Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders (HSP-PBP)

The aim of this study is to determine the clinical spectrum and natural progression of Hereditary Spastic Paraplegias (HSP) and related disorders in a prospective multicenter natural history study, identify digital, imaging and molecular biomarkers that can assist in diagnosis and therapy development and study the genetic etiology and molecular mechanisms of these diseases.

Study Overview

• Status: Recruiting
• Conditions: Hereditary Spastic Paraplegia
• Intervention / Treatment: Diagnostic test: Next-Gen Sequencing (NGS); Other: Clinical rating scale to measure disease severity and progression

Detailed Description

The investigators will perform a registry-based standardized prospective Natural History Study (NHS) in HSPs and related disorders. Participants will be seen annually. At study visits a standardized clinical examination will be performed including application of clinical rating scales (selection of rating scales may vary depending on the individual phenotype and specific genotype); data will be entered into a clinical database (HSP Registry; https://www.hsp-registry.net). At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy.

Optionally, additional examinations may be performed including imaging, quantitative movement analysis, neuropsychological examinations, analysis of patient or observer reported outcomes and OMICS analysis to characterize molecular biomarkers.

In participants without a genetic diagnosis, next generation sequencing may be performed.

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

• Study Contact: Name: Rebecca Schüle, PD Dr.; Phone Number: 85653 +49 7071 29; Email: rebecca.schuele-freyer@uni-tuebingen.de
• Study Contact Backup: Name: Ludger Schöls, Prof. Dr.; Phone Number: 85548 +49 7071 29; Email: ludger.schoels@uni-tuebingen.de

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Recruiting
    • University Innsbruck
    • Contact: Matthias Amprosi; Phone Number: +43 512 504 83686; Email: matthias.amprosi@i-med.ac.at
    • Contact: Sylvia Bösch; Phone Number: +43 512 504 83686; Email: sylvia.boesch@i-med.ac.at
    • Principal Investigator: Sylvia Bösch, MD
    • Sub-Investigator: Matthias Amprosi, MD
• Germany
  • Bonn, Germany, 53127
    • Recruiting
    • German Center for Neurodegenerative Diseases (DZNE) Bonn
    • Principal Investigator: Thomas Klockgether, MD
    • Contact: Thomas Klockgether; Phone Number: +49 228 28715726; Email: Thomas.Klockgether@dzne.de
    • Sub-Investigator: Xenia Kobeleva, MD
  • Erlangen, Germany, 91054
    • Recruiting
    • University of Erlangen
    • Contact: Susanne Seifert; Phone Number: +49 9131 85 44751; Email: susanne.seifert@uk-erlangen.de
    • Contact: Pia-Marie Pryssok; Phone Number: +49 9131 85 44751; Email: pia-marie.pryssok@uk-erlangen.de
    • Principal Investigator: Jürgen Winkler, MD
    • Sub-Investigator: Heiko Gassner, Dr. Phil.
  • Essen, Germany, 45147
    • Recruiting
    • University Medicine Essen
    • Contact: Sylwia Kante; Phone Number: +49 201 - 7236513; Email: sylwia.kante@uk-essen.de
    • Principal Investigator: Stephan Klebe, MD
  • Göttingen, Germany, 37075
    • Recruiting
    • University Göttingen
    • Contact: Anja Schadenberg; Phone Number: +49 551 39 10206; Email: aschadenberg@med.uni-goettingen.de
    • Principal Investigator: Michael Sereda, MD
    • Sub-Investigator: Sonja Fritzsch, MD
    • Sub-Investigator: Knut Brockmann, MD
    • Principal Investigator: Anne van Riesen, MD
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • University Heidelberg
    • Contact: Heike Jacobi; Phone Number: +49 6221 - 56 - 7510; Email: Heike.Jacobi@med.uni-heidelberg.de
    • Principal Investigator: Heike Jacobi, MD
  • Lübeck, Germany, 23562
    • Not yet recruiting
    • University of Lubeck
    • Contact: Maike Dümcke-Zilian; Phone Number: +49 451 3101 8215; Email: maike.duemcke-zilian@neuro.uni-luebeck.de
    • Principal Investigator: Alexander Münchau, MD
  • Magdeburg, Germany, 39120
    • Recruiting
    • German Center for Neurogedenerative Diseases (DZNE) Magdeburg
    • Contact: Michaela Butryn; Phone Number: +49 391-67-13431; Email: michaela.butryn@med.ovgu.de
    • Principal Investigator: Stefan Vielhaber, MD
    • Sub-Investigator: Michaela Butryn, MD
  • München, Germany, 80336
    • Recruiting
    • German Center for Neurodegenerative Diseases (DZNE) München
    • Principal Investigator: Thomas Klopstock, MD
    • Contact: Jasmina Al-Tamami; Phone Number: +49 89 4400 57425; Email: jasmina.altamami@med.uni-muenchen.de
    • Sub-Investigator: Florentine Radelfahrt, MD
  • Regensburg, Germany, 93053
    • Not yet recruiting
    • University of Regensburg
    • Contact: Zacharias Kohl; Phone Number: +49 941 941 3074; Email: zacharias.kohl@ukr.de
    • Principal Investigator: Zacharias Kohl, MD
  • Rostock, Germany, 18147
    • Not yet recruiting
    • German Center for Neurodegenerative Diseases (DZNE) Rostock
    • Contact: Christoph Kamm; Phone Number: +49 381 4944763; Email: christoph.kamm@med.uni-rostock.de
    • Principal Investigator: Christoph Kamm, MD
  • Tübingen, Germany, 72076
    • Recruiting
    • University of Tübingen and German Center for Neurodegenerative Diseases (DZNE) Tübingen
    • Principal Investigator: Rebecca Schüle, MD
    • Contact: Katrin Dillmann; Phone Number: +49 7071 29 85653; Email: katrin.dillmann@med.uni-tuebingen.de
    • Sub-Investigator: Ludger Schöls, MD
    • Sub-Investigator: Ingeborg Krägeloh-Mann, MD
    • Sub-Investigator: Marion Döbler-Neumann, MD
• Italy
  • Pieve di Soligo, Italy, 31053
    • Not yet recruiting
    • IRCCS Medea Scientific Institute, Conegliano-PIeve di Soligo Research Centre
    • Contact: Andrea Martinuzzi, MD; Phone Number: 0438 414337; Email: andrea.martinuzzi@lanostrafamiglia.it
    • Principal Investigator: Andrea Martinuzzi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Probands with a clinical or genetic diagnosis of an HSP and related disorders including pre-manifest individuals will be primarily enrolled in this study (primary participants).

