Biology 202
2000 Second Web Report
On Serendip

Amyotrophic Lateral Sclerosis (ALS), discovered by Ran in 1850 and named by neurologist Jean-Martin Charcot in the 1870s (for this reason, it is also called Maladie de Charcot, means (a )->"absence of"(myo) ->"muscle" (trophic)-> "nourishment"+ (lateral) ->"on the side" (sclerosis)-> "hardening." Basically, a wasting away of the nerve cells in the spinal cord, brain, and motor cortex that enervate the muscles(1)(2)(6). When the muscles stop receiving messages from the nerve cells, they get weak and die from lack of use(3) (8). With a prevalence (the number of existing cases) of about 6 people out of every 100,000, it has an incidence per year (the number of new cases) of 2 per 100,000 people. That's about 120,000 people in the world (or 328 per day). And, in the US ... 5000 new cases per year or 15 per day (4)(7)(8). Interestingly, the rate of incidence is higher in Guam, western New Guinea, and the Kii peninsula of Japan (6)(7). The degeneration of anterior horn cells (motor neurons with cell bodies in the anterior horn of the spinal cord) associated with ALS is, for a time, compensated for by neighboring anterior horn cells but, eventually (in two to five years) ends in total paralysis (2)(3)(4)7)(8).
The disease, probably most commonly associated with prematurely ending the career of baseball great Lou Gehrig in the late 1930s, usually presents itself after the age of 40 (in most cases, it's in the mid-fifties) and is always fatal, although a small percentage of people (physicist Stephen Hawking, for example) manage to live beyond the usual 2 to 5 years (2)(6). While it occurs in all races, the ratio of men to women (until age 60 when it evens out) is 2:1 (6)(7).

Features of ALS-
ALS affects both types of nerve cells that control voluntary movement: the upper and lower motor neurons. UMNs are located in the brain's cortex and act on the lower motor neurons found in the brainstem and the spinal cord (LMNs then enervate specific muscles) (1)(2). When these neurons die, most people (68%) first experience weakness in the limbs (this is known as "limb-onset" ALS). A quarter of patients first have trouble speaking or swallowing (called "bulbar ALS" because it relates to the corticobulbar region of the brainstem). And seven percent start out with dyspnea (trouble breathing). Soon, difficulty in one area progresses to others-- resulting in trouble writing, speaking, swallowing, and a decreased lung capacity (8)(7)(6)(2). However, none of the muscles involved in eye movement, bladder and bowel control, or, really, any under involuntary control are affected.
As ALS also does not affect the mind or senses, those afflicted with this disease have the same mind but are trapped in non-functioning bodies. Perhaps the best proof of this is Stephen Hawking who, diagnosed with ALS at the age of 21 and living with ALS for over 30 years, has managed to contribute an immense amount to the field of astrophysics in spite of his condition(3)(6)(9).

Types and Causes-
There are two main types of ALS, familial and sporadic. Familial is the rarer of the two, accounting for only 10% of all cases. It is inherited as an autosomal dominant trait in these instances. 20% of these cases (or 2% of all cases) are due to a mutation (on chromosome 21) of the cytosolic enzyme copper/zinc superoxide dismutase (SOD1). This mutation causes a change in the free radicals that results in destruction of motor neurons. The location of the gene(s) responsible for the other 80% of familial ALS remain(s), as of yet, undiscovered (5)(6)(7).

Sporadic ALS is the predominant form for which no definitive explanation has been found. A number of theories do exist and it is suspected that several factors in combination are responsible.
First of all, people who develop sporadic ALS probably have "susceptibility genes." That is, a study has shown that certain people with no history of the disease in their families share a common mutation. This mutation codes for a protein that is a part of the heavy neurofilament subunit in neurons.

