Developing a ‘natural history’ of HSP

Posted - February 2016 in Research Highlights

Large German study lays the foundation

 

Ludger Schöls

Ludger Schöls

The term ‘natural history of a disease’ refers to the course or progression of the condition from its pathological onset to its conclusion.

 

Rebecca Schüle

Rebecca Schüle

It is vitally important in the process of establishing effective treatments for disease as it is the benchmark against which improvements must be measured and calibrated.

 

Developing a natural history for a disease is a long and rigorous, detailed, investigative, scientific process. It is an essential requirement for clinical trials, for example.

 

This ongoing German study of 608 HSPers from 608 families, over a more than 10 year period, is a comprehensive and substantial foundation for describing the natural history of HSP.

 

Progression of the HSPs will continue to be studied and quantified in this important research.

Stephan Züchner

Stephan Züchner

 

The study team includes some of the world’s leading HSP researchers such as neurogeneticists Rebecca Schüle, Ludger Schöls and Stephan Züchner.

 

OBJECTIVE:

Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate phenotypic spectrum, prognostic factors and genotype specific differences we analyzed baseline data of 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 (SPRS). 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 higher 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.

 

SOURCE: Ann Neurol. 2016 Feb 9. doi: 10.1002/ana.24611. [Epub ahead of print] © 2016 American Neurological Association. PMID: 26856398 [PubMed – as supplied by publisher]

 

Hereditary Spastic Paraplegia -clinico-genetic lessons from 608 patients.

 

Schüle R1,2,3, Wiethoff S1,4, Martus P5, Karle KN1,2,6, Otto S7, Klebe S8,9,10, Klimpe S11,12, Gallenmüller C13,14,15, Kurzwelly D16,17, Henkel D18,19, Rimmele F20,21, Stolze H9,22, Kohl Z23, Kassubek J24, Klockgether T16,17, Vielhaber S18,19, Kamm C20,21, Klopstock T13,14,15, Bauer P25, Züchner S3, Liepelt-Scarfone I1,2, Schöls L1,2.

 

1Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany.

2German Center of Neurodegenerative Diseases (DZNE), Eberhard-Karls-University, Tübingen, Germany.

3Dr. 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, 33136, USA.

4Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom.

5Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University Tübingen, Germany.

6Department of Psychiatry and Psychotherapy, Eberhard-Karls-University, Tübingen, Germany.

7Department of Neurology, St. Josef Hospital, Bochum, Ruhr-University Bochum, Bochum, Germany.

8Department for Neurology, University Hospital Würzburg, Würzburg, Germany.

9Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

10Department for Neurology, University Hospital Freiburg, Freiburg, Germany.

11Department of Neurology, Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.

12University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany.

13Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany.

14Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

15German Center of Neurodegenerative Diseases (DZNE), Ludwig-Maximilians-University, Munich, Germany.

16Department of Neurology, University Hospital Bonn, Bonn, Germany.

17German Center for Neurodegenerative Disorder (DZNE), Bonn, Germany.

18Department of Neurology, Otto-von-Guericke-University, Magdeburg, Germany.

19German Center of Neurodegenerative Diseases (DZNE), Magdeburg, Germany.

20Department of Neurology, University of Rostock, Germany.

21German Center of Neurodegenerative Diseases (DZNE), Rostock, Germany.

22Diakonissenkrankenhaus Flensburg, Neurology Clinics, Flensburg.

23Department of Molecular Neurology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.

24Department of Neurology, University of Ulm, Ulm, Germany.

25Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.

 

 

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