Bush has announced he will reduce the forces in Iraq by 8000 by early 2009. My first thought (after "that's it? I thought we were victorious"; and let's get all of them out now as fast as we can) was to wonder what condition they will be in and what's in store for them in the future? I thought about that particularly because of the emerging scientific literature on strange and rare diseases in Gulf region veterans. One of these diseases is Lou Gehrig's Disease (medical name, amyotrophic lateral sclerosis or ALS). ALS, while rare (about 1 - 2 cases per 100,000 population in the US each year), is not the only disease of its kind, but one of a group of diseases called motor neuron diseases (MNDs). The physicist Stephen Hawking has a MND but it isn't ALS, although it is frequently mistakenly identified as such. Unlike the disease Hawking has, ALS kills pretty fast, usually within 3 years of onset.
ALS, however, has been reported to be high in Gulf War I. veterans. One paper (Horner et al.) has made the further argument that the excess in Gulf War vets occurs specifically in the decade following service, but the paper is at best suggestive. The same research group (Duke and the University of Cincinnati) has just published a study of where the ALS cases were in the Gulf region and identified some areas of higher relative odds but have yet to tie any environmental factor to these locations that might account for it. This seems to be preliminary work and the methods are not well described so I don't know what to make of it.
Is it plausible that service in the first Gulf War (and by inference Iraq) could result in this deadly disease? It is the subject of intense scrutiny by the Department of Veterans Affairs (see, for example, this paper on a new ALS registry set up to study it) and new studies in veterans on interactions between genetic and environmental factors are underway. But ALS is one of the more mysterious diseases and whether it is plausible or not is hard to say since we know so little about it. Here's some of what we know.
ALS is a progressive degenerative disease of the neuromuscular system that begins with weakness and clumsiness and spreads to become a universal paralysis that kills within a few years by paralyzing the respiratory system. It rarely strikes before the age of 40 but after that increases with each decade of life. The basic components of your neuromuscular system are a long nerve cell from your brain down to your spinal cord (the upper motor neuron) that connects to another nerve cell (the lower motor neuron) that goes from your spinal cord to the muscle it makes move. Both the upper and lower motor neurons die off in ALS, beginning with the lower neuron. This leads to muscle weakness and other abnormalities related to the lost nerve connection (this is the amyotrophic part of the name of the disease); and as the nerve cells die off they are replaced by harder non-nerve cells in the outer (lateral) part of the spinal cord (lateral sclerosis, where sclerosis is a general term for "hardening").
Whites are slightly more affected than non-whites and males slightly more than females but in the US there seems to be no geographic pattern. Most cases of ALS are of unknown origin and appear random (they are called sporadic cases and constitute 90% of US cases. About 10% of cases in the US are clearly hereditary (called familial cases). While rare, however, the familial cases have been the subject of much study since it was discovered in 1993 that they were caused by a specific mutation in the superoxide dismutase I gene (SOD1). This has been a fruitful line of investigation but to date the results have been confusing (there is a news piece on recent results in Nature; subscription required, alas).
Is there any reason to suspect environmental or occupational factors? There is a Western Pacific variant of ALS-like MND, especially on the island of Guam, that has been associated with eating Cycads (Cycas circinalis), a seed plant used to make starch. The cycads contain an amino acid that overexcites nerve cells and in animals causes an ALS-like condition. But all sorts of toxins, including heavy metals like lead, have also been suggested as triggers for ALS. With so little known about the mechanism causing the motor neuron die off, we don't even know where to look.
So we will welcome home Iraq soldiers with relief and the hope the deadly peril of combat will not be replaced by the deadly peril of a fatal neurological disease.
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A slight correction, it is superoxide dismutase. That is the Cu,Zn enzyme that takes superoxide to H2O2 in two steps. What is very interesting about the mutant SOD1, is that there are over a hundred different mutations that are associated with the disease and it is a "gain in function", that is it is not the loss of the superoxide dismutase catalytic activity that causes pathology.
What that gain in function might be is unknown. I subscribe to the findings of Joan Mannick, where she found that mutant SOD1 did cleave NO from S-nitrosothiols and caused a reduction in S-nitrosothiols in cells containing the mutant protein.
http://www.pnas.org/content/103/7/2404
This might be sufficient to explain the long term degradation due to ATP depletion and reduced mitochondria biogenesis.
There doesn't seem to be much of a pattern in where the mutations that cause ALS show in the SOD1 molecule. They are all over the place, but do seem to destabilize it and render it more susceptible to being denatured. It is the apo protein (the protein without any Zn or Cu) that is most sensitive to being denatured. SOD1 is a protein with a high turn-over, that turn-over requires ATP to support. Mutations that decrease the stability of SOD1 increase metabolic load by increasing the requirement for protein synthesis and degradation.
SOD1 does seem to do other things, one thing it might do is be a trap for Cu ions which might be liberated from damaged proteins. Cu ions are very bad things to have around not bound up tightly in proteins because they are Fenton active metals, they catalyze the cleavage of H2O2 and generate a hydroxyl radical (which is so reactive it damages everything it touches and anti-oxidants are not effective against because everything is highly reactive with hydroxyl).
daedulus: Wow. I must really be losing it. I know quite well what it is and I must be the victim of some kind of automatic writing here or I must have been distracted while typing away. Anyway, thanks for catching it.
A soil bacteria that brings nitrogen to the cycad is now thought to be responsible for the neurotoxin involved in BMAA. Soil bacteria might be a good place to start looking for a cause.
http://en.wikipedia.org/wiki/BMAA
Food Chain of Evidence Points to Brain Toxin
Hampton
JAMA.2003; 290: 2788-2789.
Gulf war 1 soldiers were given preparatory anti-nerve gas treatment that bound nerve cell receptors. People have suggested that the combination of this plus the insecticides in insect repellents may have contributing to problems for gulf war 1 veterans.
The iraq invasion and ongoing forces in iraq (trying to keep the terms neutral) did not receive the nerve gas prophylaxis, so there has been less messing around with their nerves. I think this gives reason to hope that the increase in ALS will not occur in this group.
davidp: I am pretty familiar with the GW illness issue. The anti-nerve gas pills were really nerve agents themselves but it hasn't turned out that the problems are obviously related to their use. Unfortunately we don't have good dose information. Unbelievably, the quartermater corps doesn't even know how many tablets they shipped, had or dispensed and the soldiers are often not very clear on how many they took and when. Then there were oil well fires, actualy nerve gas exposure to some (the Khamisiyeh affair), leishmaniasis, pterolium spread in tents for dust suppression, etc., etc. The question isn't so much why are some of them sick as why aren't they all sick, as a colleague said to me.
ALS is a terrible disease. Some of my clinical colleagues are involved in their care. It's a disease the medics truly hate both for it's effects and the lack of treatment options.
Revere:
Whilst having quantified the background rate for ALS you didn't mention what the increased risk was? How big a problem is this proposed to be?