Recruiting

R-Loops

Sponsor:

National Institute of Neurological Disorders and Stroke (NINDS)

Code:

NCT04394871

Conditions

Amyotrophic Lateral Sclerosis Type 4

Inherited Neurological Disorders of RNA Processing

Eligibility Criteria

Sex: All

Age: 5 - 70+

Healthy Volunteers: Accepted

Study Details

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.

...

Conditions

Amyotrophic Lateral Sclerosis Type 4

Inherited Neurological Disorders of RNA Processing

Study ID

NCT04394871

Start date

Dec 14, 2020

Status verified date

Nov 25, 2025

Completion date

Dec 31, 2030

Anticipated

Primary completion date

Dec 25, 2030

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 5 - 70+

Healthy Volunteers: Accepted

  • 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

Study Design

Enrollment

330 participants

Anticipated

Interventions and Outcome Measures

Arms

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\[AOA2\]).

Gain of Function

patients with gain of function mutations in genes that result in other forms of neurological disease, as well as select patients with mutation in the SETX gene (select ALS4 patients), will be enrolled and followed annuallt for 5 years.

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 measure

  • Disease progression as measured by thigh muscle volume and other study measures [ Time Frame: Baseline and annually at visits 2 - 4 ]

Central Contacts and Locations

Central contacts

Angela D Kokkinis, R.N.

(301) 451-8146akokkinis@mail.cc.nih.gov

Christopher Grunseich, M.D.

(301) 402-5423grunseichc@mail.nih.gov

Locations

National Institutes of Health Clinical Center

Recruiting

Bethesda, Maryland, United States, 20892

Contacts

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

800-411-1222prpl@cc.nih.gov

More Information

Sponsor

National Institute of Neurological Disorders and Stroke (NINDS)

Last update posted

Nov 28, 2025

Last verified

Nov 25, 2025

Keywords

  • Natural History Study
  • Biomarker Development
  • Natural History

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Institute of Neurological Disorders and Stroke (NINDS) on 2025-11-28.