Broadly speaking there are two main classifications of ALS, familial (fALS) and sporadic (sALS). The two forms of ALS are generally clinically indistinguishable from each other. Though symptoms often present themselves earlier in familial cases compared to sporadic cases. People with fALS will usually begin showing signs and symptoms in their late forties to early fifties whereas people with sALS usually begin showing symptoms in their late fifties to early sixties. This can vary dramatically by person. However, the main difference between fALS and sALS lies in whether or not the disease is inherited.
Familial ALS (fALS) is when there is a family history of having ALS and it is passed down through generations. It accounts for about 10% of all cases of ALS. So far there are over 30 different genes that have been identified to have an association with ALS.
These genes by themselves do not cause ALS, as they are found in all humans, but rather certain mutations of these genes can cause ALS. For example the SOD1 gene, the first gene discovered to have a connection to ALS in 1993, has over 100 different mutations that affect the gene’s ability to properly function within the body and have been linked to ALS. Each gene associated with ALS will have its own unique mutations that are linked to causing ALS.
A mouse model of SOD1 associated ALS is commonly used in ALS research today. SOD1 is also one of the two most common genes linked to fALS, along with the C9orf72 gene.
In most familial cases ALS is inherited in an autosomal dominant pattern. This means that the gene with the ALS associated mutation is located on a chromosome that is not one of the sex chromosomes (autosomal) and a single (dominant) copy of the gene is sufficient to cause ALS. It is possible but less common for it to be inherited in an autosomal recessive pattern. In this case the person inherits two copies of the gene with an ALS associated mutation, one from each parent, on a non sex chromosome. Often neither of the parents will show signs of ALS before passing down the mutation to their offspring, but because ALS risk is associated with old age, the pattern of inheritance will reveal itself as mutation carriers age.
Even less common than autosomal recessive familial ALS is X-linked dominant familial ALS. This is when the gene with an ALS associated mutation is located on the X chromosome, one of the two sex chromosomes. Males tend to be more drastically affected by this – developing symptoms earlier and having a shorter life span – as they only have one X chromosome compared to females who have two. Mutations in the gene encoding UBQLN2 can cause X-linked dominant familial ALS.
In familial cases, genetic testing can be done on the family members to determine if they also possess the mutation that causes ALS. Having the mutation does not guarantee that the person will develop ALS. It is not known why some people who inherit a familial mutation never show signs of ALS.
Knowing the underlying cause of the disease in familial cases does not currently result in better or different treatment options compared to sporadic cases, though therapeutic strategies targeting specific forms of gene mutation associated ALS are currently in research and clinical drug development pipelines.
Sporadic ALS (sALS) accounts for the other 90% of cases of ALS. It occurs randomly in people that have no known history of the disease in their family.
It is unknown what causes sALS but it is believed to be from a combination of genetic and environmental factors. It is hypothesized by many that genetic variations can change people’s susceptibility to ALS even if these variations independently do not cause the disease.
In cases of either fALS or sALS, a genetic counselor can help advise people living with ALS about the risk that their family members may be at for having ALS or if they could pass it on to their children.
To learn more about how the ALS Therapy Development Institute is working to cure all forms of ALS please visit https://www.als.net/als-research/.