Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders

Conditions
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Hereditary Spastic Paraplegia

Intervention / Treatment
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* Other: Clinical rating scale to measure disease severity and progression
* Diagnostic Test: Next-Gen Sequencing (NGS)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: One of the following: Primary participant: Clinical or genetic diagnosis of HSP or a related disorder 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 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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Primary participant:<br>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. | Other: Clinical rating scale to measure disease severity and progression<br>* 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.<br>* Other names: Spastic Paraplegia Rating Scale (SPRS);Diagnostic Test: Next-Gen Sequencing (NGS)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|
| Secondary participant/ First or second-degree<br>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)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|
| Unrelated healthy control<br>Unrelated healthy controls Healthy controls may undergo the same study procedures as primary participants. | Diagnostic Test: Next-Gen Sequencing (NGS)<br>* Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hereditary Spastic Paraplegia, Biomarker, Genetic etiology, Molecular mechanisms