Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive disease that affects 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). Motor neurons are important for controlling muscle movement and strength. Most people with amyotrophic lateral sclerosis have a form of the condition that is described as sporadic or noninherited. The cause of sporadic amyotrophic lateral sclerosis is largely unknown but probably involves a combination of genetic and environmental factors. About 10 percent of people with amyotrophic lateral sclerosis have a familial form of the condition, which is caused by an inherited genetic mutation.

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. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue is lost (atrophies). 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 amyotrophic lateral sclerosis die from respiratory failure.

Different types of familial amyotrophic lateral sclerosis are distinguished by genetic cause, age when symptoms begin, and disease progression. Researchers have identified genetic mutations that cause amyotrophic lateral sclerosis types 1, 2, 4, and 8. Onset of symptoms in adulthood is characteristic of types 1 and 8. Symptoms of type 1 usually begin between ages 40 and 60. 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) but progress slowly over several years to several decades. 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.

About 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 have a known genetic cause.

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

Variations of the ANG, DCTN1, NEFH, PRPH, 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. It is unclear how mutations in these genes contribute to the death of motor neurons, which leads to muscle weakness and atrophy. Research findings suggest that these mutations lead to the production of toxic substances or clumps (aggregates) of misshapen proteins that accumulate and damage motor neurons. Another possible effect is the altered development of axons, 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, which leads to muscle weakness and atrophy. Other genes are thought to cause familial amyotrophic lateral sclerosis, but they have not been identified or fully characterized.

Mutations in the ANG, DCTN1, NEFH, or PRPH 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 may lead to an increased chance of developing this disorder. It is unclear how variations in these genes lead to increased susceptibility.

Read more about the ALS2, ANG, DCTN1, NEFH, PRPH, SETX, SMN1, SMN2, SOD1, and VAPB genes.

About 90 percent of amyotrophic lateral sclerosis cases are sporadic and are not inherited.

Among the estimated 10 percent of familial cases of this disorder, 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 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 signs and symptoms of the condition.

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 revealed a small number of type 1 cases that are inherited in an autosomal recessive pattern.