Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that primarily affects the nerve cells (neurons) responsible for controlling voluntary muscle movement (those muscles we choose to move). Voluntary muscles produce movements like chewing, walking, and talking. The disease is progressive, meaning the 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. As motor neurons degenerate, they stop sending messages to the muscles and the muscles gradually weaken, start to twitch, and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.

Early symptoms of ALS usually include muscle weakness or stiffness. Gradually all voluntary muscles are affected, and individuals lose their strength and the ability to speak, eat, move, and even breathe. Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10 percent of people with ALS survive for 10 or more years.

ALS was once commonly known as Lou Gehrig’s disease, following the retirement of the famous ballplayer in the 1940s due to the disease.

ALS and Motor Neurons

It’s a disease that affects your motor neurons. These nerve cells send messages from your brain to your spinal cord and then to your muscles. You have two main types:

• Upper motor neurons: Nerve cells in the brain.
• Lower motor neurons: Nerve cells in the spinal cord to muscle.

These motor neurons control all your voluntary movements -- the muscles in your arms, legs, and face. They tell your muscles to contract so you can walk, run, pick up your smartphone, chew and swallow food, and even breathe.

ALS is one of a few motor neuron diseases. Some others include:

• primary lateral sclerosis (PLS)
• progressive bulbar palsy (PBP)
• pseudobulbar palsy

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.

Early symptoms include:

· Muscle twitches in the arm, leg, shoulder, or tongue

· Muscle cramps

· Tight and stiff muscles (spasticity)

· Muscle weakness affecting an arm, a leg, the neck, or diaphragm

· Slurred and nasal speech

· Difficulty chewing or swallowing

The first sign of ALS usually appears in the hand or arm and can show as difficulty with simple tasks such as buttoning a shirt, writing, or turning a key in a lock. In other cases, symptoms initially affect one leg. People experience awkwardness when walking or running, or they may trip or stumble more often. When symptoms begin in the arms or legs, it is referred to as “limb onset” ALS, and when individuals first notice speech or swallowing problems, it is termed “bulbar onset” ALS.

As the disease progresses, muscle weakness and atrophy spread to other parts of the body. Individuals may develop problems with moving, swallowing (called dysphagia), speaking or forming words (dysarthria), and breathing (dyspnea). Although the sequence of emerging symptoms and the rate of disease progression can 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. 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 can 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 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).

Types

There are mainly two types of ALS:

• Sporadic ALS is the most common form. It affects up to 95% of people with the disease. Sporadic means it happens sometimes without a clear cause.

Nearly all cases of ALS 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. Although family members of people with sporadic ALS are at an increased risk for the disease, the overall risk is very low and most will not develop ALS.

• Familial ALS (FALS) runs in families. About 5% to 10% of people with ALS have this type. FALS is caused by changes to a gene. Parents pass the faulty gene to their children. If one parent has the gene for ALS, each of their children will have a 50% chance of getting the gene and having the disease.

About 5 to 10 percent of all ALS cases are familial, which means that an individual inherits the disease from a parent. The familial form of ALS usually only requires one parent to carry the disease-causing gene. 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 the C9ORF72 gene (which makes a protein that is found in motor neurons and nerve cells in the brain). In 2011, scientists found that a defect in the C9ORF72 gene is not only present in a significant subset of individuals with ALS but also in some people with a type of frontotemporal dementia (FTD) that results from atrophy to the brain’s temporal and frontal lobes. This observation provides evidence for genetic ties between these two neurodegenerative disorders. 

· Another 12 to 20 percent of familial cases result from mutations in the SOD1 gene that is involved in production of the enzyme copper-zinc superoxide dismutase 1.

On June 1, 2021, a team of scientists let by the NIH and the Uniformed Services University announced it had discovered a unique form of genetic ALS that affects children as early as age 4 years.  This childhood form of ALS is linked to the gene SPTLC1, that is part of the body's fat production system, and may be caused by changes in the way the body metabolizes fatty materials called lipids.

Making a proper diagnosis in ALS is complicated because symptoms can vary in each patient. For greater accuracy, physicians have classified every known form:

Classical ALS - a progressive neurological disease characterized by a deterioration of upper and lower motor neurons (nerve cells). This type of ALS affects more than two-thirds of those with the disease.

Primary Lateral Sclerosis (PLS) - a progressive neurological disease in which the upper motor neurons (nerve cells) deteriorate. If the lower motor neurons are not affected within two years, the disease usually remains a pure upper motor neuron disease. This is the rarest form of ALS.

Progressive Bulbar Palsy (PBP) - a condition that starts with difficulties in speaking, chewing and swallowing due to lower motor neuron (nerve cell) deterioration. This disorder affects about 25% of those with ALS.

Progressive Muscular Atrophy (PMA) - a progressive neurological disease in which the lower motor neurons (nerve cells) deteriorate. If the upper motor neurons are unaffected within two years, the disease usually remains a pure lower motor neuron disease.

Familial - a progressive neurological disease that affects more than one member of the same family. This type of ALS accounts for a very small number of people with ALS in the United States (between five and ten percent).

Causes

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

Genetics
In 1993, 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. Since then, more than a dozen additional genetic mutations have been identified, many through NINDS-supported research.

Research on certain gene mutations suggests that changes in the processing of RNA molecules may lead to ALS-related motor neuron degeneration. RNA molecules are involved with the production of molecules in the cell and with gene activity.

Other gene mutations indicate there may be defects in protein recycling—a naturally occurring process in which malfunctioning proteins are broken down and used to build new working ones. Still others point to possible defects in the structure and shape of motor neurons, as well as increased susceptibility to environmental toxins.

Environmental factors
Researchers are studying the impact of environmental factors, such as exposure to toxic or infectious agents, viruses, physical trauma, diet, and behavioral and occupational factors. For example, 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. Ongoing research may show that some factors are involved in the development or progression of the disease.