Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons, causing them to lose function and die. Motor neurons are specialized nerve cells in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). They transmit electrical signals from the brain to the muscles. Motor neurons are important for controlling muscle movement and strength.

ALS causes progressive weakness, which may at first be mild and subtle, but becomes severe and eventually affects the breathing muscle machinery. This disease ultimately results in death.

Other Names

ALS has three other names:

• Lou Gehrig disease
• Motor neuron disease (in the United Kingdom)
• Maladie de Charcot disease (after the physician that first described it in the 1870s)

Types

Sporadic

Most people with ALS have the sporadic form (not inherited). The cause of sporadic ALS is not known, but it probably involves a combination of genetic and environmental factors.

Familial

About 10% of people with ALS have the familial form, which is caused by an inherited genetic mutation.

There are several different types of ALS. The different types of familial ALS are distinguished by genetic cause, age when symptoms begin, and disease progression. Researchers have identified genetic mutations that cause ALS types 1, 2, 4, and 8. Types 1 and 8 are characterized by late-onset symptoms that appear in adulthood. Symptoms of type 1 usually begin between ages 40 and 60 years. Depending on the genetic mutation involved, the condition may progress slowly or rapidly. Symptoms of type 8 amyotrophic lateral sclerosis begin earlier than type 1 (usually between ages 25 and 44 years) but progress slowly over years to decades. Types 2 and 4 ALS are characterized by early-onset symptoms. Type 2 symptoms usually begin in early childhood or adolescence and slowly worsen over 10 to 15 years. Symptoms of type 4 typically begin before age 25 years and slowly progress over several decades.

Additional types of ALS have been reported, but the mutations that cause them have not been adequately described.

Signs and Symptoms

The first symptoms of ALS may be so subtle that they are overlooked:

• Muscle twitching
• Cramping
• Stiffness
• Weakness
• Involuntary jerking movements
• Tremor
• Inability to control the bowels or bladder
• Inability to move or open the eyes completely

As the weakness in the limb muscles progresses, muscle tissue is lost (atrophies), and the arms and legs begin to look thinner. Speech may become slurred, and later chewing and swallowing become difficult. Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with ALS die from respiratory failure.

Causes

The different types of ALS have different causes.

Familial ALS

In familial ALS, the pattern of inheritance varies with the type. Type 2 ALS is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but do not show symptoms of the condition.

Types 1, 4, and 8 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Studies in Sweden and Finland, however, revealed a small number of type 1 cases that are inherited in an autosomal recessive pattern.

Each type of familial ALS is caused by mutations in a specific gene. Mutations in the SOD1, ALS2, SETX, and VAPB genes cause ALS Type 1, 2, 4, and 8, respectively. How these mutations cause the death of motor neurons and subsequent muscle weakness and atrophy is unclear. Research suggests that these mutations lead to the production of toxic substances or clumps (aggregates) of misshapen proteins that accumulate and damage motor neurons. Another possible explanation is altered development of axons, which are the specialized extensions of nerve cells (such as motor neurons) that transmit nerve impulses. The altered axons may impair transmission of impulses from nerves to muscles.

Other genes are thought to contribute to familial ALS, but they have not been identified or fully characterized. For example, mutations in the ANG, DCTN1, NEFH, or PRPH genes, or a reduction in the number of SMN1 or SMN2 genes may also increase the risk of ALS. How variations in these genes contribute to ALS is unclear.

Sporadic ALS

The cause of sporadic ALS, which makes up 90% of all cases, is not known. The only clear risk factors are age, which is unsurprising given that this is a slowly progressive disease, and having family members with the disease. Because of the latter cause, sporadic ALS may have some genetic basis. In this case, a person with sporadic ALS would have inherited a gene or a pattern of genes that increases the risk of developing the disease. The difference between this and familial ALS is that familial ALS is associated with one known gene, which results in a much higher chance of suffering from the disease.

Below are some other factors that may increase the risk of developing ALS:

• Cigarette smoking
• Military service
• Exposure to lead and other heavy metals
• Intensive exercise

Diagnosis

A diagnosis can be made using medical history, physical exam, and diagnostic tests.

History and physical exam

Progressive weakness in the large central muscles, like the pectoral muscles and buttock muscles, as well as in the small, distant muscles of the fingers and toes is suggestive of ALS. ALS, however, does not cause unusual sensations, numbness or tingling, and it does not cause pain. If these symptoms are present, another condition is most likely present.

