A novel p.N66T mutation in exon 3 of the SOD1 gene: report of two families of ALS patients with early cognitive impairment

Introduction: To date more than 180 different mutations in the SOD1 gene have been described in ALS; some of these mutations are associated to peculiar clinical features and have contributed to the understanding of disease heterogeneity. Only 5% of SOD1 mutations involve exon 3. Here we report a novel mutation c.197A > C in the exon 3 of the SOD1 gene in two apparently unrelated ALS families with early respiratory and cognitive impairment. Case report: In the first family two brothers developed ALS in their seventies, with arm weakness followed by bulbar involvement and behavioral breakdown. An unrelated 57-year-old man presented with progressive leg weakness and mild compromised executive functions without known family history for ALS/FTD and underwent invasive ventilation in a few months. A novel missense mutation A to C at codon 197 in exon 3 causing aminoacid substitution of arginine by threonine (N66T) was found for all of them. Harmful consequences of c.197A > C mutation on SOD1 function were suggested by in silico prediction and homology with other known mutations at the same position. Discussion and conclusion: Here, we report two apparently unrelated ALS families carrying a novel SOD1 mutation (N66T), supporting its pathogenic role by primary analysis, and characterized by early bulbar, respiratory, and cognitive involvement. Early cognitive impairment has been rarely described in ALS caused by SOD1 mutations, and mainly in the later phases of the disease. This report provides additional data on the SOD1 mutation spectrum and clinical presentation of ALS, widening phenotypical characterization of SOD1 ALS.