Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease - CNRS - Centre national de la recherche scientifique
Article Dans Une Revue Neurology Année : 2021

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease

1 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
2 Eberhard Karls Universität Tübingen = University of Tübingen
3 UCL Institute of Neurology, Queen Square [London]
4 UNIPV - Università degli Studi di Pavia = University of Pavia
5 University Hospital Bonn
6 Heidelberg University Hospital [Heidelberg]
7 MLU - Martin-Luther-Universität Halle Wittenberg
8 Hôpital de Hautepierre [Strasbourg]
9 HUS - Les Hôpitaux Universitaires de Strasbourg
10 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
11 Petites Molécules de neuroprotection, neurorégénération et remyélinisation
12 MCPN - Mécanismes Centraux et Périphériques de la Neurodégénérescence
13 UZH - Universität Zürich [Zürich] = University of Zurich
14 Institute of Medical Genetics and Applied Genomics [Tübingen]
15 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
16 Radboud University Medical Center [Nijmegen]
17 Karolinska Institute
18 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
19 RWTH - Rheinisch-Westfälische Technische Hochschule Aachen University
20 Hospital Universitario Miguel Servet
21 LMU - Ludwig-Maximilians University [Munich]
22 University of Naples Federico II = Università degli studi di Napoli Federico II
23 Martin-Luther-University Halle-Wittenberg
24 UC / UniCan - Universidad de Cantabria [Santander] = University of Cantabria [Spain] = Université de Cantabrie [Espagne]
25 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas

Résumé

OBJECTIVE: 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 approximately 1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up
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Dates et versions

hal-03709465 , version 1 (18-11-2022)

Identifiants

Citer

Andreas Traschutz, Andrea Cortese, Selina Reich, Natalia Dominik, Jennifer Faber, et al.. Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. Neurology, 2021, 96 (9), ⟨10.1212/WNL.0000000000011528⟩. ⟨hal-03709465⟩
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