Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that control muscle movement. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die (atrophy) over time, leading to muscle weakness, a loss of muscle mass, and an inability to control 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 ALS or a related condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. 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 rare 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 (dysarthria) 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 atrophies. Individuals with ALS eventually lose muscle strength and the ability to walk. Affected individuals eventually become wheelchair-dependent and increasingly require help with personal care and other activities of daily living. 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 FTD. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. 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.

A rare form of ALS that often runs in families is known as ALS-parkinsonism-dementia complex (ALS-PDC). This disorder is characterized by the signs and symptoms of ALS, in addition to a pattern of movement abnormalities known as parkinsonism, and a progressive loss of intellectual function (dementia). Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms.

About 5,000 people in the United States are diagnosed with ALS each year. Worldwide, this disorder occurs in 2 to 5 per 100,000 individuals. Only a small percentage of cases have a known genetic cause.

Among the Chamorro people of Guam and people from the Kii Peninsula of Japan, ALS-PDC can be 100 times more frequent than ALS is in other populations. ALS-PDC has not been reported outside of these populations.

Mutations in several genes can cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72 gene account for 30 to 40 percent of familial ALS in the United States and Europe. Worldwide, SOD1 gene mutations cause 15 to 20 percent of familial ALS, and TARDBP and FUS gene mutations each account for about 5 percent of cases. 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 is unknown.

The C9orf72, SOD1, TARDBP, and FUS genes are key to the normal functioning of motor neurons and other cells. It is unclear how mutations in these genes contribute to the death of motor neurons, but it is thought that motor neurons are more sensitive to disruptions in function because of their large size. 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.

In some cases of familial ALS due to mutations in other genes, studies have identified the mechanisms that lead to ALS. Some gene 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, including the previously mentioned genes involved in transmission of nerve impulses and transportation of materials within neurons, 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. While genetic variations have been associated with sporadic ALS, not all genetic factors have been identified and it is unclear how most genetic changes influence the development of the disease. People with a gene variation that increases their risk of ALS likely require additional genetic and environmental triggers to develop the disorder.

About 90 to 95 percent of ALS cases are sporadic, which means they 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. Some people who inherit a familial genetic 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.

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 tend to develop the disease earlier and have a decreased life expectancy compared with females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Normal Function

The ALS2 gene provides instructions for making a protein called alsin. Alsin is produced in a wide range of tissues, with highest amounts in the brain. This protein is particularly abundant in motor neurons, the specialized nerve cells in the brain and spinal cord that control the movement of muscles.

Alsin turns on (activates) multiple proteins called GTPases that convert a molecule called GTP into another molecule called GDP. GTPases play important roles in cell division, the process by which cells mature to carry out specific functions (differentiation), and the self-destruction of cells (apoptosis). The GTPases play important roles in several cell processes. The GTPases that are activated by alsin are involved in the proper placement of the various proteins and fats that make up the cell membrane, the transport of molecules from the cell membrane to the interior of the cell (endocytosis), and the development of specialized structures called axons and dendrites that project from neurons and are essential for the transmission of nerve impulses.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

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Infantile-onset ascending hereditary spastic paralysis

At least 20 ALS2 gene mutations have been found to cause infantile-onset ascending hereditary spastic paralysis. This disorder is characterized by progressive weakness and stiffness of muscles in the legs, arms, neck, and head that begins within the first 2 years of life. Mutations in the ALS2 gene alter the instructions for making alsin, often resulting in the production of an abnormally short alsin protein that is unstable and rapidly broken down. It is unclear exactly how ALS2 gene mutations cause infantile-onset ascending hereditary spastic paralysis. Research suggests that a lack of alsin and the subsequent loss of GTPase functions, such as endocytosis and the development of axons and dendrites, contribute to the progressive atrophy of motor neurons that is characteristic of this condition.

Juvenile primary lateral sclerosis

Researchers have identified three mutations in the ALS2 gene that cause juvenile primary lateral sclerosis, which is characterized by progressive weakness and stiffness of muscles in the arms, legs, and face that typically begins in childhood. Two of the mutations that cause this disorder delete nucleotides, and one mutation replaces one nucleotide with an incorrect nucleotide. These mutations alter the instructions for producing alsin. As a result, alsin is unstable and is broken down rapidly by the cell, or it is disabled and cannot function properly.

