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@ARTICLE{Traschtz:263799,
      author       = {Traschütz, Andreas and Heindl, Felix and Bilal, Muhammad
                      and Hartmann, Annette M and Dufke, Claudia and Riess, Olaf
                      and Zwergal, Andreas and Rujescu, Dan and Haack, Tobias and
                      Synofzik, Matthis and Strupp, Michael},
      title        = {{F}requency and {P}henotype of {RFC}1 {R}epeat {E}xpansions
                      in {B}ilateral {V}estibulopathy.},
      journal      = {Neurology},
      volume       = {101},
      number       = {10},
      issn         = {0028-3878},
      address      = {[Erscheinungsort nicht ermittelbar]},
      publisher    = {Ovid},
      reportid     = {DZNE-2023-00885},
      pages        = {e1001 - e1013},
      year         = {2023},
      abstract     = {Bilateral vestibulopathy (BVP) is a chronic debilitating
                      neurologic disorder with no monogenic cause established so
                      far despite familiar presentations. We hypothesized that
                      replication factor complex subunit 1 (RFC1) repeat
                      expansions might present a recurrent monogenic cause of
                      BVP.The study involved RFC1 screening and in-depth
                      neurologic, vestibulo-oculomotor, and disease evolution
                      phenotyping of 168 consecutive patients with idiopathic at
                      least 'probable BVP' from a tertiary referral center for
                      balance disorders, with127 of them meeting current
                      diagnostic criteria of BVP (Bárány Society
                      Classification).Biallelic AAGGG repeat expansions in RFC1
                      were identified in 10/127 patients $(8\%)$ with BVP and 1/41
                      with probable BVP. Heterozygous expansions in 10/127
                      patients were enriched compared with those in reference
                      populations. RFC1-related BVP manifested at a median age of
                      60 years (range 34-72 years) and co-occurred predominantly
                      with mild polyneuropathy (10/11). Additional cerebellar
                      involvement (7/11) was subtle and limited to oculomotor
                      signs in early stages, below recognition of classic
                      cerebellar ataxia, neuropathy, and vestibular areflexia
                      syndrome. Clear dysarthria, appendicular ataxia, or
                      cerebellar atrophy developed 6-8 years after onset.
                      Dysarthria, absent patellar reflexes, and downbeat nystagmus
                      best discriminated RFC1-positive BVP from RFC1-negative BVP,
                      but neither sensory symptoms nor fine motor problems. Video
                      head impulse gains of patients with RFC1-positive BVP were
                      lower relative to those of patients with RFC1-negative BVP
                      and decreased until 10 years disease duration, indicating a
                      potential progression and outcome marker for
                      RFC1-disease.This study identifies RFC1 as the first-and
                      frequent-monogenic cause of BVP. It characterizes
                      RFC1-related BVP as part of the multisystemic evolution of
                      RFC1 spectrum disease, with implications for designing
                      natural history studies and future treatment trials.This
                      study provides Class II evidence that RFC1 repeat expansions
                      cause BVP.},
      keywords     = {Humans / Bilateral Vestibulopathy: genetics / Bilateral
                      Vestibulopathy: diagnosis / Dysarthria / Cerebellar Ataxia:
                      diagnosis / Ataxia / Vestibular Diseases: genetics /
                      Phenotype / Reflex, Abnormal / RFC1 protein, human (NLM
                      Chemicals)},
      cin          = {AG Gasser},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10491447},
      pubmed       = {pmid:37460231},
      doi          = {10.1212/WNL.0000000000207553},
      url          = {https://pub.dzne.de/record/263799},
}