Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, inevitably fatal neurological disease that attacks nerve cells responsible for the voluntary muscles. It is characterized by rapid degeneration and selective death of cerebral cortex, brainstem and spinal motor neurons (MNs) .
4. What Causes ALS?
Currently, it is believed that the mechanisms related to ALS may be caused by glutamate excitability, free radical production, cytoplasmic protein aggregation, complex interactions of SOD1 enzyme, mitochondrial dysfunction, and destruction of axon transport process by accumulation of intracellular neurofilament aggregates. Mutations of TARDBP and FUS lead to the formation of intracellular aggregates that are harmful to neurons. In addition, it was also found that the influence of astrocytes and microglia on the motor neuron microenvironment is also one of the causes of ALS . The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental.
Figure 1 Pathogenesis of amyotrophic lateral sclerosis
4.2 Factors Affecting Amyotrophic Lateral Sclerosis
The cause of amyotrophic lateral sclerosis is still unknown. It may be related to heredity and genetic defects. In addition, some environmental factors, such as heavy metal poisoning, may cause damage.
There are 5% of patients with amyotrophic lateral sclerosis who have a family history , which is characterized by Mendelian inheritance. To date, 13 genes and loci that mainly affect amyotrophic lateral sclerosis have been identified. Among the known genes，typical genes are SOD1 , TARDBP, FUS, ANG and OPTN.
The hexanucleotide GGGGCC repeat amplification of the open reading frame 72 gene (C9orf72) on chromosome 9 is the most common genetic cause of known ALS, accounting for 30% to 40% of familial ALS, and can also cause frontotemporal dementia ( FTD)  .
Rare mutations in TDP43 are also associated with ALS and FTD  . In addition, there is a correlation between DNA methylation and ALS .
Environmental factors also play an important role in the pathogenesis of ALS . Possible influencing factors: exposure to toxic or infectious pathogens, viruses, physical trauma, diet, behaviour and occupational factors.
Toxic substances: heavy metal poisoning such as lead (Pb) and manganese (Mn).
Excitations of excitotoxicaminoacids and freeradicals resulted in the death of motor neurons.
For example, the researchers suggest that exposure to lead, pesticides, and other environmental toxins during war or intense physical activity may be the cause of increased risk of amyotrophic lateral sclerosis in some veterans and athletes.
As a complex disease, both genetic and environmental factors play an important role in the occurrence and development of ALS.
Amyotrophic lateral sclerosis is also associated with several potential risk factors:
- Age: Although it also occur in young people, even children, and very old people. Amyotrophic lateral sclerosis has a peak onset age of 50 to 75 years old , with sporadic disease of 58 to 63 years old, and familial disease of 47 to 52 years old, and the incidence is rapidly decreasing after age 80 .
- Gender: Men are slightly more likely to have ALS than women. Studies have shown that, overall, the ratio of men to women with the disease is about 1.2.
- Race and ethnicity: The most likely to get this disease is Caucasian and non-Hispanic. Research shows the incidence of ALS may be lower among African, Asian, and Hispanic ethnicities than among whites .
Fortunately, ALS cannot be "infected" or transmitted from one person to another.
5. Symptoms of Amyotrophic Lateral Sclerosis
Clinical symptoms of ALS: muscle atrophy, muscle weakness, fasciculation, muscle spasm, and cognitive dysfunction .
5.1 Stages of Amyotrophic Lateral Sclerosis
In amyotrophic lateral sclerosis, both upper and lower motor neurons degenerate or die leading to muscle atrophy. Gradually, all muscles under autonomous control are affected, and individuals lose power and the ability to speak, eat, move, and even breathe. According to its progress, it can be divided into several stages: Early Stages, Middle Stages, Late Stages, At the End.
Table 1 Stages of ALS
||Weak, soft or stiff
Tight and spasmodic
Cramps and twitches
Tripping while walking
||Some muscles are paralyzed.
The joints become stiff, painful and sometimes deformed
Difficult to eat and control saliva
||Most voluntary muscles are paralyzed
The muscles of the lungs are severely damaged
|Mobility is extremely limited
susceptibility to pneumonia
Can't talk, or eat and drink
|At the End
||Death due to respiratory failure
5.2 Early Symptoms of Amyotrophic Lateral Sclerosis
Early symptoms of amyotrophic lateral sclerosis are mild, and some early symptoms include:
- Fasciculations (muscle twitches) in the arm, leg, shoulder, or tongue.
