Rebecca Schüle1,2,3, Sarah Wiethoff1,4, Peter Martus5, Kathrin N Karle1,2,6, Susanne Otto7, Stephan Klebe8,9,10, Sven Klimpe11,12, Constanze Gallenmüller13,14,15, Delia Kurzwelly16,17, Dorothea Henkel18,19, Florian Rimmele20,21, Henning Stolze9,22, Zacharias Kohl23, Jan Kassubek24, Thomas Klockgether16,17, Stefan Vielhaber18,19, Christoph Kamm20,21, Thomas Klopstock13,14,15, Peter Bauer25, Stephan Züchner3, Inga Liepelt-Scarfone1,2, Ludger Schöls1,2. 1. Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tübingen, Germany. 2. German Center for Neurodegenerative Diseases (DZNE), Eberhard Karls University, Tübingen, Germany. 3. 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. 4. Institute of Neurology, London, United Kingdom. 5. Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University, Tübingen, Germany. 6. Department of Psychiatry and Psychotherapy, Eberhard Karls University, Tübingen, Germany. 7. Department of Neurology, St Josef Hospital Bochum/Ruhr University Bochum, Bochum, Germany. 8. Department for Neurology, University Hospital Würzburg, Würzburg, Germany. 9. Department of Neurology, Campus Kiel, University Hospital Schleswig-Holstein, Kiel, Germany. 10. University Hospital Freiburg, Department for Neurology, Freiburg, Germany. 11. Department of Neurology, Horst Schmidt Clinics Wiesbaden, Wiesbaden, Germany. 12. University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. 13. Department of Neurology, Friedrich Baur Institute, Ludwig-Maximilians-University, Munich, Germany. 14. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 15. German Center for Neurodegenerative Diseases (DZNE), Ludwig Maximilians University, Munich, Germany. 16. Department of Neurology, University Hospital Bonn, Bonn, Germany. 17. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 18. Department of Neurology, Otto von Guericke University, Magdeburg, Germany. 19. German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany. 20. Department of Neurology, University of Rostock, Rostock, Germany. 21. German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany. 22. Neurology Clinics, Diakonissen Hospital Flensburg, Flensburg, Germany. 23. Department of Molecular Neurology, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany. 24. Department of Neurology, University of Ulm, Ulm, Germany. 25. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
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.
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.
Authors: Tim W Rattay; Tobias Lindig; Jonathan Baets; Katrien Smets; Tine Deconinck; Anne S Söhn; Konstanze Hörtnagel; Kathrin N Eckstein; Sarah Wiethoff; Jennifer Reichbauer; Marion Döbler-Neumann; Ingeborg Krägeloh-Mann; Michaela Auer-Grumbach; Barbara Plecko; Alexander Münchau; Bernd Wilken; Marc Janauschek; Anne-Katrin Giese; Jan L De Bleecker; Els Ortibus; Martine Debyser; Adolfo Lopez de Munain; Aurora Pujol; Maria Teresa Bassi; Maria Grazia D'Angelo; Peter De Jonghe; Stephan Züchner; Peter Bauer; Ludger Schöls; Rebecca Schüle Journal: Brain Date: 2019-06-01 Impact factor: 13.501
Authors: Mohammad Ali Farazi Fard; Adriana P Rebelo; Elena Buglo; Hamid Nemati; Hassan Dastsooz; Ina Gehweiler; Selina Reich; Jennifer Reichbauer; Beatriz Quintáns; Andrés Ordóñez-Ugalde; Andrea Cortese; Steve Courel; Lisa Abreu; Eric Powell; Matt C Danzi; Nicole B Martuscelli; Dana M Bis-Brewer; Feifei Tao; Fariba Zarei; Parham Habibzadeh; Majid Yavarian; Farzaneh Modarresi; Mohammad Silawi; Zahra Tabatabaei; Masoume Yousefi; Hamid Reza Farpour; Christoph Kessler; Elisabeth Mangold; Xenia Kobeleva; Ivailo Tournev; Teodora Chamova; Amelie J Mueller; Tobias B Haack; Mark Tarnopolsky; Ziv Gan-Or; Guy A Rouleau; Matthis Synofzik; María-Jesús Sobrido; Albena Jordanova; Rebecca Schüle; Stephan Zuchner; Mohammad Ali Faghihi Journal: Am J Hum Genet Date: 2019-03-28 Impact factor: 11.025
Authors: Ludger Schöls; Tim W Rattay; Peter Martus; Christoph Meisner; Jonathan Baets; Imma Fischer; Christine Jägle; Matthew J Fraidakis; Andrea Martinuzzi; Jonas Alex Saute; Marina Scarlato; Antonella Antenora; Claudia Stendel; Philip Höflinger; Charles Marques Lourenco; Lisa Abreu; Katrien Smets; Martin Paucar; Tine Deconinck; Dana M Bis; Sarah Wiethoff; Peter Bauer; Alessia Arnoldi; Wilson Marques; Laura Bannach Jardim; Stefan Hauser; Chiara Criscuolo; Alessandro Filla; Stephan Züchner; Maria Teresa Bassi; Thomas Klopstock; Peter De Jonghe; Ingemar Björkhem; Rebecca Schüle Journal: Brain Date: 2017-12-01 Impact factor: 13.501