brain

Amyotrophic Lateral Sclerosis (Nicolas, 2019)

Is ALS genetic? A study by Nicolas et al. 2019 shows a link between ALS and the gene KIF5A. This study used a combination of GWAS and rare variant burden analysis to analyze over 125,000 samples.

STUDY TITLE: Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

SUMMARY: Discovery of genetic variants in the KIF5A gene that are associated with amyotrophic lateral sclerosis (ALS).

OVERVIEW:  Amyotrophic lateral sclerosis, or ALS, is a progressive degeneration of nerve cells that control muscle movements which results in worsening weakness. ALS patients lose the ability to walk, use their hands, speak, swallow, and eventually breathe. This study analyzed the genomes of over 20,000 ALS patients of European ancestry and discovered a novel ALS-associated gene. The KIF5A gene encodes a protein that functions as a motor that helps transport cargo within cells. In nerve cells, motor proteins like KIF5A play an important role in transport along nerve fibers. Nerve cells that control movements have particularly long nerve fibers that might be particularly susceptible to disruption of cellular transport.

DID YOU KNOW? Smoking and exposure to environmental toxins (e.g. lead) might trigger ALS. Early signs of ALS include chronic muscle cramps, twitches, weakness in the hands and feet, and a loss of balance. [SOURCE]

SAMPLE RESULTS: Learn more about the Nebula Research Library.

ALS sample results

ALS-ASSOCIATED VARIANTS: rs3849943, rs12973192, rs75087725, rs142321490, rs113247976, rs116900480, rs74654358, rs118082508, rs117027576, rs10463311

ADDITIONAL RESOURCES:
ALS
Motor proteins (Video)

WEEKLY UPDATE: October 27, 2020

More about ALS

ice bucket challenge to raise awareness for ALS

Figure: Did you know that the 2014 Ice bucket challenge was aimed at raising awareness towards ALS?

Introduction

Amyotrophic lateral sclerosis (ALS) is a rare degenerative disease of the nervous system. ALS adversely affects the motor neurons. Hence, any activity that requires the use of voluntary muscles, like walking, talking or chewing, gradually weakens over time in this disease. This disease is incurable but its progress can be slowed down.

History of ALS

In 1869, neurologist Jean-Martin Charcot first diagnosed a case of ALS. During the period of 1865-69, Charcot and Joffroy investigated the mechanisms involved with progressive chronic paralysis.  

Current research scenario: ALS & its genetic component

A number of organisations are working towards understanding ALS at the fundamental, preclinical, clinical, and translational level.

ALS is also known as  Lou Gehrig’s Disease? Lou Gehrig was a New York Yankees baseball player and had to retire after being diagnosed with ALS. Gehrig’s fate made the rare disease known to a large public for the first time. The famous Ice Bucket Challenge from 2014 was instrumental in raising funds towards ALS research [Information source: ALS Association: Ice Bucket Challenge].

From investigating the basics of ALS, characterizing several components like physiological factors or genetic factors, to looking for potential treatment approaches – these ALS related research are in progress, as of the year 2020. 

And you can have a detailed information of ALS research from the websites below:

ALS TDI: Research

ALS Association: Funded work

CDC: Grants and research

Forms of ALS

Primarily there are three main forms of ALS. 

Sporadic ALS: This type of ALS occurs randomly without any probable cause. A majority of the ALS cases are sporadic.

Familial ALS: In the US familial ALS is seen in a minority of the cases, where people inherit ALS from a family member. 

Guamanian ALS: Guamanian ALS has been observed in the population of Guam where the cause is the consumption of false sago palm, Cycas micronesia.

Pathophysiology of ALS

In ALS, both the upper and lower motor neurons are affected.  The upper motor neurons occupy the brain while the lower motor neurons are in the spinal cord. According to the website of ALS Pathways, ALS usually spreads from a focal point thereby disrupting all the motor neurons in the body.  And multiple factors are responsible for this type of neurodegenerative disease. 

The degeneration of the upper motor neurons leads to increased muscle tone or spastic paralysis. While the damage of the lower motor neuron leads to an increase in muscle weakness. This interferes with the proper functioning of daily activity.

motor neuron
Figure. An illustration of the upper and lower motor neurons: the key components affected by ALS. Image source: Rcchang16, Wikimedia Commons, CC BY-SA 4.0

Prevalence and incidence: ALS and its genetics

As of 2014, CDC has reported 16,000 cases of ALS in the United States. An exact record regarding its very recent statistics is not much known. In the US, about 5-7 cases exist for every population of 1,00,000. It is in the age range of 55-75 years, that the disease is finally diagnosed. However, it’s worth noting that ALS rarely affects younger patients between 25 and 35 years of age. ALS is more common in men than in women (the gender ratio is about 1.5:1).

