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 language | English (US) |
|---|---|
| Journal | Annals of Neurology |
| DOIs | |
| State | Accepted/In press - 2016 |
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ASJC Scopus subject areas
- Neurology
- Clinical Neurology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Hereditary spastic paraplegia
T2 - Clinicogenetic lessons from 608 patients
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
PY - 2016
Y1 - 2016
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84960372305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960372305&partnerID=8YFLogxK
U2 - 10.1002/ana.24611
DO - 10.1002/ana.24611
M3 - Article
C2 - 26856398
AN - SCOPUS:84960372305
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
ER -