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@ARTICLE{Aziz:140098,
      author       = {Aziz, Ahmad and van der Burg, Jorien M M and Tabrizi, Sarah
                      J and Landwehrmeyer, G Bernhard},
      title        = {{O}verlap between age-at-onset and disease-progression
                      determinants in {H}untington disease.},
      journal      = {Neurology},
      volume       = {90},
      number       = {24},
      issn         = {0028-3878},
      address      = {[S.l.]},
      publisher    = {Ovid},
      reportid     = {DZNE-2020-06420},
      pages        = {e2099-e2106},
      year         = {2018},
      abstract     = {A fundamental but still unresolved issue regarding
                      Huntington disease (HD) pathogenesis is whether the factors
                      that determine age at onset are the same as those that
                      govern disease progression. Because elucidation of this
                      issue is crucial for the development as well as optimal
                      timing of administration of novel disease-modifying
                      therapies, we aimed to assess the extent of overlap between
                      age-at-onset and disease-progression determinants in
                      HD.Using observational data from Enroll-HD, the largest
                      cohort of patients with HD worldwide, in this study we
                      present, validate, and apply an intuitive method based on
                      linear mixed-effect models to quantify the variability in
                      the rate of disease progression in HD.A total of 3,411
                      patients with HD met inclusion criteria. We found that (1)
                      about two-thirds of the rate of functional, motor, and
                      cognitive progression in HD is determined by the same
                      factors that also determine age at onset, with CAG
                      repeat-dependent mechanisms having by far the largest
                      effect; (2) although expanded HTT CAG repeat size had a
                      large influence on average body weight, the rate of weight
                      loss was largely independent of factors that determine age
                      at onset in HD; and (3) about one-third of the factors that
                      determine the rate of functional, motor, and cognitive
                      progression are different from those that govern age at
                      onset and need further elucidation.Our findings imply that
                      targeting of CAG repeat-dependent mechanisms, for example
                      through gene-silencing approaches, is likely to affect the
                      rate of functional, motor, and cognitive impairment, but not
                      weight loss, in manifest HD mutation carriers.},
      keywords     = {Age of Onset / Disease Progression / Humans / Huntington
                      Disease: epidemiology / Huntington Disease: genetics /
                      Huntington Disease: pathology},
      cin          = {AG Breteler 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1012001},
      pnm          = {345 - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29743208},
      pmc          = {pmc:PMC5996832},
      doi          = {10.1212/WNL.0000000000005690},
      url          = {https://pub.dzne.de/record/140098},
}