Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease.
The early symptoms of amyotrophic lateral sclerosis include slight muscle weakness, clumsy hand movements, and/or difficulty performing tasks that require delicate movements of the fingers and/or hands. Muscle weakness in the legs may cause tripping and falling. Affected individuals may have difficulty swallowing (dysphagia), and speech may be slowed. Other symptoms of this disorder include progressive weakness of the lips and impairment and/or loss of function of the tongue, mouth, and/or voice box (bulbar symptoms). Leg cramps may occur during the night, most frequently in the calf and/or thigh muscles. Gradually, additional muscles become involved. Amyotrophic lateral sclerosis may progress quickly or slowly.
Other symptoms may include the uncontrolled twitching of muscles (fasciculations), stiffness in the legs, and/or coughing. People with this disorder will have exaggerated deep muscle reflexes. Marked weight loss occurs in approximately 5 percent of cases. As the ability to move becomes progressively impaired, people with this disease are at increased risk for respiratory failure. People with amyotrophic lateral sclerosis are also at increased risk for acute inflammation of the lungs, caused by the inhalation of food or stomach contents (aspiration pneumonia). An overall decrease in the ability to move, including the ability to swallow, may also result in inadequate nutrition.
Cognitive abilities usually are not affected. As the disease progresses, typically over the course of three to five years, the individual will gradually lose the ability to stand or walk. In time, many patients will require mechanical assistance to breath. A small percentage of people with ALS experience a gradual stabilization of symptoms and may maintain that level (plateau) for a few years.
The exact underlying cause of amyotrophic lateral sclerosis is not known. Several factors have been proposed as possible causes of the disease, including infection with an unidentified virus, an abnormal immune response (e.g., autoimmunity), toxic exposure to certain minerals (e.g., aluminum), and/or other factors. However, none has been substantiated.
A study reported in the January 2000 issue of the journal, Neurology, lends support to the theory that there is a viral link. Researchers at the University of California at Irvine College of Medicine and the Rockefeller University in Lyon, France, discovered a virus in the spinal cords of 15 of 17 patients with ALS. The virus, similar to Echovirus-7 which is known to cause meningitis and rare cases of encephalitis, was found in only one of 29 people who died of other causes.
According to researchers, approximately 10 percent of all cases of ALS are familial. Reports in the medical literature indicate that there are several forms of hereditary ALS that may have autosomal dominant or autosomal recessive inheritance. Symptoms associated with autosomal dominant ALS usually become apparent during adulthood, however, in rare cases, adolescent onset may occur. Individuals with autosomal recessive forms of ALS tend to develop symptoms during childhood or adolescence (juvenile onset).
Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
In approximately 15 to 20 percent of cases of hereditary ALS, the disorder is inherited as an autosomal dominant trait due to abnormal changes (mutations) of a gene known as superoxide dismutase-1 (SOD1). (Such cases of the disorder are sometimes referred to as ALS1.) The SOD1 gene encodes the enzyme called superoxide dismutase. Mutations of the SOD1 gene may also occur spontaneously for unknown reasons (sporadically), resulting in isolated cases of the disease (sporadic ALS). As with autosomal dominant ALS, sporadic ALS typically becomes apparent during adulthood. The SOD1 gene is located on the long arm (q) of chromosome 21 (21q22.1).
Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
In some rare cases of sporadic or autosomal dominant ALS, susceptibility to the disease may result from absence of genetic material (deletions) from, or the presence of extra genetic material (insertions) within, a gene known as the NEFH (or neurofilament protein, heavy polypeptide) gene. The NEFH gene is located on the long arm of chromosome 22 (22q12.2).
In addition, a rare form of autosomal dominant ALS (designated as ALS4) has been mapped to the long arm of chromosome 9 (9q34). Although autosomal dominant ALS usually has adult onset, this form of the disorder typically becomes apparent by the second decade of life.
One autosomal recessive form of the disorder (known as ALS2) has been linked to the long arm of chromosome 2 (2q33). ALS2 is a slowly progressive, early-onset form of the disease, sometimes called juvenile inherited ALS and found in populations in North Africa and the Middle East.
In October 2001, a research team reported the discovery of a gene mutation responsible for ALS2. The findings also clarify why clinicians have confused ALS2 with another neurodegenerative disease known as juvenile primary lateral sclerosis. Different mutations of the same gene are found in the two conditions, indicating a common genetic origin.
With ALS2, symptoms generally appear in the first or second decade of life and progress slowly for 10 to 15 years. With ALS1, symptoms generally occur when the individual is in his 40s or 50s, and the disease progresses more rapidly.
In addition, another autosomal recessive form of ALS (designated ALS5) has been mapped to the long arm of chromosome 15 (15q15.1-q21.1). Ongoing research is being conducted to further characterize the different hereditary forms of ALS.
