Important genetic risk factor for amyotrophic lateral sclerosis

Dec 6 2004

Two Hershey, Pa., researchers were part of a team that has uncovered what may be an important genetic risk factor for amyotrophic lateral sclerosis (ALS).

MDA grantee James Connor, professor of neurosurgery at Pennsylvania State College of Medicine, and Zachary Simmons, professor of neurology at Penn State and director of the MDA clinic at Hershey Medical Center, found that a defect in a gene on chromosome 6 known as Hfe is a likely risk factor for ALS. Connor, Simmons and colleagues published their results online Sept. 18 in the Journal of the Neurological Sciences.

While defects in the Hfe gene have previously been associated with the iron overload disease hemochromatosis and with Alzheimer’s disease, this is the first connection made with ALS.

The protein normally made by the Hfe gene is thought to limit the uptake of iron by cells, to protect against oxidative stress and possibly to dampen inflammatory reactions. (Oxidative stress is a common form of cellular damage caused by electrically charged oxygen compounds, and is strongly associated with ALS.)

Mutations in the Hfe gene are associated with increased cellular iron uptake, more oxidative stress and possibly with an altered inflammatory response.

The researchers studied 121 people with ALS and found that a particular mutation in the Hfe gene was more than twice as likely to occur in the ALS-affected group than in a control group. In the ALS group, 30.6 percent of the subjects carried the mutation, compared to 14.3 percent of those in the group without ALS.

The researchers then studied the effects of the Hfe mutation on nerve cells. They found it resulted in decreases in three proteins: beta-actin, which forms part of the cellular scaffolding; alpha-tubulin, which contributes to the formation of microtubules used for transport of substances in the cell; and superoxide dismutase 1, or SOD1, which is needed to detoxify molecules that contribute to oxidative stress. All these protein deficiencies are consistent with the types of changes in nerve cells that occur in ALS.

The authors say they don’t believe an Hfe mutation is sufficient to cause ALS by itself, but that it could be a contributing factor in disease causation in at least some cases.

They also say that “those patients with ALS who possess the Hfe mutation may differ from those without the mutation in their response to antioxidant therapy, and may respond to therapies that reduce iron intake or increase iron elimination.”