Recurrent K3E mutation in Cu/Zn superoxide dismutase gene associated with amyotrophic lateral sclerosis

Cu/Zn superoxide dismutase (SOD1) gene mutations are the most frequently reported genetic causes of amyotrophic lateral sclerosis (ALS). The objective of the study was to describe a clinical phenotype and haplotype background of Polish and Japanese ALS patients harbouring the K3E SOD1 mutation. The K3E mutation was identified by direct sequencing, high resolution melting analysis or high-throughput microarray-based resequencing system. Microsatellite polymorphic markers flanking SOD1 were genotyped in members of six kindreds and two SALS patients. Results demonstrated that the K3E mutation was responsible for classic ALS. The median age of onset was 54 years. The clinical phenotype did not substantially differ between SALS and FALS cases of either ethnic origin, with some intrafamiliar variabilities. There was a limb onset in 92% of patients. In patients with bulbar syndrome, dysphagia predominated over dysarthria. Respiratory insufficiency was found in 61.1% of patients (19-84 months after the first symptoms onset). Median survival was 101 months with age of death ranging from 45 to 77 years. K3E was the most frequent SOD1 mutation among Polish FALS patients. It originated independently, on different haplotype background in the Polish and Japanese populations. In conclusion, recurrent K3E mutation results in a relatively slowly progressing limb onset ALS with classic phenotype.