• 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