The etiology of amyotrophic lateral sclerosis (ALS) is unknown. The presence of 
mutations in the superoxide dismutase gene (SOD1) has led to theories regarding 
a role for oxidative stress in the pathogenesis of this disease. A primary cause 
of oxidative stress is perturbations in cellular iron homeostasis. Cellular iron 
mismanagement and oxidative stress are associated with a number of 
neurodegenerative diseases. One mechanism by which cells fail to properly 
regulate their iron status is through a mutation in the Hfe gene. Mutations in 
the Hfe gene are associated with the iron overload disease, hemochromatosis. In 
the current study, 31% of patients with sporadic ALS carried a mutation in the 
Hfe gene, compared to only 14% of patients without identifiable neuromuscular 
disease, or with neuromuscular diseases other than ALS (p<0.005). To determine 
the cellular consequences of carrying an Hfe mutation, a human neuronal cell 
line was transfected with genes carrying the Hfe mutation. The presence of the 
Hfe mutation disrupted expression of tubulin and actin at the protein levels 
potentially consistent with the disruption of axonal transport seen in ALS and 
was also associated with a decrease in CuZnSOD1 expression. These data provide 
compelling evidence for a role for the Hfe mutation in etiopathogenesis of ALS 
and warrant further investigation.