Factors responsible for ALS

Studies strongly support genetic factors linked to ALS. However, studies implying the role of some of the environmental factors are not very consistent.

Genetic background 

In a majority of cases, the exact cause of ALS is not known. But in the rest of the small cohort (5-10%), genetic factors may explain ALS. Other factors such as family history, gender, geography, etc. might also have associations with ALS.

Disease incidence in the US population, in population from various countries of Europe as well as from those of Asia differs. This suggests that population background apparently impacts the disease incidence.

Genetic variants associated with ALS

A number of genetic variants are closely linked to ALS. 

Specific gene mutations linked with ALS lead to the pathological accumulation or premature degradation of misfolded proteins which ultimately triggers neurodegeneration.

Major genetic components in ALS

SOD1

The SOD1 gene codes for an enzyme known as superoxide dismutase. This enzyme plays an important role in the anti-defense mechanism. The misfolded variants of SOD1 proteins lead to ALS progression.

TARDBP

This gene encodes TDP-43, a protein that regulates gene expression. TDP-43 is crucial to various stages of RNA processing. Some dominant genetic mutations in TARDBP results in faulty TDP-43, thereby causing neurodegeneration in ALS. Hence, changes in the distribution and functions of this protein have a strong association with ALS. 

FUS

The FUS gene expresses the FUS protein which is a type of RNA binding protein. Some of its functions are similar to those of the TDP-43 protein. Therefore, the FUS protein monitors a number of processes in RNA metabolism. In ALS, pathogenic variants of this gene sometimes cause improper folding and distribution of the FUS protein, thereby interfering with the normal cellular physiology.  

C9ORF72

Although the exact role of this gene is not yet clear, few reports have indicated its involvement in protein transport especially in the form of endosomal activity and autophagy. And a decreased expression of C9ORF72 might be associated with ALS, as noted in a few animal studies. However, this downregulation alone does not result in ALS, but in fact, works in a complex of a few other proteins. 

Minor genetic components of ALS

Few other genetic modifiers in ALS are ATXN1, ATXN2, UNC13A. Mutations in these genes likely make people susceptible to ALS. But they do not strongly correlate with this disease.

Nongenetic component of ALS

Occupational risk factor

A number of reports have proposed that professional athletes most likely develop ALS. And this could be mainly due to severe head injuries or intense physical activities.

Other examples of workplace exposure are cases where people are exposed to magnetic fields or strenuous physical work. However, such studies are association based, not consistent, and with unknown etiology. 

Toxic chemicals

The results of a study at the University of Michigan in Ann Arbor (May 2016) confirmed the long-standing suspicion that exposure to environmental toxins may increase the risk of developing ALS. In this study, the researchers observed a significant association between ALS and the presence of chlorinated hydrocarbons, polychlorinated biphenyls and polybrominated biphenyls. 

Beta methylamino L-alanine (BMAA)

BMAA is a neurotoxin associated with ALS. An indigenous population living in Guam has been reportedly at a heightened risk of having ALS. The diet of this population is rich in BMAA. Generally, cyanobacteria in the Pacific islands water produce BMAA. And given that the people of Guam depend on seafood, this may put the population at risk of developing ALS. 

Microbiome

The gut microbiome often influences the disease outcome, as reported in animal studies. Gut microbiome studies in mice have demonstrated that there is an important link between some of the bacterial strains and ALS. Moreover, in this study, a strain of Akkermansia muciniphila tends to slow down the progress of ALS in mice. Another 2020 study in mice has reported that gut microbial communities influence the survival outcome with ALS. This was especially noted, because the ALS-susceptible mice, despite having similar genetic backgrounds, showed significant differences in lifespan. The diversity patterns of the microbial communities were significantly different – one of the factors that could have contributed towards the differences in the survival span of those mice.

Symptoms

  • In ALS, a progressive and irreversible degeneration of the motor neurons is responsible for muscle movement. ALS damages the neurons located in the motor cortex of the brain as well as the anterior horn cells of the spinal cord.
  • The degeneration of the upper motor neurons results in increased muscle tone or spastic paralysis. And damage to the lower motor neuron causes muscle weakness and eventually amyotrophy. 
  • The paralysis of the muscles results in gait, speech and swallowing disorders. Additionally, this also causes impaired coordination, and weakness of the arm and hand muscles. These affect the day to day activities of the ALS patients.
  • The average survival time of the patient is about three to five years from the onset of the disease, however, 10-20 percent of the ALS patients can survive for a longer duration.

is als genetic: modelling of various factors linked with als

Figure: A number of mechanisms could be linked to ALS. Image source: van Damme et al. 2017. Wikimedia Commons, CC-BY-3.0

Clinical picture

Onset 

  • Amyotrophic lateral sclerosis has a variable clinical picture, especially in the early stages. Characteristic features of ALS are degeneration and the associated dysfunction of the upper and lower motor neuron.
  • Accordingly, the clinical symptoms are a combination of spastic and flaccid paralysis of the musculature. 
  • Depending on the localization of the damage, functional impairment of the muscles of the upper and lower extremities, the bulbar muscles, and the trunk muscles occurs.

