Furthermore, we speculate that due to these modest in vitro effects observed with the A90V variant, carriers might not develop a disease phenotype in the absence of a “second hit.” However, it is possible that the A90V mutant could lower the threshold required for an additional stressor or other genetic risk factor to cause the catastrophic effects on TDP-43 and its functions observed in ALS and FTD. The gene discussed is TARDBP; the disease is frontotemporal dementia.