SOD1 – Amyotrophic Lateral Sclerosis

Cu/Zn superoxide dismutase 1 (SOD1) was the first gene linked to familial amyotrophic lateral sclerosis (ALS) and accounts for approximately 20% of autosomal dominant ALS cases. The initial discovery of the Leu38Val substitution in a large Belgian pedigree demonstrated reduced SOD1 activity in mutation carriers years before symptom onset ([PMID:8263541]). This finding established SOD1 mutation as a causative factor and introduced an assayable biochemical marker for FALS.

Extensive genetic screening has identified over 160 distinct SOD1 variants distributed across all five exons, including missense, frameshift, splice‐site, and truncating mutations ([PMID:28291249]). These variants occur in both familial and sporadic ALS, with some alleles exhibiting founder effects, such as the p.Ala90Val mutation in Finnish cohorts ([PMID:31086828]). Many variants co‐segregate with disease and alter enzymatic activity or protein stability.

Segregation analyses in diverse populations, including a German series of 217 families, confirmed clear co‐segregation in multiple pedigrees and identified recurrent mutations with defined genotype–phenotype correlations ([PMID:20309572]). Founder haplotypes and reduced penetrance have been documented, underscoring the importance of family studies for accurate risk assessment and genetic counseling.

Functional studies reveal that mutant SOD1 proteins acquire toxic gain‐of‐function properties. In vitro assays show impaired copper binding and enhanced peroxidase activity, while transgenic mice expressing SOD1^G37R or SOD1^G93A recapitulate human ALS with mitochondrial vacuolation, motor neuron loss, and progressive paralysis ([PMID:7605627]; [PMID:9547233]). These models support a dominant toxic mechanism rather than simple enzyme deficiency.

In contrast, rare homozygous truncating or frameshift SOD1 variants produce an infantile SOD1 deficiency syndrome characterized by early-onset spastic tetraplegia distinct from classical ALS, confirming that adult-onset dominant ALS arises from mutant‐specific toxicity ([PMID:36935613]).

Together, genetic and experimental data over >25 years substantiate a definitive SOD1–ALS association. SOD1 testing should be offered to all FALS patients and selected SALS cases, guiding prognosis, family counseling, and eligibility for SOD1‐targeted therapies.

Key take-home: Screening of SOD1 variants is a high-yield diagnostic approach in ALS and informs personalized therapeutic strategies.

References

• Journal of neurochemistry • 1994 • Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis. PMID:8263541
• Scientific reports • 2017 • Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review. PMID:28291249
• Journal of neurology • 2010 • The epidemiology of CuZn-SOD mutations in Germany: a study of 217 families. PMID:20309572
• Neurology. Genetics • 2019 • Oligogenic basis of sporadic ALS: The example of SOD1 p.Ala90Val mutation. PMID:31086828
• Neuron • 1995 • An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. PMID:7605627
• The Journal of neuroscience • 1998 • Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. PMID:9547233
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2023 • A novel homozygous loss-of-function variant in SOD1 causing progressive spastic tetraplegia and axial hypotonia. PMID:36935613

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