Diseases and Disorders

The Pathology of Amyotrophic Lateral Sclerosis

Christian Gonzalez


Introduction

In 2014 an explosive internet trend was started that raised approximately $115 million for scientific research focused on curing a disease. Millions of people viewed celebrities such as Bill Gates and Mark Zuckerberg dumping numbingly cold buckets of water on their head and the reactions that followed. Through this simple act, public awareness of ALS surged and a great deal of vital funding for research was raised. Unfortunately, it is reasonably inferable that many who enjoyed the challenge watched without ever learning what ALS actually is. Moreover, although the ALS Ice Bucket Challenge reached such a vast crowd across the globe, it was likely not enough to spur a significant amount of progress toward ending one of the least understood of neurological conditions (Song, 2014).

 

    ALS is a rare neurodegenerative disease affecting about 450,000 people worldwide. The disease begins either spontaneously or occurs in a patient genetically, being passed on from an earlier generation. It is invariably fatal and progresses rapidly; every 90 minutes a patient will receive a diagnosis of ALS and most patients die just 2.5 years after the onset of their symptoms (with only 10% of patients surviving for 10 years).  Currently, there is no cure for the disease, and the cause remains unknown in 90-95% of patients (“ALS Frequently Asked Questions,” n.d.).

    The course of ALS is the result of neurodegeneration of two different types of motor neurons called upper motor neurons and lower motor neurons. Accordingly, ALS is also referred to as motor neuron disease in several countries (“Amyotrophic Lateral Sclerosis Fact Sheet,” n.d.). When damage occurs, the regular functionality of these nerve cells gets disrupted, which makes it difficult and eventually impossible for ALS patients to move most or all of their voluntary muscles. Typically, involuntary muscles remain healthy for much longer during ALS, which is why normal body functions such as breathing and digestion are less affected. Unfortunately, even involuntary movement eventually becomes greatly impaired and thus the most common cause of death in ALS is respiratory failure. Often times, when the disease progresses, the neurotransmitter glutamate is found at elevated levels within the brain and is believed to cause the excitotoxicity associated with certain types of further damage (Shaw & Ince, 1997).

 

Symptoms and Traits

    The symptoms of ALS vary widely and are dependent upon the stage of progression in which a patient is in. Moreover, symptoms are extremely dynamic within stages and vary from patient to patient. During the beginning of the disease, some of the most common symptoms include difficulty walking, clumsiness, weakness, fasciculations, and muscle cramps. As the disease progresses, breathing becomes difficult due to weakened muscles, and eventually patients will lose the ability to walk on their own and perform simple tasks. Speech becomes difficult to perform, and communication between patient and caretaker can sometimes be very tedious. Throughout the progression of ALS, patients typically experience muscle spasms and cramps, extreme fatigue, constipation, spasticity, depression, and excessive salivation. Shortness of breath and dysphagia (difficulty swallowing) are also commonly experienced before the eventual paralysis that results from the death of a large number of motor neurons over time (“ALS, Amyotrophic Lateral Sclerosis, Lou Gehrig’s disease,” n.d.).

 

Precursory Indicators

    With over 90% of all cases diagnosed without a known cause, the molecular origins of ALS are poorly understood. Only 5% patients have identifiable genetic histories with relatives affected by ALS. Although nine out of every ten patients suffer from sporadic ALS, there is currently no evidential correlation between a patient’s lifestyle and their probability of developing the disease. Factors that can often influence other diseases like Alzheimer’s, multiple sclerosis, and diabetes such as weight, geographic location or diet have not been linked to the onset or progression of the disease (“ALS, Amyotrophic Lateral Sclerosis, Lou Gehrig’s disease,” n.d.).

 

Genetic Factors

    There are many different genes involved in the development of familial ALS. Specifically, approximately 30-40% of familial ALS cases are the result of mutations in the gene C9orf72. Other genes such as FUS and TARDB account for one out of every twenty cases of ALS, and about one out of every five patients with familial ALS have mutations in the SOD1 gene. Gene mutations in ALS can result in the inability to break down toxic substances, which contributes to a buildup of toxins in neurons. As these toxins accumulate, motor neurons can be killed off, resulting in the array of symptoms in ALS. Alternatively, gene mutations directly disrupt axonal development, which can impair the functional transmission of muscle nerve impulses and cause atrophy (“Amyotrophic lateral sclerosis,” n.d.).

