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@ARTICLE{Zimmermann:273945,
      author       = {Zimmermann, Milan and Mengel, David and Raupach, Katrin and
                      Haack, Tobias and Neumann, Manuela and Synofzik, Matthis},
      title        = {{F}requency and neuropathology of {HTT} repeat expansions
                      in {FTD}/{ALS}: co-existence rather than causation.},
      journal      = {Journal of neurology},
      volume       = {272},
      number       = {1},
      issn         = {0367-004X},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2024-01419},
      pages        = {58},
      year         = {2025},
      abstract     = {While ≥ 40 CAG repeat expansions in HTT present a
                      well-established cause of Huntington's disease (HD), an
                      enrichment of HTT repeat expansions was recently reported
                      also in patients with amyotrophic lateral sclerosis (ALS)
                      and frontotemporal dementia (FTD), including FTD/ALS
                      patients with additional HD neuropathology. This raises the
                      question whether the phenotypic spectrum of HTT expansions
                      can be extended to ALS and FTD, and whether HTT should be
                      considered as a new causative gene of FTD/ALS. If HTT repeat
                      expansions were indeed systematically related to FTD/ALS,
                      one would expect an increased frequency of HTT carriers in
                      FTD/ALS, who can clinically/neuropathologically not be
                      explained better than by the presence of the HTT repeat
                      expansions.Screening of HTT repeat expansions in 249
                      consecutive patients with ALS or FTD by short-read genome
                      sequencing took place. The post-mortem neuropathological
                      examination was performed in the identified HTT repeat
                      expansion carrier.One HTT repeat expansion [40/22 repeats
                      (± 1)] was identified in an ALS patient, giving a frequency
                      of $0.4\%$ (1/249) (frequency in the general population:
                      $0.03-0.18\%).$ This patient showed a classic ALS phenotype,
                      but no clinical or imaging signs of HD. Post-mortem brain
                      examination revealed-in addition to ALS-typical degeneration
                      of upper and lower motor neurons with TDP-43
                      inclusions-HD-typical polyQ-aggregates in gyrus cinguli,
                      striatum and frontal lobe, yet without evidence of striatal
                      degeneration.Our study does not support the notion of an
                      increased frequency of HTT repeat expansions in FTD/ALS.
                      Moreover, the phenotype of the HTT carrier identified can be
                      better explained by two co-existent, but independent
                      diseases: (i) ALS and (ii) presymptomatic HD, which-given
                      the low repeat number-is likely to become manifest only
                      later in life. These findings corroborate the concept that
                      HTT repeat expansions are likely co-existent/coincidental,
                      but not causative in FTD/ALS.},
      keywords     = {Humans / Frontotemporal Dementia: genetics / Frontotemporal
                      Dementia: pathology / Amyotrophic Lateral Sclerosis:
                      genetics / Amyotrophic Lateral Sclerosis: pathology / Male /
                      Female / Huntingtin Protein: genetics / Middle Aged / Aged /
                      Trinucleotide Repeat Expansion: genetics / Brain: pathology
                      / Brain: diagnostic imaging / ALS (Other) / Amyotrophic
                      lateral sclerosis (Other) / Frontotemporal dementia (Other)
                      / HTT (Other) / Huntington (Other) / MAPT (Other) /
                      Huntingtin Protein (NLM Chemicals) / HTT protein, human (NLM
                      Chemicals)},
      cin          = {AG Gasser / AG Neumann},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)1210003},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11638390},
      pubmed       = {pmid:39666103},
      doi          = {10.1007/s00415-024-12822-2},
      url          = {https://pub.dzne.de/record/273945},
}