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

National Institute of Neurological Disorders and Stroke (NINDS) · NCT04394871

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Key facts

Compensation
Not posted. Ask the study team before screening.
Who can join
Ages 5–120 · All sexes
Healthy volunteers
Accepted
Study type
Observational
Target enrollment
330
US sites recruiting
1
Study start
December 14, 2020
Record last updated
September 30, 2026

Status re-checked against ClinicalTrials.gov within the last 12 hours.

What the 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. 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

Eligibility criteria

Copied from the official record. The study team makes the final decision at screening.

Show full criteria
  • 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

Recruiting US locations

  • National Institutes of Health Clinical Center

    Bethesda, MD 20892

    Site contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) · 800-411-1222 · prpl@cc.nih.gov

Study contacts (from the official record)

  • Angela D Kokkinis, R.N. · (301) 451-8146 · akokkinis@mail.cc.nih.gov
  • Christopher Grunseich, M.D. · (301) 402-5423 · grunseichc@mail.nih.gov
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Clinical Manifestations and Biomarkers in Amyotrophic Lateral… (NCT04394871) | Bored Studies