Phenotypic Characterization of ALS-Causing SOD1 Mutations Affecting Polypeptide Length.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Over 234 mutations in the *SOD1* gene are linked to amyotrophic lateral sclerosis (ALS), but pathogenic mechanisms, especially those altering polypeptide length, remain debated.
• The clinical relevance of all reported nonsense *SOD1* mutations in causing ALS is not fully established.
• Developing targeted anti-SOD1 therapies necessitates a deeper understanding of the clinical-genetic landscape of ALS for patient stratification in trials and clinical practice.

Purpose of the Study:

• To comprehensively analyze the clinical phenotypes of ALS patients with *SOD1* mutations that alter polypeptide length.
• To specifically investigate the impact of these mutations on age at symptom onset and patient survival duration.
• To compare clinical outcomes between frameshift and nonframeshift *SOD1* variants.

Main Methods:

• Data compilation from web databases, published literature, conference abstracts, and personal communications up to November 2023.
• Survival analysis of clinical endpoints, including age at symptom onset and age at death.
• Comparative analysis of frameshift versus nonframeshift *SOD1* variants.

Main Results:

• Analysis of 146 ALS patients with 38 distinct nonmissense *SOD1* variants revealed a mean age of onset of 46.9 years and mean survival of 49 months.
• Significant heterogeneity in clinical outcomes was observed, with certain mutations correlating with earlier onset and reduced survival.
• Frameshift mutations located proximally to the N-terminus were associated with a higher risk of early ALS onset compared to distal mutations.

Conclusions:

• The clinical presentation of ALS in patients with nonmissense *SOD1* mutations is highly variable and mutation-specific.
• Diverse *SOD1* mutation carriers should be included in therapeutic trials to ensure broad efficacy.
• Findings suggest that both loss-of-function and gain-of-function mechanisms may underlie ALS pathogenesis in these patients.