Abstract
Background A genetic cause for amyotrophic lateral sclerosis (ALS) is evident in 10–15% of patients. Mutations in superoxide dismutase 1 (SOD1) are the second most commonly implicated linkage, comprising 14% of genetic cases. More than 185 variants of SOD1 mutations have been identified, with few variants linked to a defined clinical phenotype. Of relevance, the antisense oligonucleotide (ASO) therapy tofersen is being trialled for SOD1 ALS patients, prompting discussion about which variants should be considered pathogenic.
Case Three patients living with rare SOD1 mutations, all with slow disease progression, are presented. Case 1 (49F): SOD1 mutation A-G, H43R has a 15 year history of disease with only bulbar symptoms and mild weakness of distal upper limbs. Case 2 (39M): SOD1 mutation Asn66Ser has an 11 year history of distal lower limb weakness, still able to mobilise with aids (AFO, SPS), with disease progression to distal upper limbs and no bulbar symptoms. Case 3 (61M): SOD1 mutation His49Arg has a 22 year history of disease, initially right lower limb onset ALS which has progressed to weakness of all limbs. He uses a mobility scooter though remains independent for transfers, with no bulbar symptoms.
Discussion The present case series highlights the complexities of 3 patients with rare SOD1 variants, unified by remarkably slow disease progression. In the context of focussed genetic therapies for ALS such as ASO, patients and clinicians need precise information about rare variants to project individual disease trajectory and thereby establish the optimal time to commence therapy.
