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

Study Overview
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Brief Summary
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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. ...

Detailed Description
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Objective: Amyotrophic lateral sclerosis type 4 (ALS4) is an inherited form of motor neuron disease caused by mutation in the senataxin (SETX) gene. The main goal of this study will be to collect clinical and molecular biomarkers from patients with ALS4 to understand the natural history and progression of the disease. The biomarkers identified will serve as potential tools for the evaluation of efficacy in future therapeutic studies in ALS4. The protocol will primarily seek to enroll patients with mutation in the SETX gene and follow these individuals annually for 3 years. Individuals with mutation in genes that are predicted to result in a similar disruption of RNA processing (such as ribonuclease H1 and H2 (RNASEH1+2) genes and recessive mutations in SETX will serve as disease controls and participate in follow-up for 3 years to collect clinical and molecular biomarkers. ALS4 and disease control subjects who have had their mutation identified in protocol 00-N-0043 or protocol 12-N-0095, or those who have had previous genetic testing will be potential candidates for enrollment in this study. Healthy control populations (related, unaffected healthy controls and unrelated, healthy controls) will be screened for under this study and participate in a single visit to collect clinical and molecular biomarkers. Healthy control populations will participate in clinical and molecular biomarker collection for comparison to the ALS4 cohort. Related, unaffected healthy controls may also be screened under protocol 00-N-0043. No clinical genetic testing will take place under this protocol; however, research testing of genetic modifiers may be performed. Study population: There will be a total of 315 subjects enrolled under this protocol. The protocol will seek to enroll up to 65 participants with mutation in SETX (ALS4) for annual follow-up, and up to 50 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]). Up to 150 related, unaffected healthy relatives of the ALS4 and disease control groups may also be enrolled as controls. Additionally, a maximum of 50 unrelated healthy volunteers who are age and sex matched to the affected ALS4 and disease control participants will also be enrolled. Study Design: Patients with ALS4 inherited defect in SETX will be evaluated at the NIH clinical center to characterize clinical features of the disease and collect clinical and molecular biomarkers. Disease controls will be evaluated to collect molecular biomarkers and clinical measurements at the discretion of the investigator. Patients with ALS4 and Disease Control participants will report to the NIH every 12 months (plus or minus 60 days) for clinical and molecular studies for a total of 4 visits. Healthy control populations (related, unaffected healthy controls and unrelated healthy controls) will be evaluated for a single visit to collect clinical and molecular biomarkers. An offsite visit, conducted in person at the participant s home, may be completed for the related, unaffected healthy control group, the disease control group, and in up to 15 ALS4 participants. Outcome measures: No specific primary and secondary outcomes will be specified; however, the change in the following measures from baseline may be used to characterize the baseline status and disease progression over the course of the study: magnetic resonance imaging (MRI) evaluation of the lower extremity (muscle volume and fat fraction), dual-energy X-ray absorptiometry (DEXA) scan of whole body composition (lean body mass), quantitative muscle strength testing (QMT) of the upper and lower extremities, 6 minute timed walk test (6MTWT), timed up and go (TUG), 30 second chair stand test, pinch strength test, activity card sort (ACS), disabilities of the arm, shoulder, and hand (DASH), and the grooved pegboard test. Molecular biomarkers of RNA processing will be evaluated in the ALS4 group and control groups (healthy and disease) to identify those molecular biomarkers that are disease specific (disease vs. control) as well as those that are informative of disease progression in ALS4 (early vs. advanced disease). Clinical measurements of neuromuscular ultrasound, MRI, DEXA scan of whole body composition (lean body mass), QMT of the upper and lower extremities, 6MTWT, TUG, 30 second chair stand test, pinch strength, ACS, DASH, SF36 questionnaire, ALS Health Index (ALS-HI) questionnaire, Patient-Perceived Change in Function Question, and grooved pegboard test will provide a determination of disease severity in ALS4 patients and other inherited neurological disorders of RNA processing. The molecular biomarkers from ALS4 patients will be compared to the healthy control groups and the disease control group in order to determine which measurements are specific to the ALS4 disease.

Official Title
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An Observational Study to Assess Clinical Manifestations and Biomarkers in Amyotrophic Lateral Sclerosis Type 4 and Other Inherited Neurological Disorders of RNA Processing.

Conditions
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Amyotrophic Lateral Sclerosis Type 4, Inherited Neurological Disorders of RNA Processing

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: ALS4 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 EXCLUSION CRITERIA: ALS4 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 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

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ALS4 Patients<br>Patients with ALS4 inherited defect in the senataxin (SETX) gene. | |
| Disease Control Participants<br>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]). | |
| Related, Unaffected Healthy Controls<br>Unrelated, unaffected healthy relatives of the ALS4 and disease control groups enrolled as controls. | |
| Unrelated, Healthy Controls<br>Unrelated, healthy volunteers who are age and sex matched to the affected ALS4 and disease control participants. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease progression as measured by thigh muscle volume and other study measures | Clinical and molecular measurements in ALS4 patients and other inherited neurological disorders of RNA processing will be assessed over the course of the study. | Baseline and annually at visits 2 - 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Natural History Study, Biomarker Development, Natural History