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@ARTICLE{Schle:138498,
      author       = {Schüle, Rebecca and Wiethoff, Sarah and Martus, Peter and
                      Karle, Kathrin N and Otto, Susanne and Klebe, Stephan and
                      Klimpe, Sven and Gallenmüller, Constanze and Kurzwelly,
                      Delia and Henkel, Dorothea and Rimmele, Florian and Stolze,
                      Henning and Kohl, Zacharias and Kassubek, Jan and
                      Klockgether, Thomas and Vielhaber, Stefan and Kamm,
                      Christoph and Klopstock, Thomas and Bauer, Peter and
                      Züchner, Stephan and Liepelt-Scarfone, Inga and Schöls,
                      Ludger},
      title        = {{H}ereditary spastic paraplegia: {C}linicogenetic lessons
                      from 608 patients.},
      journal      = {Annals of neurology},
      volume       = {79},
      number       = {4},
      issn         = {0364-5134},
      address      = {Hoboken, NJ},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2020-04820},
      pages        = {646-658},
      year         = {2016},
      abstract     = {Hereditary spastic paraplegias (HSPs) are genetically
                      driven disorders with the hallmark of progressive spastic
                      gait disturbance. To investigate the phenotypic spectrum,
                      prognostic factors, and genotype-specific differences, we
                      analyzed baseline data from a continuous, prospective
                      cohort.We recruited 608 HSP cases from 519 families of
                      mostly German origin. Clinical severity was assessed by the
                      Spastic Paraplegia Rating Scale. Complicating symptoms were
                      recorded by a standardized inventory.Family history
                      indicated dominant $(43\%),$ recessive $(10\%),$ and simplex
                      $(47\%)$ disease. We observed a significant male
                      predominance, particularly in simplex cases without a
                      genetic diagnosis. Disease severity increased with disease
                      duration. Earlier disease onset was associated with less
                      severe disease. Specific complicating features including
                      cognitive impairment, extrapyramidal or peripheral motor
                      involvement, and ataxia were associated with worse disease
                      severity. Disease severity also depended on the genotype.
                      HSP cases maintained the ability to walk independently for a
                      median disease duration of 22 years. Early onset cases were
                      able to maintain free walking significantly longer and were
                      at less risk to become wheelchair dependent.This
                      cross-sectional cohort study provides the first large-scale
                      data on disease manifestation, progression, and modifying
                      factors, with relevance for counseling of HSP families and
                      planning of future cross-sectional and natural history
                      studies. Later age of onset, specific complicating features,
                      and the SPG11 genotype are strongly associated with more
                      severe disease. Future interventional studies will require
                      stratification for modifiers of disease progression
                      identified in this study. Prospective longitudinal studies
                      will verify progression rates calculated in this baseline
                      analysis.},
      keywords     = {Adult / Aged / Cross-Sectional Studies / Female / Germany:
                      epidemiology / Humans / Male / Middle Aged / Pedigree /
                      Severity of Illness Index / Spastic Paraplegia, Hereditary:
                      epidemiology / Spastic Paraplegia, Hereditary: genetics /
                      Spastic Paraplegia, Hereditary: physiopathology},
      cin          = {Ext HIH / Ext LMU Klinik / Patient Studies Bonn / Magdeburg
                      common / Rostock / Greifswald common / AG Jessen / AG Düzel
                      / AG Levin / AG Gasser / AG Kahle / AG Maetzler},
      ddc          = {610},
      cid          = {I:(DE-2719)5000057 / I:(DE-2719)5000049 /
                      I:(DE-2719)1011101 / I:(DE-2719)6000015 / I:(DE-2719)6000017
                      / I:(DE-2719)1011102 / I:(DE-2719)5000006 /
                      I:(DE-2719)1111016 / I:(DE-2719)1210000 /
                      I:(DE-2719)1210000-4 / I:(DE-2719)5000024},
      pnm          = {344 - Clinical and Health Care Research (POF3-344) / 345 -
                      Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-344 / G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26856398},
      doi          = {10.1002/ana.24611},
      url          = {https://pub.dzne.de/record/138498},
}