There is significant phenotypic heterogeneity in relation to the site of first symptoms, the relative balance of UMN and LMN signs, the extent of cognitive and behavioural involvement, and rate of clinical progression.3 Despite this clinical variation and strong evidence for multiple upstream biological pathways underpinning disease risk and progression, the vast majority of ALS cases are defined by a common histopathological signature of neuronal and glial cytoplasmic aggregates of phosphorylated transactive response DNA binding protein (TDP-43).4,5. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.