Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients

Rebecca Schüle, Sarah Wiethoff, Peter Martus, Kathrin N. Karle, Susanne Otto, Stephan Klebe, Sven Klimpe, Constanze Gallenmüller, Delia Kurzwelly, Dorothea Henkel, Florian Rimmele, Henning Stolze, Zacharias Kohl, Jan Kassubek, Thomas Klockgether, Stefan Vielhaber, Christoph Kamm, Thomas Klopstock, Peter Bauer, Stephan L ZuchnerInga Liepelt-Scarfone, Ludger Schöls

Research output: Contribution to journalArticle

66 Citations (Scopus)

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. Interpretation: 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.

Original languageEnglish (US)
JournalAnnals of Neurology
DOIs
StateAccepted/In press - 2016

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Hereditary Spastic Paraplegia
Genotype
Disease Progression
Neurologic Gait Disorders
Wheelchairs
Aptitude
Paraplegia
Family Planning Services
Ataxia
Natural History
Age of Onset
Walking
Longitudinal Studies
Counseling
Cohort Studies
Cross-Sectional Studies
Prospective Studies

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Schüle, R., Wiethoff, S., Martus, P., Karle, K. N., Otto, S., Klebe, S., ... Schöls, L. (Accepted/In press). Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Annals of Neurology. https://doi.org/10.1002/ana.24611

Hereditary spastic paraplegia : Clinicogenetic lessons from 608 patients. / Schüle, Rebecca; Wiethoff, Sarah; Martus, Peter; Karle, Kathrin N.; Otto, Susanne; Klebe, Stephan; Klimpe, Sven; Gallenmüller, Constanze; Kurzwelly, Delia; Henkel, Dorothea; Rimmele, Florian; Stolze, Henning; Kohl, Zacharias; Kassubek, Jan; Klockgether, Thomas; Vielhaber, Stefan; Kamm, Christoph; Klopstock, Thomas; Bauer, Peter; Zuchner, Stephan L; Liepelt-Scarfone, Inga; Schöls, Ludger.

In: Annals of Neurology, 2016.

Research output: Contribution to journalArticle

Schüle, R, Wiethoff, S, Martus, P, Karle, KN, Otto, S, Klebe, S, Klimpe, S, Gallenmüller, C, Kurzwelly, D, Henkel, D, Rimmele, F, Stolze, H, Kohl, Z, Kassubek, J, Klockgether, T, Vielhaber, S, Kamm, C, Klopstock, T, Bauer, P, Zuchner, SL, Liepelt-Scarfone, I & Schöls, L 2016, 'Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients', Annals of Neurology. https://doi.org/10.1002/ana.24611
Schüle, Rebecca ; Wiethoff, Sarah ; Martus, Peter ; Karle, Kathrin N. ; Otto, Susanne ; Klebe, Stephan ; Klimpe, Sven ; Gallenmüller, Constanze ; Kurzwelly, Delia ; Henkel, Dorothea ; Rimmele, Florian ; Stolze, Henning ; Kohl, Zacharias ; Kassubek, Jan ; Klockgether, Thomas ; Vielhaber, Stefan ; Kamm, Christoph ; Klopstock, Thomas ; Bauer, Peter ; Zuchner, Stephan L ; Liepelt-Scarfone, Inga ; Schöls, Ludger. / Hereditary spastic paraplegia : Clinicogenetic lessons from 608 patients. In: Annals of Neurology. 2016.
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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. Interpretation: 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.",
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AU - Schüle, Rebecca

AU - Wiethoff, Sarah

AU - Martus, Peter

AU - Karle, Kathrin N.

AU - Otto, Susanne

AU - Klebe, Stephan

AU - Klimpe, Sven

AU - Gallenmüller, Constanze

AU - Kurzwelly, Delia

AU - Henkel, Dorothea

AU - Rimmele, Florian

AU - Stolze, Henning

AU - Kohl, Zacharias

AU - Kassubek, Jan

AU - Klockgether, Thomas

AU - Vielhaber, Stefan

AU - Kamm, Christoph

AU - Klopstock, Thomas

AU - Bauer, Peter

AU - Zuchner, Stephan L

AU - Liepelt-Scarfone, Inga

AU - Schöls, Ludger

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N2 - 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. Interpretation: 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.

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