Amyotrophic lateral sclerosis (ALS) is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement (e.g. chewing, walking, and talking). The disease is progressive, and symptoms get worse over time. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. ALS belongs to a wider group of disorders known as motor neuron diseases, which are caused by gradual deterioration (degeneration) and death of motor neurons. Motor neurons are nerve cells that extend from the brain to the spinal cord and to muscles throughout the body. These motor neurons initiate and provide vital communication links between the brain and the voluntary muscles. Messages from motor neurons in the brain (called upper motor neurons) are transmitted to motor neurons in the spinal cord and to motor nuclei of brain (called lower motor neurons) and from the spinal cord and motor nuclei of brain to a particular muscle or muscles. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch (called fasciculations), and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.

There are several potential risk factors for ALS including:

• Age. Although the disease can strike at any age, symptoms most commonly develop between the ages of 55 and 75. Some studies suggest that military veterans are about 1.5 to 2 times more likely to develop ALS.
• Gender. Men are slightly more likely than women to develop ALS. However, as we age the difference between men and women disappears.
• Race and ethnicity. Most likely to develop the disease are Caucasians and non-Hispanics.

SPORADIC ALS – The majority of ALS cases (90 percent or more) are considered sporadic. This means the disease seems to occur at random with no clearly associated risk factors and no family history of the disease.

FAMILIAL (GENETIC) ALS – About 5 to 10 percent of all ALS cases are familial, which means that an individual inherits the disease from his or her parents. The familial form of ALS usually only requires one parent to carry the gene responsible for the disease. Mutations in more than a dozen genes have been found to cause familial ALS. About 25 to 40 percent of all familial cases (and a small percentage of sporadic cases) are caused by a defect in a gene known as “chromosome 9 open reading frame 72,” or C9ORF72. Interestingly, the same mutation can be associated with atrophy of frontal-temporal lobes of the brain causing frontal-temporal lobe dementia. Some individuals carrying this mutation may show signs of both motor neuron and dementia symptoms (ALS-FTD). Another 12 to 20 percent of familial cases result from mutations in the gene that provides instructions for the production of the enzyme copper-zinc superoxide dismutase 1 (SOD1).

SYMPTOMS

The onset of ALS can be so subtle that the symptoms are overlooked but gradually these symptoms develop into more obvious weakness or atrophy that may cause a physician to suspect ALS. Some of the early symptoms include:

• fasciculations (muscle twitches) in the arm, leg, shoulder, or tongue
• muscle cramps
• tight and stiff muscles (spasticity)
• muscle weakness affecting an arm, a leg, neck or diaphragm.
• slurred and nasal speech
• difficulty chewing or swallowing.

For many individuals the first sign of ALS may appear in the hand or arm as they experience difficulty with simple tasks such as buttoning a shirt, writing, or turning a key in a lock.  In other cases, symptoms initially affect one of the legs, and people experience awkwardness when walking or running or they notice that they are tripping or stumbling more often.

When symptoms begin in the arms or legs, it is referred to as “limb onset” ALS.  Other individuals first notice speech or swallowing problems, termed “bulbar onset” ALS.

Regardless of where the symptoms first appear, muscle weakness and atrophy spread to other parts of the body as the disease progresses. Individuals may develop problems with moving, swallowing (dysphagia), speaking or forming words (dysarthria), and breathing (dyspnea).

Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually individuals will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms.

Individuals with ALS usually have difficulty swallowing and chewing food, which makes it hard to eat normally and increases the risk of choking. They also burn calories at a faster rate than most people without ALS. Due to these factors, people with ALS tend to lose weight rapidly and can become malnourished.

Because people with ALS usually retain their ability to perform higher mental processes such as reasoning, remembering, understanding, and problem solving, they are aware of their progressive loss of function and may become anxious and depressed.

A small percentage of individuals may experience problems with language or decision-making, and there is growing evidence that some may even develop a form of dementia over time.

Individuals with ALS will have difficulty breathing as the muscles of the respiratory system weaken. They eventually lose the ability to breathe on their own and must depend on a ventilator. Affected individuals also face an increased risk of pneumonia during later stages of the disease. Besides muscle cramps that may cause discomfort, some individuals with ALS may develop painful neuropathy (nerve disease or damage).

DIAGNOSIS

No one test can provide a definitive diagnosis of ALS. ALS is primarily diagnosed based on detailed history of the symptoms and signs observed by a physician during physical examination along with a series of tests to rule out other mimicking diseases. However, the presence of upper and lower motor neuron symptoms strongly suggests the presence of the disease. Physicians will review an individual’s full medical history and conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, and spasticity are getting progressively worse. ALS symptoms in the early stages of the disease can be similar to those of a wide variety of other, more treatable diseases or disorders.  Appropriate tests can exclude the possibility of other conditions.

Muscle and imaging tests
Electromyography (EMG), a special recording technique that detects electrical activity of muscle fibers, can help diagnose ALS. Another common test is a nerve conduction study (NCS), which measures electrical activity of the nerves and muscles by assessing the nerve’s ability to send a signal along the nerve or to the muscle. Specific abnormalities in the NCS and EMG may suggest, for example, that the individual has a form of peripheral neuropathy (damage to peripheral nerves outside of the brain and spinal cord) or myopathy (muscle disease) rather than ALS.

A physician may also order a magnetic resonance imaging (MRI) test, a noninvasive procedure that uses a magnetic field and radio waves to produce detailed images of the brain and spinal cord. Standard MRI scans are generally normal in people with ALS. However, they can reveal other problems that may be causing the symptoms, such as a spinal cord tumor, a herniated disk in the neck that compresses the spinal cord, syringomyelia (a cyst in the spinal cord), or cervical spondylosis (abnormal wear affecting the spine in the neck).

