1. Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease
- Author
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Traschuetz, Andreas, Cortese, Andrea, Erer, Sevda, Schütz, Valerie Cornelia, Tarnutzer, Alexander A, Sturm, Marc, Haack, Tobias B, Vaucamps-Diedhiou, Nadège, Puccio, Helene, Schöls, Ludger, Klockgether, Thomas, van de Warrenburg, Bart P, Reich, Selina, Paucar, Martin, Timmann, Dagmar, Hilgers, Ralf-Dieter, Gazulla, Jose, Strupp, Michael, Moris, German, Filla, Alessandro, Houlden, Henry, Anheim, Mathieu, Infante, Jon, Dominik, Natalia, Basak, A Nazli, Synofzik, Matthis, Group, RFC1 Study, Barut, Banu Özen, Bilgic, Basar, Boz, Cavit, Cauquil, Cécile, Deininger, Natalie, Dufke, Claudia, Elibol, Bülent, Faber, Jennifer, Erbas, Furkan, Ertan, Sibel, Genc, Fatma, Giegling, Ina, Parman, Yesim, Rossi, Salvatore, Salcin, Celal, Tan, Meliha, Taştekin, Hilal, Tranchant, Christine, Jacobi, Heike, Uygun, Günes, Yassa, Özge Yagcioglu, Hartmann, Annette M, Rujescu, Dan, Montaut, Solveig, Echaniz-Laguna, Andoni, Universidad de Cantabria, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschütz, A., Cortese, A., Reich, S., Dominik, N., Faber, J., Jacobi, H., 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., Klockgether, T., 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., Synofzik, M., RFC1 study group, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Tübingen, Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), Università degli Studi di Pavia = University of Pavia (UNIPV), University Hospital Bonn, Heidelberg University Hospital [Heidelberg], Martin-Luther-Universität Halle Wittenberg (MLU), Hôpital de Hautepierre [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Medical Genetics and Applied Genomics [Tübingen], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Karolinska Institute, University of Duisburg-Essen, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Hospital Universitario Miguel Servet, Ludwig-Maximilians University [Munich] (LMU), University of Naples Federico II = Università degli studi di Napoli Federico II, Martin-Luther-University Halle-Wittenberg, Universidad de Cantabria [Santander], Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), and univOAK, Archive ouverte
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0301 basic medicine ,Male ,Turkey ,Bilateral Vestibulopathy ,Medizin ,Disease ,Cohort Studies ,0302 clinical medicine ,Medicine ,Exome ,Replication Protein C ,RFC1 protein, human ,Dystonia ,DNA Repeat Expansion ,Genetics ,Middle Aged ,diagnostic imaging [Multiple System Atrophy] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Magnetic Resonance Imaging ,Europe ,Phenotype ,diagnosis [Multiple System Atrophy] ,Vestibular Diseases ,Cohort ,Disease Progression ,Ataxia ,Disease progression ,Bilateral vestibulopathy ,Cohort studies ,DNA repeat expansion ,Female ,genetics [Multiple System Atrophy] ,medicine.symptom ,Adult ,medicine.medical_specialty ,Article ,03 medical and health sciences ,Atrophy ,Predictive Value of Tests ,Internal medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,ddc:610 ,Genetic Testing ,Aged ,Cerebellar ataxia ,business.industry ,Dysautonomia ,Chorea ,Multiple System Atrophy ,medicine.disease ,genetics [Replication Protein C] ,030104 developmental biology ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
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 ≈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. Conclusions: 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., European Union (EU); Horizon 2020; Research and Innovation Program; BMBF; E-Rare-3 network; PREPARE; DFG; EJP-RD network; PROSPAX; Solve-RD; University of Tubingen Medical Faculty; Clinician Scientist Program; Medical Research Council; Fondazione CARIPLO; ZonMW; Hersenstichting; Gossweiler Foundation; uniQure; Radboud University Medical Centre; Suna and İnan Kıraç Foundation; Koç University School of Medicine
- Published
- 2021