It is unclear how the loss of functional alsin protein causes juvenile primary lateral sclerosis. Loss of alsin may result in a disruption of the movement of molecules within cells or impair the development of axons and dendrites. Researchers suggest that motor neurons and their long axons may be particularly vulnerable to changes in cell development. As a result, motor neuron function declines and eventually these nerve cells die, leading to the signs and symptoms of juvenile primary lateral sclerosis.

Other Names for This Gene

• ALS2_HUMAN
• ALS2CR6
• ALSJ
• amyotrophic lateral sclerosis 2 (juvenile)
• IAHSP
• KIAA1563
• PLSJ

Genomic Location

Normal Function

The ATXN2 gene provides instructions for making a protein called ataxin-2. This protein is found throughout the body, but its function is unknown. Ataxin-2 is found in the fluid inside cells (cytoplasm) and seems to interact with a cell structure called the endoplasmic reticulum. The endoplasmic reticulum is involved in protein production, processing, and transport. Researchers believe that ataxin-2 may be involved in processing RNA, a chemical cousin of DNA. Ataxin-2 is also thought to play a role in the translation of genetic information to produce proteins.

One region of the ATXN2 gene contains a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated approximately 22 times within the gene.

Health Conditions Related to Genetic Changes

Spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) is a condition characterized by progressive problems with movement. SCA2 results from a mutation in the ATXN2 gene known as a trinucleotide repeat expansion. This mutation increases the length of the repeated CAG segment in the ATXN2 gene. People with 32 or more repeats CAG repeats in the ATXN2 gene develop SCA2.

It is unclear how the abnormally long CAG segment affects the function of the ataxin-2 protein. The abnormal protein apparently leads to cell death, as people with SCA2 show a loss of brain cells. Certain brain cells called Purkinje cells seem to be particularly sensitive to the presence of abnormal ataxin-2. Purkinje cells are located in the part of the brain that coordinates movement (cerebellum) and are involved in chemical signaling between nerve cells (neurons). It is unknown how the abnormal ataxin-2 protein leads to the death of Purkinje and other brain cells. Over time, the loss of these cells causes the movement problems characteristic of SCA2.

Amyotrophic lateral sclerosis

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Other Names for This Gene

• ataxin-2
• ATX2
• ATX2_HUMAN
• SCA2

Genomic Location

Normal Function

The C9orf72 gene provides instructions for making a protein that is found in various tissues. The protein is abundant in nerve cells (neurons) in the outer layers of the brain (cerebral cortex) and in specialized neurons in the brain and spinal cord that control movement (motor neurons). The C9orf72 protein is thought to be located at the tip of the neuron in a region called the presynaptic terminal. This area is important for sending and receiving signals between neurons.

The C9orf72 protein likely plays a role in many processes involving the chemical cousin of DNA, known as RNA. This protein is thought to influence the production of RNA from genes, the production of proteins from RNA, and the transport of RNA within the cell.

The C9orf72 gene contains a segment of DNA made up of a series of six DNA building blocks (nucleotides), four guanines followed by two cytosines (written as GGGGCC). This segment (known as a hexanucleotide repeat) can occur once or be repeated multiple times in a row; estimates suggest repeats of up to 30 times have no negative effect on gene function.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

Mutations in the C9orf72 gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. These mutations affect the GGGGCC segment of the gene. When this series of nucleotides is repeated too many times, it can cause ALS. This type of mutation is called a hexanucleotide repeat expansion. Although it is not clear exactly how many hexanucleotide repeats are needed to cause disease, researchers believe that having more than about 30 repeats can lead to ALS.

It is unclear whether the hexanucleotide repeat expansion reduces C9orf72 protein function or leads to the production of a protein with abnormal function that disrupts RNA and protein production in the cell, resulting in the formation of protein clumps (aggregates). In ALS, the large size of motor neurons is thought to make these cells vulnerable to impairments in normal cell function. Disruptions in C9orf72 protein function may lead to premature motor neuron cell death, resulting in the signs and symptoms of ALS.

Some people with ALS caused by C9orf72 gene mutations also develop a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. It is unclear why some people with C9orf72 gene mutations develop FTD and others do not. Individuals who develop both conditions are diagnosed as having ALS-FTD.

Other Names for This Gene

• CI072_HUMAN
• MGC23980
• uncharacterized protein C9orf72

Genomic Location

Normal Function

The CHMP2B gene provides instructions for making a protein called charged multivesicular body protein 2B. This protein is active in the brain, where it appears to be essential for the survival of nerve cells (neurons).

