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Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing

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ClinicalTrials.gov Identifier: NCT04394871
Recruitment Status : Recruiting
First Posted : May 20, 2020
Last Update Posted : June 2, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Brief Summary:

Background:

Amyotrophic lateral sclerosis type 4 (ALS4) is an inherited motor neuron disease. People with ALS4 have a change in the amount of RNA and DNA that bind together. This binding of RNA with DNA forms units called R-loops. Researchers want to learn how R-loops are related to ALS4. To do this, they will study people with inherited neurological conditions that may affect R-loop levels. These include ALS4, progressive external opthalmoplegia with mitochondrial deletions (PEOB2), Aicardi-Goutieres syndrome (AGS), and ataxia and oculomotor apraxia type 2 (AOA2).

Objective:

To learn how the binding of RNA with DNA (R-loops) is related to neurological disease.

Eligibility:

People age 5 and older with ALS4, PEOB2, AGS, and AOA2. Healthy relatives and nonrelatives are also needed.

Design:

Participants may be screened with a review of x-rays and other medical records.

Healthy relative and nonrelative participants will have 1 visit. All other participants will have 4 visits over 3 years.

At visits, participants will undergo some or all of the following:

Medical history

Physical exam

Tests of muscle strength and volume and physical function

Blood tests

Pregnancy test (for some females)

Skin biopsy of forearm

Magnetic resonance imaging (MRI)

Dual x-ray absorptiometry (DEXA).

Some tests are optional.

The MRI uses a magnetic field and radio waves to take pictures. Participants will lie on a table that slides in and out of the scanner. The scanner makes noise. They will get earplugs.

The DEXA scan uses x-rays to take pictures.

MRI and DEXA will be used to measure muscle, fat, and lean body mass.

...


Condition or disease
Amyotrophic Lateral Sclerosis Type 4 Inherited Neurological Disorders of RNA Processing

Show Show detailed description

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Study Type : Observational
Estimated Enrollment : 315 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: An Observational Study to Assess Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing
Estimated Study Start Date : June 5, 2020
Estimated Primary Completion Date : September 30, 2025
Estimated Study Completion Date : December 31, 2025


Group/Cohort
ALS4 Patients
Patients with ALS4 inherited defect in the senataxin (SETX) gene.
Disease Control Participants
Disease control participants with mutation in other genes which alter RNA processing (e.g., RNASEH1+2 and loss of function SETX mutations in patients with ataxia and oculomotor apraxia type 2[AOA2]).
Related, Unaffected Healthy Controls
Unrelated, unaffected healthy relatives of the ALS4 and disease control groups enrolled as controls.
Unrelated, Healthy Controls
Unrelated, healthy volunteers who are age and sex matched to the affected ALS4 and disease control participants.



Primary Outcome Measures :
  1. Disease progression as measured by thigh muscle volume and other study measures [ Time Frame: Baseline and annually at visits 2 - 4 ]
    Clinical and molecular measurements in ALS4 patients and other inherited neurological disorders of RNA processing will be assessed over the course of the study.



Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Disease cohorts with defined mutations
Criteria
  • INCLUSION CRITERIA:

ALS4 inclusion criteria:

  • Age 5 or above
  • Genetic diagnosis of ALS4 (heterozygous mutation in SETX)
  • Able to communicate well with the investigator, to understand and comply with the requirements of the study
  • Capacity to consent (adults) or assent (pediatric subjects) to the study

Disease control inclusion criteria:

  • Age 5 or above
  • Genetic diagnosis of RNA processing defect mutation (RNaseH1, RNaseH2, recessive mutations in SETX)
  • Able to communicate well with the investigator, to understand and comply with the requirements of the study
  • Capacity to consent (adults) or assent (pediatric subjects) to the study

Related, unaffected healthy control inclusion criteria:

  • Age 5 or above
  • Family history (first, second, or third degree relative) of RNA processing defect mutation (RNaseH1, RNaseH2, heterozygous or recessive mutations in SETX)
  • Able to communicate well with the investigator, to understand and comply with the requirements of the study
  • Capacity to consent (adults) or assent (pediatric subjects) to the study

Unrelated, healthy control inclusion criteria:

  • Age 5 or above
  • Able to communicate well with the investigator, to understand and comply with the requirements of the study
  • Capacity to consent (adults) or assent (pediatric subjects) to the study

EXCLUSION CRITERIA:

ALS4 exclusion criteria:

-Patients with known claustrophobia, presence of pacemaker, ferromagnetic material in their body, or any other condition that would preclude MRI assessments

Related, unaffected healthy control exclusion criteria:

  • Diagnosis of neuromuscular disease or weakness on physical examination
  • Pregnancy

Unrelated, healthy control exclusion criteria:

  • Diagnosis of neuromuscular disease or weakness on physical examination
  • Patients with known claustrophobia, presence of pacemaker, ferromagnetic material in their body, or any other condition that would preclude MRI assessments

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04394871


Contacts
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Contact: Angela Kokkinis, R.N. (301) 451-8146 akokkinis@mail.cc.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Christopher Grunseich, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
Additional Information:
Publications:
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Responsible Party: National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier: NCT04394871    
Other Study ID Numbers: 200064
20-N-0064
First Posted: May 20, 2020    Key Record Dates
Last Update Posted: June 2, 2020
Last Verified: May 18, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) ):
Natural History Study
Biomarker Development
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Nervous System Diseases
Pathologic Processes
Neurodegenerative Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases