title: Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Eberhard Karls University, Tübingen, Germany.|Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.
authors: Rebecca
authors: R
authors: Schüle
authors: Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany.|Institute of Neurology, London, United Kingdom.
authors: Sarah
authors: S
authors: Wiethoff
authors: Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University, Tübingen, Germany.
authors: Peter
authors: P
authors: Martus
authors: Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Eberhard Karls University, Tübingen, Germany.|Department of Psychiatry and Psychotherapy, Eberhard Karls University, Tübingen, Germany.
authors: Kathrin N
authors: KN
authors: Karle
authors: Department of Neurology, St Josef Hospital Bochum/Ruhr University Bochum, Bochum, Germany.
authors: Susanne
authors: S
authors: Otto
authors: Department for Neurology, University Hospital Würzburg, Würzburg, Germany.|Department of Neurology, Campus Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.|University Hospital Freiburg, Department for Neurology, Freiburg, Germany.
authors: Stephan
authors: S
authors: Klebe
authors: Department of Neurology, Horst Schmidt Clinics Wiesbaden, Wiesbaden, Germany.|University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors: Sven
authors: S
authors: Klimpe
authors: Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilians University, Munich, Germany.
authors: Constanze
authors: C
authors: Gallenmüller
authors: Department of Neurology, University Hospital Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors: Delia
authors: D
authors: Kurzwelly
authors: Department of Neurology, Otto von Guericke University, Magdeburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors: Dorothea
authors: D
authors: Henkel
authors: Department of Neurology, University of Rostock, Rostock, Germany.|German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
authors: Florian
authors: F
authors: Rimmele
authors: Department of Neurology, Campus Kiel, University Hospital Schleswig-Holstein, Kiel, Germany.|Neurology Clinics, Diakonissen Hospital Flensburg, Flensburg, Germany.
authors: Henning
authors: H
authors: Stolze
authors: Department of Molecular Neurology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors: Zacharias
authors: Z
authors: Kohl
authors: Department of Neurology, University of Ulm, Ulm, Germany.
authors: Jan
authors: J
authors: Kassubek
authors: Department of Neurology, University Hospital Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors: Thomas
authors: T
authors: Klockgether
authors: Department of Neurology, Otto von Guericke University, Magdeburg, Germany.|German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
authors: Stefan
authors: S
authors: Vielhaber
authors: Department of Neurology, University of Rostock, Rostock, Germany.|German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
authors: Christoph
authors: C
authors: Kamm
authors: Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilians University, Munich, Germany.
authors: Thomas
authors: T
authors: Klopstock
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Peter
authors: P
authors: Bauer
authors: Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL.
authors: Stephan
authors: S
authors: Züchner
authors: Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Eberhard Karls University, Tübingen, Germany.
authors: Inga
authors: I
authors: Liepelt-Scarfone
authors: Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany.|German Center for Neurodegenerative Diseases (DZNE), Eberhard Karls University, Tübingen, Germany.
authors: Ludger
authors: L
authors: Schöls
mesh_terms: D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology