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@ARTICLE{Traschuetz:156023,
      author       = {Traschuetz, Andreas and Cortese, Andrea and Reich, Selina
                      and Dominik, Natalia and Faber, Jennifer and Jacobi, Heike
                      and Hartmann, Annette M and Rujescu, Dan and Montaut,
                      Solveig and Echaniz-Laguna, Andoni and Erer, Sevda and
                      Schütz, Valerie Cornelia and Tarnutzer, Alexander A and
                      Sturm, Marc and Haack, Tobias B and Vaucamps-Diedhiou,
                      Nadège and Puccio, Helene and Schöls, Ludger and
                      Klockgether, Thomas and van de Warrenburg, Bart P and
                      Paucar, Martin and Timmann, Dagmar and Hilgers, Ralf-Dieter
                      and Gazulla, Jose and Strupp, Michael and Moris, German and
                      Filla, Alessandro and Houlden, Henry and Anheim, Mathieu and
                      Infante, Jon and Basak, A Nazli and Synofzik, Matthis and
                      Barut, Banu Özen and Bilgic, Basar and Boz, Cavit and
                      Cauquil, Cécile and Deininger, Natalie and Dufke, Claudia
                      and Elibol, Bülent and Erbas, Furkan and Ertan, Sibel and
                      Genc, Fatma and Giegling, Ina and Parman, Yesim and Rossi,
                      Salvatore and Salcin, Celal and Tan, Meliha and Taştekin,
                      Hilal and Tranchant, Christine and Uygun, Günes and Yassa,
                      Özge Yagcioglu},
      collaboration = {Group, RFC1 Study},
      title        = {{N}atural {H}istory, {P}henotypic {S}pectrum, and
                      {D}iscriminative {F}eatures of {M}ultisystemic {RFC}1
                      {D}isease.},
      journal      = {Neurology},
      volume       = {96},
      number       = {9},
      issn         = {1526-632X},
      address      = {[S.l.]},
      publisher    = {Ovid},
      reportid     = {DZNE-2021-01155},
      pages        = {e1369 - e1382},
      year         = {2021},
      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.},
      keywords     = {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 / Multiple System Atrophy:
                      diagnostic imaging / Multiple System Atrophy: genetics /
                      Phenotype / Predictive Value of Tests / Replication Protein
                      C: genetics / Turkey / Vestibular Diseases / RFC1 protein,
                      human (NLM Chemicals) / Replication Protein C (NLM
                      Chemicals)},
      cin          = {AG Gasser / Patient Studies Bonn / AG Klockgether},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1011101 /
                      I:(DE-2719)1011001},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33495376},
      pmc          = {pmc:PMC8055326},
      doi          = {10.1212/WNL.0000000000011528},
      url          = {https://pub.dzne.de/record/156023},
}