NCT04394871 Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing

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What to Expect as a Participant

This is an observational study. You will not receive an experimental treatment; researchers will collect data based on your existing condition or standard treatment.

This trial targets 330 participants in total. It began in 2020-12-14 with a primary completion date of 2030-12-25.

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. ...

Eligibility 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

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