Despite the advances in modern medicine, no one knows for sure what causes amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease. Scientists can only theorize and speculate as to what causes it, but they still don’t have a conclusive answer to this question.
Forms of ALS: Sporadic vs. Familial
Research indicates that 90% to 95% of ALS cases are “sporadic” (not inherited), and so may be caused by an interaction between genetic and environmental factors. So, even when there is no family history of the disease, an individual may still develop ALS it if he or she carries the genetic variants associated with the disease and is exposed to certain environmental triggers such as oxidative stress, chemical imbalance, an overactive immune response, or exposure to certain germs, environmental toxins, chemicals, and other occupational hazards.
On the other hand, the “familial” (inherited) form of ALS, which accounts for about 10% of ALS cases, may develop when one of several genes responsible for the disease (which was passed from parent to offspring through an oligogenic mode of inheritance) undergoes mutation.
Notice that both forms of ALS are influenced by genetics. So, even while sporadic ALS does not seem to run in the family and familial ALS is manifested in more than one member of the family, the ALS-causing gene can easily be passed on from one generation to the next.
Genetic Causes of ALS
Out of the 25 or so genes associated with ALS, C9orf72 and SOD1 are the most common, with C9orf72 (Chromosome 9 open reading frame 72) causing 40% of familial ALS (fALS) cases and 15% of sporadic ALS (sALS) cases. On the other hand, SOD1 (copper-zinc superoxide dismutase 1) is responsible for roughly 12% of fALS and 2% of sALS.
C9orf72
Researchers discovered that hexanucleotide repeat expansions in C9orf72 lead to the development of the disease. Additionally, they noticed that the number of repeat units tends to correlate with the pathogenicity of the disease. To illustrate, people with ALS caused by C9orf72 mutation have hundreds or thousands of repeat units, while those that are not infected with the disease have less than 25 repeat units.
ALS caused by the C9orf72 gene is mostly passed from generation to generation through autosomal dominant inheritance, meaning the mutation occurs in a chromosome other than X and Y and that it takes one copy of the gene to cause the disease.
SOD1
In some cases, ALS is caused by mutations in the gene that codes for the production of SOD1, the enzyme responsible for breaking down the superoxide radical by-products resulting from normal cell processes. If these toxic molecules are not broken down regularly, as will be the case if the SOD1 enzyme is not working properly, they will accumulate in the nerve cells and cause irreversible damage, leading to ALS.
At present, researchers are able to identify more than 150 mutations in SOD1, with the predominant mode of inheritance identified as autosomal dominant. However, a small percentage of cases were observed to be transmitted through autosomal recessive inheritance.
Other ALS-Causing Genes
There are several other genes that may cause ALS, including TARDBP, which codes for TAR DNA-binding protein (TDP-43), FUS, which codes for fused in sarcoma protein, and UBQLN2, which codes for the protein ubiquilin 2.
Here is a partial list of other genes associated with various types of ALS.
- ALS2, which codes for the protein alsin
- SETX, which codes for the enzyme probable helicase senataxin
- SPG11, which produces the protein spatacsin
- ANG, which encodes the amino acid protein angiogenin
- OPTN, which codes for the protein optineurin
- VCP, which codes for valosin-containing protein
- CHCHD10, which codes for Protein N27C7-4
- SQSTM1, which codes for the protein sequestosome-1
- TBK-1, which codes for the enzyme TBK-1 (TANK-binding kinase 1)
Aside from being associated with ALS, mutations in CHCHD10, FUS, SQSTM1, TARDP, TBK-1, and C9orf72 are also seen in some people with both ALS and frontotemporal dementia (FTD-ALS).
