Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a motor neuron disease in which the neurons responsible for controlling the voluntary muscle movements of body start to degenerate and ultimately die. This disease is progressive in nature and thus gradually worsens leading to difficulty in chewing, walking, talking etc. Motor neurons are those that extend from the brain to the spinal cord and spread throughout the muscles, initiating and communicating signals to and from the brain. The upper motor neurons in the brain transmit signals to the lower motor neurons present in the motor nuclei of brain and neurons of spinal cord. The same is applicable for the reverse case.

In ALS, the upper and lower motor neurons both stop functioning and degenerate thereby obstructing all communications to the muscles. Due to this, the muscles start to weaken, fasciculate and wither away. Although 90-95% ALS cases are sporadic, around 5-10% are attributed to have a genetic cause i.e. a mutated gene inherited from one or both parents.

The average life expectancy of a person suffering from ALS is said to be 2-4 years with some cases extending to more than 10 years. However the most shocking of them all was the story of the famous English theoretical physicist, cosmologist and author, Stephen Hawking CH CBE FRS FRSA who died on 14 March 2018 aged 76 years, nearly 6 decades longer than was predicted at the time of his diagnoses in 1963.

This disease is not restricted to a particular age group but is seen to largely affect people above the age of 60 in sporadic cases and 50 years in inherited cases. It is also observed to generally affect males rather than females. Furthermore, people belonging to Caucasian and non- Hispanic races are regarded as the most likely people to get affected by this disease. The disease was first historically described by Charles Bell in 1824. However the relation between the exhibited symptoms and its possible causes was made by Jean-Martin Charcot in 1874 who actually named this condition as amyotrophic lateral sclerosis. Till date there has been no definitive cure for this disease. However drugs like riluzole and non-invasive ventilation can be provided to extended life by 2-3 months and improve the quality of life respectively.   

CLASSIFICATION OF ALS

Not all cases of ALS are the same. Depending on where the symptoms first project, their inherited or sporadic behaviour and the progression rate, ALS has several categories.

  1. Classical ALS

Almost 70% of the cases encountered come under this category. Classical ALS can be further bifurcated into spinal-onset ALS and bulbar-onset ALS. Their survival rate is between 2-2.6 years.

  • Spinal-onset ALS: About 2/3rd of the cases observed, the patients first felt weakness in their limbs
  • Bulbar-onset ALS: The remaining 1/3rd cases suffered from weakened muscles of chewing, swallowing and speech.
  • Primary Lateral Sclerosis (PLA)

Unlike ALS, only the upper motor neurons are affected in this disease and it constituted 5% of the total ALS cases recorded. Although a definite diagnosis cannot be mad, its prognosis is much better than ALS. This condition progresses very slowly and thus its symptoms are less severe and complicated. However within 4 years of its onset, the chances of if transforming into amyotrophic lateral sclerosis are significantly higher.

  • Progressive Muscular Atrophy (PMA)

  It accounts for5% of total classical ALS and mainly affects the lower motor neurons. Its survival rate is generally higher although it does over time manifest in other regions and causes respiratory failure and death. Similar to PLA, PMA over time develops symptoms like ALS.

  • Regional variants of ALS

These diseases progress very slowly and are said to have a longer survival rate.

  • Flail arm syndrome: Also called as brachial amyotrophic diplegia is a disease in which lower motor neurons of the cervical spinal cord are damaged. Reflexive movements of the limbs is severely affected. 
  • Flail leg syndrome: Also called as the leg amyotrophic diplegia is a disease   which damages the lower motor neurons of the lumbosacral spinal cord causing the weakening of reflexes of the arms and legs.
  • Isolated bulbar ALS: This type affects either lower or upper motor neurons or both leading to speech. Swallowing and breathing problems.
  • Age dependent ALS

ALS can also be categorised based on the most likely age of onset of any of its type.

  • Adult-Onset: In this, the sporadic ALS is generally seen between 58-63 years while familial ALS (inherited) arises at 42-57 years.
  • Young-Onset: 10% of the total ALS cases are encountered in patients below the age of 45. Most of the time the affected individuals are males and the disease progresses extremely slowly.
  • Juvenile-Onset: It’s the rarest of all where only 1% of total cases get affected at before the age of 25. These cases of ALS are usually inherited by nature. Some genes that are associated with causing the juvenile ALS are ALS2, SETX, SPG11, FUS and SIGMAR1. The prognosis is generally difficult but the affected people are generally assumed to live longer than the adult onset ALS.
  • Respiratory Onset of ALS

Only about 3% of total ALS cases get afflicted with this type of disease. It is named so because of the initial symptoms of ALS which are dsypnea i.e. difficulty in breathing during exertion/at rest and orthopnea i.e. breathing difficulty while lying down. It is found to be common in males. Of all the possible variants of ALS, respiratory onset ALS has the worst prognosis with an average survival rate if 1.4 years.

