Article 8: Non-SOD1 Adult-Onset Dominant Forms of Familial ALS: ALS3, ALS4, ALS6, and ALS7
Headline: Beyond SOD1: Clinical and Genetic Profiles of Non-SOD1 Adult-Onset Dominant Familial ALS*
Introduction: While SOD1 mutations dominate early hereditary ALS registries, a wide array of non-SOD1 autosomal dominant loci drive atypical and typical adult-onset familial forms. These genetic discoveries highlight diverse cellular pathways, ranging from RNA processing deficits to cytoskeletal instability.
Key Non-SOD1 Dominant Loci:
ALS3 (18q21): Presents as typical adult-onset ALS with predominant lower limb presentation and a standard 5-year disease duration.
ALS4 (SETX / 9q34): Caused by mutations in the SETX gene encoding senataxin (a DNA/RNA helicase); characterized by adolescent onset, slowly progressive distal muscle weakness, pyramidal signs, and normal life-span without bulbar involvement.
ALS6 (FUS / 16q12): Typical ALS with variable age of onset (third to seventh decade) and high penetrance.
ALS7 (20p): Characterized by adult-onset familial ALS with potential incomplete penetrance.