NCT04394871 · National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing
What this study is about
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.
View original scientific description
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. ...
Primary outcome measures
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.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- ALS4 RNA metabolism 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 Gain of function inclusion criteria:
- Age 5 or above
- Genetic diagnosis of mutation resulting in a gain of function mechanism (for example, heterozygous mutations in SETX or heterozygous mutations in KCC3)
- Able to communicate well with the investigator, to understand and comply with the requirements of the studyCapacity to consent (adults) or assent (pediatric subjects) to the study
- Capacity to consent (adults) or assent (pediatric subjects) to the study
Exclusion criteria
- ALS4 RNA metabolism 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 RNA metabolism 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
- Use of anticoagulants
- Disease control exclusion criteria: --Pregnancy
- Related, unaffected healthy control exclusion criteria:
- Diagnosis of neuromuscular disease or weakness on physical examination
- Pregnancy 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
- Use of anticoagulants
- 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 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 Gain of function exclusion criteria: -Pregnancy Note: An Adult Gain of Function 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
- Use of anticoagulants
Where
- Bethesda, Maryland
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Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
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Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
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How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced Nov 28, 2025 · Source of record for eligibility and locations