Impact on the upper neurons

  • The degeneration of the upper motor neuron leads to spastic paralysis. Depending on the location of the damage, the disorder is manifested by the onset of spastic and slowed gait patterns as well as limited dexterity of the hands.
  • Some other manifestations include speech and swallowing disorders, difficulties opening the mouth as well as a lockjaw. Additionally, spastic speech disorders are characterized by strained and slowed speech.

Impact on the lower neurons

  • Damage to the lower motor neurons causes flaccid paralysis. Next, atrophy follows, and this results in muscle weakness. Fasciculations and painful muscle cramps are also typical at this stage. 

Symptoms in progress

  • Speech and swallowing disorders accompany bulbar dysfunction owing to muscle weakness. Also, people with ALS suffer uncontrolled twitches in their tongue.
  • Severity in muscular atrophy, especially of the hand muscles, and malignant muscle twitches progress further. 
  • Malignant muscle twitches differ from the much more common benign muscle twitches in their irregularity and lower frequency. They even significantly increase, especially at the beginning as a sign of a lesion of the upper motor neuron. The patients sometimes show a loss of control when laughing, crying, or yawning.
  • Besides, ALS impacts the nerve tracts running between the precentral cortex and spinal cord.

Diagnosis of ALS

Mostly, the symptoms vary from one person to another. Hence, the doctor conducts a thorough examination using multiple tests. As of now, there is no clinical genetic testing for ALS.

Physical examination: In most cases, increasing muscle weakness, muscle atrophy, or even muscle twitches lead patients to a doctor for the first time. It should be noted that muscle twitches alone almost always represent benign fasciculations. At first, the symptoms can appear anywhere on the body. During the examination, the simultaneous appearance of signs of flaccid and spastic paralysis reinforces the suspicion of the diagnosis of ALS.

Electromyography: An electromyographic and electroneurographic examination is indispensable for making a diagnosis. Electromyography analyses the electrical activity in the muscles. Internationally standardized criteria have been developed for making the diagnosis (El Escorial criteria). According to these criteria, ALS diagnosis requires examining the degeneration in the upper and lower motor neurons, their progress, and also the absence of any other neurodegenerative disease.

Spinal tap:  The physician draws out a small volume of cerebrospinal fluid and looks for the presence of inflammatory conditions or abnormal cells. This test is important only incases of ALS with unusual symptoms. 


Biopsy: Generally, a surgeon removes a part of the muscle from the upper arm or upper thigh. The surgeon then looks for any damage using staining and microscopy.

Treatment

Ideally, an interdisciplinary team of health and nursing staff, occupational therapists, etc. carry out the treatment of patients with ALS.

Usually, treatment comprises a combination of drug therapy and symptomatic oriented therapy. Symptomatic therapy intends to help avoid complications of muscular weakness and improve the patient’s quality of life. In animal models and human stem cells, genetic studies on ALS have identified potential drug targets, which could be a step forward towards developing drug therapy.

Sometimes, people might want to undergo genetic testing especially in cases with a family history of ALS. Then, in such cases, the genetic counselor may help in evaluating not only the family history, but also the medical background, and any other potential risks. For familial ALS, a positive test result is usually observed in 60-70 percent of the cases.

Neuroprotective therapy

Riluzole is the common drug in neuroprotective therapy. This drug inhibits the destruction of motor nerve cells by blocking the release of the neurotransmitter glutamate from neurons

 The administration of riluzole reportedly prolongs survival by about three months. Besides, it also prolongs the earlier stages of the disease. However, it should be noted that the progression of the disease cannot be entirely stopped by riluzole. 

–As of 2017, the US Food and Drug Administration has granted the approval of yet another drug Edaravone. It indicatively slows down ALS development. 

Below are the treatments associated with specific symptoms that are observed in ALS cases.

Symptomatic therapy

The complaints and complications typically occurring in the course of the disease can be treated by a variety of therapeutic measures. Important areas of application for symptomatic therapy are swallowing disorders, speech disorders, cramps or increased muscle tone, impaired respiratory muscles, and psychological changes such as depression or anxiety.

Muscle cramps 

Muscle cramps are few of the unspecific early symptoms of ALS. They can occur spontaneously without any apparent immediate cause. Or they might also occur right after physical activity, cold stimulus, sleep deprivation, alcohol or nicotine consumption. 