Physical examination helps doctors assess the symptoms, especially weak, shrunken, or twitching muscles. These symptoms are caused by a loss of motor neurons that connect to muscles, the lower motor neurons. Reflexes are often increased because of the loss of upper motor neurons, (motor neurons in the brain). The diagnosis of ALS depends on finding evidence that both upper and lower motor neurons are affected.

Electrophysiology studies

Diagnostic tests are used to confirm the ALS diagnosis. Electrophysiology studies the electrical impulses from the brain, nerves and muscles, and studies how well the nerves and body conduction systems work. It involves placing stimulators on the scalp, peripheral nerves and muscles, and measuring the waveform of the signals that are conducted away. In ALS the conduction between the brain, nerves and muscles are reduced in many different muscles. These studies can be used to estimate the number of nerve cells and fibers in each nerve. The number is always reduced in ALS.

Radiology studies

Radiology studies include x-rays and scans. The most important radiology study in ALS is the magnetic resonance imaging scan (MRI) of the brain and spine. MRI takes very high resolution pictures of the inside of the brain and the spinal cord, which contains high numbers of upper motor neurons. The main use of MRI is to rule out other conditions that can mimic, or appear very similar to, ALS. These include compression of the spinal cord from a slipped disc or fracture of the spine, as well as strokes and multiple sclerosis. Unlike with these other conditions, an MRI scan appears normal in a person with ALS.

Blood tests

ALS cannot be detected by a blood test. Blood tests are used to eliminate other possible diagnoses. For this reason, muscle enzyme creatine kinase (CK) is tested to make sure the weakness is not due to muscle disease. Blood tests also rule out organ failure, cancer and upset of the body chemistry (metabolic disturbance).

Treatment

Treatments for ALS are divided into pharmacological (medicine), behavioral (physical therapy) and supportive (not designed to treat the disease but to prevent its complications) approaches. Currently, ALS has no cure, so treatments try to slow its progression.

Medication

Riluzole (Rilutek) is the first and only medicine approved to delay progression of ALS. It sometimes delays the need for devices that assist breathing, such as a ventilator. It blocks several types of protein channels in the brain that allow calcium to enter neurons, including the N-methyl-D-aspartate, or NMDA, receptor. Normally the NMDA receptor is activated by the amino acid glutamate. Over-activation of the receptor, and the massive influx of calcium, may contribute to the degeneration and death of motor neurons seen in ALS.

Behavioral therapy

Some evidence suggests that exercising muscles, particularly those in the face and those that control swallowing and chewing, can slow the progression of ALS. Strong swallowing muscles prevent food from going into the windpipe. When these muscles do no work properly, food can enter the windpipe and go into the lungs, causing aspiration pneumonia, which is often the cause of death in people with ALS.

Speech therapy

Because of motor weakness and paralysis, speech may be difficult in ALS. A speech therapist can teach techniques to make the speech more easily understood.

Physical therapy

Physical therapy can be helpful in performing range of motion activity and exercises to maintain strength and flexibility. Therapists can also assist with use of a wheelchair and other devices (walker, braces and ramps) that help with mobility.

Occupational therapy

Occupational therapists work with patients to maximize their achievement, competence and satisfaction by improving both physical and psychological well being. Examples of interventions may include assessment for electronic assistive technology such as environmental controls, housing adaptations, and help with eating and drinking

Supportive therapy

Drooling is a problem in people with ALS. Atropine is used to control drooling. Excessive saliva can also make someone more likely to have aspiration pneumonia. The muscle jerks and cramps in late stage ALS can be reduced with muscle relaxants. In very advanced ALS, feeding may be impossible through the mouth and feeding tubes may be needed. Eventually, when the breathing muscles are affected, patients need to have mechanically assisted ventilation.

Prevention

ALS cannot be prevented, just as it cannot be cured. The small proportion of hereditary cases can be avoided by testing the fetus of parents who carry the genes that predict a high probability of ALS. This practic is controversial.

Living with Amyotropic Lateral Sclerosis

In its early stages, ALS usually goes unnoticed. This is particularly true in sporadic cases. This is because the signs are not specific for ALS, and may not, at the start, be particularly troublesome. Once the diagnosis is made, the disease progresses over the next three to five years. During this progression, muscle strenth is lost throughout the body.