Charged multivesicular body protein 2B forms one part (subunit) of a group of proteins known as the ESCRT-III complex. This complex helps transport other proteins from the cell membrane to the interior of the cell, a process known as endocytosis. In particular, the ESCRT-III complex is involved in the endocytosis of proteins that need to be broken down (degraded) by the cell. The complex helps sort these proteins into structures called multivesicular bodies (MVBs), which deliver them to lysosomes. Lysosomes are compartments within cells that digest and recycle many different types of molecules.

Charged multivesicular body protein 2B is regulated by a segment at one end of the protein known as the C-terminal domain. This domain usually keeps the protein turned off (inactive). The inactive protein is unable to interact with other subunits of the ESCRT-III complex, which prevents the complex from forming when it is not needed. The C-terminal domain also plays an important role in disassembling the ESCRT-III complex through its interaction with a protein called vacuolar protein sorting 4 (Vps4).

Health Conditions Related to Genetic Changes

CHMP2B-related frontotemporal dementia

Several changes in the CHMP2B gene have been identified in people with frontotemporal dementia. At least two of these genetic changes are thought to be mutations that cause the disease. It is unclear whether the other genetic changes also cause disease; they may be rare variations that are unrelated to the development of frontotemporal dementia.

Most people with CHMP2B-related frontotemporal dementia are members of a single, large Danish family. Affected individuals in this family have a particular mutation, written as 532-1G>C, that changes a single DNA building block (base pair) in the CHMP2B gene. This mutation leads to the production of two abnormal versions of charged multivesicular body protein 2B, both of which are missing the C-terminal domain.

Without the C-terminal domain, charged multivesicular body protein 2B is constantly turned on (active) as part of the ESCRT-III complex. It cannot interact with Vps4, so the complex cannot be disassembled when it is no longer needed. As a result, the ESCRT-III complex builds up within cells and disrupts the transport and degradation of other proteins. These abnormalities ultimately lead to the death of neurons in the brain.

A gradual loss of neurons throughout the brain is characteristic of CHMP2B-related frontotemporal dementia. Many of the features of this disease result from neuronal death in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. It is unclear why the signs and symptoms of this disease are related primarily to the frontal and temporal lobes.

Amyotrophic lateral sclerosis

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Other Names for This Gene

• CHM2B_HUMAN
• CHMP family, member 2B
• CHMP2.5
• chromatin modifying protein 2B
• DMT1
• hVps2-2
• vacuolar protein sorting-associated protein 2-2
• VPS2 homolog B
• VPS2-2
• VPS2B

Genomic Location

Normal Function

The DCTN1 gene provides instructions for making a protein called dynactin-1. At least two different versions of this protein are produced in cells. The two versions differ in size; the larger version is called p150-glued, and the smaller version is called p135.

Both versions of the dynactin-1 protein interact with several other proteins to form a group (a complex) of proteins called dynactin. The p150-glued version of dynactin-1 is the largest component (subunit) of the dynactin complex. This complex plays a critical role in cell division and the transport of materials within cells. To carry out these roles, the complex's p150-glued subunit attaches (binds) to a protein called dynein, which acts as a motor, and also binds to a track-like system of small tubes called microtubules. The dynactin complex, dynein, and microtubules work together like a conveyer belt to move materials within cells.

Researchers believe that the dynactin complex is particularly important for the proper function of axons, which are specialized extensions of nerve cells (neurons). Axons transmit impulses from nerve to nerve and from nerves to muscles. Axons can be quite long; some are more than 3 feet in length. The dynactin complex is a critical part of a rapid transport system that supplies axons with materials to keep them healthy and functioning efficiently.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Perry syndrome

At least five mutations in the DCTN1 gene have been found to cause Perry syndrome. This progressive brain disease is characterized by a pattern of movement abnormalities known as parkinsonism, psychiatric changes, weight loss, and abnormally slow breathing (hypoventilation).

Most of the mutations that cause Perry syndrome change single protein building blocks (amino acids) in the dynactin-1 protein. These genetic changes impair the ability of the p150-glued version of dynactin-1 to bind to the dynactin complex and to microtubules. An incomplete dynactin complex has a reduced ability to transport materials within cells. Slow or abnormal transport of materials needed for the normal function of neurons causes these cells to malfunction and ultimately die. A gradual loss of neurons in areas of the brain that regulate movement, emotion, and breathing underlies the signs and symptoms of Perry syndrome.

