Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, or nerve cells that control muscle movements.
There are two forms of ALS classified according to the underlying cause of the disease: sporadic and familial. Sporadic ALS is the most common, thought to make up at least 90 percent of all cases. In rare cases, ALS can be passed from parents to their children and is called familial ALS.
Genetic mutations associated with ALS
A large number of genetic mutations have been associated with ALS. These mutations do not definitely cause ALS but can increase a person’s risk of developing the disease.
The C9ORF72 gene is the most frequently mutated gene in ALS patients. Mutations in this gene account for 25 to 40 percent of familial ALS cases and 7 percent of sporadic cases. A mutation in this gene can also cause another neurodegenerative disease called frontotemporal dementia (FTD). Some individuals with a mutation in the C9ORF72 gene develop ALS, some develop FTD, and some have symptoms of both conditions.
It is not entirely clear how mutations in C9ORF72 cause ALS or FTD, but it is thought that the mutated gene might either result in toxicity or what is known as haploinsufficiency. Toxicity means that the mutation leads to the production of a defective protein that is toxic for the cells. Haploinsufficiency occurs when one of the gene’s two copies is mutated or missing, and cells do not produce sufficient amounts of functional protein. Because the protein that C9ORF72 encodes for is crucial for cell function, insufficient amounts may lead to the symptoms of ALS.
Mutations in the SOD1 gene account for 12 to 20 percent of familial ALS and 1 to 2 percent of sporadic ALS cases. This gene provides instructions to build an enzyme called superoxide dismutase. The enzyme neutralizes free radicals, which are by-products of normal cellular processes and are harmful to the cells. Scientists do not understand fully how SOD1 mutations cause ALS, but think that they lead to the formation of superoxide dismutase aggregates that are harmful to the cells.
Mutations in the TARDBP gene are found in about 4 percent of familial ALS cases and about 1 percent of sporadic ALS cases. This gene provides the instructions to build the so-called TDP-43 protein, which is normally located in the nucleus (where genetic information is stored in cells) and involved in various steps of protein production. Mutations in the TARDBP gene cause the TDP-43 protein to form aggregates outside the nucleus, harming cells and leading to ALS.
The FUS gene is mutated in about 5 percent of familial ALS and about 1 percent of sporadic ALS cases. The FUS protein plays a role in cells similar to that of TDP-43. Aggregates of FUS protein are sometimes found in the motor neurons of ALS patients.
Other genes associated with ALS
Inheritance of ALS
Each person has 46 chromosomes: 22 pairs of autosomes and two sex chromosomes (also called allosomes). Men have an X and a Y chromosome, and women have two X chromosomes. Because all autosomes come in duplicates, each person has two copies of each autosomal gene. In a disease inherited in an autosomal dominant manner, a mutation in one of the two gene copies is sufficient to cause the disease. An individual with an autosomal dominant disease has a 50 percent risk of passing the mutated gene to a child.
ALS can also be inherited in an autosomal recessive manner, but this is less common. In a disease that is inherited in an autosomal recessive manner, both copies of the gene must be mutated for a person to develop that disease. Therefore, individuals with an autosomal recessive disease must inherit one mutated copy of the gene from each parent. This means that both parents must either have had the condition themselves or be carriers of the condition. ALS inherited in this way may be mistaken for sporadic ALS.
In very care cases, ALS is inherited in an X-linked dominant manner. Because women have two copies of the X-chromosome, a mutation in a gene located on the X-chromosome is not usually disease-causing. But men only have one X-chromosome, so an ALS-causing mutation located on the X-chromosome in a man can lead to the disease — men have no second copy of the gene that can compensate for the mutation. Because men pass their X-chromosome only to a daughter, they cannot pass X-linked traits to a son.
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