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

* 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