According to a study in the August 1999 issue of the journal “Nature Structural Biology,” the transport of copper into cells may play some role in causing ALS. Copper is a heavy metal that is a component of several proteins and is necessary for the proper functioning of cells. In normal circumstances, a specialized protein known as a “copper transporter” escorts copper to its appropriate target within cells. One of the targets is the superoxide dismutase (SOD) enzyme, which is encoded by the SOD1 gene. (For more information on the SOD1 gene, please see above.) The SOD enzyme plays an important role in neutralizing damaging “free radicals” that accumulate in cells.
Free radicals are compounds produced during chemical reactions in the body. The accumulation of free radicals within bodily tissues is thought to eventually cause damage to, and impaired functioning of, cells. Certain enzymes, including the SOD enzyme, serve to neutralize or promote the elimination of harmful free radicals. Enzymes are proteins produced by cells that accelerate the rate of chemical reactions in the body.
As mentioned above, some individuals with autosomal dominant or sporadic ALS have mutations of the gene that encodes the SOD enzyme (SOD1 gene). In such cases, when copper reaches the mutated SOD1 gene, it may react abnormally, resulting in cellular damage that may ultimately cause the muscle wasting (atrophy) seen in individuals with ALS. Researchers have characterized the structure of a “copper transporter” protein and obtained an increased understanding of the protein’s functioning. This information may enable researchers to determine ways in which to inhibit the transfer of copper to the mutated SOD1 gene, possibly delaying or preventing symptoms associated with ALS. However, much additional research is required before it may be determined whether such findings have practical treatment implications.
Amyotrophic lateral sclerosis is a rare disorder that affects approximately 30,000 people in the United States. Although the median age at which symptoms develop is 55 years, symptoms may begin at any adult age. ALS affects more males than females. Approximately 60 percent of those affected are men; 40 percent of affected individuals are women. An estimated 5,000 new cases are diagnosed each year in the U.S.
Amyotrophic lateral sclerosis is characterized by degeneration of both the upper and lower motor neurons. Some patients with ALS may initially present only with findings due to degeneration of the upper motor neurons. Lower motor neuron degeneration usually appears within three to five years in these patients.
Early symptoms of ALS may resemble those of other diseases, so diagnosis may be largely a matter of ruling out other conditions. For that purpose, certain diagnostic procedures such as magnetic resonance imaging (MRI) or a test to detect electrical activity in muscles (electromyography or EMG) may be employed.
The treatment of amyotrophic lateral sclerosis generally requires a team approach and should include physicians, physical therapists, speech pathologists, pulmonary therapists, medical social workers, and nurses.
The drug riluzole (Rilutek) is the first drug to be approved by the FDA for the treatment of amyotrophic lateral sclerosis. The drug is manufactured by the French pharmaceutical firm, Aventis. In studies, Rilutek was shown to prolong survival on an average of three to five months, although it did not substantially delay muscle deterioration.
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Several other drugs may be used to help alleviate the symptoms of amyotrophic lateral sclerosis. Baclofen may reduce muscle spasms in some patients. Patients troubled by leg cramps may benefit from quinine compounds. The uncontrolled twitching of small muscles (fasciculations), which may interfere with sleep, may respond to the administration of muscle relaxant drugs such as diazepem.
It is essential that people with amyotrophic lateral sclerosis maintain proper nutrition. Soft foods should be carefully chosen for patients who have difficulty swallowing (dysphagia). When adequate nutrition and fluids can not be maintained because of dysphagia, a gastric feeding tube should be considered. Specific vitamin therapy does not affect the course of ALS.
Physical therapy is very important and should consist of daily range-of- motion exercises. These exercises can help maintain the flexibility of affected joints and prevent the fixation of muscles (contractures).
Communication devices can be useful for individuals with amyotrophic lateral sclerosis who have difficulty speaking (dysarthria). For those affected individuals who are able to use their hands, the use of written messages, typing, or the use of small computers with artificial speech articulation may help to combat feelings of isolation. A communication device called “The Talking Board” is useful for those individuals who can point their fingers. One side of the board has phrases and the other side has the alphabet, numbers and a blank space to write on. Another communication device called the Etran Board may be helpful to those individuals who have lost their ability to speak as well as use of their hands. For information on assistive devices, contact:
The ALS Association
Patient Services Department
For affected individuals who may have difficulty breathing, positive pressure ventilation may be initiated.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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September 26, 2008)-Congress took a major step in the fight against Lou Gehrig’s Disease today when the House of Representatives passed the ALS Registry Act (S. 1382). The legislation, which passed the U.S. Senate on September 23, now heads to President Bush, who is expected to sign the bill into law.
The ALS Registry Act would establish the first ever national patient registry of people with Lou Gehrig’s Disease, or amyotrophic lateral sclerosis, to be administered by the Centers for Disease Control and Prevention. The registry would collect information leading to the cause, treatment and cure of the deadly neurological disease that took the life of baseball legend Lou Gehrig in 1941.
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