CAUSES

Predominantly a definite cause of ALS doesn’t exist; but it is believed that certain genetic factors and consequence of small mutations that get accumulated over time and ultimately are triggered due to environmental influences are the plausible causes.

  1. Genetic Factors

An estimated 25 genes are considered responsible for causing ALS when they get5 mutated. Of these some like the C9ORF72, SOD1, FUS and TARDBP are the most commonly mutated genes and are responsible for causing inheritable ALS. ALS is a type of disorder that follows an oligogenic mode of inheritance i.e. it requires mutations in more than 2 genes to effectively cause ALS in an individual. The following includes a detailed analysis of the most commonly affected genes.

  • C9ORF72

This accounts for 40% of the total familial ALS cases till date. Discovered in 2011, mutations in the chromosome 9 at the Opening Reading Frame (thus the name C9ORF72) are responsible for causing 25-40% of familial ALS cases and about 7% of the sporadic ALS cases. It is a dominant mutation and is passed to every generation.

  • SOD1

Discovered in 1993, it was the very first gene to be associated to ALS when mutations in Cu/Zn Superoxide Dismutase (SOD1) was observed. It is also a dominant mutation causing 10-20% of total familial cases and about 1-2% of the sporadic ones. Although it is not clear how mutated SOD1 can lead to ALS, it is know that this is an enzyme frequently found to protect cells from toxic metabolic wastes. It is possible that mutated SOD1 causes aggregation and ultimately death of astrocytes.

  • TDP43

The link between TAR DNA binding protein 43 and ALS was established in 2008. It is a dominant mutation which causes 4% of familial ALS and about 1% of sporadic ALS. Under normal conditions, TDP43 protein binds with RNA and performs its function, but when mutated it gets aggregated in the cytoplasm of motor neurons. Since abnormal levels of TDP43 are found in every Amyotrophic lateral sclerosis affected individual, it’s believed TDP43 plays a major role in ALS variants.

  • UBQLN2

The Ubiquiline-2 gene is present on the X-chromosome which is responsible for clearing out degraded proteins within the cell. Thus in its mutated form, this function is disturbed and leads to accumulation of harmful material in the cell. This link was established in 2011. Men and women are equally affected.

  • Others

Some other important genes associated with ALS are KIF5A (Kinesin Family Member 5A), ALS2 (Alsin), SETX (Senataxin), ANG (Angiogenin), VLS (Valosin-containing protein) etc.

2. Environmental Factors

Even though genetic factors play a pivotal role in ALS, in most cases, the actual is unknown. Thus it is believed that certain influences from the environment are responsible in triggering early onset of ALS.

Some of most common triggers are:-

  • Chronic exposure to lead and other heavy metals
  • Chemical or electromagnetic exposure
  • Pesticides and organochlorine insecticides like aldrin, dieldrin, DDT and toxaphene.
  • Severe head/brain injury
  • Extreme strenuous sports like football or soccer is said to increase the risk of ALS by 4 times.
  • Possible risk by smoking

SYMPTOMS

The most common symptoms observed in all variants of ALS:-

  1. Fasciculation in the limbs and muscles of the mouth
  2. Cramps and stiffness of muscles
  3. Difficulty in speech, swallowing and hyperreflexia
  4. Difficulty in breathing and pneumonia
  5. Restriction in body movements

DIAGNOSIS & TREATMENT

Amyotrophic lateral sclerosis doesn’t have a definite cure or treatment. All the drugs and treatment options administered only downregulate the adverse symptoms displayed by the disease. The most common treatments provided to affected individuals are:-

  1. Riluzole– Decreases glutamate levels thus reducing neuronal damage. It is said to extend survival by 2-3 months especially in bulbar onset ALS.
  2. Edaravone– May possibly reduce oxidative stress of neurons. Its administration is uncomfortable and very expensive.
  3. Baclofen & Diazepam for muscle stiffness; Amitriptyline for swallowing problems.
  4. Non-invasive ventilation- for respiratory failure.
  5. Invasive ventilation- Possibly prolongs survival but is said decrease the quality of life.
  6. Therapy- For physical rejuvenation and speech improvement.
  7. Nutrition- Food rich in fibres, vitamin E and high calorific value are recommended.

Published by Allena Andress

||Bibliophile|| Biotechnologist|| Aspiring Forensic Science specialist|| Researcher|| Closet singer and dancer|| Motivational Speaker||

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