Therefore, for acute therapy passive stretching of the muscle is useful. And, for prevention, regular physical training, physiotherapeutic exercises, and massages can be helpful. If the patient suffers from a corresponding degree of suffering, quinine sulfate, magnesium or carbamazepine can also be used.

Dysphagia

Due to a weakness of the pharyngeal muscles, ALS patients suffer from swallowing disorder or dysphagia.The normal swallowing process ensures that no parts of the food or fluids ingested reach the respiratory tract. 

However, in an impaired swallowing mechanism there is an increased risk of  aspiration pneumonia, a condition which occurs when liquids enter the lungs. In addition, the difficulty in eating with frequent swallowing can lead to weight loss and insufficient fluid intake.

If such symptoms occur, a liquid diet usually replaces solid foods. Also, using energy-rich food supplements can compensate for the patient’s energy requirements. Additionally, using logopaedic measures can make swallowing easier.

As the disease progresses, the above measures are often no longer sufficient to ensure the necessary food and fluid intake. So the use of a feeding tube (PEG tube) is recommended. However, patients should begin using this at an early stage, as the complications increase in cases that are at advanced stages. Oral feeding is still possible even after the insertion of a feeding tube.

Salivation

Salivation from the mouth or sialorrhea occurs as a result of swallowing difficulties and impairment of the mouth and neck muscles. In ALS patients there is no increased saliva production. 

Sialorrhea is socially stigmatizing and is often stressful for the patients. However, drugs that inhibit salivary production, such as amitriptyline, scopolamine, or glycopyrronium bromide can treat sialorrhea. Besides, physiotherapeutic, orthopedic, and logopedic measures are also useful in dealing with sialorrhea. 

Speech disorder and communication

The impairment of tongue, mouth, and palate muscles as well as speech-dependent shortness of breath lead to a progressive speech disorder in ALS patients. So, to help relieve this disorder, logopedic treatment facilitates breathing and speaking with the help of exercises. 

In addition, therapists also recommend using communication aids such as alphabet and picture boards. Also, computer-supported aids enable communication with others in the further course of the disease.

Pathological laughter and crying

Pathological laughing and crying are known as pseudobulbar emotional instability. This disorder is a sudden laughing or crying of the patient which might be inappropriate to a situation. Symptoms associated with pseudobulbar emotional instability occurs in up to 50 percent of ALS patients.

The physician may prescribe amitriptyline or other serotonin reuptake inhibitors such as fluvoxamine or citalopram to the person with ALS. These drugs act as antidepressants and help relieve stress.

Respiratory Disorder

In advanced ALS, severe impairment of the respiratory muscles causes reduced ventilation of the lungs. Respiratory insufficiency is the most important cause of limited life expectancy in ALS patients. Then, this ultimately leads to reduced oxygen content and an increased carbon dioxide content in the blood.

Symptoms of impaired respiratory function are sleep disorders, morning headaches, fatigue, restlessness, and in advanced cases, shortness of breath. Moreover, respiratory tract infections can further worsen the function of the lungs. 

If symptoms of respiratory insufficiency occur, it is possible to adapt to mechanical ventilation. And in this regard, there is a distinction between non-invasive and invasive ventilation. 

Non-invasive ventilation is machine-assisted ventilation. The person with ALS uses a breathing mask mainly at night for 6 to 8 hours. It can alleviate the symptoms of lung dysfunction and improve the quality of life. 

In advanced respiratory insufficiency, mechanical ventilation clubbed with surgical tracheostomy is also possible. And this is known as invasive ventilation. The physician discusses all these therapy options of non-invasive ventilation, tracheostomy machine ventilation with the patient at an early stage.

About 15 percent of patients choose nocturnal non-invasive ventilation and less than 10 percent choose mechanical ventilation via tracheostomy. The percentage of patients who use machine ventilation varies between different cultures, countries and ethnic groups.

Depression, sleep disorders and anxiety

A depressive syndrome with low motivation, dejection, and joylessness can considerably reduce the patient’s quality of life. And in these cases, antidepressants such as amitriptyline, sertraline, fluoxetine, or paroxetine, as well as psychotherapeutic measures, can treat the depressive episodes. 

Treatments for this syndrome include a combination of proper sleep hygiene measures and drugs like zolpidem, diphenhydramine. Additionally, the physician may prescribe antidepressants to the patient for improving sleep disorders that occur in the course of depressive bouts.


Recent news (2020)

Researchers at Trinity College Dublin have initiated the Phase 1 clinical trial of gene therapy at the Clinical Research Facility, St. James Hospital Dublin (as of September 1, 2020). This gene-based therapy targets the gene C9ORF72. The U.S. pharmaceutical company Biogen has sponsored this clinical trial.


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