Laboratory tests
Based on the person’s symptoms, test results, and findings from the examination, a physician may order tests on blood and urine samples to eliminate the possibility of other diseases.

Tests for other diseases and disorders
Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), polio, and West Nile virus can, in some cases, cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, and spinal and bulbar muscular atrophy (Kennedy’s disease) also can mimic certain features of the disease and should be considered by physicians attempting to make a diagnosis. Fasciculations and muscle cramps also occur in benign conditions.

Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, individuals may wish to obtain a second neurological opinion.

CAUSES 

The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others. However, evidence from scientific studies suggests that both genetics and environment play a role in the development of ALS.

Genetics
An important step toward determining ALS risk factors was made in 1993 when scientists supported by the National Institute of Neurological Disorders and Stroke (NINDS) discovered that mutations in the SOD1 gene were associated with some cases of familial ALS. Although it is still not clear how mutations in the SOD1 gene lead to motor neuron degeneration, there is increasing evidence that the gene playing a role in producing mutant SOD1 protein can become toxic. Since then, more than a dozen additional genetic mutations have been identified, many through NINDS-supported research, and each of these gene discoveries is providing new insights into possible mechanisms of ALS. The discovery of certain genetic mutations involved in ALS suggests that changes in the processing of RNA molecules may lead to ALS-related motor neuron degeneration. RNA molecules are one of the major macromolecules in the cell involved in directing the synthesis of specific proteins as well as gene regulation and activity.

Environmental factors
In searching for the cause of ALS, researchers are also studying the impact of environmental factors. Researchers are investigating a number of possible causes such as exposure to toxic or infectious agents, viruses, physical trauma, diet, and behavioral and occupational factors. For example, researchers have suggested that exposure to toxins during warfare, or strenuous physical activity, are possible reasons for why some veterans and athletes may be at increased risk of developing ALS. Although there has been no consistent association between any environmental factor and the risk of developing ALS, future research may show that some factors are involved in the development or progression of the disease.

TREATMENTS

No cure has yet been found for ALS. However, there are treatments available that can help control symptoms, prevent unnecessary complications, and make living with the disease easier.

Medication – the U.S. Food and Drug Administration (FDA) has approved the drugs riluzole (Rilutek) and edaravone (Radicava) to treat ALS. Riluzole is believed to reduce damage to motor neurons by decreasing levels of glutamate, which transports messages between nerve cells and motor neurons. Clinical trials in people with ALS showed that riluzole prolongs survival by a few months, particularly in the bulbar form of the disease, but does not reverse the damage already done to motor neurons. Edaravone has been shown to slow the decline in clinical assessment of daily functioning in persons with ALS.

Physical therapy – physical therapy and special equipment can enhance an individual’s independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles.

Speech therapy – people with ALS who have difficulty speaking may benefit from working with a speech therapist, who can teach adaptive strategies to speak louder and more clearly. As ALS progresses, speech therapists can help people maintain the ability to communicate. They can recommend aids such as computer-based speech synthesizers that use eye-tracking technology and can help people develop ways for responding to yes-or-no questions with their eyes or by other nonverbal means.

Nutritional support – nutritional support is an important part of the care of people with ALS. It has been shown that individuals with ALS will get weaker if they lose weight. Nutritionists can teach individuals and caregivers how to plan and prepare small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. People may begin using suction devices to remove excess fluids or saliva and prevent choking. When individuals can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs.

Breathing support – as the muscles responsible for breathing start to weaken, people may experience shortness of breath during physical activity and difficulty breathing at night or when lying down. Doctors may test an individual’s breathing to determine when to recommend a treatment called noninvasive ventilation (NIV). NIV refers to breathing support that is usually delivered through a mask over the nose and/or mouth. Initially, NIV may only be necessary at night. When muscles are no longer able to maintain normal oxygen and carbon dioxide levels, NIV may be used full-time. NIV improves the quality of life and prolongs survival for many people with ALS.

Cellular defects – scientists are seeking to understand the mechanisms that selectively trigger motor neurons to degenerate in ALS, and to find effective approaches to halt the processes leading to cell death. Using both animal models and cell culture systems, scientists are trying to determine how and why ALS – causing gene mutations lead to the destruction of neurons. These animal models include fruit flies, zebrafish, and rodents. Initially, genetically modified animal models focused on mutations in the SOD1 gene but more recently, models have been developed for defects in the C9ORF72, TARDP, FUS, PFN1, TUBA4A, and UBQLN2 genes. 

Stem Cells – in addition to animal models, scientists are also using innovative stem cells models to study ALS. Scientists have developed ways to take skin or blood cells from individuals with ALS and turn them into stem cells, which are capable of becoming any cell type in the body, including motor neurons and other cell types that may be involved in the disease.

Familial versus sporadic ALS – overall, the work in familial ALS is already leading to a greater understanding of the more common sporadic form of the disease. Because familial ALS and sporadic ALS show many of the same signs and symptoms, some researchers believe that some familial ALS genes may also be involved in sporadic ALS. Clinical research studies supported by NINDS are looking into how ALS symptoms change over time in people with C9ORF72 mutations. Other NINDS-supported research studies are working to identify additional genes that may cause or put a person at risk for either familial or sporadic ALS. 

Biomarkers biological measures that help to identify the presence or rate of progression of a disease or the effectiveness of a therapeutic intervention. Since ALS is difficult to diagnose, biomarkers could potentially help clinicians diagnose ALS earlier and faster.

Resources:

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet

https://www.mda.org/disease/amyotrophic-lateral-sclerosis