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Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis

Reviewed August 2012

What is amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that are important for controlling muscle movement and strength. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die over time, leading to problems with muscle control and movement.

There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of the condition. The signs and symptoms of familial ALS typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a form of the disorder known as juvenile ALS.

The first signs and symptoms of ALS may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech and, later, difficulty chewing or swallowing (dysphagia). Many people with ALS experience malnutrition because of reduced food intake due to dysphagia and an increase in their body's energy demands (metabolism) due to prolonged illness. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue wastes away (atrophies). Individuals with ALS lose their strength and the ability to walk. Affected individuals eventually become wheelchair-dependent. Over time, muscle weakness causes affected individuals to lose the 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 within 2 to 10 years after the signs and symptoms of ALS first appear; however, disease progression varies widely among affected individuals.

Approximately 20 percent of individuals with ALS also develop a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. People with FTD increasingly require help with personal care and other activities of daily living. Communication skills worsen as the disease progresses. It is unclear how the development of ALS and FTD are related. Individuals who develop both conditions are diagnosed as having ALS-FTD.

How common is amyotrophic lateral sclerosis?

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.

What genes are related to amyotrophic lateral sclerosis?

Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe. Worldwide, SOD1 gene mutations cause about 20 percent of familial ALS, TARDBP gene mutations account for about 5 percent, FUS gene mutations cause about 5 percent, and ANG gene mutations account for around 1 percent. The other genes that have been associated with familial ALS each account for a small proportion of cases. It is estimated that 60 percent of individuals with familial ALS have an identified genetic mutation. The cause of the condition in the remaining individuals remains unknown.

The genes associated with ALS play a role in the functioning of neurons or are involved in regulating the production of various proteins, although the specific role of the C9orf72 gene is not known. It is unclear how mutations in the genes associated with ALS contribute to the death of motor neurons. Most motor neurons affected by ALS have a buildup of protein clumps (aggregates); however, it is unknown whether these aggregates are involved in causing ALS or are a byproduct of the dying cell. Mutations in the SOD1, TARDBP, or FUS gene lead to the production of misfolded proteins that form protein aggregates in motor neurons. When ALS is caused by mutations in other genes, the composition of the protein aggregates is usually a mix of different proteins, although the aggregates are primarily made up of the protein produced from the TARDBP gene. It is unclear how the TARDBP gene's protein product plays a role in ALS when the gene is not mutated. C9orf72 gene mutations do not appear to cause protein aggregates. Mutations in this gene likely result in a decrease in normal C9orf72 protein and possibly the production of an altered protein that interferes with cell function.

Studies have identified multiple mechanisms by which gene mutations associated with ALS cause the disorder. Some mutations lead to a disruption in the 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, leading to muscle weakness and atrophy. Other mutations lead to a slowing in the transport of materials needed for the proper function of axons in motor neurons, eventually causing the motor neurons to die. Additional gene mutations prevent the breakdown of toxic substances, leading to their buildup in nerve cells. The accumulation of toxic substances can damage motor neurons and eventually cause cell death. In some cases of ALS, it is unknown how the gene mutation causes the condition.

The cause of sporadic ALS is largely unknown but probably involves a combination of genetic and environmental factors. Variations in many genes that are involved in transmission of nerve impulses and transporting materials within neurons, including the DCTN1, NEFH, PRPH, and SMN1 genes, increase the risk of developing ALS. Gene mutations that are risk factors for ALS may add, delete, or change DNA building blocks (nucleotides), resulting in the production of a protein with an altered or reduced function. A genetic variation can cause an increase in the number of copies of the whole SMN1 gene. This type of mutation leads to increased production of protein from the SMN1 gene, which is thought to raise the risk of developing ALS. While variations in these genes have been associated with ALS, it is unclear how these changes influence the development of the disease. People with a gene variation that increases their risk for ALS likely require additional genetic and environmental triggers to develop the disorder.

Read more about the ALS2, ANG, C9orf72, DCTN1, FUS, NEFH, PRPH, SETX, SMN1, SOD1, TARDBP, and VAPB genes.

See a list of genes associated with amyotrophic lateral sclerosis.

How do people inherit amyotrophic lateral sclerosis?

About 90 to 95 percent of ALS cases are sporadic and are not inherited.

An estimated 5 to 10 percent of ALS is familial and caused by mutations in one of several genes. The pattern of inheritance varies depending on the gene involved. Most cases are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Less frequently, ALS is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Because an affected person's parents are not affected, autosomal recessive ALS is often mistaken for sporadic ALS even though it is caused by a familial genetic mutation.

Very rarely, ALS is inherited in an X-linked dominant pattern. X-linked conditions occur when the gene associated with the condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Some people who inherit a gene mutation known to cause ALS never develop features of the condition. (This situation is known as reduced penetrance.) It is unclear why some people with a mutated gene develop the disease and other people with a mutated gene do not.

Where can I find information about diagnosis or management of amyotrophic lateral sclerosis?

These resources address the diagnosis or management of amyotrophic lateral sclerosis and may include treatment providers.

You might also find information on the diagnosis or management of amyotrophic lateral sclerosis in Educational resources and Patient support.

General information about the diagnosis and management of genetic conditions is available in the Handbook. Read more about genetic testing, particularly the difference between clinical tests and research tests.

To locate a healthcare provider, see How can I find a genetics professional in my area? in the Handbook.

Where can I find additional information about amyotrophic lateral sclerosis?

You may find the following resources about amyotrophic lateral sclerosis helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for amyotrophic lateral sclerosis?

  • ALS
  • amyotrophic lateral sclerosis with dementia
  • Charcot disease
  • dementia with amyotrophic lateral sclerosis
  • Lou Gehrig disease
  • motor neuron disease, amyotrophic lateral sclerosis

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines and How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about amyotrophic lateral sclerosis?

Where can I find general information about genetic conditions?

What glossary definitions help with understanding amyotrophic lateral sclerosis?

References (19 links)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.

 
Reviewed: August 2012
Published: August 25, 2014