Pathophysiology of ALS

ALS is the most common neurodegenerative disease of motor neurons. As I've said in my previous posts, there is currently no known cause of ALS.

Disease Progression:  Most people diagnosed with ALS begin showing symptoms that involve movement of their limbs. It starts out as "clumsiness" or stumbling on their feet when they run, this progresses to "slapping gait," which is also known as foot drop. As for the arms, there is reduced dexterity and ability to do activities that involve fine detail and intricate handy work. Hands get cramped and stiff, and it eventually can affect work performance. Later, problems with the throat (which is a lot more debilitating and noticeable) progress to high risk of choking while eating, slurred speech and difficulty talking loudly. ALS patients can also have a hard time with their emotions, such as involuntary laughing or crying, and depression.

As the diseases advances, you see more ALS patients having spasticity, or involuntary tightening of their muscles, which can significantly impair the way they walk and their dexterity. Their muscles have atrophied significantly, and you can start to see it visibly. They also commonly get muscle cramps and contractures due to inability or difficulty moving their limbs.

There are many theories and studies that explore the cause of ALS. One of them suggests that excessive stimulation of glutamate receptors can cause the "excitotoxicity" that happens in ALS. Excitotoxicity is usually controlled by Sodium-dependent glutamate transporters that bind to glutamate and clear it out of the synaptic gap. The one medication that I talked about in my first post "riluzole" actually works through this pathway and gets rid of glutamate. Excitotoxicity causes the death of motor neurons in patients with ALS, and so by getting rid of glutamate (the agent that causes excitotoxicity), you can essentially slow down the progression of the disease.

As you can see in the image above, in a normal person, glutamate removal is regulated and there is not an excessive amount of it in the synaptic cleft (no excitotoxicity would be present here). In the image on the left, the person with ALS has a very excessive amount of glutamate in the synaptic cleft, and this is what causes the cell to have excitotoxicity, and cause death of a motor neuron.

Sources:

Medscape. (2014, May 2). Amyotrophic Lateral Sclerosis. Retrieved from Medscape: http://emedicine.medscape.com/article/1170097-overview

Image Source:

Youtube Video: "Amyotrophic Lateral Sclerosis"