- Muscle spasm.
- Muscle stiffness.
- Muscle weakness affects the arms, legs, neck or diaphragm.
- Speech is vague, with nasal sounds.
- It is difficult to chew or swallow.
When symptoms begin in the arms or legs, it is called amyotrophic lateral sclerosis. When symptoms begin with speech or swallowing problems, they are known as bulbous amyotrophic lateral sclerosis.
Figure 2 Upper and lower neurons associated with ALS
Figure 3 Differences between normal and ALS patients in muscle
5.3 Advanced Symptoms of Amyotrophic Lateral Sclerosis
In the late amyotrophic lateral sclerosis (ALS) stage, most of the voluntary muscle paralysis. Involuntary muscles in patients with amyotrophic lateral sclerosis, such as muscles that control heartbeat, gastrointestinal tract, intestines, bladder, and sexual function, are not directly affected. Feelings such as sight, hearing and touch are also unaffected.
As the disease progresses, individuals may have the following symptoms:
- Mobile problem.
- Dysphagia: Dysphagia causes ALS patients to lose weight quickly and may be malnourished.
- It is difficult to speak or build words.
- Difficulty breathing: Breathing in patients with amyotrophic lateral sclerosis is difficult due to weakened muscles in the respiratory system. They will eventually lose their ability to breathe and must rely on a ventilator. Infected individuals have an increased risk of pneumonia at late-stage.
Some patients with amyotrophic lateral sclerosis may experience involuntary laughter or crying that is unrelated to their emotional state. This symptom is called "pseudobulbar affect" . Some ALS patients may develop painful neuropathy (neurological disease or injury).
5.4 What Is The Life Expectancy of Someone with ALS?
Respiratory failure related to muscle strength decline is the main cause of death of ALS patients. Without assistive techniques such as mechanical ventilation and feeding tubes, the average life expectancy after ALS diagnosis is 3 to 5 years  . However, about 4% to 10% of patients can live for 10 years, and some can live for decades, such as the British physicist Stephen Hawking.
7. Treatment of Amyotrophic Lateral Sclerosis
No treatment has been found for ALS yet. However, there are some treatments that can help control symptoms, prevent unnecessary complications.
7.1 Medical Treatement
Riluzole-The first drug to treat this disease, is thought to reduce motor neuron damage by reducing the release of glutamate. However, this drug only slightly delays disease progression . Another drug, Edaravone, an intravenous drug used to treat ALS, was first approved for treatment of cerebrovascular accidents in Japan in 2001 and received FDA approval in May 2017.
Figure 4 The mechanism of Riluzole
7.2 Physical Therapy
Physical therapy and special equipment can improve individual independence and safety throughout the ALS process.
Mild, low-intensity aerobic exercises, such as walking, swimming, and stationary bicycles, can enhance unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Occupational therapists can recommend the use of ramps, harnesses, walkers and wheelchairs to help individuals save energy and stay active.
7.3 Speech Therapy
Speech therapists can teach patients with amyotrophic lateral sclerosis (ALS) how they speak louder and more clearly. Some auxiliary tools, such as computer speech synthesizers using eye tracking technology, voice banking, can help people communicate.
7.4 Nutritional Support
Nutritional support is an important part of caring for ALS patients. Losing weight can make people with amyotrophic lateral sclerosis worse. When an individual is unable to get enough nutrients from the diet, the doctor may recommend inserting the feeding tube into the stomach.
7.5 Respiratory Support
Respiratory failure associated with decreased muscle strength is the leading cause of death in ALS patients. Therefore, monitoring respiratory status is critical for the treatment of ALS. Pulmonary function tests (PFTs) were used to determine when to start non-invasive ventilation (NIV).
7.6 Future Treatment
Stem cell transplantation is a potential therapeutic strategy that is not only based on cell replacement, but alters the environment of extracellular motor neurons through nutrition and neuroprotection .
Current clinical trials are based on two main transplantation strategies: system transplantation  and local transplantation . Transplantation of mesenchymal stem cells into the spinal cord of ALS patients has been described, and the authors report that this method is safe .
Biomarkers are biological measures that help determine the presence or progression of a disease or the effectiveness of therapeutic interventions. Since ALS is difficult to diagnose, biomarkers may help clinicians diagnose ALS sooner and faster. In addition, biomarkers are needed to help predict and accurately measure disease progression.
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