: 32333430
Cough. 2013 Mar 06;9(1):7
pubmed: 23497672
Ann Neurol. 2020 Aug;88(2):251-263
pubmed: 32337771
Brain. 2018 Jan 1;141(1):248-270
pubmed: 29206893
Am J Hum Genet. 2019 Jul 3;105(1):151-165
pubmed: 31230722
Neurology. 2006 Jun 13;66(11):1717-20
pubmed: 16769946
Brain. 2009 Oct;132(Pt 10):2688-98
pubmed: 19696032
Arch Neurol. 2006 Apr;63(4):553-5
pubmed: 16606768
Brain. 2020 Feb 1;143(2):480-490
pubmed: 32040566
Chest. 2016 Jan;149(1):27-44
pubmed: 26426314
Brain. 2014 Oct;137(Pt 10):2649-56
pubmed: 25070514
Cerebellum. 2014 Apr;13(2):215-21
pubmed: 24097205
Ann Neurol. 2016 Apr;79(4):646-58
pubmed: 26856398
Nat Genet. 2019 Apr;51(4):649-658
pubmed: 30926972