Studies how RNA and DNA binding relates to inherited nerve diseases

Trial details

Who runs it

National Institute of Neurological Disorders and Stroke (NINDS)

Trial code

NCT04394871

Record updated

30 September 2026

Original description

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An Observational Study to Assess Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4, Other Inherited Neurological Disorders With RNA Processing Defects, and Other Neurological Diseases With a Gain of Function Mechanism.

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.

...

Exclusion: Patients with known claustrophobia, presence of pacemaker, ferromagnetic material in their body, or any other condition that would preclude MRI assessments; 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:; 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:; History of a bleeding disorder; History of a bleeding disorder; 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; 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; 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; 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; ALS4 RNA metabolism exclusion criteria:; Pregnancy; Note: An Adult RNA metabolism ALS4 Patient who meets any of the following criteria will be excluded from the lumbar puncture procedure:; 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:; Use of anticoagulants.

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.

ClinicalTrials.gov NCT04394871