Charcot-Marie-Tooth disease

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Other disorders

Researchers have identified at least one DCTN1 gene mutation that causes a nervous system disorder called distal hereditary motor neuronopathy type VIIB. Signs and symptoms of this disorder first appear in early adulthood and include breathing difficulties and progressive weakness of muscles in the face and hands. Muscle weakness in the feet and legs develops later. The mutation that causes this disorder changes one of the amino acids used to make dynactin-1. Specifically, it replaces the amino acid glycine with the amino acid serine at protein position 59 (written as Gly59Ser or G59S). It is unclear how this mutation causes distal hereditary motor neuronopathy type VIIB. The altered protein may result in an abnormal dynactin complex and disturb interactions between the complex and microtubules, which would disrupt transport activities and impair the function of axons in neurons.

At least one DCTN1 gene mutation is associated with a brain disorder called frontotemporal dementia (FTD) without the features of amyotrophic lateral sclerosis (ALS). This disorder occurs in mid- to late adulthood and is characterized by changes in personality and behavior that may make it difficult for affected individuals to interact with others in a socially appropriate manner. Changes in speech and language can also occur, such as problems using the correct word and difficulty with language comprehension. The DCTN1 gene mutation associated with this disorder replaces the amino acid arginine with the amino acid lysine at protein position 1101 (written as Arg1101Lys or R1101K). It is unclear how this mutation causes FTD. This mutation likely alters the 3-dimensional shape of dynactin-1, which may impair its binding with the dynactin complex and microtubules. This impaired binding may slow the transport of materials needed for the proper function of axons and the efficient transmission of nerve impulses.

Other Names for This Gene

• 150 kDa dynein-associated polypeptide
• DAP-150
• DP-150
• DYNA_HUMAN
• dynactin 1
• dynactin 1 (p150, glued homolog, Drosophila)

Genomic Location

Normal Function

The FUS gene provides instructions for making a protein that is found within the cell nucleus in most tissues and is involved in many of the steps of protein production.

The FUS protein attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. The FUS protein is also involved in processing molecules called messenger RNA (mRNA), which serve as the genetic blueprints for making proteins. By cutting and rearranging mRNA molecules in different ways, the FUS protein controls the production of different versions of certain proteins. This process is known as alternative splicing. Once the FUS protein processes the mRNA, it transports the mRNA out of the nucleus where it gets taken up by other cell structures to be further processed into a mature protein. The FUS protein also helps repair errors in DNA, which prevents cells from accumulating genetic damage.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

At least 85 mutations in the FUS gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most of these mutations change single protein building blocks in the FUS protein and often affect the region of the protein involved in DNA binding and mRNA processing. These mutations may interfere with the transport of mRNA out of the nucleus of cells. As a result, FUS protein and mRNA are trapped within cells and likely form clumps (aggregates), which have been found in nerve cells that control muscle movement (motor neurons) in some people with ALS. It is unclear if protein aggregates cause the nerve cell death that leads to ALS. People with ALS caused by mutations in the FUS gene tend to develop the disease at a younger age and have a decreased life expectancy compared with individuals who have sporadic ALS or ALS caused by mutations in other genes.

Rarely, people with ALS caused by FUS gene mutations also develop a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. It is unclear why some people with FUS gene mutations develop FTD and others do not. Individuals who develop both conditions are diagnosed as having ALS-FTD.

Ewing sarcoma

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Cancers

Specific mutations involving the FUS gene are involved in several types of cancer. The mutations that cause these tumors are acquired during a person's lifetime and are present only in the tumor cells. This type of genetic change, called a somatic mutation, is not inherited. Most commonly, mutations in this gene are found in tumors called soft tissue sarcomas, which develop in bones or in soft tissues such as nerves or cartilage. FUS gene mutations have also been found in myxoid liposarcomas, which occur in fatty tissues of the body, and in cancer of the blood-forming cells in the bone marrow called acute myeloid leukemia (AML). The genetic changes associated with these cancers are rearrangements (translocations) of genetic material between chromosome 16 (where the FUS gene is located) and other chromosomes. These translocations break chromosome 16 in the middle of the FUS gene and fuse it with another gene on a different chromosome, creating a fusion gene. Fusion genes usually have partial function of both genes involved. The FUS gene promotes DNA transcription and protein production, which helps promote cell growth; this gene might fuse with another gene that could allow cell growth to continue at a rapid pace. When cell growth is left uncontrolled, cancer can develop.

