Amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis -ALS-) - Genes C9ORF72, SOD1, and FUS TARDBP

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons. These nerve cells are found in the spinal cord and brain. In ALS, motor neurons eventually die, resulting in problems with muscle control and movement.

There are several different types of amyotrophic lateral sclerosis, which are distinguished by their signs and symptoms and their genetic cause. Most people with ALS have a form of the disease described as sporadic, which means that occurs in people with no apparent history of the disease in your family. Usually, people with sporadic develop the characteristics of the disease in the late 50's or early 60 years old. Approximately between 5% and 10% of people with ALS, a family history of the disease or a related condition called frontotemporal dementia (FTD). Signs and symptoms of familial ALS usually appear first around fifty years old. Rarely, people with familial ALS symptoms develop in childhood or adolescence. These people have a form of the disease known as juvenile amyotrophic lateral sclerosis.

Early signs and symptoms of the disease may include muscle spasms, cramps, stiffness or weakness. Affected individuals may develop difficulty speaking and, later, dysphagia. As the disease progresses, the muscles weaken, and arms and legs begin to present atrophies. People with ALS lose their strength and ability to walk. In addition, breathing becomes difficult because the breathing muscles weaken. Approximately 20% of people with ALS develop frontotemporal dementia (FTD). It is unclear how the development of ALS and FTD are related. Individuals who develop both disorders are diagnosed with ALS-FTD. Most people with ALS die of respiratory failure between 2 and 10 years after the first signs and symptoms appear, even though the disease progression varies widely among affected individuals.

A rare form of ALS, which frequently occurs in families is known as ALS-Parkinsonism-dementia (ALS-PDC) complex. This form is characterized by signs and symptoms of ALS, parkinsonism plus, and dementia. The signs of parkinsonism include bradykinesia, rigidity and tremors. The affected members of the same family may have different combinations of signs and symptoms.

Mutations in several genes may cause familial ALS and help develop sporadic ALS. Mutations in the gene C9ORF72 (chromosome 9 open reading frame 72) is responsible for approximately 30 to 40% of familial ALS cases in the United States and Europe. Globally, the SOD1 gene mutations (superoxide dismutase 1, soluble) represent 15 to 20% of familial ALS. Mutations in TARDBP (TAR DNA binding protein) and FUS (FUS RNA binding protein) genes each represent approximately 5% of cases. Other genes that have been associated with familial ALS each represent a small proportion of cases. It is estimated that 60% of people with familial ALS has a genetic mutation identified. The cause of the disease in other individuals is unknown.

The C9ORF72 gene (chromosome 9 open reading frame 72), located on the short arm of chromosome 9 (9p21.2), encodes a protein found in many tissues, but whose function is unknown. The C9ORF72 protein is encoded in many regions of the brain. This protein appears to be located in the presynaptic terminals. Mutations in the gene C9ORF72 in people with amyotrophic lateral sclerosis (ALS), consist of hexanucleotídica repeat expansions. It is believed that these individuals have more than about 30 repetitions. These mutations reduce the amount of encoded protein C9ORF72. In addition, the encoded altered protein can interfere with cell function. It is unclear how the reduction or alteration of this protein leads to the signs and symptoms of ALS. Some people with genetic mutations C9ORF72 also develop frontotemporal dementia (FTD). It is not clear why some people with genetic mutations C9ORF72 develop FTD and others not. Individuals who develop both disorders are diagnosed with ALS-FTD.

The SOD1 gene (superoxide dismutase 1, soluble), located on the long arm of chromosome 21 (21q22.11), encoding the enzyme superoxide dismutase, abundant in cells throughout the body. This enzyme plays a role in the breakdown of toxic oxygen molecules, called superoxide radicals. They have identified at least 200 mutations in the SOD1 gene in people with amyotrophic lateral sclerosis (ALS). Most of these mutations change amino acids in the enzyme superoxide dismutase. About half of people with ALS in the United States have a particular mutation that replaces the amino acid alanine for the amino acid valine at position 5 in the enzyme (Ala5Val or A5V), which results in an enzyme with altered function. Often the A5V mutation is associated with more severe signs and symptoms. Although ALS is associated with the death of motor neurons, it is not clear why these cells are particularly sensitive to the SOD1 gene mutations. It has been suggested several ways in which the altered enzyme may cause the death of motor neurons. Possibilities include an increase in harmful superoxide radicals, increased production of other toxic radicals, increased cell death, or accumulation of superoxide dismutase which can be toxic to cells.

The TARDBP gene (TAR DNA binding protein), located on the short arm of chromosome 1 (1p36.22), encoding the TDP-43 protein. This protein is found in the cell nucleus in most tissues and is involved in many processes of protein production. TDP-43 protein is involved in mRNA processing. They have identified at least 60 mutations in the gene responsible TARDBP amyotrophic lateral sclerosis (ALS). Most mutations change amino acids in the TDP-43 protein. Most of these changes affect the region of the protein involved in RNA processing, probably disrupts subsequent encoding other proteins and alters the function of the TDP-43 protein. Some people with the disease due to genetic mutations TARDBP also develop frontotemporal dementia (FTD). It is not clear why some people with genetic mutations TARDBP develop FTD and others not. Individuals who develop both conditions are diagnosed with ALS-FTD.

FUS gene (FUS RNA binding protein), located on the short arm of chromosome 16 (16p11.2), encodes a protein called fusion protein sarcoma (FUS). This protein is found in the cell nucleus in most tissues and is involved in many of the processes of production of proteins and transcriptional activation. This protein also helps repair DNA errors. In addition, the FUS protein is also involved in mRNA processing. They have identified at least 85 mutations in the FUS gene in amyotrophic lateral sclerosis people (ALS). Most of these mutations change amino acids in the protein that affects the region involved in DNA binding and mRNA processing. These mutations may interfere with the transport of mRNA outside the cell nucleus, particularly of nerve cells controlling muscle movement. A disruption in mRNA transport protein accumulation probably generates FUS inside nerve cells. It is unclear whether an accumulation of protein aggregates kills nerve cells. People with lateral sclerosis due to mutations in the gene FUS sclerosis tend to develop the disease before and have a lower life expectancy compared to individuals with mutations in other genes. Rarely, people with ALS due to mutations of the gene FUS also develop frontotemporal dementia (FTD). It is not clear why some people with mutations in the FUS gene develop FTD and others not.

About 90 to 95% of cases are sporadic amyotrophic lateral sclerosis and not inherited. Between 5 and 10% of the cases associated with ALS are familial inheritance pattern and varies depending on the gene involved. Most cases are inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In most cases, an affected person has a parent with the disease. Less often, ALS is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. Rarely, ALS is inherited in a dominant X-linked pattern in women, a mutation in one of the two copies of the gene in each cell is sufficient to express the disease. In males (who have only one X chromosome), a mutation in the single gene copy in each cell gives rise to the disease. In most cases, men report more severe symptoms of the disease than women. A feature of the X-linked inheritance is that fathers can not pass X-linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with amyotrophic lateral sclerosis (ALS), by complete PCR amplification of the exons of C9ORF72, SOD1, TARDBP and FUS, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).