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 : January 27, 2023
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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.
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Condition or disease |
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Amyotrophic Lateral Sclerosis Type 4 Inherited Neurological Disorders of RNA Processing |

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. |
Actual Study Start Date : | December 14, 2020 |
Estimated Primary Completion Date : | December 25, 2030 |
Estimated Study Completion Date : | December 31, 2030 |

Group/Cohort |
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ALS4 Patients
Patients with ALS4 inherited defect in the senataxin (SETX) gene.
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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]).
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Related, Unaffected Healthy Controls
Unrelated, unaffected healthy relatives of the ALS4 and disease control groups enrolled as controls.
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Unrelated, Healthy Controls
Unrelated, healthy volunteers who are age and sex matched to the affected ALS4 and disease control participants.
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- 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.

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Ages Eligible for Study: | 5 Years and older (Child, Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | Yes |
Sampling Method: | Non-Probability Sample |
- 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
- Pregnancy
Note: An Adult ALS4 Patient who meets any of the following criteria will be excluded from the lumbar puncture procedure:
- PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants)
- INR greater than or equal to 1.5, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction
- History of a bleeding disorder
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Use of anticoagulants
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Disease control exclusion criteria:
--Pregnancy
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Related, unaffected healthy control exclusion criteria:
- Diagnosis of neuromuscular disease or weakness on physical examination
- Pregnancy
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- Note: An Adult Related, Unaffected Healthy Control who meets any of the following criteria will be excluded from the lumbar puncture procedure:
- PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants)
- INR greater than or equal to 1.5, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction
- History of a bleeding disorder
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Use of anticoagulants
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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
- Pregnancy
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Note: An Adult Unrelated, Healthy Control who meets any of the following criteria will be excluded from the lumbar puncture procedure:
- PT/PTT values that are prolonged greater than or equal to 3 seconds from the upper limit of normal (including treatment with oral and parenteral anticoagulants)
- INR greater than or equal to 1.5, thrombocytopenia (<70,000), or abnormal bleeding time or platelet dysfunction
- History of a bleeding disorder
- Use of anticoagulants

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
Contact: Angela Kokkinis, R.N. | (301) 451-8146 | akokkinis@mail.cc.nih.gov | |
Contact: Christopher Grunseich, M.D. | (301) 402-5423 | grunseichc@mail.nih.gov |
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 |
Principal Investigator: | Christopher Grunseich, M.D. | National Institute of Neurological Disorders and Stroke (NINDS) |
Publications:
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: | January 27, 2023 |
Last Verified: | January 25, 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Natural History Study Biomarker Development Natural History |
Motor Neuron Disease Amyotrophic Lateral Sclerosis Nervous System Diseases Sclerosis Pathologic Processes Neurodegenerative Diseases |
Neuromuscular Diseases Spinal Cord Diseases Central Nervous System Diseases TDP-43 Proteinopathies Proteostasis Deficiencies Metabolic Diseases |