Additionally, unaffected family members of primary participants will be enrolled if they are of legal age (>= 18 years) and able to give informed consent (secondary participants).

Unaffected minors will only be enrolled under special circumstances as detailed in paragraph 5.1 (Special Populations - Unaffected minors).

Lastly, healthy unrelated controls will be enrolled; these are necessary to contrast unspecific, gender- or age-related findings to disease specific findings.

Description

Inclusion criteria:

• One of the following:

  1. Primary participant: Clinical or genetic diagnosis of HSP or a related disorder
  2. Secondary participant: Unaffected family member (1st or 2nd degree relative) of primary participant (with the above-mentioned restrictions for special populations) able to give informed consent

  3. Unrelated healthy control able to give informed consent

     AND

• Written informed consent

AND

- Participants are willing and able to comply with study procedures

Exclusion criteria:

• Missing informed consent of primary or secondary participant/ healthy control/ legal representatives
• For controls: evidence of a neurodegenerative disease or movement disorders; inability to give informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Primary participant: Participants affected by hereditary spastic paraplegia (HSP) or a phenotypically related disorder Primary participants will be followed at annual intervals. The workup includes clinical, imaging, sensor-based, patient/observer reported and molecular outcome parameters and biosampling. Participants with unknown genetic diagnosis may receive genetic testing including whole exome or whole genome sequencing and other OMICS techniques.	Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics; Other: Clinical rating scale to measure disease severity and progression; A 13-item scale to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory.; Other Names: Spastic Paraplegia Rating Scale (SPRS)
Secondary participant/ First or second-degree; First or second degree unaffected family members of primary participants. Secondary participants may undergo the same study procedures as primary participants.	Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics
Unrelated healthy control; Unrelated healthy controls Healthy controls may undergo the same study procedures as primary participants.	Diagnostic test: Next-Gen Sequencing (NGS); Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline of Spastic Paraplegia Rating Scale (SPRS) total score at 2 years	Disease severity will be assessed by application of the Spastic Paraplegia Rating Scale (SPRS), a clinical rating scale measuring disease severity in Hereditary Spastic Paraplegia (Schüle et al. Neurology 2006). The SPRS contains 13 items, each ranging from 0 to 4 points. The total score is calculated as the sum of all items, yielding a range for the total score between 0 and 52. Hereby, higher SPRS total scores indicate more severe disease.	up to 2 years

Collaborators and Investigators

• Sponsor: Dr. Rebecca Schule
• Collaborators: German Federal Ministry of Education and Research; German Center for Neurodegenerative Diseases (DZNE)
• Investigators: Principal Investigator: Rebecca Schüle, PD Dr., University Hospital Tübingen

Publications and helpful links

Helpful Links

• Website of the TreatHSP consortium
• Website of the HSP Registry

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2019
• Primary Completion (Anticipated): August 1, 2039
• Study Completion (Anticipated): August 1, 2041

Study Registration Dates

• First Submitted: June 4, 2019
• First Submitted That Met QC Criteria: June 7, 2019
• First Posted (Actual): June 10, 2019

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: May 18, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Biomarker; Genetic etiology; Molecular mechanisms; Hereditary Spastic Paraplegia
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Manifestations; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Paralysis; Muscle Hypertonia; Polyneuropathies; Hereditary Sensory and Motor Neuropathy; Muscle Spasticity; Paraplegia; Spastic Paraplegia, Hereditary
• Other Study ID Numbers: HSP-PBP; 01GM1905 (Other Grant/Funding Number: Bundesministerium für Bildung und Forschung (BMBF))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No