The other major theories involve excitotoxicity, free radical damage, autoimmunity, and trophic factors.
Excitotoxicity studies suggest that high concentrations of the amino acid glutamate causes cell death. Experiments have shown that tissue removed from the spinal cords of ALS victims is not able to take up glutamate. This implies that the level of glutamate might be elevated due to the inability of the tissue to take it up. It has been hypothesized that a defect in the glutamate hydrogenase causes glutamate levels to be low intracellularly and high extracellularly. A subsequent study demonstrated that only ALS patients have defective glutamate transporters and these transporters are only defective in the motor area. Also, in Guam, where incidence of ALS is especially high, the commonly consumed cycad nut was found to contain beta-N-methylamino-L-alanine, another excitotoxic amino acid. BMAA produces ALS-like symptoms in primates. While it is not clear whether glutamate causes ALS, it likely does play a role in neuronal damage(5)(6).
Free radicals may also be responsible for cell damage since elevated levels of altered (nitrated or carbonylated) proteins are found in the spinal cords of sporadic ALS patients. Also, looking at their motor terminals, changes in the mitochondria (associated with free radical production) can be seen(5)(6).
Autoimmunity is another factor to consider as ALS patients have a high incidence of autoimmune disorders, as well. In an animal model for the destruction of motor neurons, guinea pigs injected with motor neurons from cow spinal cords produce the IgG antibody. When IgG is given to mice, it causes a change in motor neurons. Then, more calcium enters and destroys the motor neurons (7)(6)).
Finally, neurotrophic factors, protein nutritive hormones that govern motor neuron growth and maintenance, may function in the ability of motor neurons to repair themselves. Therefore, they may be an element in the cause of ALS (7)(6).

Treatment-
The only drug currently approved by the FDA is Riluzole, a glutamate release inhibitor that can cross the blood-brain barrier. It has been shown to extend lives of ALS patients by decreasing motor neuron cell death induced by glutamate(7)(6).
Neurotrophic drugs have also been tested with the hope that they might be capable of bolstering the survival of motor neurons. Unfortunately, they have been mostly ineffective as they do not cross the blood-brain barrier in sufficient enough concentrations(7)(5).
Known anti-oxidants (for example, vitamin E and n-acetyl cysteine) have also been tested to see if they can fill the role of the missing anti-oxidant product of the SOD gene.
At present, a combination of drugs, physical therapy, and counseling seems to be the best means of slowing down the progress of this disease(5).

After this brief exploration of some of the likely causes of and possible treatments for Amyotrophic Lateral Sclerosis, it is important once again to consider the people who are suffering from (or have lost the fight against) this debilitating disease. While ALS patients are said not to suffer much physical pain, the mental pain must be immense. My own interest in learning more was the result of knowing someone with this disease, Fred Bowen, one of the captains of the Manhattan Beach Fire Department where I worked as a volunteer for a few years in high school and college. While I did not see him after his diagnosis, I was aware of his intelligence from the conversations I'd had with him during my many hours at the fire department. With this in mind, I cannot imagine how frustrating it must have been for him to gradually lose the use of the majority of his body with his mind still very intact. Although a person with the highest degree of physical fitness like Lou Gehrig, a firefighter's training was not defense enough against this disease. In this case, the old question of "Is the brain equal to behavior? seems to be answerable with a "Yes." A person with ALS remains the same person, located in the brain, even when the body no longer functions. The person can still think about lifting up an arm even if the muscles cannot do it. And that person can still function on a normal intellctual level. We just need to find a way to stop this degeneration of motor neurons.

WWW Sources

2)New England Medical Center, This is the page from the Munsat ALS clinic with a description of the disease

3)ALS Society of Canada, This site has answers to some FAQs about ALS

4)International Alliance of ALS/MND Associations, This site describes ALS and gives some statistical information

5)World Federation of Neurology, ALS,This is an article on the possible causes and treatment

6)ALS Clinic, This is a site at Baylor College of Medicine with a description, causes, etc

7)Amyotrophic Lateral Sclerosis, This is a page at Yale medical school with information on diagnosis, treatment...

8)ALS Survival Guide, What is ALS? and 41 other FAQs

9)Stephen Hawking's Page, Stephen Hawking talks about his life with ALS

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