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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) [1].
1. What Is Amyotrophic Lateral Sclerosis?
2. Amyotrophic Lateral Sclerosis Name Origin
3. Type of Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) (UK), is a rare diseases of the nervous system, involving upper motor neurons (brain, brainstem, spinal cord) and lower motor neurons (cranial nerve nuclei, anterior horn cells of the spinal cord) as well as the trunk, limbs and head and face muscles. Amyotrophic lateral sclerosis is also known as Charcot disease (France). According to international classification of icd-10, the disease code for ALS is G12.2.
The term amyotrophic comes from the Greek root, meaning no nutrients to the muscles. It refers to the loss of signal that nerve cells pass to muscle cells. Lateral refers to one side, the location of spinal cord injury. Sclerosis means hardened and refers to the hardened nature of the spinal cord in advanced ALS. The disease, commonly known as Lou Gehrig's disease in the United States, is named after Lou Gehrig, a Yankee baseball player who was diagnosed with ALS at the Mayo Clinic in 1939.
According to clinical symptoms, it can be roughly divided into two types:
Limb Onset: The symptoms begin with progressive muscle atrophy, weakness, and finally respiratory failure.
Medullary Onset: There are already difficulties in swallowing and speaking when the movements of the limbs are still good, and soon progress to respiratory failure.
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 [2]. The pathogenesis is incompletely understood, but defects of RNA processing and protein clearance may be fundamental.
Figure 1 Pathogenesis of 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 [3], 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 [4], 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) [5] [6].
Rare mutations in TDP43 are also associated with ALS and FTD [7] [8]. In addition, there is a correlation between DNA methylation and ALS [9].
Environmental factors also play an important role in the pathogenesis of ALS [10]. 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:
Fortunately, ALS cannot be "infected" or transmitted from one person to another.
Clinical symptoms of ALS: muscle atrophy, muscle weakness, fasciculation, muscle spasm, and cognitive dysfunction [14].
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
| Stages | Muscle | Physiological effects |
|---|---|---|
| Early Stages | Weak, soft or stiff Tight and spasmodic Cramps and twitches Muscle atrophy |
Fatigue Imbalance Slurred speech Poor grip Tripping while walking |
| Middle Stages | Some muscles are paralyzed. | Muscle contracture The joints become stiff, painful and sometimes deformed Difficult to eat and control saliva Respiratory Insufficiency "Pseudobulbar affect" |
| Late Stages | Most voluntary muscles are paralyzed The muscles of the lungs are severely damaged |
Mobility is extremely limited Fatigue Foggy thinking Headaches susceptibility to pneumonia Can't talk, or eat and drink |
| At the End | / | Death due to respiratory failure |
Early symptoms of amyotrophic lateral sclerosis are mild, and some early symptoms include:
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
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:
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" [15]. Some ALS patients may develop painful neuropathy (neurological disease or injury).
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 [16] [17]. 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.
None of the tests provided the final diagnosis of ALS. The diagnosis of amyotrophic lateral sclerosis is based primarily on observed symptoms and detailed medical history, as well as a series of tests to exclude other similar diseases. However, the presence of upper motor neurons and lower motor neuron symptoms strongly suggests the presence of the disease.
Depending on the patient's symptoms, test results and examination results, doctors may require blood and urine samples to be tested to eliminate the possibility of other diseases.
Infectious diseases such as human immunodeficiency virus (HIV), human t-cell leukemia virus (HTLV), polio, and West Nile virus, as well as neurological diseases such as multiple sclerosis, post-polio syndrome, multifocal Motor neuropathy, spinal cord, and Kennedy's disease can also mimic certain characteristics of the disease.
No treatment has been found for ALS yet. However, there are some treatments that can help control symptoms, prevent unnecessary complications.
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 [18]. 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
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.
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.
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.
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).
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 [19].
Current clinical trials are based on two main transplantation strategies: system transplantation [20] and local transplantation [21]. Transplantation of mesenchymal stem cells into the spinal cord of ALS patients has been described, and the authors report that this method is safe [22].
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.
It is well known that the RNA binding protein TDP-43 is closely related to neurodegenerative diseases. However, the underlying mechanisms remain unresolved. Researchers have explored these mechanisms and found that TDP-43 enhances the translation of specific mRNAs associated with neurodegenerative diseases [23].
Potential treatments for ALS are being studied in a range of disease models (fruit flies, zebrafish, and rodents). Inhibition of the expression of a mutated gene is a potential therapeutic approach. The artificial microRNA (miRNA) targeting SOD1 was used to study the silencing of SOD1. The results support that artificial miRNA gene therapy targeting SOD1 is safe and worthy of further development for the treatment of mutant SOD1-related ALS.
For more information on ALS, you can also follow these sites:
References
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