Amyotrophic Lateral Sclerosis

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What is amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis is a progressive disease that affects the control of muscle movement by damaging motor neurons, which are specialized nerve cells in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). More than 90 percent of amyotrophic lateral sclerosis cases occur in people with no family history of the disorder (sporadic cases). The cause of sporadic cases remains largely unknown. Only a small percentage of amyotrophic lateral sclerosis cases are caused by a known genetic mutation; these cases are referred to as inherited or familial.

The first signs and symptoms of amyotrophic lateral sclerosis may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Speech may become slurred, and later there is difficulty chewing or swallowing. The muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue wastes away (atrophies). Individuals with this disorder lose their strength, the ability to walk, and use of their hands and arms. In late stages of the disease, breathing becomes difficult because the muscles of the respiratory system weaken. Most people with amyotrophic lateral sclerosis die from respiratory failure.

Different types of familial amyotrophic lateral sclerosis are distinguished by genetic cause, pattern of inheritance, age when symptoms begin, and disease progression. Onset of symptoms in adulthood is characteristic of amyotrophic lateral sclerosis types 1 and 8. Symptoms of type 1 usually begin between 40 and 60 years of age and progress rapidly. Most individuals with type 1 amyotrophic lateral sclerosis die of respiratory failure within 3 to 5 years of the onset of symptoms. Symptoms of type 8 amyotrophic lateral sclerosis begin earlier than type 1 (between 25 and 44 years of age) but progress slowly over several years to several decades. Juvenile or early onset of symptoms is characteristic of amyotrophic lateral sclerosis types 2 and 4. Type 2 symptoms usually begin in early childhood or adolescence and slowly worsen for 10 to 15 years. Symptoms of type 4 amyotrophic lateral sclerosis typically begin before age 25 and slowly progress over several decades.

Additional types of amyotrophic lateral sclerosis have been reported, but the responsible mutations have not been adequately described.

How common is amyotrophic lateral sclerosis?

An estimated 5,000 people in the United States are diagnosed with amyotrophic lateral sclerosis each year. Worldwide, this disorder occurs in 4 to 8 per 100,000 individuals. Only a small percentage of cases arise from a known genetic cause. About 3 percent of sporadic cases and 20 percent of familial cases are considered type 1. Types 2, 4, and 8 are rare disorders, reported in a small number of families.

What genes are related to amyotrophic lateral sclerosis?

Mutations in the ALS2, SETX, SOD1, and VAPB genes cause amyotrophic lateral sclerosis.

Variations of the NEFH, SMN1, and SMN2 genes increase the risk of developing amyotrophic lateral sclerosis.

Each type of familial amyotrophic lateral sclerosis is caused by mutations in a specific gene. Type 1 is caused by mutations in the SOD1 gene, type 2 by ALS2 mutations, type 4 by mutations in the SETX gene, and type 8 by VAPB mutations. These mutations contribute to the decline and death of motor neurons, which leads to muscle weakness and atrophy. Not all familial cases are due to SOD1, ALS2, SETX, or VAPB mutations. Other genes are thought to cause amyotrophic lateral sclerosis, but they have not been identified or fully characterized.

Mutations in the NEFH gene appear to increase the risk of developing amyotrophic lateral sclerosis. Research findings also suggest that a decrease in the number of SMN1 or SMN2 genes leads to an increased chance of developing this disorder. It is unclear how variations in these gene lead to an increased risk.

How do people inherit amyotrophic lateral sclerosis?

The pattern of inheritance varies with the type of amyotrophic lateral sclerosis. Type 2 amyotrophic lateral sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Amyotrophic lateral sclerosis 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.

Source: National Institutes of Health

Research from Massachusetts General Hospital in the area of amyotrophic lateral sclerosis published

"End-of-life discussions were addressed at each visit. Other variables recorded included the amount of time afflicted with ALS, serial pulmonary function test results, and the subjective level of bulbar dysfunction We saw 43 patients (age range 39-94 y) between June 1999 and September 2004. One patient was on a ventilator at the initial visit, and was therefore excluded from the study. Discussion about the patients' end-of-life care preferences were initiated at the first pulmonary visit with 40 patients. With 2 patients, end-of-life decisions were discussed at the second office visit. Twenty-five patients chose do-not-resuscitate and do-not-intubate (DNR/DNI) orders after the initial end-of-life discussion with the pulmonologist. Five other patients chose DNR/DNI orders during subsequent clinic visits. Four patients were still undecided at their last clinic visit. Six patients were lost to follow-up before a decision was made. Two patients requested full ventilatory support. Both the forced vital capacity and the level of bulbar dysfunction were not statistically different between the patients who chose DNR/DNI and the patients who were either undecided or requested full ventilatory support Decisions about end-of-life care are often delayed in patients with ALS," wrote C.A. Munroe and colleagues, Massachusetts General Hospital.

The researchers concluded: "These patients' final decisions seem to be independent of their level of respiratory insufficiency or bulbar function, and most related to the physician addressing endof-life care decisions in a timely manner."

Munroe and colleagues published their study in Respiratory Care (End-of-life decision making in 42 patients with amyotrophic lateral sclerosis. Respiratory Care, 2007;52(8):996-999).

For additional information, contact C.A. Munroe, Massachusetts General Hospital, Dept. of Medical, 55 Fruit St., Boston, MA 02114, USA.

Publisher contact information for the journal Respiratory Care is: Daedalus Enterprises Inc., 9425 N Mac Arthur Blvd., Ste. 100, Irving, TX 75063-4706, USA.

Keywords: United States, Boston, Amyotrophic Lateral Sclerosis, Massachusetts General Hospital.

This article was prepared by Pain & Central Nervous System Week editors from staff and other reports. Copyright 2007, Pain & Central Nervous System Week via NewsRx.com.