Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31

Disease Natural History and Biomarkers of SPG3A, SPG4 and SPG31

Background:

Hereditary spastic paraplegia (HSP) usually progresses slowly. Researchers want to learn more about how its symptoms change over time. They want to look for changes in the blood and cells of people with the most common forms of HSP that might allow them to better understand the disease.

Objectives:

To learn more about common forms of hereditary spastic paraplegia and find out how it progresses over time.

Eligibility:

People age 7 and older with SPG3A, SPG4A, or SPG31

Design:

Participants will have 1 two-hour visit each year for up to 5 years.

At 1 visit, adult participants may have a skin biopsy. An area of skin will be numbed then a tool will remove a small piece of skin.

At all visits, all participants will have a physical exam and blood drawn.

At all visits, participants will do a few tasks like walking quickly and climbing stairs.

Participants can give permission for their skin cells, DNA samples, and data to be used in other studies. The samples and data will have no identifying information.

Study Overview

• Status: Terminated
• Conditions: Hereditary Spastic Paraplegia

Detailed Description

The Neurogenetics Branch (NGB) within the National Institute of Neurological Disorders and Stroke (NINDS) is conducting a study to evaluate patients with hereditary spastic paraplegia types 3A, 4 and 31. The objective of this study is to understand disease progression in these closely related forms of hereditary spastic paraplegia using validated rating scales such as the Spastic Paraplegia Rating Scale (SPRS), and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36). We also hope to develop biomarkers that could be used in future treatment trials from human serum and by utilizing transcranial magnetic stimulation (TMS) to determine central motor conduction times and resting motor thresholds.

OBJECTIVES

The primary objective of this protocol is to study the natural history of the most common forms of autosomal dominant hereditary spastic paraplegia. The information obtained from validated rating scales (SPRS and SF-36), TMS, and serum biomarkers, will allow for the development of treatment trials. In some cases, blood or other biologic samples (including skin biopsies) will be obtained for future laboratory studies.

STUDY POPULATION

The number of participants to be enrolled will be set to 300.

DESIGN

This is an observational study of autosomal dominant forms of hereditary spastic paraplegia progression, pathophysiology, and biomarkers.

OUTCOME MEASURES

In this study we will track disease progression using the Spastic Paraplegia Rating Scale (SPRS) and SF-36. Also, we will measure levels of plasma lipids, insulin, leptin, and of certain micro RNAs to investigate their utility as biomarkers. We will utilize TMS (combined with nerve conducting studies) to assess central motor conduction times (CMCT) and resting motor thresholds (RMT).

• Study Type: Observational
• Enrollment (Actual): 51

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with a diagnosis of HSP caused by mutations of known pathological significance or variants of unknown significance at the genomic loci associated with the genes ATL1, SPAST and REEP1.

Description

• INCLUSION CRITERIA:
• 7 years or older.
• Proven genetic diagnosis or variant of unknown significance considered by the Principal Investigator (PI) to be likely pathogenic at genomic loci associated with SPG3A, SPG4 and SPG31.
• For the subcomponent involving transcranial magnetic stimulation (TMS) / nerve conduction studies, patients must be greater than or equal to 18 years of age and would be willing to undergo the procedure.

EXCLUSION CRITERIA:

• Adults unable to provide consent or minors without a parent or a guardian.
• Unwillingness to consent for collection of biological samples or their cryopreservation.
• Any bleeding disorder that would prevent or present any danger either during blood extraction or skin biopsy, such hemophilia, or the long-term use of anticoagulants such as Coumadin.

• For the subcomponent of this study involving transcranial magnetic stimulation (TMS), performed with nerve conduction studies:

  • Patients under 18 years of age.
  • Patients withwith implanted devices, such as pacemakers, pumps or stimulators.
  • Patients withor metal in the cranium (excluding dental work) or eye.
  • Patients with known seizure disorder.
  • Patients who are unwilling or unable to participate.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients with hereditary spastic paraplegia (HSP); Patients with hereditary spastic paraplegia types 3A, 4 and 31.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spastic Paraplegia Rating Scale (SPRS)	Disease progression as measured by the SPRS and SF-36 scales.	Once a year for five years
SF-36	Disease progression as measured by the SPRS and SF-36 scales.	Once a year for five years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical silent period	Cortical silent period	Once a year for five years
CMCT, resting motor thresholds, MEP amplitude and MEP latency	CMCT, resting motor thresholds, MEP amplitude and MEP latency	Once a year for five years
miRNA relative quantity.	miRNA relative quantity.	Once a year for five years
Fasting Triglycerides, total Cholesterol, HDL and LDL, Leptin, Insulin levels.	Fasting Triglycerides, total Cholesterol, HDL and LDL, Leptin, Insulin levels.	Once a year for five years

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Craig D Blackstone, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2016
• Primary Completion (Actual): October 16, 2020
• Study Completion (Actual): October 16, 2020

Study Registration Dates

• First Submitted: August 6, 2016
• First Submitted That Met QC Criteria: August 6, 2016
• First Posted (Estimate): August 9, 2016

Study Record Updates

• Last Update Posted (Actual): October 20, 2020
• Last Update Submitted That Met QC Criteria: October 16, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: 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: 160158; 16-N-0158