Instituto Valenciano de Microbiología
(IVAMI)

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
Email: 
www.ivami.com
CIF B-96337217

Print

Genetic testing - Amyotrophic lateral sclerosis - C9ORF72, SOD1, TARDBP and FUS genes.

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

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons. 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 several different types of amyotrophic lateral sclerosis, distinguished by their signs and symptoms and their genetic cause. Most people with ALS have a form of the disease that is described as sporadic, meaning that it occurs in people with no apparent family history of the disease. People with the sporadic type usually develop features of the disease in their late 50s or early 60s. About 5% to 10% of people with ALS have a family history of the disease or a related condition called frontotemporal dementia (FTD). The signs and symptoms of familial ALS usually first appear around the age of fifty. Rarely, people with familial ALS develop symptoms 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 slurred speech and, later, dysphagia. As the disease progresses, the muscles weaken, and the arms and legs begin to atrophy. People with ALS lose their strength and the ability to walk. Also, breathing becomes difficult because the muscles of the respiratory system weaken. About 20% of people with ALS develop frontotemporal dementia (FTD). It is not clear how the development of ALS and FTD are related. Individuals who develop both alterations 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, however, the progression of the disease varies widely among affected individuals.

A rare form of ALS that often runs in families is known as ALS-parkinsonism-dementia complex (ALS-PDC). This form is characterized by the signs and symptoms of ALS, in addition to Parkinsonism, and dementia. Signs of parkinsonism include bradykinesia, rigidity, and tremors. Affected members of the same family may have different combinations of signs and symptoms.

Mutations in several genes can cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9ORF72 (chromosome 9 open reading frame 72) gene are responsible for approximately 30% to 40% of cases of familial ALS in the United States and Europe. Worldwide, mutations in the SOD1 (superoxide dismutase 1, soluble) gene account for 15-20% of familial ALS. Mutations in the TARDBP (TAR DNA binding protein) and FUS (FUS RNA binding protein) genes each represent approximately 5% 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% of people with familial ALS have an identified genetic mutation. The cause of the disease in the remaining 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 C9ORF72 gene in people with amyotrophic lateral sclerosis (ALS) consist of hexanucleotide repeat expansions. These individuals are believed to have more than about 30 repeats. These mutations reduce the amount of C9ORF72 protein encoded. In addition, the altered protein encoded can interfere with cellular function. It is not clear how the decrease or alteration of this protein gives rise to the signs and symptoms of ALS. Some people with C9ORF72 gene mutations also develop frontotemporal dementia (FTD). It is not clear why some people with C9ORF72 gene mutations develop FTD and others do not. Individuals who develop both alterations are diagnosed with ALS-FTD.

The SOD1 gene (superoxide dismutase 1, soluble), located on the long arm of chromosome 21 (21q22.11), encodes the enzyme superoxide dismutase, abundant in cells throughout the body. This enzyme plays a role in breaking down toxic oxygen molecules, called superoxide radicals. At least 200 mutations in the SOD1 gene have been identified in people with amyotrophic lateral sclerosis (ALS). Most of these mutations change aminoacids 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 with the amino acid valine at position 5 in the enzyme (Ala5Val or A5V), resulting in an enzyme with altered function. The A5V mutation is often associated with the most severe signs and symptoms. Although ALS is due to the death of motor neurons, it is not clear why these cells are particularly sensitive to mutations in the SOD1 gene. Various ways have been suggested in which the altered enzyme may cause motor neuron death. These possibilities include an increase in harmful superoxide radicals, increased production of other types of toxic radicals, increased cell death, or accumulations of superoxide dismutase that can be toxic to cells.

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

The FUS gene (FUS RNA binding protein), located on the short arm of chromosome 16 (16p11.2), encodes a protein called sarcoma fusion protein (FUS). This protein is found within the cell nucleus in most tissues and is involved in many of the processes of protein production and transcriptional activation. This protein also helps repair mistakes in DNA. Furthermore, the FUS protein is also involved in mRNA processing. At least 85 mutations in the FUS gene have been identified in people with amyotrophic lateral sclerosis (ALS). Most of these mutations change amino acids in the protein affecting the region involved in DNA binding and mRNA processing. These mutations can interfere with the transport of mRNA outside the cell nucleus, particularly nerve cells that control muscle movement. An interruption in the transport of mRNA probably generates accumulations of FUS protein inside nerve cells. It is not clear whether a buildup of protein aggregates causes nerve cell death. People with amyotrophic lateral sclerosis due to mutations in the FUS gene tend to develop the disease earlier and have a shorter life expectancy compared to individuals with mutations in other genes. Rarely, people with ALS due to FUS gene mutations also develop frontotemporal dementia (FTD). It is not clear why some people with FUS gene mutations develop FTD and others do not.

About 90-95% of cases of ALS are sporadic and not inherited. Between 5 and 10% of cases associated with ALS are familial and the pattern of inheritance varies depending on the gene involved. Most cases are inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to cause the disease. In most cases, an affected person has a parent with the disease. Less commonly, ALS is inherited in an autosomal recessive pattern, which means that both copies of the gene in each cell must have the mutations for the disorder to be expressed. The parents of an individual with an autosomal recessive disease have one copy of the mutated gene, but usually do not show signs and symptoms of the disease. Very rarely, ALS is inherited in an X-linked dominant pattern. In females, a mutation in one of the two copies of the gene in each cell is sufficient to cause the disease. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disease. In most cases, men show more intense symptoms of the disease than women. One characteristic of X-linked inheritance is that parents cannot pass X-linked traits to their children.

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

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).