 

Diagnosis

    ALS is typically diagnosed with a variety of methods that are collectively referred to as the El Escorial criteria. The four identifying factors that this criteria looks for are degeneration of upper motor neurons, degeneration of lower motor neurons, absence of other explanations for symptoms, and progressive worsening of physical signs (“Criteria For the Diagnosis of ALS,” n.d.). Typically, the first step in reaching an accurate diagnosis involves a complete examination of family medical history. This is often done to rule out whether or not a patient might have familial ALS. Neurologists conduct simple evaluations of muscle and nerve health initially as well. MRI scans can also be used to diagnose patients based on changes in biomarkers. In order to differentiate ALS from other similar diseases in its earliest stages, tests such as electromyography (EMG) and nerve conduction studies can assess muscle health and peripheral nerve damage, which can also aid in the diagnosis of the disease. Even with these tests though, the main component in a diagnosis is symptoms (“Amyotrophic Lateral Sclerosis Fact Sheet,” n.d.).

 

Treatment

    While there is no cure available today, there are several drugs that can aid in slowing the progression of ALS and lessening the severity of the symptoms that many patients experience. The most common drug is riluzole. This drug can slow disease progression in certain patients by inhibiting the neurotransmitter glutamate. Additionally, the drug gabapentin can be used to lessen pain, and the drugs diazepam and baclofen are prescribed to control spasticity, or muscle stiffness (“ALS Treatment,” n.d.).

 

Advocacy and Awareness

    To get involved in the fight against ALS and assist in efforts that aim to develop novel treatments and eventually find cures for the disease, please contact the ALS Association and find out how you can help. If you want to help improve public awareness, sign up an Advocate today athttp://www.alsa.org/advocacy/get-involved/.

    ALS Association - http://www.alsa.org/

 

KEY TERMS

Neurodegeneration- The progressive destruction of the function and structure of neurons

Upper Motor Neurons - Nerve cells in the motor cortex involved in voluntary movement

Lower Motor Neurons - Motor neurons located in the brainstem and spinal nerve roots that play an important role in voluntary movement

Motor Neuron Diseases- Group of neurodegenerative diseases that destroy motor neurons

Glutamate - Main excitatory neurotransmitter in the human nervous system

Excitotoxicity- Process of neuron death by overstimulation of glutamate receptors

Fasciculations - Brief and spontaneous muscle contractions under skin visible by the human eye

Spasticity - Muscle stiffness

Dysphagia - Difficulty swallowing

C9orf72- Most common gene mutation associated with familial ALS

FUS- Gene mutated in 5% of familial ALS patients

TARDB- Gene mutated in 5% of familial ALS patients

SOD1 - Gene mutated in 20% of familial ALS patients

El Escorial criteria- Method for diagnosing ALS based on four main factors

Electromyography - Diagnostic method that assesses muscle health based on electrical activity

Riluzole - Glutamate blocker used to treat ALS

Gabapentin - ALS medication used to treat nerve pain

Diazepam - Benzodiazepine drug used to treat muscle spasms in ALS

Baclofen- Muscle relaxant used to treat muscle spasms in ALS


References


  1. Shaw, P. J., & Ince, P. G. (1997). Glutamate, excitotoxicity and amyotrophic lateral sclerosis. Journal of Neurology J Neurol, 244(S2), 3-14. doi:10.1007/bf03160574

  2. Song, P. (2014). The Ice Bucket Challenge: The public sector should get ready to promptly promote the sustained development of a system of medical care for and research into rare diseases. Intractable & Rare Diseases Research, 3(3), 94-96. Retrieved June 26, 2016.

  3. Criteria For the Diagnosis of ALS. (n.d.). Retrieved June 26, 2016, from http://www.alsa.org/als-care/resources/publications-videos/factsheets/criteria-for- diagnosis.html?referrer=https://www.google.com/

  4. Amyotrophic Lateral Sclerosis Fact Sheet. (n.d.). Retrieved June 26, 2016, from http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_ALS.

  5. Amyotrophic lateral sclerosis. (n.d.). Retrieved June 26, 2016, from https://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis#genes

  6. ALS Treatment. (n.d.). Retrieved June 26, 2016, from https://www.ucsfhealth.org/conditions/als/treatment.html

  7. ALS Frequently Asked Questions. (n.d.). Retrieved June 26, 2016, from http://www.alstdi.org/about-als-tdi/als-faq/

  8. ALS, Amyotrophic Lateral Sclerosis, Lou Gehrig's disease. (n.d.). Retrieved June 26, 2016, from http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/als/conditions/ als_amyotrophic_lateral_sclerosis.html

Christian Gonzalez

Christian Gonzalez


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