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

Launched by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) · May 19, 2020

Keywords

ClinConnect Summary

This clinical trial is studying a type of inherited neurological disease called Amyotrophic Lateral Sclerosis type 4 (ALS4) and other related conditions. Researchers want to understand how certain structures formed by RNA and DNA, known as R-loops, are connected to these diseases. By studying individuals with ALS4 and similar disorders, including several other rare genetic conditions, the team hopes to learn more about how these diseases affect the body and brain.

To participate in the study, you must be at least 5 years old and have a genetic diagnosis of ALS4 or one of the related conditions. The trial is open to affected individuals as well as healthy relatives and non-relatives for comparison. Participants will undergo a few visits over three years, which may include medical history reviews, physical exams, blood tests, and imaging studies like MRIs. These tests will help researchers gather important information about muscle and overall health. It’s important to note that some tests are optional, and participants will receive guidance throughout the process.

Gender

ALL

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