Other Names for This Gene

• ALS6
• ETM4
• FUS1
• FUS_HUMAN
• fused in sarcoma
• heterogeneous nuclear ribonucleoprotein P2
• hnRNP-P2
• HNRNPP2
• oncogene FUS
• oncogene TLS
• POMP75
• RNA-binding protein FUS
• TLS
• translocated in liposarcoma protein

Genomic Location

Normal Function

The MATR3 gene provides instructions for making a protein called matrin 3, which is found in the nucleus of the cell as part of the nuclear matrix. The nuclear matrix is a network of proteins that provides structural support for the nucleus and aids in several important nuclear functions.

The function of the matrin 3 protein is unknown. This protein can attach to (bind) RNA, which is a chemical cousin of DNA. Some studies indicate that matrin 3 binds and stabilizes a type of RNA called messenger RNA (mRNA), which provides the genetic blueprint for proteins. Matrin 3 may also bind certain abnormal RNAs that could lead to nonfunctional or harmful proteins, thereby blocking the formation of such proteins. Other studies suggest that the matrin 3 protein may be involved in cell survival.

Health Conditions Related to Genetic Changes

Distal myopathy 2

At least one mutation in the MATR3 gene has been identified in people with distal myopathy 2, a condition characterized by muscle and vocal cord weakness. The MATR3 gene mutation associated with distal myopathy 2 changes a single protein building block (amino acid) in the matrin 3 protein. This mutation, known as Ser85Cys (or S85C), replaces the amino acid serine with the amino acid cysteine at position 85 of the protein.

The effect of the S85C mutation on the function of the matrin 3 protein is unknown, although one study indicates that the mutation may change the location of the protein in the nucleus. Researchers are working to determine how this gene mutation leads to the signs and symptoms of distal myopathy 2.

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Other Names for This Gene

• MATR3_HUMAN
• matrin-3
• matrin-3 isoform a
• matrin-3 isoform b
• MGC9105
• MPD2

Genomic Location

Normal Function

The SETX gene provides instructions for making a protein called senataxin. Senataxin is produced in a wide range of tissues, including the brain, spinal cord, and muscles. Based on the structure of senataxin, researchers believe that it is one of a class of proteins called helicases, which attach to particular regions of DNA or RNA (a chemical cousin of DNA) and temporarily unwind the strands of the molecule. By unwinding the strands, helicases allow other proteins to reach the strands to perform their function. Although senataxin's role in cells is not completely understood, it appears to be involved in the production of proteins from genes (transcription), the processing of RNA molecules, and the repair of damaged DNA.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Ataxia with oculomotor apraxia

At least 125 mutations in the SETX gene have been found to cause ataxia with oculomotor apraxia type 2. This condition is characterized by difficulty coordinating movements (ataxia) and problems with side-to-side movements of the eyes (oculomotor apraxia). Most mutations replace single protein building blocks (amino acids) in senataxin. The mutations associated with ataxia with oculomotor apraxia type 2 are thought to disrupt the helicase function of senataxin. Although it is unclear how impaired senataxin function leads to the signs and symptoms of ataxia with oculomotor apraxia type 2, some researchers suggest that it disrupts DNA repair and can lead to an accumulation of DNA damage in cells. This accumulation can lead to cell death and seems particularly harmful to cells in the part of the brain involved in coordinating movements (the cerebellum), causing the characteristic movement problems of ataxia with oculomotor apraxia type 2.

Charcot-Marie-Tooth disease

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Other Names for This Gene

• ALS4
• AOA2
• KIAA0625
• SCAR1
• Sen1
• SETX_HUMAN

Genomic Location

Normal Function

The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein. The SMN protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

In cells, the SMN complex plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble the cellular machinery needed to process pre-mRNA. The SMN complex is also important for the development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses between neurons and from neurons to muscles.

A small amount of SMN protein is produced from a gene similar to SMN1 called SMN2. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are smaller and quickly broken down.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Spinal muscular atrophy

Many mutations in the SMN1 gene have been found to cause spinal muscular atrophy. This condition is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. About 95 percent of individuals with spinal muscular atrophy have mutations that delete a piece of the SMN1 gene in both copies of the gene in each cell. As a result, SMN protein production is impaired. In about 5 percent of people with this disorder, one copy of the SMN1 gene is missing a section, and the other copy has a different kind of mutation that disrupts the production or function of the SMN protein.

Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA, and subsequently the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to a reduction in the amount of SMN protein. Some research findings indicate that a shortage of this protein impairs the formation and function of axons and dendrites, leading to the death of motor neurons.

Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. Multiple copies of the SMN2 gene are usually associated with less severe features of the condition that develop later in life. The small amount of SMN protein produced by the SMN2 genes can help make up for the protein deficiency caused by SMN1 gene mutations. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Other Names for This Gene

• BCD541
• SMA1
• SMA2
• SMA3
• SMA4
• SMN_HUMAN
• SMNT
• T-BCD541
• telomeric SMN

Genomic Location

Normal Function

The SOD1 gene provides instructions for making an enzyme called superoxide dismutase, which is abundant in cells throughout the body. This enzyme attaches (binds) to molecules of copper and zinc to break down toxic, charged oxygen molecules called superoxide radicals. The molecules are byproducts of normal cell processes, and they must be broken down regularly to avoid damaging cells.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

At least 200 mutations in the SOD1 gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most of these mutations change one of the protein building blocks (amino acids) in the superoxide dismutase enzyme. About half of all Americans with ALS caused by SOD1 gene mutations have a particular mutation that replaces the amino acid alanine with the amino acid valine at position 5 in the enzyme, written as Ala5Val or A5V. (Because of variations in the ways amino acids are counted in proteins, this mutation is sometimes called Ala4Val or A4V.) ALS caused by the A5V mutation is generally associated with a shorter life expectancy compared with ALS caused by other genetic mutations.

ALS is caused by the death of nerve cells that control muscle movement (motor neurons). It is unclear why these cells are particularly sensitive to SOD1 gene mutations. Researchers have suggested several ways in which the altered enzyme may cause the death of motor neurons. These possibilities include an increase in harmful superoxide radicals, increased production of other types of toxic radicals, increased cell death, or accumulation of clumps (aggregates) of misfolded superoxide dismutase that may be toxic to cells.

Other Names for This Gene

• ALS1
• Cu/Zn superoxide dismutase
• indophenoloxidase A
• IPOA
• SODC_HUMAN
• superoxide dismutase 1, soluble
• superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))
• superoxide dismutase, cystolic
• superoxide dismutase-1, soluble

Genomic Location

Normal Function

The SPG11 gene provides instructions for making the protein spatacsin. Spatacsin is active (expressed) throughout the nervous system, although its exact function is unknown. Researchers speculate that it may help control the activity of particular genes (gene expression) or play a role in the transport (trafficking) of proteins. Spatacsin may also be involved in the maintenance of axons, which are specialized extensions of nerve cells (neurons) that transmit impulses throughout the nervous system.

Health Conditions Related to Genetic Changes

Spastic paraplegia type 11

More than 65 mutations in the SPG11 gene have been found to cause spastic paraplegia type 11. Most of these mutations change the structure of the spatacsin protein. The effect that the altered spatacsin protein has on the nervous system is not known. Researchers suggest that mutations in spatacsin may cause the signs and symptoms of spastic paraplegia type 11 by interfering with the protein's proposed role in the maintenance of axons.

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other Names for This Gene

• FLJ21439
• KIAA1840
• spastic paraplegia 11 (autosomal recessive)
• SPATACSIN
• SPTCS_HUMAN

Genomic Location

Normal Function

The SQSTM1 gene provides instructions for making a protein called p62. This protein plays an important role in bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. The p62 protein helps regulate this process through its role in a chemical signaling pathway that promotes the formation of osteoclasts. Osteoclasts are specialized cells that break down bone tissue during bone remodeling.

Studies suggest that p62 may have other functions in addition to its role in bone remodeling. It may be involved in recycling worn-out cell parts and unneeded proteins (autophagy), the self-destruction of cells (apoptosis), and the body's immune responses and inflammatory reactions.

Health Conditions Related to Genetic Changes

Paget disease of bone

More than 20 mutations in the SQSTM1 gene have been found to cause Paget disease of bone. Many SQSTM1 gene mutations change single protein building blocks (amino acids) in the p62 protein. The most common mutation replaces the amino acid proline with the amino acid leucine at protein position 392 (written as Pro392Leu or P392L).

