Understanding RNA Binding in Inherited Neurological Disorders
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.
This study is trying to see how RNA-DNA binding is connected to inherited neurological disorders like ALS4 and others, by looking at both affected individuals and their healthy family members.
Quick facts
| Study type | Observational |
|---|---|
| Enrollment | 330 (estimated) |
| Ages | 5 Years to 120 Years |
| Sex | All |
| Sponsor | National Institutes of Health Clinical Center (CC) NIH |
| Locations | 1 site (Bethesda, Maryland) |
| Trial ID | NCT04394871 on ClinicalTrials.gov |
What this trial studies
This observational study aims to investigate the relationship between RNA-DNA binding, known as R-loops, and inherited neurological disorders, specifically focusing on Amyotrophic Lateral Sclerosis Type 4 (ALS4) and other related conditions. Participants aged 5 and older with ALS4, progressive external ophthalmoplegia with mitochondrial deletions, Aicardi-Goutieres syndrome, and ataxia and oculomotor apraxia type 2 will be enrolled, along with healthy relatives. The study will involve multiple visits over three years to collect clinical and molecular biomarkers, which may aid in understanding disease progression and inform future therapeutic strategies.
Who should consider this trial
Good fit: Ideal candidates include individuals aged 5 and older diagnosed with ALS4 or other specified inherited neurological disorders.
Not a fit: Patients without a genetic diagnosis of ALS4 or related RNA processing disorders may not benefit from this study.
Why it matters
Potential benefit: If successful, this study could lead to improved understanding and potential biomarkers for ALS4 and similar neurological disorders, paving the way for better treatment options.
How similar studies have performed: While this study focuses on a specific genetic mechanism, similar studies exploring RNA processing disorders have shown promise in understanding disease mechanisms.
Eligibility criteria
Show full inclusion / exclusion 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
Where this trial is running
Bethesda, Maryland
- National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)
Study contacts
- Principal investigator: Christopher Grunseich, M.D. — National Institute of Neurological Disorders and Stroke (NINDS)
- Study coordinator: Angela D Kokkinis, R.N.
- Email: akokkinis@mail.cc.nih.gov
- Phone: (301) 451-8146
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.