Initially mobility becomes a problem and patients become wheelchair and bed bound. They become incontinent (unable to control the bladder) and may be unable to self feed. Usually the breathing muscles are the last to be affected. Once this happens, pneumonia and death result. The speed at which ALS progresses is variable. Progression and lifespan cannot be predicted. Those whose speech and swallowing are affected early have the worst outlook.

Most people with ALS live three to five years.^[1] About 30% of patients with ALS live 5 years after diagnosis, and about 10%–20% live for more than 10 years.

Research

Research in 2008 has discovered changes occurring at the molecular level that precede the death of motor neurons in ALS.^[2] The research used an animal model of ALS, genetically-engineered mice that had a mutation in the SOD1 gene. In these mice, the blood vessels that feed the spinal cord become leaky and allow toxic substances to flood the central nervous system. This damage occurs before any signs of nerve degeneration. The authors of the study suggest that these leaky vessels play a major role in the progression of ALS and that this represents a new approach to studying the disease.^[3] The same process may contribute to sporadic forms of ALS.^[3]

The genetic basis of ALS continues to be investigated. Recently, mutations in the TTP-43 gene have been found to be a cause of some forms of ALS.^[4][5] Mutations in genes often encode proteins that function improperly. Mutations in TTP-43 form proteins that do not properly modify RNA (ribonucleic acid) in motor neurons. This is thought to contribute to the disease process. Identifying the genes and their abnormal protein products helps identify targets for treatment.

The ALS Association has a recent press releases related to ALS:

• ALS Risk Appears Increased in Veterans: New Government Report Agrees
• Evidence of Retrovirus in Blood of ALS Patients

The ALS association also reports research into the following topics:

• Role of toxins in ALS
• Reasons behind an increased rate of ALS symptoms in the people of Guam. It has been proposed that trace metals or metal in the soil may be possible culprits but nothing has yet been proven.
• The relationship between heavy metal exposure and an increased risk of ALS.
• An observed increase in cases of ALS among veterans (possibly resulting from pesticide exposure or heavy exercise). The study size has been small so a relationship has not been proven.
• A possible viral infection leading to ALS. This has also not been proven.

Researchers at Brigham and Women's Hospital (BWH) reported in 2003 that the antibiotic minocycline used in combination with creatine may be effective in slowing the progression of ALS. ^[6]

Epidemiology

Prevalence

About 5,000 people in the United States are diagnosed with ALS each year. Worldwide, this disorder occurs in 4 to 8 per 100,000 individuals. Only a small percentage of cases have a known genetic cause.

Interesting Facts

Famous people

• The famous baseball player Lou Gehrig died of ALS, hence the name Lou Gehrig disease.

• Stephen Hawking, a Cambridge professor and one of the world experts in planetary physics, has ALS. He has been dependent on a ventilator for breathing since 1985. He lectures using eye movements that are detected by computer and translated into his distinctive computer voice synthesizer. The distinctive computer voice of Stephen Hawking speaks with an American accent, while Hawking himself would speak in an English accent. Far better and more lifelike computer speech synthesizers are available, but Stephen Hawking prefers the one he has been using for the past 20 years.

• Former Baltimore Raven's linebacker O.J. Brigance announced on May 3, 2008, that he has been diagnosed with ALS.

References

1. ↑ Clem K. eMedicine. Amyotrophic Lateral Sclerosis (Lou Gehrig Disease)
2. ↑ Zhong Z, Deane R, Ali Z. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008 Apr;11(4):420-2. Abstract
3. ↑ ^{3.0 3.1} EurekAlert. Leaky blood vessels open up nerve cells to toxic assault in Lou Gehrig's disease.
4. ↑ EurekAlert. More genes for Lou Gehrig's disease identified.
5. ↑ EurekAlert. Researchers identify a gene responsible for cases of Lou Gehrig's disease.
6. ↑ Zhang W, Narayanan M, and Friedlander R. Additive Neuroprotective Effects of Minocycline with Creatine in a Mouse Model of ALS. Ann Neurol. 2003 Feb;53(2):267-70. Abstract | PDF | Press Release

External Links

Gene Reviews: Amyotrophic lateral sclerosis overview

ALS Society of Canada

ALS Association