Through a mechanism that is not well understood, SQSTM1 gene mutations appear to overactivate the chemical signaling pathway that promotes osteoclast formation. The increased signaling stimulates the production of too many osteoclasts and triggers these cells to break down bone abnormally. In people with Paget disease of bone, affected bone is broken down and replaced much faster than usual. When the new bone tissue grows, it is weaker and less organized than normal bone. These problems with bone remodeling cause certain bones to become unusually large, misshapen, and easily broken (fractured). It is unclear why the disease affects some bones but not others.

Amyotrophic lateral sclerosis

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Other Names for This Gene

• A170
• EBI3-associated protein p60
• OSIL
• oxidative stress induced like
• p60
• p62
• p62B
• PDB3
• phosphotyrosine independent ligand for the Lck SH2 domain p62
• SQSTM_HUMAN
• ubiquitin-binding protein p62
• ZIP3

Genomic Location

Normal Function

The TARDBP gene provides instructions for making a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein is found within the cell nucleus in most tissues and is involved in many of the steps of protein production. The TDP-43 protein attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. This protein can also bind to RNA, a chemical cousin of DNA, to ensure the RNA's stability. The TDP-43 protein is involved in processing molecules called messenger RNA (mRNA), which serve as the genetic blueprints for making proteins. By cutting and rearranging mRNA molecules in different ways, the TDP-43 protein controls the production of different versions of certain proteins. This process is known as alternative splicing. The TDP-43 protein can influence various functions of a cell by regulating protein production.

The TARDBP gene is particularly active (expressed) during early development before birth when new tissues are forming. Many of the proteins whose production is influenced by the TDP-43 protein are involved in nervous system and organ development.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

At least 60 mutations in the TARDBP gene have been found to cause amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement. Most mutations change single protein building blocks (amino acids) in the TDP-43 protein. The majority of these changes affect the region of the protein involved in mRNA processing, likely disrupting the production of other proteins. Changes to the TDP-43 protein cause the protein to misfold and form protein clumps (aggregates), which have been found in nerve cells that control muscle movement (motor neurons) in some people with ALS. It is unclear whether TDP-43 protein aggregates causes the nerve cell death that leads to ALS or if they are a byproduct of a dying cell.

Some people with ALS caused by TARDBP gene mutations also develop a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. It is unclear why some people with TARDBP gene mutations develop FTD and others do not. Individuals who develop both conditions are diagnosed as having ALS-FTD.

Other disorders

Mutations in the TARDBP gene have been found to cause frontotemporal dementia (FTD) without features of amyotrophic lateral sclerosis (ALS, described above). FTD caused by TARDBP gene mutations is characterized by a gradual loss of problem-solving skills and language comprehension. Affected individuals often have changes in personality and behavior that may make it difficult to interact with others in a socially appropriate manner. Most TARDBP gene mutations that cause FTD change single amino acids in the TDP-43 protein. These mutations are thought to affect only part of the protein, leaving other parts of the protein functional. Because these TARDBP gene mutations result in a protein with some residual function, the features of the condition tend to appear later in life, in one's late sixties or early seventies. Some people who inherit the altered TARDBP gene never develop FTD, a situation known as reduced penetrance.

Other Names for This Gene

• ALS10
• TADBP_HUMAN
• TAR DNA-binding protein 43
• TAR DNA-binding protein-43
• TDP-43

Genomic Location

Normal Function

The VCP gene provides instructions for making an enzyme called valosin-containing protein. This enzyme is found throughout the body and has a wide variety of functions within cells. It is involved in cell division, joining (fusing) membranes within cells, reassembling cell structures after cells have divided, preventing the self-destruction of cells (apoptosis), and repairing damaged DNA.

Valosin-containing protein is part of the ubiquitin-proteasome system, which is the machinery that breaks down (degrades) unneeded proteins within cells. This system provides quality control by disposing of damaged, misshapen, and excess proteins. It also regulates the level of proteins involved in several critical cell activities, such as the timing of cell division and growth. Researchers believe that most of the functions of valosin-containing protein are directly or indirectly related to the ubiquitin-proteasome system.

Health Conditions Related to Genetic Changes

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia

Many variants (also known as mutations) in the VCP gene have been identified in people who have inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD). This rare disease causes muscle weakness (myopathy) and can also include a painful bone condition called Paget disease of bone and a brain condition called frontotemporal dementia that worsens over time.

The variants associated with IBMPFD each change a single protein building block (amino acid) in valosin-containing protein. Changes in the structure of this enzyme impair its ability to break down other proteins as part of the ubiquitin-proteasome system. As a result, excess and abnormal proteins build up in muscle, bone, and brain cells. The proteins form clumps (aggregates) that interfere with the normal functions of these cells. It remains unclear how damage to muscle, bone, and brain cells leads to the specific features of IBMPFD.

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Charcot-Marie-Tooth disease

MedlinePlus Genetics provides information about Charcot-Marie-Tooth disease

Other Names for This Gene

• 15S Mg(2+)-ATPase p97 subunit
• CDC48
• IBMPFD
• MGC131997
• MGC148092
• MGC8560
• p97
• TER ATPase
• TERA
• TERA_HUMAN

Genomic Location

What is ALS?
ALS is a disease that affects the nerve cells in both the upper and lower parts of the body. This disease causes the nerve cells to stop working and die. The nerves lose the ability to trigger specific muscles, which causes the muscles to become weak and leads to paralysis.

What causes ALS?
No one knows what causes most cases of ALS. Scientists have been studying many factors that could be linked with ALS, such as heredity and environmental exposures. Other scientists have looked at diet or injury. No cause has been found for most cases of ALS. In the future, scientists may find that many factors together cause ALS.

Is ALS linked to the environment?
Health studies have not found definite environmental factors that are linked with either ALS or other MNDs. Some studies suggested a possible link with exposure to heavy metals (e.g., lead and mercury). Other studies suggested a link with exposure to trace elements, solvents, radiation, and agricultural chemicals. No confirmed link was found with infections, diet, physical activity, and injury

How many people with ALS have been identified in the United States ?
Although no one knows for sure, reports suggest less than 20,000 people in the United States have ALS; every year about 5,000 people are told by their doctor that they have the disease. Because no records on ALS have been kept throughout the country, it is hard to estimate the number of ALS cases in the United States. CDC does not require doctors to report ALS cases.

Is ALS equally common among men and women?
ALS is slightly more common in men than women, but recent studies suggest that this difference is decreasing over time. Familial ALS is equally common in men and women.

Is ALS related to age?
ALS is age related; most people with ALS find out they have it when they are between 55 and 75 years of age.

How long do people with ALS live?
Most people live from 2 to 5 years after symptoms develop. How long a person lives with ALS seems to be related to age; people who are younger when the illness starts live slightly longer.

Can ALS be inherited?
About 5–10% of ALS cases occur within families. This is called familial ALS and it means that two or more people in a family have ALS. These cases are caused by several inherited factors. The most common is in a gene called SOD1.

Is familial ALS equally common among men and women?
Familial ALS is found equally among men and women.

How long do people with familial ALS live?
People with familial ALS usually do not fare as well as a person with ALS who are not related, and typically live only one to two years after symptoms appear.

Do clusters of ALS possibly exist? (I have been told by the doctor that I have ALS. Several other people from my town/school/ community/neighborhood have also been told by their doctor that they have ALS. Could these cases of ALS all be related?)
It is unknown whether clusters of ALS exist. Although it is possible that cases of ALS are related, studying clusters does not help when trying to determine what factors cause or trigger ALS. While ATSDR does not specifically conduct cluster investigations, suspected clusters of the disease have made it possible to conduct activities to identify the number of ALS cases in selected areas and the possible related environmental factors.

What are the problems with studying possible clusters of ALS?
The cause of most cases of ALS is unknown so we don’t know what to look for in a person’s past.We do not have current or complete data on the number of people with ALS. As a result, we cannot determine the “normal” or “expected” number of cases among a group of people or in a specific area. The expected number of cases of a disease is often found in an existing disease Registry, as with cancer. However, there are no registries or ongoing tracking efforts for ALS in the United States.The small number of cases in a possible cluster limits the ability to tell the difference between the number of cases that would occur naturally by chance and a number of cases that is greater than would be expected. Studies with large numbers of people are needed to determine the causes of such a disease.

What are motor neuron (nerve cell) diseases?
ALS is one of a group of conditions known as motor neuron diseases (MNDs). ALS affects nerve cells for muscles of both the upper and lower body. ALS accounts for 85 percent of MND cases. Other MNDs affect nerve cells for muscles of either the upper or lower body. Other MNDs include progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis.

What is MND prognosis?
Eighty-five percent of people with an MND have ALS. Most persons who are first diagnosed with progressive muscular atrophy, progressive bulbar palsy, or primary lateral sclerosis will develop problems with nerve cells for both upper and lower body muscles. The person will then be told they have ALS.